What is Porphyria

Porphyria is the umbrella term for a group of rare inherited disorders or passed down from parents to children caused by abnormalities in the chemical steps that lead to ‘heme’ or ‘haem’ production. Heme (haem) is a vital molecule for all of your body’s organs, although it is most abundant in the blood, bone marrow, and liver. Heme is a component of several iron-containing proteins called hemoproteins, including hemoglobin (the protein that carries oxygen in the blood). Heme (haem) is also found in myoglobin, a protein found in certain muscles. Normally, your body makes heme in a multi-step process (see Figures 5 and 6 below). Porphyrins are made during several steps of this process. People with porphyria are lacking certain enzymes needed for this process. This causes abnormal amounts of porphyrins or related chemicals to build up in your body. Porphyria occurs when the body cannot convert naturally occurring compounds called ‘porphyrins’ into heme (haem). Porphyrins are substances that are required for the production of red blood cells. A common feature in all porphyrias is the accumulation in the body of porphyrins or porphyrin precursors. Although these are normal body chemicals, they normally do not accumulate. Precisely which of these chemicals builds up depends on the type of porphyria. Drugs, infection, alcohol, and hormones such as estrogen may trigger attacks of certain types of porphyria.

Researchers have identified at least 8 types of porphyria, which are distinguished by their genetic cause and their signs and symptoms and are all caused by a build up of porphyrins in the cells of the body. People who have porphyria can experience a wide range of symptoms depending on the type of porphyria they have. There are 2 main types of porphyrias. One affects the skin (cutaneous porphyrias) and the other affects the nervous system (acute porphyrias). Some types of porphyria, called cutaneous porphyrias, primarily affect the skin. The most common type is porphyria cutanea tarda (PCT), which affects about 5 to 10 out of every 100,000 people ¹. Areas of skin exposed to the sun become fragile and blistered, which can lead to infection, scarring, changes in skin coloring (pigmentation), and increased hair growth. Cutaneous porphyrias include congenital erythropoietic porphyria (CEP), erythropoietic protoporphyria (EPP), hepatoerythropoietic porphyria (HEP), and porphyria cutanea tarda (PCT). The most common type of porphyria in children is a cutaneous porphyria called erythropoietic protoporphyria (EPP) ².

Symptoms of cutaneous porphyrias include:

• oversensitivity to sunlight
• blisters on exposed areas of the skin
• itching and swelling on exposed areas of the skin

The nervous system type of porphyria is called acute porphyria. Symptoms include pain in the chest, abdomen, limbs, or back; muscle numbness, tingling, paralysis, or cramping; vomiting; constipation; and personality changes or mental disorders. These symptoms come and go. Acute porphyrias are described as “acute” because their signs and symptoms appear quickly and usually last a short time. Episodes of acute porphyria can cause abdominal pain, vomiting, constipation, and diarrhea. During an episode, a person may also experience muscle weakness, seizures, fever, and mental changes such as anxiety and hallucinations. These signs and symptoms can be life-threatening, especially if the muscles that control breathing become paralyzed. Acute porphyrias include acute intermittent porphyria (AIP) and ALA dehydratase deficiency porphyria. The most common type of acute porphyria is acute intermittent porphyria (AIP). Two other forms of acute porphyria, hereditary coproporphyria (HCP) and variegate porphyria (VP), can have both acute (nervous system) and cutaneous (skin) symptoms (see Table 1 below).

Certain triggers can cause an attack, including some medicines, smoking, drinking alcohol, infections, stress, and sun exposure. Attacks develop over hours or days. They can last for days or weeks.

Symptoms of acute porphyrias include:

• pain in the abdomen—the area between the chest and hips
• pain in the chest, limbs, or back
• nausea and vomiting
• constipation—a condition in which an adult has fewer than three bowel movements a week or a child has fewer than two bowel movements a week,
• depending on the person
• urinary retention—the inability to empty the bladder completely
• confusion
• hallucinations
• seizures and muscle weakness

Symptoms of acute porphyrias can develop over hours or days and last for days or weeks. These symptoms can come and go over time, while symptoms of cutaneous porphyrias tend to be more continuous. Porphyria symptoms can vary widely in severity.

Environmental factors can strongly influence the occurrence and severity of signs and symptoms of porphyria. Alcohol, smoking, certain drugs, hormones, other illnesses, stress, and dieting or periods without food (fasting) can all trigger the signs and symptoms of some forms of the disorder. Additionally, exposure to sunlight worsens the skin damage in people with cutaneous porphyrias.

The porphyrias are rare diseases. Taken together, all forms of porphyria afflict fewer than 200,000 people in the United States ³. Based on European studies, the prevalence of the most common porphyria, porphyria cutanea tarda (PCT) is 1 in 10,000 and the most common acute porphyria, acute intermittent porphyria (AIP) is about 1 in 20,000, and the most common erythropoietic porphyria, erythropoietic protoporphyria (EPP), is estimated at 1 in 50,000 to 75,000 ⁴. Congenital erythropoietic porphyria (CEP) is extremely rare with prevalence estimates of 1 in 1,000,000 or less. Only 6 cases of ALA dehydratase-deficiency porphyria (ADP) are documented ⁴.

Acute porphyria is more common in females than in males and often begins when people are between the ages of 15 and 45 ⁵. Among types of cutaneous porphyria, porphyria cutanea tarda most often develops in people older than age 40, usually men ¹. For other types of cutaneous porphyria, symptoms often appear in early childhood.

The porphyrias can also be split into erythropoietic (red blood cell) and hepatic (liver) types, depending on where damaging compounds called porphyrins and porphyrin precursors first build up in the body. In erythropoietic porphyrias, these compounds originate in the bone marrow. Erythropoietic porphyrias include erythropoietic protoporphyria (EPP) and congenital erythropoietic porphyria (CEP). Health problems associated with erythropoietic porphyrias include a low number of red blood cells (anemia) and enlargement of the spleen (splenomegaly). The other types of porphyrias are considered hepatic porphyrias. In these disorders, porphyrins and porphyrin precursors originate primarily in the liver, leading to abnormal liver function and an increased risk of developing liver cancer.

Figure 1. Porphyrin molecular structure

Footnote: Molecular structure of porphyrin (M represent metal ions, such as Mg, Cu, Fe, Zn, etc.).

Figure 2. Hemoglobin molecular structure

Figure 3. Heme (haem) – oxygenation of heme protein

Figure 4. Heme (haem) molecular structure

Footnote: Heme A and heme B molecular structures

Figure 5. Heme biosynthesis pathway

Heme synthesis

Figure 6. Heme synthesis pathway

Footnotes: The heme biosynthetic pathway requires 8 enzymatic steps. Heme synthesis pathway showing the enzymes involved in the heme synthesis pathway and the associated porphyrias with the disruption of each specific enzyme. Gain-of-function variants in ALAS2 result in X-linked protoporphyria (XLP), and loss-of-functions variants in FECH result in erythropoietic protoporphyria (EPP). In both X-linked protoporphyria (XLP) and erythropoietic protoporphyria (EPP), metal-free protoporphyrin IX (PPIX) accumulates in erythroblasts, erythrocytes, the plasma, and the biliary system. Metal-free protoporphyrin IX (PPIX) is photosensitive, particularly to visible light in the blue range, and the light-mediated activation of metal-free protoporphyrin IX (PPIX) produces free radicals that damage the surrounding tissues.

Enzymes, encoded by genes, catalyze each of the steps. Gene mutations cause deficient enzyme production. Disruptions are indicated by red lines connecting enzymes with the resultant porphyrias. ALAS (ALAS2) = aminolevulinate synthase (aminolevulinate synthase 2); ALAD = delta-aminolevulinic acid dehydratase; PBGD = porphobilinogen dehydratase; HMBS = hydroxymethylbilane synthase; UROS = uroporphyrinogen-III synthase; UROD = uroporphyrinogen III decarboxylase; CPOX = coproporphyrinogen-III oxidase; PPOX = protoporphyrinogen oxidase; FECH = ferrochelatase.

Porphyrias resulting from disruption of enzyme production. XLP (X-linked protoporphyria); ADP (aminolevulinic acid dehydratase porphyria); AIP (acute intermittent porphyria); CEP (congenital erythropoietic porphyria); PCT (porphyria cutanea tarda); HCP (hereditary coproporphyria); VP (variegate porphyria); EPP (erythropoietic protoporphyria).

Abbreviations: ALA = aminolevulinic acid; PBG = porphobilinogen; HMB = hydroxymethylbilane; URO III = uroporphyrinogen III; COPRO III = coproporphyrinogen III; PROTO’gen IX protoporphyrinogen IX; PPIX = protoporphyrin IX; Fe2+ = iron.

Porphyria common triggers

Various triggers can prompt the development of porphyria. Environmental factors can strongly influence the occurrence and severity of signs and symptoms of porphyria. Alcohol, smoking, certain drugs, hormones, other illnesses, stress, and dieting or periods without food (fasting) can all trigger the signs and symptoms of some forms of porphyria. Additionally, exposure to sunlight worsens the skin damage in people with cutaneous porphyrias.

While the factors in the following list may seem to have nothing in common, each one demands increased heme production, which overwhelms the body’s ability to deal with the increased levels of porphyrins.

Common triggers include:

• Prescription drugs such as barbiturates, tranquilizers, sedatives, oral contraceptives and some types of antibiotics
• Female sex hormones
• Sunlight
• Alcohol
• Cigarette smoking
• Infection
• Surgery
• Fasting.

In most cases, the cause is a combination of genetic and environmental factors. More women than men are affected for reasons unknown. There is no cure but treatments are available to manage the symptoms.

Porphyria can be hard to diagnose. It requires blood, urine, and stool tests. Each type of porphyria is treated differently. Treatment may involve avoiding triggers, receiving heme through a vein, taking medicines to relieve symptoms, or having blood drawn to reduce iron in the body. People who have severe attacks may need to be hospitalized.

Porphyria types

There are at least 8 types of porphyria, with the two most common being:

• Cutaneous porphyrias. All but one of the cutaneous porphyrias cause painful skin blistering and fragility on sun-exposed areas of the body, most commonly the backs of the hands, forearms, face, ears and neck (photosensitivity):
  • The cutaneous porphyrias are sub-categorized as:
    • Porphyria cutanea tarda (PCT)
    • Hepatoerythropoietic Porphyria (HEP)
    • Erythropoietic protoporphyria (EPP)
    • Congenital erythropoietic porphyria (CEP)
    • X-Linked Protoporphyria (XLP)
  • Congenital erythropoietic porphyria (CEP) and hepatoerythropoietic porphyria (HEP) occur in childhood with severe blistering skin lesions. Porphyria cutanea tarda (PCT) occurs in adulthood generally and has less severe blistering skin lesions after sun exposure. Erythropoietic Protoporphyria (EPP) and X-linked Protoporphyria (XLP) have the same symptoms of painful, but non-blistering, reactions to sunlight. There can also be swelling and redness of the sun exposed areas of the skin with Erythropoietic Protoporphyria (EPP) and X-linked Protoporphyria (XLP).
• Acute porphyrias, mainly affecting the neurological system characterized by intense pain, confusion and limb weakness:
  • The acute porphyrias are sub-categorized as:
    • Acute intermittent porphyria (AIP)
    • Hereditary coproporphyria (HCP)
    • Variegate porphyria (VP)
    • ALA dehydratase deficiency porphyria (ADP)

Porphyria is usually inherited, but it can also occur without anyone else in the family having it.

Experts also classify porphyrias as erythropoietic (red blood cell) or hepatic (liver):

• In erythropoietic porphyrias, the body overproduces porphyrins, mainly in the bone marrow.
• In hepatic porphyrias, the body overproduces porphyrins and porphyrin precursors, mainly in the liver.

Table 1 lists each type of porphyria, the deficient enzyme responsible for the disorder, and the main location of porphyrin buildup.

Table 1. Types of porphyria

Porphyria Cutanea Tarda

Porphyria Cutanea Tarda (PCT) is the most common of all porphyrias (one of the hepatic porphyrias) and results from a deficiency of the enzyme uroporphyrinogen decarboxylase or uroporphyrinogen III decarboxylase (UROD) ¹¹, ¹², ¹³, ¹⁴, ¹⁵, ¹⁶, ¹⁷. The hallmark of porphyria cutanea tarda (PCT) is photosensitivity (sunlight sensitivity or abnormal skin reaction triggered by exposure to sunlight or other forms of ultraviolet (UV) light) ¹⁸, ¹⁹. Liver (hepatic) uroporphyrinogen decarboxylase or uroporphyrinogen III decarboxylase (UROD) enzyme is tasked with the conversion of uroporphyrinogen III to coproporphyrinogen III, the fifth step in heme biosynthesis and failure to do so results in the accumulation of the preceding compounds (highly carboxylated porphyrinogens predominately uroporphyrinogen and the porphyrinogens that get oxidized to their respective porphyrins, uroporphyrin and 7-carboxylate porphyrin) in the liver that eventually appears in the plasma and urine ²⁰, ²¹. The accumulation of these toxic compounds (uroporphyrin and 7-carboxylate porphyrin) in different organs, especially the liver and skin, leads to the signs and symptoms seen in porphyria cutanea tarda patients. Porphyrins are photoactive molecules that efficiently absorb light energy in the visible violet spectrum. Photoexcited porphyrins in the skin cause oxidative damage to biomolecular targets, causing the skin lesions in porphyria cutanea tarda. The most common photocutaneous manifestations of porphyria cutanea tarda are due to increased mechanical fragility after sunlight exposure; erosions and blisters form painful indolent sores that heal with milia, dyspigmentation, and scarring. An important point to note is that the uroporphyrinogen decarboxylase or uroporphyrinogen III decarboxylase (UROD) enzymatic activity should drop below 20% before signs and symptoms can be seen ¹¹.

Porphyria cutanea tarda (PCT) is essentially an acquired disease, but some individuals have a genetic (autosomal dominant) deficiency of enzyme uroporphyrinogen decarboxylase (UROD) that contributes to development of familial porphyria cutanea tarda (F-PCT).

• Porphyria cutanea tarda type 1 (Sporadic porphyria cutanea tarda): In approximately 75% to 80% of cases the uroporphyrinogen decarboxylase (UROD) enzyme deficiency is associated with an underlying liver diseases that include iron overload from hemochromatosis, multiple blood transfusions, or iron supplements, chronic hepatitis B and hepatitis C infection and excessive alcohol consumption resulting in the inhibition of uroporphyrinogen decarboxylase (UROD) enzyme, the fifth enzyme in the heme synthetic pathway in the liver. Hormones such as oral contraceptive or hormone replacement therapy may also trigger porphyria cutanea tarda. Kidney dialysis patients can also develop porphyria cutanea tarda as they cannot excrete the porphyrins. Rarely, other conditions such as systemic lupus erythematosus (SLE) and human immunodeficiency virus (HIV) infection can cause porphyria cutanea tarda. Furthermore, many patients have more than one risk factor.
• Porphyria cutanea tarda type 2 (Familial porphyria cutanea tarda or F-PCT): In the remaining cases (20% to 25%), individuals have a genetic predisposition to developing porphyria cutanea tarda (PCT), specifically a mutation in the UROD (uroporphyrinogen decarboxylase) gene inherited from one parent and are classified as having familial porphyria cutanea tarda (F-PCT). Most individuals with UROD genetic mutation do not develop porphyria cutanea tarda (PCT); the mutation is a predisposing factor and additional factors are required for the development of the disorder in these individuals. These factors are called susceptibility factors and are required for the development of both sporadic and familial porphyria cutanea tarda.
• Porphyria cutanea tarda type 3. This rare type of porphyria cutanea tarda is very similar to type 1 porphyria cutanea tarda because of normal UROD genes ²². Yet, type 3 porphyria cutanea tarda is observed in more than one family member suggesting the presence of a genetic mechanism other than UROD gene mutation ²³.
• In extremely rare cases, individuals have mutations in both UROD (uroporphyrinogen decarboxylase) genes. This autosomal recessive form of familial porphyria cutanea tarda or Homozygous familial porphyria cutanea tarda is known as hepatoerythropoietic porphyria (HEP). Hepatoerythropoietic porphyria (HEP) occurs in childhood and is usually more severe than porphyria cutanea tarda types 1 sporadic or 2 familial porphyria cutanea tarda ²⁴. Mild cases of hepatoerythropoietic porphyria (HEP) may resemble porphyria cutanea tarda (PCT) but are readily differentiated by marked elevation in erythrocyte zinc protoporphyrin.

Generally, porphyria cutanea tarda develops in mid to late adulthood. Porphyria cutanea tarda symptoms usually occur after the age of 30 and its onset in childhood is rare. The symptoms of porphyria cutanea tarda (PCT) are limited to your skin. It does not cause people to become acutely unwell, as in the acute types of porphyria. Sun-exposed areas of your skin most commonly the backs of your hands can become friable and prone to blistering, scarring and excess hair growth.

Porphyria cutanea tarda is found worldwide that affect both males and females equally and in individuals of all races. Porphyria cutanea tarda is a rare disorder with the prevalence being estimated to be approximately 1 in 10,000 to 25,000 individuals in the general population. Porphyria cutanea tarda (PCT) has a prevalence of about 1 in 10,000 people according to a Norwegian study and occurs most commonly in middle-aged adults ²⁵. A 1 in 25000 prevalence has been reported in the United States ²³.

Porphyria cutanea tarda (PCT) is a multifactorial disorder, which means that several different factors such as genetic and environmental factors occurring in combination are necessary for the development of porphyria cutanea tarda. These factors are not necessarily the same for each individual. These factors contribute either directly or indirectly to decreased levels or ineffectiveness of an enzyme known as uroporphyrinogen decarboxylase (UROD) within your liver. When uroporphyrinogen decarboxylase (UROD) levels in your liver decrease to approximately 20% of normal levels, the symptoms of porphyria cutanea tarda may develop.

The uroporphyrinogen decarboxylase (UROD) enzyme is essential for breaking down (metabolizing) certain chemicals in the body known as porphyrins. Low levels of functional uroporphyrinogen decarboxylase (UROD) result in the abnormal accumulation of specific porphyrins in your body, especially within the blood, liver and skin. The symptoms of porphyria cutanea tarda occur because of this abnormal accumulation of porphyrins and related chemicals. For example when porphyrins accumulate in your skin, they absorb sunlight and enter an excited state (photoactivation). This abnormal activation results in the characteristic damage to the skin (photosensitivity) found in individuals with porphyria cutanea tarda. Your liver removes porphyrins from the blood plasma and secretes it into the bile. When porphyrins accumulate in your liver, they can cause toxic damage to your liver.

The exact, underlying mechanisms that cause porphyria cutanea tarda are complex and varied. It is determined that iron accumulation within the liver plays a central role in the development of the disorder in most individuals (sporadic or acquired porphyria cutanea tarda [PCT type 1]). Recently, researchers have discovered that a substance called uroporphomethene, which is an oxidized form of a specific porphyrin known as uroporphyrinogen, is an inhibitor that reduces the activity of the uroporphyrinogen decarboxylase (UROD) enzyme in the liver. The oxidation of uroporphyrinogen into uroporphomethene has been shown to be iron dependent, emphasizing the importance or elevated iron levels in the development of porphyria cutanea tarda.

The relationship between iron levels and porphyria cutanea tarda has long been established and porphyria cutanea tarda is classified as an iron-dependent disease. Clinical symptoms often correlate with abnormally elevated levels of iron in the liver (iron overloading). Iron overloading in the liver may only be mild or moderate. The exact relationship between iron accumulation and porphyria cutanea tarda is not fully understood, however, as there is no specific level of iron in the liver that correlates to disease in porphyria cutanea tarda (e.g. some individuals with symptomatic porphyria cutanea tarda have normal iron levels).

Porphyria Cutanea Tarda (PCT) becomes active when predisposing factors such as excess iron, alcohol, chronic hepatitis C (hepatitis C Virus [HCV]), HIV infection, estrogens (used, for example, in oral contraceptives and prostate cancer treatment) and possibly smoking, combine to cause a deficiency of enzyme uroporphyrinogen decarboxylase (UROD) in the liver ²⁶. Hemochromatosis, a inherited iron overload disorder, also can predispose individuals to porphyria cutanea tarda. Some of these factors and marked accumulation of porphyrins in the liver due to porphyria cutanea tarda (PCT) itself can lead to chronic liver damage and liver cancer.

The treatment of porphyria cutanea tarda is directed toward the underlying liver problem and the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, general internists, hematologists, dermatologists, hepatologists, and other healthcare professionals may need to systematically and comprehensively plan your treatment.

The first step in the management of porphyria cutanea tarda is the avoidance of all risk factors such as strictly avoiding alcohol, smoking, and estrogen therapy, along with limiting any excess intake of iron. Since porphyria cutanea tarda (PCT) is a photosensitive skin condition, sunlight avoidance is the key until the porphyrin levels have normalized. The wavelengths inducing porphyrins are in the range of 400-410 nm, and only titanium dioxide or zinc oxide containing sunscreen is effective ²⁷. Protective clothing is also helpful in protecting the skin from harmful sunlight rays. Any affected skin areas should be kept clean to prevent the development of skin infections, and associated pain can be managed with oral analgesics.

Presently, there are no effective treatments that restore UROD enzyme levels in individuals with familial porphyria cutanea tarda (F-PCT) ²⁸. However, treatment seems to be equally effective in familial porphyria cutanea tarda (F-PCT) and non-familial porphyria cutanea tarda. Factors that tend to activate the disease should be removed and may result in the resolution of porphyria cutanea tarda. Treatment may include reducing alcohol consumption, stopping estrogen or hormone treatment, avoiding excessive iron intake, or antiviral treatment for underlying hepatitis C.

Reduction of liver iron content is the general recommendation and the most widely recommended treatment is a schedule of repeated phlebotomies (removal of blood), with the aim of reducing iron in the liver ²⁸, ²³, ²⁹, ³⁰, ³¹. This actually reduces iron stores throughout the body. Usually, removal of only 5 to 6 pints of blood (one pint [approximately 450 ml of blood] every one to two weeks) is sufficient, which indicates that iron stores are not excessively increased in most porphyria cutanea tarda patients. The best guides to response are measurements of serum ferritin and plasma porphyrins. Phlebotomies are stopped when the ferritin falls to ~20 ng/ml ³², ³³. Normal ferritin levels vary by gender and age, but generally, for adult males, ferritin level is between 30-300 ng/mL, and for adult females, it’s between 13-150 ng/mL.

Iron chelation therapy i.e., deferasirox or deferoxamine may be considered when phlebotomy is contraindicated, and low iron diet may be beneficial if the latter fails ²⁸.

If phlebotomy cannot be done, as in elderly patients or those who are anemic, antimalarial tablets such as low doses of either chloroquine (125mg twice weekly) or hydroxychloroquine (100mg twice weekly) to allow the porphyrins to be excreted more easily. Usual dosages of these drugs should not be used because they can cause transient but sometimes severe liver damage and worsening of photosensitivity in porphyria cutanea tarda patients.

Furthermore, use of antiviral therapy may benefit patients with chronic hepatitis C infections and reduce risk of progressing to liver cancer ²⁹.

After treatment for porphyria cutanea tarda, periodic measurement of plasma porphyrins may be advised, especially if a contributing factor such as estrogen exposure is resumed. If a recurrence does occur, it can be detected early and treated promptly. The treatment of porphyria cutanea tarda is almost always successful, and the prognosis is usually excellent.

Figure 7. Porphyria Cutanea Tarda

Footnotes: Porphyria cutanea tarda (PCT) is caused by deficiency in uroporphyrinogen decarboxylase (UROD) enzyme, and is subdivided into two categories: Type 1 (sporadic PCT), and Type 2 (familial PCT). Porphyria cutanea tarda (PCT) presents mainly with skin manifestations which are triggered by susceptibility factors (risk factors) such as alcohol, hepatitis C virus (HCV), estrogen, hemochromatosis, smoking, and others. Porphyria cutanea tarda (PCT) is the most common type of porphyria, and is managed by reduction of hepatic iron content and avoidance of susceptibility factors.

Figure 8. Porphyria cutanea tarda

Figure 9. Porphyria cutanea tarda pathophysiology

Footnotes: Inhibition of uroporphyrinogen decarboxylase (UROD) enzyme by uroporphomethene leads to the accumulation of porphyrins and manifestations of disease in porphyria cutanea tarda (PCT). Under normal conditions, UROD (uroporphyrinogen decarboxylase) converts uroporphyrinogen to coproporphyrinogen by a series of 4 sequential decarboxylations. In the presence of iron and free radicals, uroporphyrinogen is partially oxidized, leading to the formation of a uroporphomethene inhibitor of UROD (uroporphyrinogen decarboxylase). Decarboxylated uroporphyrinogen intermediates subsequently accumulate and auto-oxidize to their corresponding porphyrins, predominantly uroporphyrins. Photosensitive porphyrins accumulate in the plasma and are responsible for the cutaneous manifestations of porphyria cutanea tarda (PCT).

Abbreviations: Fe = iron; PCT = porphyria cutanea tarda; UROD = uroporphyrinogen decarboxylase; ROS = reactive oxygen species.

Figure 10. Porphyria cutanea tarda diagnostic and treatment algorithm

Abbreviations: HAV = hepatitis A virus; HBV = hepatitis B virus; PBG = porphobilinogen deaminase; TIBC = total iron-binding capacity.

Porphyria cutanea tarda causes

Porphyria cutanea tarda (PCT) is a multifactorial disorder, which means that several different factors such as genetic, infectious and environmental factors occurring in combination are necessary for the development of porphyria cutanea tarda ³⁵. These factors are not necessarily the same for each individual. These factors contribute either directly or indirectly to decreased levels or ineffectiveness of an enzyme known as uroporphyrinogen decarboxylase (UROD) within your liver ³⁶, ³⁷, ³⁸. When uroporphyrinogen decarboxylase (UROD) levels in your liver decrease to approximately 20% of normal levels, the symptoms of porphyria cutanea tarda may develop.

The uroporphyrinogen decarboxylase (UROD) enzyme is essential for breaking down (metabolizing) certain chemicals in the body known as porphyrins. Low levels of functional uroporphyrinogen decarboxylase (UROD) result in the abnormal accumulation of specific porphyrins in your body, especially within the blood, liver and skin. The symptoms of porphyria cutanea tarda occur because of this abnormal accumulation of porphyrins and related chemicals. For example when porphyrins accumulate in your skin, they absorb sunlight and enter an excited state (photoactivation). This abnormal activation results in the characteristic damage to the skin (photosensitivity) found in individuals with porphyria cutanea tarda. Your liver removes porphyrins from the blood plasma and secretes it into the bile. When porphyrins accumulate in your liver, they can cause toxic damage to your liver.

The exact, underlying mechanisms that cause porphyria cutanea tarda are complex and varied. It is determined that iron accumulation within the liver plays a central role in the development of the disorder in most individuals (sporadic or acquired porphyria cutanea tarda [PCT type 1]). Recently, researchers have discovered that a substance called uroporphomethene, which is an oxidized form of a specific porphyrin known as uroporphyrinogen, is an inhibitor that reduces the activity of the uroporphyrinogen decarboxylase (UROD) enzyme in the liver. The oxidation of uroporphyrinogen into uroporphomethene has been shown to be iron dependent, emphasizing the importance or elevated iron levels in the development of porphyria cutanea tarda.

The relationship between iron levels and porphyria cutanea tarda has long been established and porphyria cutanea tarda is classified as an iron-dependent disease. Clinical symptoms often correlate with abnormally elevated levels of iron in the liver (iron overloading). Iron overloading in the liver may only be mild or moderate. The exact relationship between iron accumulation and porphyria cutanea tarda is not fully understood, however, as there is no specific level of iron in the liver that correlates to disease in porphyria cutanea tarda (e.g. some individuals with symptomatic porphyria cutanea tarda have normal iron levels).

There is an increased prevalence of mutations in the HFE (homeostatic iron regulator) gene in individuals with porphyria cutanea tarda ²⁶. The HFE gene provides instructions for producing a protein called HFE protein that is located on the surface of cells, primarily liver and intestinal cells ³⁹. The HFE protein is also found on some immune system cells ³⁹. The HFE protein interacts with other proteins on the cell surface to detect the amount of iron in the body. When the HFE protein is attached (bound) to a protein called transferrin receptor 1, the receptor cannot bind to a protein called transferrin. When transferrin receptor 1 is bound to transferrin, iron enters liver cells. So, it is likely that the HFE protein regulates iron levels in liver cells by preventing transferrin from binding to transferrin receptor 1. The HFE protein regulates the production of a protein called hepcidin ³⁹. Hepcidin is produced by the liver, and it determines how much iron is absorbed from your diet and released from storage sites in your body ³⁹. When the HFE protein is not bound to transferrin receptor 1, it binds to a group of other proteins that includes hepcidin. The formation of this protein complex (HFE protein+Hepcidin) triggers the production of hepcidin. So when the HFE protein is bound to transferrin receptor 1, hepcidin production is turned off and when the HFE protein is not bound to transferrin receptor 1, hepcidin production is turned on. When the proteins involved in iron sensing and absorption are functioning properly, iron absorption is tightly regulated. On average, the body absorbs about 10 percent of the iron obtained from the diet.

Mutations in the HFE gene can cause hemochromatosis, a genetic disorder causing the body to absorb and store excessive amounts of iron especially the liver, leading to potential organ damage ⁴⁰. It’s also known as iron overload, and if left untreated, the excess iron can accumulate in vital organs like the liver, heart, and pancreas. Hemochromatosis occurs when a person inherited two mutated HFE genes (one from each parent). Hemochromatosis is associated with low levels of hepcidin, a specialized protein that is the primary regulator of iron absorption in the body, including regulating the uptake of iron by the gastrointestinal tract and liver.

Additional risk factors that have been associated with porphyria cutanea tarda include alcohol, certain infections such as hepatitis C or HIV, and drugs such as estrogens. Some studies have indicated that smoking is a risk factor for porphyria cutanea tarda in susceptible individuals. Less often, certain chemical exposures (e.g. hexachlorobenzene), kidney dialysis, and lupus appear to be connected to the development of porphyria cutanea tarda. It is believed that these susceptibility factors reduce hepcidin in the body and consequently lead to iron accumulation in the liver. However, the exact relationship among most susceptibility factors with the development of symptoms in porphyria cutanea tarda is not fully understood. For example, alcohol clearly contributes to the development of the disorder in some cases, but porphyria cutanea tarda is not common in alcoholics. Most individuals with porphyria cutanea tarda have three or more susceptibility factors present.

In some cases, individuals develop porphyria cutanea tarda without a known susceptibility factor, suggesting that additional, as yet unidentified risk factors exist.

The underlying cause of uroporphyrinogen decarboxylase deficiency in the acquired form of porphyria cutanea tarda is unknown. Affected individuals have approximately 50% residual uroporphyrinogen decarboxylase activity and do not develop symptoms unless additional factors are present. The most common factors associated with acquired porphyria cutanea tarda are hemochromatosis or chronic hepatitis C infection. In individuals with acquired porphyria cutanea tarda, uroporphyrinogen decarboxylase levels are only deficient in the liver.

In the familial form of porphyria cutanea tarda (familial porphyria cutanea tarda [PCT type 2]), individuals have a mutation in the uroporphyrinogen decarboxylase (UROD) gene. This mutation is inherited as an autosomal dominant trait. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new (de novo) mutation in the affected individual with no family history. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child.

The uroporphyrinogen decarboxylase (UROD) gene creates (encodes) the uroporphyrinogen decarboxylase enzyme, which is the fifth enzyme in the heme synthesis pathway. A mutation in one of these genes leads to abnormally low levels of this enzyme in all tissues of the body (not just the liver). However, one mutation alone is insufficient to cause familial porphyria cutanea tarda (F-PCT) as residual uroporphyrinogen decarboxylase enzyme levels remain above 20% of normal. In fact, most individuals with a mutation in the uroporphyrinogen decarboxylase gene do not develop the disorder. Additional factors must be present for the disorder to develop.

Risk Factors for developing porphyria cutanea tarda

Mild to moderate iron overload alongside amplified serum ferritin levels and hepatic siderosis reportedly occurs in 90% of porphyria cutanea tarda cases ⁴¹, ⁴², ⁴³. Iron overload can also be caused by mutations in the hemochromatosis gene (HFE gene) ⁴⁴, ⁴³. Hereditary hemochromatosis is a inherited disease causes the body to absorb too much iron from the diet triggering iron accumulation in organs such as liver ⁴⁴, ⁴⁵. The excess iron is stored in the body’s tissues and organs, particularly the skin, heart, liver, pancreas, and joints. Because humans cannot increase the excretion of iron, excess iron can overload and eventually damage tissues and organs. For this reason, hereditary hemochromatosis is also called an iron overload disorder. Early symptoms of hereditary hemochromatosis may include extreme tiredness (fatigue), joint pain, abdominal pain, weight loss, and loss of sex drive. As the condition worsens, affected individuals may develop arthritis, liver disease (cirrhosis) or liver cancer, diabetes, heart abnormalities, or skin discoloration. The appearance and severity of symptoms can be affected by environmental and lifestyle factors such as the amount of iron in the diet, alcohol use, and infections.

Mutations in several genes can cause hereditary hemochromatosis. Type 1 hemochromatosis results from mutations in the HFE gene, and type 2 hemochromatosis results from mutations in either the HJV or HAMP gene ⁴⁴, ⁴⁵. Mutations in the TFR2 gene cause type 3 hemochromatosis, and mutations in the SLC40A1 gene cause type 4 hemochromatosis ⁴⁴, ⁴⁵.

In type 1 hereditary hemochromatosis you inherit one HFE gene from each of your parents. The HFE gene has two common mutations, C282Y and H63D. Genetic testing can reveal whether you have these changes in your HFE gene. If you inherit two altered genes, you may develop hemochromatosis. You also can pass the altered gene on to your children. But not everyone who inherits two genes develops problems linked to the iron overload of hemochromatosis. If you inherit one altered gene, you’re unlikely to develop hemochromatosis. However, you are considered a carrier and can pass the altered gene on to your children. But your children wouldn’t develop hemochromatosis unless they also inherited another altered gene from the other parent.

Patients with porphyria cutanea tarda express more mutations in the HFE gene than the general population ⁴¹, ⁴³. Data from several large studies indicate that the HFE gene mutation is present in almost 73% of porphyria cutanea tarda cases ⁴¹. Another study found 64.9% of porphyria cutanea tarda patients carried at least one HFE mutated allele ⁴⁶. Other factors that can increase iron levels include hepatitis C virus infection, alcohol, and increased absorption of iron ⁴¹.

Heavy alcohol use (>40g/day) is recorded in almost 90% of porphyria cutanea tarda cases ⁴¹, and is more prevalent in males ⁴⁶. Alcohol consumption exacerbates porphyria cutanea tarda by inhibiting the activity of delta-aminolevulinic acid dehydratase (ALAD), uroporphyrinogen decarboxylase (UROD), coproporphyrinogen-III oxidase (CPOX) and ferrochelatase (FECH), while enhancing the activity of aminolevulinate synthase (ALAS) and hydroxymethylbilane synthase (HMBS) thereby promoting accumulation of porphyrin ³⁴. While the correlation between the effects of alcohol on aminolevulinate synthase (ALAS) and clinical expression of porphyria cutanea tarda is yet to be elucidated, chronic alcoholics are known to suffer from suppression of erythropoiesis and increased dietary iron absorption ²⁹, ⁴⁷. Alcohol is also thought to contribute to increased iron absorption, alcohol induced oxidative stress, and downregulation of hepcidin ⁴¹.

Smoking can induce earlier onset of Type 1 porphyria cutanea tarda (sporadic porphyria cutanea tarda) and is therefore a risk factor ⁴⁸. Mechanisms of smoking mediating the development of porphyria cutanea tarda remain unclear, but increased oxidative stress and induction of hepatic cytochrome P450 enzymes are thought to contribute to disease pathology ⁴¹.

Infections with Hepatitis C Virus (HCV), and comorbid Hepatitis C Virus (HCV) and Human Immunodeficiency Virus (HIV) infections are associated with development of porphyria cutanea tarda ³⁷. Hepatitis C Virus (HCV) is the most common porphyria cutanea tarda-related viral infection, and although associated with both subtypes, it is observed more frequently in Type 1 porphyria cutanea tarda (sporadic porphyria cutanea tarda) and Type 2 porphyria cutanea tarda (familial porphyria cutanea tarda) ⁴⁹, ²⁹, ⁵⁰. A large study of 152 patients with porphyria cutanea tarda indicated that Hepatitis C Virus (HCV) infection is the most prevalent risk factor, especially in men ⁴⁶. Although mechanisms are unclear, there is some indication that hepatitis C virus (HCV)-induced reactive oxygen species can trigger disease manifestations by fostering reduced hepcidin levels and promoting hepatic iron accumulation ⁵¹. Chronic hepatitis C virus (HCV) infection also lessens glutathione in hepatocytes, decreasing their ability to reduce oxidized porphyrins and causing their accumulation ²⁹. It is important to note that hepatitis C virus (HCV)-infected persons develop porphyria cutanea tarda at an earlier age than those without the virus. HFE gene mutations also cause iron overload that further promote hepatocellular injury and fibrosis in patients with hepatitis C virus (HCV) ²⁹.

Estrogens have been identified as precipitating factors for women with type 2 porphyria cutanea tarda (familial porphyria cutanea tarda [F-PCT]) ⁴⁶, ³⁷. Reports indicate use of oral contraceptives, hormone replacement therapy, and use of tamoxifen for breast cancer to be associated with porphyria cutanea tarda ⁴¹, ⁵², ⁵³. Diethylstilbestrol, a synthetic nonsteroidal estrogen, also induces hepatic aminolevulinate synthase (ALAS), though there is currently no clear understanding of the accompanying increased porphyrin excretion in porphyria cutanea tarda patients ²⁹. Estrogen as a treatment for prostate cancer has also been identified as a risk factor in men ⁵⁴. Administration of estrogens via transdermal route is safe and recommended for at-risk women previously treated for porphyria cutanea tarda ⁵³.

Hepatic siderosis (hepatic iron overload or the abnormal accumulation of iron in the liver caused by various factors, including hereditary hemochromatosis and secondary causes like chronic liver disease or repeated blood transfusions), systemic lupus erythematosus (SLE), end-stage renal disease on hemodialysis, diabetes mellitus, and hematologic malignancies are all associated with the development of porphyria cutanea tarda ⁵⁵, ⁵³, ⁵⁶, ⁵⁷, ⁵⁸, ⁵⁹, ⁴¹, ²⁹.

Exposure to toxins such as polychlorinated biphenyls, hexachlorobenzene, and other polyhalogenated hydrocarbons that significantly induce cytochrome P450 enzymes are also associated with the development of porphyria cutanea tarda ²⁸.

Porphyria cutanea tarda pathophysiology

Porphyria cutanea tarda results from the inhibition of liver uroporphyrinogen decarboxylase (UROD) enzyme, a cytoplasmic housekeeping enzyme that converts uroporphyrinogen to coproporphyrinogen ¹². The uroporphyrinogen decarboxylase (UROD) enzyme is encoded by the UROD gene, located on chromosome 1 with 10 exons spanning over 3  kb ⁶⁰, ⁶¹. The uroporphyrinogen decarboxylase (UROD) enzyme carries out a complex reaction, sequentially decarboxylating the 4 acetyl groups of uroporphyrinogen (an octacarboxyl porphyrin) to hepta-, hexa-, penta-, and finally coproporphyrinogen (a tetracarboxyl porphyrin) ⁴¹, ⁶². Both uroporphyrinogen I and III isomers are decarboxylated by uroporphyrinogen decarboxylase (UROD), but uroporphyrinogen III is preferred because coproporphyrinogen oxidase is specific for coproporphyrinogen III, and the III isomers are intermediates in heme synthesis ⁶³, ⁶⁴, ⁶⁵, ⁶⁵.

The liver uroporphyrinogen decarboxylase (UROD) protein level remains at its genetically determined level in all types of porphyria cutanea tarda, but liver enzyme activity is reduced to less than about 20% of normal, suggesting the presence of an enzyme inhibitor ¹². Phillips and colleagues ²⁰ identified this inhibitor as a uroporphomethene, probably derived from the partial oxidization of uroporphyrinogen. At least in mice models, cytochrome P450 enzyme activity is involved in the generation of uroporphomethene inhibitor. Uroporphomethene differs from uroporphyrinogen by a single oxidized bridge carbon, and although it is able to bind strongly to the active site of UROD, it is unable to serve as a substrate ²⁰ However, other researchers have questioned whether uroporphomethene is in fact a true inhibitor of UROD based on its fragmentation pattern on mass spectrometry ⁶⁶.

When hepatic UROD activity is reduced to less than 20% of normal activity, uroporphyrinogen and the porphyrinogens that are intermediates in its 4-step decarboxylation accumulate in the liver and are auto-oxidized to their corresponding porphyrins ⁶⁷. After considerable accumulation in the liver, these porphyrins (uroporphyrinogen and porphyrinogens) appear in plasma and bile and are excreted in the urine and stool ⁶³. These porphyrins are activated by light exposure (especially at wavelengths near 400 nm) and generate reactive oxygen species that damage sun-exposed skin ⁶⁷. Furthermore, in UROD-deficient mice, the upregulation of delta-aminolevulinic acid synthase 1 (ALAS-1) by drugs that induce hepatic P450 enzymes and the supplementation of δ-aminolevulinic acid (ALA) in the drinking water have been shown to induce a porphyria cutanea tarda phenotype ⁶⁸.

Porphyria cutanea tarda symptoms

The symptoms of porphyria cutanea tarda (PCT) can vary greatly from one individual to another. The symptoms of porphyria cutanea tarda are confined mostly to your skin. Excess porphyrin in your skin results in photosensitivity (a condition in which the skin becomes very sensitive to sunlight or other forms of ultraviolet light and may burn easily). Individuals with porphyria cutanea tarda (PCT) develop blisters on sun-exposed areas of their skin (photosensitivity), such as the back of the hands and the forearms. Other sun-exposed sites such as the face, scalp, neck, and arms may also be affected. The skin in these areas may blister or peel after minor trauma. Eventually, scarring may develop and affected skin may darken (hyperpigmentation) or fade (hypopigmentation) in color. Abnormal, excessive hair growth (hypertrichosis), especially on the face may also occur. The hair may be very fine or coarse and can differ in color. In some patients, their hair may grow, thicken and darken. Small bumps with a distinct white head (milia) may also develop, especially on the backs of the hands. In some cases, the skin in affected areas may thickened and harden, resembling a condition known as sclerosis, this is sometimes known as pseudosclerosis. Pseudosclerosis in individuals with porphyria cutanea tarda appears as scattered, waxy, harden patches or plaques of skin. Characteristically, the urine is darker than usual, with a reddish or tea-colored hue.

Neurological and abdominal symptoms are not characteristic of porphyria cutanea tarda.

Liver abnormalities may develop in some affected individuals including the accumulation of iron in the liver (hepatic siderosis), the accumulation of fat in the liver (steatosis), inflammation of certain parts of the liver (portal triaditis), and thickening and scarring around the portal vein (periportal fibrosis). Affected individuals may be at a greater risk than the general population of developing scarring of the liver (cirrhosis) or liver cancer known as hepatocellular carcinoma (HCC). Advanced liver disease is uncommon, except in older individuals with recurrent disease. In some cases, liver disease is due to an associated condition such as hepatitis B or hepatitis C infection.

Porphyria cutanea tarda, Hepatitis C Virus and HIV

Because porphyria cutanea tarda is frequently associated with hepatitis C virus infection, it is worth noting the issues involved in treating a patient with both porphyria cutanea tarda and hepatitis C virus infection.

Infection with hepatitis C virus is much more common than porphyria cutanea tarda, and most people with hepatitis C virus do not have porphyria cutanea tarda. However, at least in some locations, as many as 80 percent of individuals with porphyria cutanea tarda are infected with hepatitis C virus. Therefore, hepatitis C virus needs to be added to the list of factors that can activate porphyria cutanea tarda alongside alcohol, iron and estrogens. Other hepatitis viruses are seldom implicated in porphyria cutanea tarda, and it is not known how hepatitis C virus activates porphyria cutanea tarda.

There are several different viruses that cause hepatitis. A blood test for hepatitis C virus infection has not been available for very long. Hepatitis C virus is most readily transmitted from one person to another by blood products. Although most people who are infected with hepatitis C virus have a history of exposure to blood or needles contaminated with blood, in some cases it is not known how the infection was acquired. Hepatitis C virus (unlike the hepatitis B Virus and HIV) is seldom transmitted by sexual contact. It is also not readily transmitted by casual contact with other people. Therefore, people infected with hepatitis C virus are not hazardous unless they somehow expose others to their blood.

It is recommended that patients with porphyria cutanea tarda be tested for hepatitis C virus infection. This is done by a blood test that detects antibodies to the virus. If hepatitis C virus infection is found, it may not change the treatment of porphyria cutanea tarda (by phlebotomy or low-dose chloroquine). Treatment for porphyria cutanea tarda is highly successful even in patients with hepatitis C virus. Therefore, it is reasonable to treat the porphyria cutanea tarda first and then look into treatment for hepatitis C virus later.

There are reasons not to treat the hepatitis C virus infection before treating the porphyria cutanea tarda. Hepatitis C virus treatment with alpha-interferon and ribavirin is available but is often not effective. Also, liver damage progresses slowly if at all in many people with hepatitis C virus. However, once the porphyria cutanea tarda is in remission it is important to assess the amount of liver damage the virus has already caused and to have follow-up visits to a doctor to monitor the liver. In some cases it may be important to treat hepatitis C virus infection to try and prevent progressive liver damage.

Porphyria cutanea tarda complications

Although the signs and symptoms of porphyria cutanea tarda are limited to the skin, patients are also at a high risk of liver complications. Liver biopsies usually reveal fatty changes along with porphyrin deposits and sometimes lobular necrosis. Porphyria cutanea tarda independently increases the risk of liver cirrhosis and hepatocellular carcinoma, which may be accentuated by co-existing hepatitis C virus (HCV) infection, alcoholic hepatitis, or iron overload ⁶⁹.

Porphyria cutanea tarda diagnosis

Porphyria cutanea tarda (PCT) may be clinically suspected but should always be confirmed by laboratory tests. The preferred screening test for porphyria cutanea tarda is a measurement of porphyrins in plasma and urin. This can differentiate porphyria cutanea tarda (PCT) from Variegate Porphyria (VP). Urine and feces need to be sent to analyse the porphyrin levels, which will be elevated. The specimens need to be protected from light with aluminium foil to ensure testing is accurate. Examination of the urine with a Wood’s lamp (Wood’s lamp emits long-wave ultraviolet (UV) light) may reveal coral pink fluorescence due to excessive porphyrins.

Porphyria cutanea tarda (PCT) is diagnosed biochemically by high levels of porphyrins in the plasma and urine, with a predominance of uroporphyrinogen and hepta- and hexa- and pentacarboxyl porphyrins. This pattern of porphyrin elevation is characteristic but not completely specific since uroporphyrin elevation occurs in other porphyrias, and a PCT-like pattern occurs in some patients with variegate porphyria (VP) ⁷⁰. Therefore, analysis of porphyrins in the red blood cells (erythrocytes) and feces should be considered. Urine measurements using random urine samples with normalization to creatinine is recommended. Urine porphobilinogen is normal in porphyria cutanea tarda (PCT), and delta-aminolevulinic acid (ALA) is normal or only mildly increased ⁴¹. The patterns of porphyrins in urine (predominately uroporphyrin and 7-carboxylate porphyrin) and feces (predominately isocoproporphyrin) help to confirm the diagnosis. Plasma fluorescence scanning is useful for rapid differentiation of variegate porphyria (VP), which has a diagnostic peak at approximately 626  nm. Fecal total porphyrins may be normal or elevated in porphyria cutanea tarda (PCT), and an elevation of fecal isocoproporphyrins is specific for UROD inhibition ⁷⁰, ⁷¹.

Familial porphyria cutanea tarda (F-PCT), an inherited deficiency of uroporphyrinogen decarboxylase (UROD) enzyme, can be diagnosed by the presence of a reduced amount of the uroporphyrinogen decarboxylase (UROD) enzyme in red blood cells (erythrocytes) and is present in about 20% of patients with porphyria cutanea tarda ⁶³. Molecular genetic testing is available for familial porphyria cutanea tarda if the diagnosis has been confirmed in the patient or a family member by urinary porphyrin analysis and/or enzyme assay of uroporphyrinogen decarboxylase activity ⁷², ⁷³.

A skin biopsy can be helpful to distinguish porphyria cutanea tarda (PCT) from other skin blistering conditions. The skin changes are identical to Variegate Porphyria (VP) and Hereditary Coproporphyria (HCP).

Tests to determine the cause of the porphyria may include:

• Blood count, liver function, and kidney function tests
• Iron studies (ferritin level)
• Hepatitis B, C, and human immunodeficiency virus (HIV) serology
• Transferrin saturation and genotyping for HFE gene mutations for hereditary hemochromatosis ⁴⁴
• Tests for cutaneous lupus erythematosus and diabetes
• Urodecarboxylase (UROD) enzyme levels and genetic tests.

Porphyria cutanea tarda treatment

Porphyria cutanea tarda is the most treatable of the porphyrias. The treatment of porphyria cutanea tarda is directed toward the underlying liver problem and the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, general internists, hematologists, dermatologists, hepatologists, and other healthcare professionals may need to systematically and comprehensively plan your treatment.

The first step in the management of porphyria cutanea tarda is the avoidance of all risk factors such as strictly avoiding alcohol, smoking, and estrogen therapy, along with limiting any excess intake of iron. Since porphyria cutanea tarda (PCT) is a photosensitive skin condition, sunlight avoidance is the key until the porphyrin levels have normalized. The wavelengths inducing porphyrins are in the range of 400-410 nm, and only titanium dioxide or zinc oxide containing sunscreen is effective ²⁷. Protective clothing is also helpful in protecting the skin from harmful sunlight rays. Any affected skin areas should be kept clean to prevent the development of skin infections, and associated pain can be managed with oral analgesics.

Presently, there are no effective treatments that restore UROD enzyme levels in individuals with familial porphyria cutanea tarda (F-PCT) ²⁸. However, treatment seems to be equally effective in familial porphyria cutanea tarda (F-PCT) and non-familial porphyria cutanea tarda. Factors that tend to activate the disease should be removed and may result in the resolution of porphyria cutanea tarda. Treatment may include reducing alcohol consumption, stopping estrogen or hormone treatment, avoiding excessive iron intake, or antiviral treatment for underlying hepatitis C.

Reduction of liver iron content is the general recommendation and the most widely recommended treatment is a schedule of repeated phlebotomies (removal of blood), with the aim of reducing iron in the liver ²⁸, ²³, ²⁹, ³⁰, ³¹. This actually reduces iron stores throughout the body. Usually, removal of only 5 to 6 pints of blood (one pint [approximately 450 ml of blood] every one to two weeks) is sufficient, which indicates that iron stores are not excessively increased in most porphyria cutanea tarda patients. The best guides to response are measurements of serum ferritin and plasma porphyrins. Phlebotomies are stopped when the ferritin falls to ~20 ng/ml ³², ³³. Normal ferritin levels vary by gender and age, but generally, for adult males, ferritin level is between 30-300 ng/mL, and for adult females, it’s between 13-150 ng/mL.

Iron chelation therapy i.e., deferasirox or deferoxamine may be considered when phlebotomy is contraindicated, and low iron diet may be beneficial if the latter fails ²⁸.

If phlebotomy cannot be done, as in elderly patients or those who are anemic, antimalarial tablets such as low doses of either chloroquine (125mg twice weekly) or hydroxychloroquine (100mg twice weekly) to allow the porphyrins to be excreted more easily. Usual dosages of these drugs should not be used because they can cause transient but sometimes severe liver damage and worsening of photosensitivity in porphyria cutanea tarda patients.

Furthermore, use of antiviral therapy may benefit patients with chronic hepatitis C infections and reduce risk of progressing to liver cancer ²⁹.

After treatment for porphyria cutanea tarda, periodic measurement of plasma porphyrins may be advised, especially if a contributing factor such as estrogen exposure is resumed. If a recurrence does occur, it can be detected early and treated promptly. The treatment of porphyria cutanea tarda is almost always successful, and the prognosis is usually excellent.

Phlebotomy

Any condition leading to iron overload in the patient is a clear indication for phlebotomy, and in porphyria cutanea tarda cases, phlebotomy is preferred over hydroxychloroquine. Different protocols have been tried, such as removing one unit or 450 ml of blood every two weeks. Strict serial monitoring of ferritin levels is done, and a downward trend in serum ferritin level is the goal of phlebotomy (till a ferritin level of less than 20 ng/ml is seen) ³², ³³. Alternatively, 300ml of blood removed weekly is another treatment strategy that can be used. Care should be taken not to induce anemia or hemoglobin less than 10 gm/dL. Contraindications to phlebotomy include patients with pulmonary or coronary artery disease.

The skin manifestations resolve within four months, but the porphyrin levels can take up to 12 months to normalize ²³. Serum ferritin levels may be used as an indicator to monitor for relapse of porphyria cutanea tarda since the levels change before porphyrin levels ⁷⁴.

Hydroxychloroquine or chloroquine

Figure 12. Hepatoerythropoietic porphyria (HEP)

Footnotes: A 5-year-old boy, with no relevant personal or family history, had a syndrome of skin hyperfragility and photosensitivity since 2 years of age. His urine was dark. Skin lesions appeared as vesicles, blisters, and erosions on the face and the back of the hands. Lesions resolved with superficial scars and milia cysts. He presented with hypertrichosis on the face, limbs, and trunk. In the past 3 years, the patient has not presented with any active lesions, and only some superficial scars and mild hypertrichosis remained visible. (A) and (B), The patient, aged 5 years, with mild hypertrichosis of the forehead. (C) and (D) Superficial scars, after blisters and erosions, on the back of the hands. The young boy had a typical profile of porphyrin accumulation with an excess of urinary uroporphyrin and the presence of isocoproporphyrin in feces. Erythrocytic UROD catalytic activity was dramatically decreased. The diagnosis of hepatoerythropoietic porphyria (HEP) was therefore made and confirmed by UROD gene analysis. A point mutation in the third exon of the UROD gene was found at codon 46, a phenylalanine-to-leucine substitution (F46L). The boy was homozygous and the parents were heterozygous for the mutation.

Figure 13. Hepatoerythropoietic Porphyria dark urine

Hepatoerythropoietic porphyria cause

Hepatoerythropoietic porphyria (HEP) is caused by mutations on both copies of a person’s UROD gene that provides instructions for making an enzyme known as uroporphyrinogen decarboxylase (UROD) that is crucial in the fifth step of the heme biosynthesis pathway, which means that hepatoerythropoietic porphyria (HEP) is inherited as an autosomal recessive trait ⁷⁹, ⁸². Heme (haem) is vital for all of the body’s organs, although it is most abundant in the blood, bone marrow, and liver. Heme is an essential component of iron-containing proteins called hemoproteins, including hemoglobin (the protein that carries oxygen in the blood). The production of heme (haem) is a multi-step process that requires 8 different enzymes. Uroporphyrinogen decarboxylase (UROD) is responsible for the fifth step in heme biosynthesis process, in which carbon and oxygen atoms are removed from uroporphyrinogen III (the product of the fourth step) to form coproporphyrinogen III. In subsequent steps, three other enzymes produce and modify compounds that ultimately lead to heme.

Scientists have determined that the UROD gene is located on the short arm (p) of chromosome 1 (1p34.1) ⁹⁷. Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 also known as autosomes and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 1p34.1” refers to band 34.1 on the short arm of chromosome 1. The numbered bands specify the location of the thousands of genes that are present on each chromosome. At least 30 different mutations of the UROD gene have been identified in patients with hepatoerythropoietic porphyria (HEP) and familial porphyria cutanea tarda (F-PCT), with 1 predominant missense mutation (glycine–to–glutamic acid substitution at codon 281) in Spanish patients with hepatoerythropoietic porphyria (HEP) ⁸⁶.

In hepatoerythropoietic porphyria (HEP), the uroporphyrinogen decarboxylase (UROD) enzyme activity is usually less than 10% its normal levels ⁹⁷. Such low enzyme activity results in the abnormal accumulation of specific porphyrins and related chemicals in the body, especially within the bone marrow, red blood cells, liver and skin. Symptoms develop because of this abnormal accumulation of porphyrins and related chemicals. When porphyrins accumulate in the skin, they absorb sunlight and enter an excited state (photoactivation). This abnormal activation results in the characteristic damage to the skin found in individuals with hepatoerythropoietic porphyria (HEP) ⁹⁷. The liver removes porphyrins from the blood plasma and secretes it into the bile. When porphyrins accumulate in the liver, they can cause toxic damage to the liver.

The rarity of hepatoerythropoietic porphyria (HEP) makes identification of additional risk factors difficult to assess ⁷⁹. However, the existence of instances of late-onset disease suggest that risk factors may play a role in some hepatoerythropoietic porphyria (HEP) individuals ¹⁰⁰. Excess iron may contribute to UROD inhibition by providing an oxidative environment that is apparently required for generating a UROD inhibitor ³⁰. Hepatic hepcidin expression has been shown to regulate iron homeostasis and likely plays a role in development of porphyria cutanea tarda (PCT); however, the role that
hepcidin plays in porphyria cutanea tarda (PCT) development has not been clearly defined ⁵⁵.

Alcohol and its metabolites may induce the enzymes ALAS1 and CYP2E1, generate reactive oxygen species (ROS) that contribute to oxidative damage, cause mitochondrial injury, deplete reduced glutathione and other antioxidant defenses, increase endotoxin production, and activate Kupffer cells leading to liver inflammation. In addition, alcohol has been found to impair iron-mediated expression of hepatic hepcidin and to decrease hepatic expression of hepcidin, which may help lead to increased iron in hepatocytes ¹⁰¹, ¹⁰².

Smoking may increase oxidative stress in hepatocytes and induce hepatic CYP1A2 which is important in the development of uroporphyria in rodent models. Hepatitis C is associated with excess fat, some iron accumulation, mitochondrial dysfunction, and oxidative stress in hepatocytes – all of which may contribute to the development of porphyria cutanea tarda (PCT). Dysregulation of hepcidin may contribute to iron accumulation in hepatitis C ¹⁰³, ⁵¹.

Estrogens can generate reactive oxygen species (ROS) in some experimental systems; however, the mechanism by which they are a susceptibility factor has not been established. Estrogen mimetics (e.g., tamoxifen) have been shown to be associated with porphyria cutanea tarda (PCT) in several cases. The liver is the site of estrogen metabolism; first pass kinetics leads to a much higher hepatic concentration of estrogen and may also contribute to an increased oxidative environment in some individuals ⁵³.

Hepatoerythropoietic porphyria inheritance pattern

Hepatoerythropoietic porphyria (HEP) is inherited as an autosomal recessive trait. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.

Genetic counseling is recommended for affected individuals and their families.

Resources for locating a genetics professional in your community are available online:

• The National Society of Genetic Counselors (https://www.findageneticcounselor.com/) offers a searchable directory of genetic counselors in the United States and Canada. You can search by location, name, area of practice/specialization, and/or ZIP Code.
• The American Board of Genetic Counseling (https://abgc.learningbuilder.com/Search/Public/MemberRole/Verification) provides a searchable directory of certified genetic counselors worldwide. You can search by practice area, name, organization, or location.
• The Canadian Association of Genetic Counselors (https://www.cagc-accg.ca/index.php?page=225) has a searchable directory of genetic counselors in Canada. You can search by name, distance from an address, province, or services.
• The American College of Medical Genetics and Genomics (https://clinics.acmg.net/) has a searchable database of medical genetics clinic services in the United States.

Figure 14. Hepatoerythropoietic porphyria autosomal recessive inheritance pattern

Hepatoerythropoietic porphyria pathophysiology

Reduced activity of the liver enzyme uroporphyrinogen decarboxylase (UROD) to 15%-20% of normal in all tissues leads to the accumulation of substrate, uroporphyrinogen, and the intermediate products of the reaction in all cells. Cells with a high demand for heme production include red blood cells (erythrocytes) and liver cells (hepatocytes); therefore, accumulation is more pronounced in these cell types predominantly in the liver.

The substrates uroporphyrinogen and intermediates accumulate in cells in the form of oxidized porphyrins mostly uroporphyrin and heptacarboxylporphyrin that are then transported into the plasma, where they are deposited in the skin and other tissues. In the skin, these porphyrins interact with blue light (the Soret band, ~410 nm) to produce skin damage.

Excess plasma porphyrins (i.e., uroporphyrin and heptacarboxylporphyrin) are excreted via the urine. Intermediates further along in the pathway (i.e., protoporphyrin and zinc protoporphyrin) are eliminated in the bile.

Hepatoerythropoietic porphyria sgns and symptoms

Hepatoerythropoietic porphyria (HEP) symptoms and severity can vary from one person to another. Onset is usually within the first two years of life, but mild cases that go undiagnosed until adulthood have been reported. Although hepatoerythropoietic porphyria (HEP) is associated with specific, characteristic symptoms, several factors, including the small number of identified cases, make it difficult to establish the full range of associated symptoms of hepatoerythropoietic porphyria (HEP).

Severe skin photosensitivity is usually the first sign. Affected infants may have extremely fragile skin that can peel or blister on minimal impact is common. Reddening of the skin is also common (erythema). Blistering skin lesions can develop on sun-exposed skin such as the hands and face. Photosensitivity can be severe and can cause scarring, erosion, and disfigurement. Bacterial infection of skin lesions can occur. Abnormal, excessive hair growth (hypertrichosis) may also occur on sun-exposed skin. Affected skin may darken or lose color (hyper- or hypopigmentation). Small bumps with a distinct white head (milia) may also develop. Some affected individuals have teeth that are reddish-brown colored (erythrodontia) as a result of the deposition of porphyrins in the enamel layer of the developing tooth ⁷⁹.

Low levels of circulating red blood cells (anemia) may also occur. Anemia may be due to the premature destruction of red blood cells (hemolysis). Anemia associated with hepatoerythropoietic porphyria (HEP) may be mild or severe. Severe anemia may be associated with fatigue, pale skin, irregular heartbeat, chest pain, dizziness, and abnormally cold hands and feet. Some individuals may have an abnormally enlarged liver and/or spleen (hepatosplenomegaly).

Mild cases of hepatoerythropoietic porphyria (HEP) can go undiagnosed until adulthood. Overt photosensitivity may not be seen, and mild skin damage can be mistaken for other conditions during childhood.

Note: The clinical features of hepatoerythropoietic porphyria (HEP) and familial porphyria cutanea tarda (F-PCT) are indistinguishable. However, in striking contrast to hepatoerythropoietic porphyria (HEP), familial porphyria cutanea tarda (F-PCT) rarely if ever manifests in infancy or childhood. Rather, as is the case for porphyria cutanea tarda type 1 (nonfamilial, acquired), familial porphyria cutanea tarda (F-PCT) is a disease of middle-aged persons, usually with several risk factors for development of overt disease.

Hepatoerythropoietic porphyria diagnosis

A diagnosis of hepatoerythropoietic porphyria (HEP) is based upon identification of characteristic symptoms, a detailed medical history, a thorough clinical evaluation and a variety of specialized tests.

Hepatoerythropoietic porphyria (HEP) should be suspected in infants or children with the following clinical findings, suggestive laboratory findings, and family history.

Hepatoerythropoietic porphyria (HEP) may be considered in infants and children with these clinical features:

• Blistering skin lesions/vesicles/bullae
• Abnormal, excessive hair (hypertrichosis)
• Scarring
• Passage of red or dark urine

Note: The features of hepatoerythropoietic porphyria (HEP) generally resemble those of congenital erythropoietic porphyria (CEP).

Diagnosis of hepatoerythropoietic porphyria (HEP) can be made by demonstrating significant elevations of specific porphyrins in your urine and stool, as well as identification of a specific fluorescence emission peak in plasma. DNA genetic testing to identify the specific mutations in an individual’s UROD genes is the most specific and sensitive test to confirm the diagnosis of hepatoerythropoietic porphyria (HEP).

Clinical Testing and Workup

Screening tests can help diagnose hepatoerythropoietic porphyria (HEP) by measuring the levels of certain porphyrins in blood plasma, urine and red blood cells. Urine and plasma porphyrins show an increase predominantly of uroporphyrin and heptacarboxylporphyrin. Consider erythrocyte zinc protoporphyrin levels, which are significantly increased in hepatoerythropoietic porphyria (HEP), to differentiate hepatoerythropoietic porphyria (HEP) from congenital erythropoietic porphyria (CEP).

Biochemical Characteristics of Hepatoerythropoietic Porphyria ⁷⁹

• Plasma: Increased uroporphyrin, heptacarboxylporphyrin (~620 nm) (Fluorescence emission peak of diluted plasma at neutral pH, following excitation at 400-410 nm)
• Urine: Increased uroporphyrin, heptacarboxylporphyrin
• Erythrocytes (red blood cells): Increased zinc protoporphyrin

Porphyrin patterns in hepatoerythropoietic porphyria (HEP) are similar to those seen in porphyria cutanea tarda (PCT) with elevation of highly carboxylated porphyrins and isocoproporphyrins. In contrast to porphyria cutanea tarda (PCT), there are markedly increased levels of zinc protoporphyrin in red blood cells in hepatoerythropoietic porphyria (HEP) patients which is due to accumulation of pathway intermediates being metabolized to protoporphyrins.

Hepatoerythropoietic porphyria differential diagnosis

Symptoms of the following disorders can be similar to those of hepatoerythropoietic porphyria (HEP).

Congenital erythropoietic porphyria (CEP) is a rare inherited metabolic disorder resulting from the deficient function of the enzyme uroporphyrinogen III cosynthase (UROS), the fourth enzyme in the heme biosynthetic pathway. Due to the impaired function of UROS (uroporphyrinogen III cosynthase) enzyme, excessive amounts of particular porphyrins accumulate, particularly in the bone marrow, plasma, red blood cells, urine, teeth, and bones. The major symptom of congenital erythropoietic porphyria (CEP) is hypersensitivity of the skin to sunlight and some types of artificial light, such as fluorescent lights (photosensitivity). After exposure to light, the photo-activated porphyrins in the skin cause bullae (blistering) and the fluid-filled sacs rupture, and the lesions often get infected. These infected lesions can lead to scarring, bone loss, and deformities. The hands, arms, and face are the most commonly affected areas. Congenital erythropoietic porphyria (CEP) is inherited as an autosomal recessive genetic disorder. Typically, there is no family history of the disease. Both parents are usually healthy, but each carries a defective gene that they can pass to their children. Affected offspring have two copies of the defective gene, one inherited from each parent.

There are other conditions that may cause signs and symptoms that are similar to those seen in hepatoerythropoietic porphyria (HEP). Such conditions include other cutaneous porphyrias, sporadic porphyria cutanea tarda (i.e., porphyria cutanea tarda type 1 that is not associated with a UROD pathogenic variant), drug-induced photosensitivity, epidermolysis bullosa, various forms of lupus, and solar urticarial.

Sporadic porphyria cutanea tarda also called porphyria cutanea tarda type 1 that is not associated with a UROD genetic mutation is clinically indistinguishable from hepatoerythropoietic porphyria (HEP) and familial porphyria cutanea tarda (F-PCT) and is highly influenced by susceptibility factors associated with porphyria cutanea tarda (PCT). In these cases, the excess porphyrins are produced only in the liver.

The skin histopathologic findings of pseudoporphyria are similar to those of hepatoerythropoietic porphyria (HEP), however, pseudoporphyria is not associated with porphyrin biochemical abnormalities. Medications, chronic kidney failure, and excessive sun exposure or UV radiation have been reported to cause pseudoporphyria ¹⁰⁴.

Table 2. Other Types of Porphyria in Hepatoerythropoietic Porphyria Differential Diagnosis

Hepatoerythropoietic porphyria treatment

The treatment of hepatoerythropoietic porphyria (HEP) is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, hematologists, dermatologists, hepatologists, and other healthcare professionals may need to systematically and comprehensively plan an affected child’s treatment. Genetic counseling may benefit affected individuals and their families.

There is no specific, FDA-approved therapy for individuals with hepatoerythropoietic porphyria (HEP). Because the disorder is so rare, most treatment information is based other forms of porphyria.

Avoidance and/or protection from sunlight will benefit individuals with hepatoerythropoietic porphyria (HEP) and can include the use of clothing styles with long sleeves and pant legs, made with double layers of fabric or of light-exclusive fabrics, wide brimmed hats, gloves, and sunglasses. Topical sunscreens are generally ineffective, but certain tanning products with ingredients that increase pigmentation may be helpful. Affected individuals may also benefit from window tinting and the use of vinyl or films to cover the windows of their homes and cars.

Phlebotomies (removal of blood) to lower the amount of porphyrins in the liver, which are used to treat individuals with porphyria cutanea tarda (PCT), are generally ineffective in individuals with hepatoerythropoietic porphyria (HEP) since elevated iron levels are not a feature of the disorder ²², ⁹². Another treatment for porphyria cutanea tarda (PCT), the antimalarial drug hydroxychloroquine, was effective in at least one case reported in the medical literature.

Anemia may require treatment in some cases. Blood transfusions have been used to treat some individuals. Recombinant erythropoietin (rEPO) a synthetic version of the naturally occurring hormone erythropoietin, which helps the body produce more red blood cells, was successfully used to treat severe anemia in an individual with hepatoerythropoietic porphyria (HEP) whose anemia was not associated with increased red cell destruction.

Light Avoidance

Avoiding exposure to sunlight is the most important way to manage symptoms for people with hepatoerythropoietic porphyria (HEP). People with hepatoerythropoietic porphyria (HEP) need to wear protective clothing, and have windows tinted in their cars and homes. Most sunscreens are not effective because they do not block light in the blue-violet range, which is the type of light that triggers reactions in porphyria.

Agents to avoid

Older individuals should avoid known triggering factors: alcohol, oral estrogen, iron overload, smoking, and drugs that induce the cytochrome P450s.

Blister and Wound Care

There is a risk of developing infections in blisters, particularly if they rupture. Prescription antibiotic ointments may be required to manage infections. Care from a dermatologist is recommended.

Hepatoerythropoietic Porphyria Prognosis

Due to the extreme rarity of hepatoerythropoietic porphyria (HEP) with less than 100 reported cases, little is known about the prognosis of hepatoerythropoietic porphyria (HEP) patients ⁹⁴, ¹⁰⁵, ⁹⁶. The prognosis for hepatoerythropoietic porphyria (HEP) can be complicated by liver involvement, and liver function test must be monitored regularly. However, with proper treatment and management, many patients with hepatoerythropoietic porphyria (HEP) can maintain a good quality of life ¹⁰⁶, ¹⁰⁷. No increased risk for liver cancer (hepatocellular carcinoma) has been documented in hepatoerythropoietic porphyria (HEP) ⁷⁹.

Hepatoerythropoietic porphyria (HEP) typically presents early in infancy or early childhood with signs and symptoms such as extreme photosensitivity, recurrent skin blisters (bullae) and skin erosions on sun exposed skin with secondary bacterial infections that may result in severe skin scarring, sclerodermatous change, and deformities of the hand ⁸¹. Sun-induced skin redness (erythema) and blistering occurred by age 2 years in 75% of reported cases ⁸¹. Sclerodactyly (a condition where the skin on the fingers and/or toes thickens and tightens, making them feel hard and less flexible), osteolysis (active resorption of bone tissue) and shortening of the phalanges, and progressive joint deformities can occur as well ⁸¹, ⁹².

Spontaneous improvement of acute photosensitivity during later childhood, but persistent skin fragility, has been described ¹⁰⁸, ¹⁰⁹, ¹¹⁰, ¹¹¹. Other patients have presented in the second or third decade of life with mild skin fragility or photodistributed annular plaques ¹¹², ¹¹³, ¹¹⁰, ¹¹⁴.

Other signs and symptoms inlcude abnormal excessive hair (hypertrichosis), red-brown discoloration of teeth (erythrodontia) and pink-to-red urine. There may be bone fragility due to expansion of the bone marrow and vitamin deficiencies, especially vitamin D deficiency. Red blood cells have a shortened life-span with mild or severe hemolytic anemia. Synthesis of heme and hemoglobin is actually increased to compensate for the shortened red blood cell survival and is associated with abnormal enlargement of the liver and/or spleen (hepatosplenomegaly) ⁹⁴, ⁸¹, ⁹². Current treatment recommendations resemble those for familial porphyria cutanea tarda (F-PCT) ⁷⁹.

Mild cases of hepatoerythropoietic porphyria (HEP) may go unrecognized until adulthood and can be clinically indistinguishable from porphyria cutanea tarda (PCT), the most common form of porphyria in humans where the porphyria cutanea tarda (PCT) that may be acquired in 75% to 80% of cases (also known as porphyria cutanea tarda type 1 or sporadic porphyria cutanea tarda) or occur in individuals with a mutation of one UROD gene (autosomal dominant inheritance or porphyria cutanea tarda type 2 or familial porphyria cutanea tarda). Hepatoerythropoietic Porphyria (HEP) is the autosomal recessive form of familial porphyria cutanea tarda (F-PCT). Skin photosensitivity is generally much more severe in hepatoerythropoietic porphyria (HEP) than in porphyria cutanea tarda (PCT).

Compared to porphyria cutanea tarda (PCT), the skin features of hepatoerythropoietic porphyria (HEP) typically have earlier onset, increased severity leading to disfigurement, and closer resemblance to those in congenital erythropoietic porphyria (CEP) ⁸⁵, ⁹². However, extracutaneous findings including hemolytic anemia are more frequent and severe in congenital erythropoietic porphyria (CEP) than hepatoerythropoietic porphyria (HEP) ⁸⁵, ⁹², ¹¹³.

In contrast to the autosomal recessive form of variegate porphyria (VP), which is characterized by developmental delay and seizures ¹¹⁵, neurologic abnormalities are not typically associated with hepatoerythropoietic porphyria (HEP) or congenital erythropoietic porphyria (CEP) ⁸⁵, ¹¹⁶, ¹¹⁷. Nevertheless, developmental delay and seizures have been previously reported in hepatoerythropoietic porphyria (HEP) ¹¹⁸, ⁸⁸. A 4-year-old boy had delayed speech and language skills then presented with focal seizures and acute left hemiparesis ¹¹⁸. Two young adults, ages 21 and 23 years, with severe hepatoerythropoietic porphyria (HEP) developed generalized seizures and had neuroimaging evidence of cerebral cortical atrophy and punctate calcifications in the frontal lobes, presumably related to hypoxic injury as in other porphyrias ⁸⁸. These observations, together with recent affected siblings’ developmental delay, support neurologic assessment of hepatoerythropoietic porphyria (HEP) patients in order to better define this possible complication ⁸¹.

Cantatore-Francis et al ⁸¹ reported 2 sisters with painful polyarticular arthritis, represents a typical (but heretofore unrecognized) inflammatory precedent of joint deformity in hepatoerythropoietic porphyria (HEP) or an idiosyncratic inflammatory process, perhaps triggered by porphyrin deposition together with exposure to ultraviolet light or another environmental insult, remains to be determined.

Anemia was present in more than 50% hepatoerythropoietic porphyria (HEP) patients for whom hematologic status was reported (15/27) ⁸¹, but severe anemia requiring transfusions or administration of erythropoietin (EPO) has only been observed in a few individuals ¹¹².

Erythropoietic protoporphyria (Protoporphyria)

Footnote: Acute photosensitivity reaction in erythropoietic protoporphyria (EPP).

Figure 16. Erythropoietic protoporphyria

Footnotes: a) Child with extensive edema of the face with erythema and petechiae; b) Adult patient with skin redness (erythema) and skin swelling (edema) during phototoxic episode, with hypopigmented scars and skin thickening present

Figure 17. Chronic erythropoietic protoporphyria skin lesions

Erythropoietic protoporphyria signs and symptoms

The most common symptom of erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP) is hypersensitivity of the skin to sunlight and some types of artificial light (photosensitivity), with pain, itching, and/or burning of the skin occurring after exposure to sunlight and occasionally to fluorescent light. Some patients may also be sensitive to some types of artificial light such as fluorescent lights. When the skin is exposed to sun, people with erythropoietic protoporphyria (EPP) or X-linked protoporphyria (XLP) first develop tingling, itching, and/or burning of the skin ¹²⁷. These symptoms serve as warning signs as longer exposure can result in severe pain. Affected individuals may also have an abnormal accumulation of body fluid under affected areas (edema) and/or persistent redness or inflammation of the skin (erythema) ¹²⁷. In rare cases, affected areas of the skin may develop sac-like lesions (vesicles or bullae) and scar if exposure to sunlight is prolonged ¹²⁷. However, scarring and/or discoloring of the skin (hyperpigmentation) is uncommon and rarely severe ¹²⁷. The affected areas of skin may become abnormally thick. In addition, in some cases, affected individuals may also exhibit malformations of the nails. The severity and degree of photosensitivity is different from case to case. Photosensitivity is often seen during infancy; however, in some cases, it may not occur until adolescence or adulthood.

The severity and degree of symptoms is different from case to case. Some patients may only be able to tolerate a few minutes of sun exposure while others may be able to tolerate longer sun exposure without symptoms. The amount of sun tolerated may also be different based on weather conditions. Symptoms are often seen during infancy; however, in some cases, it may not occur until adolescence or rarely in adulthood.

Symptoms usually start in childhood but diagnosis is often delayed since skin blistering is not common and because the porphyrins are insoluble, they cannot be detected on urine analysis. The diagnosis is made upon finding increased levels of the protoporphyrin IX (PPIX) in the plasma or red blood cells.

In some affected individuals, the flow of bile through the gallbladder and bile ducts (biliary system) may be interrupted (cholestasis) causing gallstones (cholelithiasis) to form. In turn, gallstones can cause obstruction and/or inflammation of the gallbladder (cholecystitis).

In some affected individuals, the flow of bile through the gallbladder and bile ducts (biliary system) may be interrupted (cholestasis) causing gallstones (cholelithiasis) to form. In turn, such stones can cause obstruction and/or inflammation of the gallbladder (cholecystitis).

Rarely, affected individuals may also develop liver damage that, in very severe cases, may lead to liver failure requiring liver transplantation. As liver transplantation does not cure erythropoietic protoporphyria (EPP) or X-linked protoporphyria (XLP), a bone marrow transplant following liver transplant may be necessary in some cases ¹²⁷.

Patients with erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP) may also have mild anemia (low blood counts). In many cases, this may be due to low iron stores (iron deficiency). They may also have high levels of liver enzymes on blood tests.

Liver involvement

Patients with erythropoietic protoporphyria (EPP) may also have liver disease that require specialist medical treatment and possibly liver transplantation. Liver disease develops in association with erythropoietic protoporphyria (EPP) in 1 to 4% of cases ¹⁴⁸, ¹⁵², with usual features of visceral enlargement and portal hypertension. Liver disease in protoporphyria is related to the excess protoporphyrin cleared by the entero-hepatic circulation leading to paracrystalin protoporphyrin deposition in liver cells (hepatocytes) and precipitation in the biliary canaliculiy. The percentage of patients who will develop liver disease is not established, nor specific factors that may influence its development. In EPP, the degree of severity of the liver disease is variable. Liver disease in EPP may include: gallstones (cholelithiasis) with possible obstructive episodes and chronic liver disease evolving to rapid acute liver failure ¹⁶⁵, ¹⁶⁶.

The incidence of gallstones (cholelithiasis) is frequent in about 20% of EPP patients EPP ¹²⁴. Gallstones with high protoporphyrin content are generated due to the accumulation of insoluble protoporphyrin and increased biliary protoporphyrin concentration ¹⁶⁷.

It is not possible to predict whether or not acute liver failure will occur. Studies have revealed that an increase in coproporphyrin urinary excretion, together with a change in isomer predominance from isomer III to isomer I, and increasing levels of protoporphyrinaemia may precede this complication ¹⁶⁸.

Progression of protoporphyric liver deterioration leads to splenomegaly, splenic sequestration of erythrocytes with haemolysis (which increases erythropoiesis) and protoporphyrin generation ending in fulminant liver failure ¹⁶⁵, ¹⁶⁸, ¹⁶⁹.

Erythropoietic protoporphyria complications

The main serious complication associated with EPP is protoporphyrin-related liver disease, which may be fatal ¹²⁶. Severe liver disease affects 2%–5% of protoporphyia patients ¹⁷⁰. Liver injury occurs from the crystallization of protoporphyrin in the bile ducts ¹⁷¹. This obstruction of the biliary system further increases plasma protoporphyrin, which is typically excreted in the bile, escalating the protoporphyrin-mediated liver damage that may progress rapidly ¹⁷¹. Previous studies indicate that higher protoporphyrin levels may be associated with an increased risk of liver disease or progression ¹⁷¹. Genetic sequencing to identify EPP patients with two pathogenic FECH variants other than c.315-48T>C may be considered, as these patients may be more likely to progress to liver failure ¹⁷². Therefore, liver function tests should be performed at the time of diagnosis and at least yearly thereafter ¹⁷³, ¹⁷⁴, ¹⁷⁵. This may allow for early identification, evaluation for additional factors contributing to liver disease, and medical management.

The extent to which alcohol use worsens protoporphyria-related liver disease or whether a safe limit alcohol use exists remains unclear ¹¹⁹. Avoidance of excessive alcohol intake is recommended for all people with EPP or XLP ¹¹⁹. Furthermore, immunization against hepatitis A and B is recommended. Although protoporphyria patients are at an increased risk for gallstones (cholelithiasis), in asymptomatic patients with normal liver chemistries, a screening ultrasound is not recommended ¹¹⁹. Surgery to remove your gallbladder (cholecystectomy) is not recommended for asymptomatic gallstones (cholelithiasis).

In the later stages of liver disease, the patient may develop peripheral nerve damage (neuropathy), which mimics the peripheral neuropathy of acute porphyria and may lead to breathing failure ¹²⁶. On repeated exposure to sunlight, the skin over the face, dorsum of hands (knuckles), can become thickened or lichenified along with loss of lunulae of fingernails. Due to regular sunlight avoidance, patients with EPP are more prone to develop a vitamin-D deficiency, which can lead to osteoporosis ¹³⁸.

Erythropoietic protoporphyria causes

Erythropoietic protoporphyria (EPP) is caused by mutations in the FECH gene. The vast majority of patients with EPP are compound heterozygotes for both a rare pathogenic FECH variant and a common low expression FECH allele that is present in ~10% of the Caucasian population (c.315-48T>C), a combination that results in ~30% of normal enzyme activity ¹⁷⁶, ¹⁷⁷. Homozygosity for FECH c.315-48T>C does not cause EPP ¹⁷⁸. The FECH gene provides instructions for making an enzyme known as ferrochelatase ¹³⁴. The ferrochelatase (FECH) enzyme is involved in the production of a molecule called heme. The production of heme is a multi-step process that requires eight different enzymes. Ferrochelatase is responsible for the eighth and final step in this process, in which an iron (Fe²⁺) atom is inserted into the center of protoporphyrin IX (the product of the seventh step) to form heme. Heme is vital for all of your body’s organs, although it is most abundant in your blood, bone marrow, and liver. Heme is an essential component of iron-containing proteins called hemoproteins, including hemoglobin (the protein that carries oxygen in the blood). Due to abnormally low levels of ferrochelatase (FECH) enzyme, excessive amounts of protoporphyrin build up in the bone marrow, blood plasma, and red blood cells. Porphyrins compounds are formed during the normal process of heme production, but reduced activity of ferrochelatase allows them to accumulate to toxic levels. The excess porphyrins can leak out of developing red blood cells and be transported through the bloodstream to your skin and other tissues such as your liver. High levels of porphyrins compounds in the skin cause the oversensitivity to sunlight that causes severe pain and inflammation resulting in symptoms of EPP. Large amounts of porphyrins in the gallbladder can also cause gallstones. Less commonly, a buildup of porphyrins in the liver can result in liver damage that leads to cirrhosis and liver failure.

Some patients with symptoms of protoporphyria have a genetic change (gain-of-function variants in exon 11 of ALAS2) in a different gene called ALAS2, a gene located on the X chromosome and follows an X-linked inheritance pattern ¹³⁶. When a patient has a genetic change in the ALAS2 gene, the condition is referred to as X-linked protoporphyria (XLP). XLP accounts for 2–10% of protoporphyria cases ¹¹⁹. The ALAS2 gene provides instructions for making an enzyme called 5′-aminolevulinate synthase 2 or erythroid ALA-synthase ¹³⁷. This version of the enzyme is found only in developing red blood cells called erythroblasts. ALA-synthase enzyme also plays an important role in the production of heme. The production of heme is a multi-step process that requires eight different enzymes. ALA-synthase is responsible for the first step in this process, the formation of a compound called delta-aminolevulinic acid (δ-ALA). The excess delta-aminolevulinic acid (δ-ALA) is converted by other enzymes to compounds called porphyrins. If porphyrins compounds build up in erythroblasts, they can leak out and be transported through the bloodstream to your skin and other tissues. High levels of porphyrins in the skin cause the oversensitivity to sunlight that is characteristic of X-linked protoporphyria (XLP).

About 4 to 6% of patients with the symptoms of erythropoietic protoporphyria (EPP) and elevated red blood cell protoporphyrin IX (PPIX) levels will not have mutations in ferrochelatase (FECH) or 5-aminolevulinate synthase 2 (ALAS2) ¹⁷⁹, ¹⁸⁰.

Recently, an autosomal dominant mutation in human CLPX, a modulator of heme biosynthesis, was found to result in the accumulation of delta-aminolevulinate synthase (ALAS) and protoporphyrin IX (PPIX) and symptoms of protoporphyria in an affected family ¹⁸¹. Acquired somatic ferrochelatase (FECH) mutations have been identified in a small number of patients in whom erythropoietic protoporphyria (EPP) has developed after the age of 40 years in association with myelodysplasia or myeloproliferative disorder ¹⁸², ¹⁸³. A case of late-onset erythropoietic protoporphyria (EPP) with myelodysplastic syndrome has also been reported in a patient who had the homozygous IVS3–48T>C polymorphism in the ferrochelatase (FECH) gene ¹⁸⁴. Late onset X-linked protoporphyria (XLP) has also been reported in a case of early myelodysplastic syndrome with somatic mosaicism in the bone marrow ¹⁸⁵.

Erythropoietic protoporphyria inheritance pattern

Erythropoietic protoporphyria (EPP) is inherited in an autosomal recessive manner ², ¹²⁷. Everyone has two copies of the FECH gene, one inherited from the mother and one from the father. Most individuals with EPP have a different gene mutation on each copy of the FECH genes. On one copy, the change, called a mutation, has stopped this copy of the FECH gene from working properly. On the other copy, there is a small change called a “low-expression allele” or a polymorphism. This alteration still affects the way the FECH gene works; it produces less ferrochelatase enzyme than normal. This small change is common in the general population, with up to 10% of Caucasians with one copy of this change. This alteration will not cause EPP by itself, and people who have the alteration on each copy of the FECH gene will NOT develop EPP. But when someone inherits the small alteration from one parent and a mutation from the other, they will develop EPP, because there will not be enough ferrochelatase (FECH) enzyme made. Most patients with EPP have the low-expression alteration on one copy of the FECH gene and a mutation on the other copy. The risk for patients with EPP to have a child who also has the condition depends on the genetic changes in their partner.

Erythropoietic protoporphyria is a rare disorder inherited as an autosomal dominant genetic trait with poor penetrance. Human traits, including the classic genetic diseases, are the product of the interaction of two genes, one received from the father and one from the mother.

In dominant disorders, a single copy of the disease gene (received from either the mother or father) will be expressed “dominating” the other normal gene and resulting in the appearance of the disease. The risk of transmitting the disorder from affected parent to offspring is 50 percent for each pregnancy regardless of the sex of the resulting child. The risk is the same for each pregnancy.

The symptoms of erythropoietic protoporphyria develop due to excessive levels of a chemical called protoporphyrin that accumulates in certain tissues of the body (i.e., the plasma, red blood cells, and the liver). Excessive protoporphyrin levels occur as the result of abnormally low levels of the enzyme ferrochelatase (FECH).

There are several different allelic variants of erythropoietic protoporphyria. An allele is any of a series of two or more genes that may occupy the same position (locus) on a specific chromosome. Symptoms of these allelic variants of erythropoietic protoporphyria are predominantly the same; however, one type may be inherited as an autosomal recessive genetic trait.

The gene that is responsible for regulating the production of the enzyme ferrochelatase (FECH) has been located on the long arm of chromosome 18 (18q21.3). Chromosomes are found in the nucleus of all body cells. They carry the genetic characteristics of each individual. Pairs of human chromosomes are numbered from 1 through 22, with an unequal 23rd pair of X and Y chromosomes for males, and two X chromosomes for females. Each chromosome has a short arm designated as “p” and a long arm identified by the letter “q”.

Some people who have inherited this defective gene may have slightly elevated levels of protoporphyrin in the body but will not exhibit the symptoms of erythropoietic protoporphyria.

Genetic counseling is recommended for affected individuals and their families.

Resources for locating a genetics professional in your community are available online:

• The National Society of Genetic Counselors (https://www.findageneticcounselor.com/) offers a searchable directory of genetic counselors in the United States and Canada. You can search by location, name, area of practice/specialization, and/or ZIP Code.
• The American Board of Genetic Counseling (https://abgc.learningbuilder.com/Search/Public/MemberRole/Verification) provides a searchable directory of certified genetic counselors worldwide. You can search by practice area, name, organization, or location.
• The Canadian Association of Genetic Counselors (https://www.cagc-accg.ca/index.php?page=225) has a searchable directory of genetic counselors in Canada. You can search by name, distance from an address, province, or services.
• The American College of Medical Genetics and Genomics (https://clinics.acmg.net/) has a searchable database of medical genetics clinic services in the United States.

Figure 18. Erythropoietic protoporphyria (EPP) autosomal recessive inheritance pattern

Erythropoietic protoporphyria diagnosis

Erythropoietic protoporphyria (EPP) should be suspected in anyone with non-blistering photosensitivity especially when it is prolonged and beginning in childhood. It is easy to make a diagnosis, or rule it out, once it is suspected. The diagnosis of erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP) may be made by a thorough clinical evaluation, and specialized laboratory tests. Total red blood cell (erythrocyte) protoporphyrin concentration, including proportions of metal-free and zinc-bound protoporphyrin, is the recommended test for the diagnosis of protoporphyria ¹⁸⁶, ¹⁸⁷, ¹⁸⁸. High performance liquid chromatography or extraction methods that measure total, metal-free, and zinc protoporphyrin are recommended for the diagnosis of protoporphyria ¹⁵⁴. Current lists of laboratories that perform such testing can be found on websites for the United Porphyrias Association, the European Porphyria Network, and the American Porphyria Foundation. These laboratories can also give advice regarding the optimal laboratory testing or differential diagnosis of biochemical abnormalities. As sample materials and pre‐analytical specifications depend on the specific diagnostic methods, it is advisable to contact the respective laboratory prior to sample collection. Genetic testing is useful to confirm the diagnosis.

The diagnosis of erythropoietic protoporphyria is established by finding an abnormally high level of total red blood cell (erythrocyte) protoporphyrin, and showing that this increase is mostly free protoporphyrin rather than zinc protoporphyrin. There is considerable confusion about which test to order. Sometimes laboratories have measured only zinc protoporphyrin and reported results incorrectly as “protoporphyrin” or “free erythrocyte protoporphyrin (FEP)”.

Porphyrins are almost always elevated in plasma in erythropoietic protoporphyria, but may be normal in mild cases. Fecal porphyrins may be normal or increased.

An experienced biochemical laboratory can usually distinguish between patients with erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP), because erythropoietic protoporphyria (EPP) have much less zinc protoporphyrin in their erythrocytes. This can be explained because in the bone marrow the enzyme ferrochelatase not only normally makes heme (iron protoporphyrin) from protoporphyrin and iron, but can also make zinc protoporphyrin, especially when excess protoporphyrin is present or iron is deficient. However, this does not replace DNA studies or genetic testing.

Genetic testing of the FECH and ALAS2 genes is useful to confirm the diagnosis and identify if it is erythropoietic protoporphyria (EPP) or X-linked protoporphyria (XLP) ¹⁷⁶. This information is useful for genetic counseling and testing family members as both are inherited in a different manner. Genetic counseling is recommended for couples with a personal or family history of protoporphyria who are planning to have children.

Erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP) are usually diagnosed during infancy or early childhood, due to characteristic symptoms, and by testing the red blood cells (erythrocytes) for increased levels of protoporphyrin IX (PPIX). The blood needs to be sent for porphyrin analysis in a tube protected from light with aluminium foil. Exposure of the blood tube to light can lead to photobleaching of protoporphyrin IX (PPIX), resulting in a decrease in measured protoporphyrin IX (PPIX) levels in the sample as compared to the actual levels in the subject. This effect is related to the ability of conjugated double bonds in the porphyrin rings to absorb the energy from visible light ¹⁵⁶. To avoid diagnostic delay, plasma porphyrins should be measured at the same time with erythrocyte protoporphyrin ¹⁰.

The normal total protoporphyrin level in red blood cells (erythrocytes) is 80 mcg/dL, but in a patient with erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP), protoporphyrin level in red blood cells (erythrocytes) is elevated up to 300 to 8000 mcg/dL ¹²⁶. There is an increased percentage of red blood cell (erythrocyte) metal-free protoporphyrin rather than zinc protoporphyrin ¹²⁶. In patients with erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP), the urinary porphyrin levels are normal.

Rarely, erythropoietic protoporphyria (EPP) develops in adults in the presence of a bone marrow disorder such as polycythemia vera, and is due to expansion of a clone of red blood cell precursors in the marrow that is deficient in ferrochelase.

DNA studies or genetic testings are important for confirming the diagnosis of erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP) and for genetic counseling. This should be completed first in a person known to have the disease, and the information about the mutations in that individual used to guide testing of family members.

When erythropoietic protoporphyria (EPP) is due to a FECH mutation the inheritance is described as autosomal recessive. It is most common to find that one severe mutation is inherited from one parent and another weak mutation inherited from the other parent. The weak mutation is quite common in normal Caucasians, rare in Blacks and even more common in Japanese and Chinese populations. This mutation is sometime referred to as “hypomorphic” because it results in formation of a less than normal amount of ferrochelatase. But is does not cause Erythropoietic protoporphyria unless it is paired with a severe mutation. The severe mutation is characteristic for an Erythropoietic protoporphyria family and is present in all affected individuals. “Carriers” of the severe mutation are not affected because they do not have the weak mutation. Affected individuals and unaffected carriers can transmit the severe mutation to the next generation. Some of their children will have Erythropoietic protoporphyria if the other parent has a copy of the weak mutation. Rarely, the weak mutation is absent in an Erythropoietic protoporphyria family and two severe mutations are found, with at least one producing some ferrochelatase.

In X-linked protoporphyria (XLP), mutations of the ALAS2 gene, which is found on the X chromosome, causes an increase in the production of the enzyme ALAS2 in the bone marrow. Several of these “gain of function” mutations have been described in different X-linked protoporphyria families. In X-linked protoporphyria protoporphyrin production exceeds that needed for heme and hemoglobin formation. Like hemophilia and other X linked genetic diseases, X-linked protoporphyria is more common in men. Women have two X chromosomes and are usually not affected because they have a normal as well as a mutated ALAS2 gene. Men have only one X chromosome and will be affected if they inherit an ALAS2 mutation. Women with an ALAS2 mutation will, on average, pass that mutation to half of their daughters (who will usually be unaffected carriers) and to half of their sons (who will be affected).

Figure 19. Erythropoietic protoporphyria diagnostic algorithm

Abbreviations: ADP = aminolevulinic acid dehydratase porphyria; AIP = acute intermittent porphyria; ALA = aminolevulinic acid; HCP = hereditary coproporphyria; HMBS = hydroxymethylbilane synthase; PBG = porphobilinogen; VP = variegate porphyria.

Pitfalls of testing

The biochemical diagnosis of protoporphyrias is based on the measurement of red blood cell (erythrocyte) total and metal-free protoporphyrin ¹²¹. The latter comprises 85% to 100% of total red blood cell (erythrocyte) protoporphyrin in EPP, and 50% to 85% in XLP ¹⁸⁹, ¹⁵⁴. Zinc protoporphyrin predominates in other conditions that increase red blood cell (erythrocyte) protoporphyrin. Plasma and fecal porphyrin levels can be variably increased, and urine porphyrin levels are normal. Genetic testing is recommended to distinguish between EPP and XLP and to confirm the diagnosis ¹⁸⁹.

Measurement of red blood cell (erythrocyte) protoporphyrin levels is fraught with a lack of standardized nomenclature and methodology ¹⁹⁰. Some large commercial laboratories measure protoporphyrin by hematofluorometry, a method that only measures zinc protoporphyrin and that was developed to screen for lead poisoning and iron deficiency. Hematofluorometers report the molar ratio of zinc protoporphyrin to heme by fluorescence but do not measure total or metal-free protoporphyrin ¹⁵⁴. Nevertheless, these major laboratories report “free erythrocyte protoporphyrin” (FEP) levels that, in actuality, reflect only zinc protoporphyrin, which may not be increased in EPP. This inappropriate method and inaccurate terminology propagates confusion that can lead to missed diagnoses of protoporphyria ¹⁹⁰. Accurate testing reports should only refer to erythrocyte total protoporphyrin, zinc protoporphyrin, and metal-free protoporphyrin, and comment whether the results are consistent with protoporphyria. The term FEP became unclear after the discovery of zinc protoporphyrin in erythrocytes in the 1970s and should no longer be used ¹²¹.

High performance liquid chromatography or extraction methods that measure total, metal-free, and zinc protoporphyrin are recommended for the diagnosis of protoporphyria ¹⁵⁴. Current lists of laboratories that perform such testing can be found on websites for the United Porphyrias Association, the European Porphyria Network, and the American Porphyria Foundation. These laboratories can also give advice regarding the optimal laboratory testing or differential diagnosis of biochemical abnormalities. As sample materials and pre‐analytical specifications depend on the specific diagnostic methods, it is advisable to contact the respective laboratory prior to sample collection.

Erythropoietic protoporphyria differential diagnosis

Erythropoietic protoporphyria differential diagnosis include ¹²⁶:

• Phototoxic drug reaction: Phototoxic drug reaction is a non-immunologic skin reaction that appears acutely within minutes to hours on sun-exposed skin after taking photosensitising medications. There must be a history of the introduction of any new drug. Phototoxic skin damage begins when the drug or its metabolite within the skin absorbs ultraviolet radiation (UVR) or visible light. Patients experience painful reddish skin immediately after sun exposure ¹⁹¹, ¹⁹².
• Hydroa vacciniforme: Hydroa vacciniforme is one of the rarest forms of photosensitivity dermatoses. Hydroa vacciniforme affects sun-exposed skin and is characterized by recurrent fluid-filled blisters (‘hydroa’) over sun-exposed sites that heal with pox-like (‘vacciniform’) scars ¹⁹³.
• Solar urticaria: Solar urticaria is a condition in which exposure to sunlight or an artificial light source emitting ultraviolet radiation causes urticaria ¹⁹⁴. Like EPP, symptoms often develop within minutes. Symptoms of solar urticaria are often itchy rather than painful. The reaction may subside within a few minutes or it may persist for up to an hour or more where it can become very disabling. The cause of solar urticaria is not clearly defined but may be due to an antigen-antibody reaction ¹⁹⁴. It seems that a chemical created in the body (a photoallergen) reacts with UV radiation to cause an allergic reaction that manifests as urticaria.
• Polymorphic light eruption (PMLE): Polymorphic light eruption also called a sun allergy or sun poisoning. Polymorphic light eruption is a common seasonal, acquired, idiopathic photodermatosis occurring in spring and early summer that typically occurs during the first three decades of life ¹⁹⁵. Symptoms occur in sun-exposed areas. Patients present with discrete lesions such as pruritic papules, vesicles, or plaques on sun-exposed areas.
• Discoid lupus erythematosus: It presents as scaly erythematous plaques on sun-exposed areas.
• Sunburn: It is a transient inflammatory skin response to ultraviolet radiation from sunlight or artificial sources. Sunburn can occur in individuals without an underlying dermatologic condition, with sensitivity depending on the degree of skin pigmentation and hair and eye color ¹⁹⁶.

Erythropoietic protoporphyria treatment

There is no cure for erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP). Lifelong photosensitivity is the main problem. To reduce pain, avoid unnecessary exposure to sunlight will be of benefit to individuals with erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP). The use of sun protective clothing such as long sleeves, wide-brimmed hats, and sunglasses will also benefit individuals with erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP). Tanning creams which increase skin pigmentation or sunscreens which contain physical reflecting agents such as zinc oxide or titanium dioxide that reflect visible light may be beneficial to some patients. Individuals with EPP and XLP may also benefit from window tinting or using films to cover the windows in their car or house. Other sources of light may also cause symptoms, including fluorescent and halogen lights. Protect the skin from exposure to operating visible light and ultraviolet A (UVA) light during a surgical procedure. Light filters that limit transmission of the wavelengths 340–470 nm (i.e., acrylate yellow filter) are recommended and should be used in operating rooms to protect the patient, especially in case of long surgical procedures like liver transplantation in a patient with erythropoietic protoporphyria (EPP) or X-linked protoporphyria (XLP) ¹⁵⁹, ¹⁶⁰, ¹⁹⁷. No specific anesthetic agents or other medications are contraindicated in protoporphyria.

X-Linked Protoporphyria Pathophysiology

Bone marrow reticulocytes are thought to be the primary source of the accumulated protoporphyrin IX (PPIX) that is excreted in bile and feces ²²². Most of the excess protoporphyrin IX (PPIX) in circulating erythrocytes is found in a small percentage of cells, and the rate of protoporphyrin IX (PPIX) leakage from these cells is proportional to their protoporphyrin content.

The skin of persons with X-linked protoporphyria (XLP) is maximally sensitive to visible blue-violet light near 400 nm, which corresponds to the so-called “Soret band” (the narrow peak absorption maximum that is characteristic for protoporphyrin and other porphyrins) ²²². When porphyrins absorb light they enter an excited energy state. This energy is presumably released as fluorescence and by formation of singlet oxygen and other oxygen radicals that can produce tissue and vessel damage. This may involve lipid peroxidation, oxidation of amino acids, and cross-linking of proteins in cell membranes ²²².

Photoactivation of the complement system and release of histamine, kinins, and chemotactic factors may mediate skin damage ²²². Histologic changes occur predominantly in the upper dermis and include deposition of amorphous material containing immunoglobulin, complement components, glycoproteins, glycosaminoglycans, and lipids around blood vessels. Damage to capillary endothelial cells in the upper dermis has been demonstrated immediately after light exposure in this disease ²⁴⁰.

Long-term observations of individuals with protoporphyria generally show little change in protoporphyrin levels in erythrocytes, plasma, and feces ²⁴¹. In contrast, severe liver complications, when they occur, often follow increasing accumulation of protoporphyrin in erythrocytes, plasma, and liver. Iron deficiency and factors that impair liver function sometimes contribute. Enterohepatic circulation of protoporphyrin may favor its return and retention in the liver, especially when liver function is impaired. Liver damage probably results at least in part from protoporphyrin accumulation itself ²²². As this porphyrin is insoluble, it tends to form crystalline structures in liver cells, can impair mitochondrial functions in liver cells, and can decrease hepatic bile formation and flow ²⁴².

X-linked protoporphyria signs and symptoms

Hypersensitivity of the skin to sunlight beginning in infancy or childhood is the characteristic finding of X-linked protoporphyria (XLP) ²²⁸, ²²². Most patients develop symptoms within 30 minutes of sun exposure. Affected individuals develop tingling, burning, pain, and itching of the skin after exposure to sunlight. Sometimes these symptoms are accompanied by swelling and redness (erythema) of the affected areas ²²⁸, ²²². Large blisters and severe scarring, which are common to other forms of cutaneous porphyria, usually do not occur in individuals with X-linked protoporphyria ²²². The back of the hands and face are most commonly affected but any sun exposed area can be affected. Symptoms may be noticed as quickly as a few minutes after exposure to the sun ²⁴³. Although most symptoms usually subside within 24-48 hours (may take up to 4–7 days), pain and a red or purple discoloration of the skin may persist for several days after the initial incident ²⁴³, ¹⁸⁰. Pain is disproportionately severe in relation to the visible skin lesions. Pain associated with X-linked protoporphyria can be excruciating and is often resistant to pain medications, even narcotics.

Photosensitivity is lifelong. Repeated episodes of photosensitivity may eventually causes changes in the skin of affected individuals. Such changes include thickening and hardening of the sun-exposed skin (lichenification), development of a rough or leathery texture, small facial pock-like pits, and grooving around the lips and loss of lunulae of the nails ²³¹, ²²².

Some individuals with X-linked protoporphyria develop liver disease, which can range from mild liver abnormalities to liver failure ²²². Information on liver disease is limited, but the risk of liver disease is believed to be higher in X-linked protoporphyria than in erythropoietic protoporphyria (EPP). Affected individuals may experience back pain and severe abdominal pain especially in the upper right area of the abdomen. In some affected individuals, the flow of bile through the gallbladder and bile ducts may be interrupted (cholestasis) leading to gallstones. These stones can cause obstruction and inflammation of the gallbladder (cholecystitis). Scarring of the liver (cirrhosis) may also develop and some individuals may eventually develop end stage liver failure.

Additional symptoms have been reported in individuals with X-linked protoporphyria including mild anemia (low levels of circulating red blood cells) and iron deficiency.

The signs and symptoms in heterozygous females (females with one normal copy and one mutated copy of ALAS2 gene on their X chromosomes) ranges from asymptomatic to as severe as in affected males ²²².

Figure 21. X-linked protoporphyria

Footnote: Skin redness (erythema) and swelling (edema) on the back of hands and forearm seen after acute phototoxic episode.

Liver disease

The excess protoporphyrin in erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP) is excreted by the liver into the bile where it enters the enterohepatic circulation ¹⁷⁰. Progressive accumulation of protoporphyrin IX (PPIX) may occur in the liver when the biliary excretion does not keep pace with the load being presented to the liver. When hepatocellular damage reaches a critical stage, protoporphyrin IX (PPIX) accumulation will rapidly accelerate due to marked impairment of biliary excretion ²³³, ², ²²². Concomitant conditions such as viral hepatitis, excessive alcohol consumption, and use of drugs which induce cholestasis may contribute to worsening liver disease. End-stage liver disease is typically preceded by an elevation in plasma and erythrocyte protoporphyrin IX (PPIX) levels. Patients may also develop a motor neuropathy in the setting of liver failure ²¹³, ²⁴⁴.

The excess amounts of free protoporphyrin IX (PPIX) may become insoluble and aggregate in the hepatocytes and small biliary canaliculi leading to obstruction to bile flow and cholestasis. About 20–30% of patients with erythropoietic protoporphyria (EPP) will have elevations in serum aminotransferases20. Protoporphyrin in bile may also crystallize forming gallstones. In one series, cholelithiasis were seen in 23.5% of patients ¹⁸⁰.

Anemia

Mild anemia, typically microcytic anemia can be seen in erythropoietic protoporphyria (EPP) patients ¹⁴⁶. Patients with erythropoietic protoporphyria (EPP) appear to have an abnormal iron metabolism but the mechanism of iron deficiency is unclear ²⁴⁵, ²⁰¹. The cause of microcytic anemia and low iron and ferritin levels in erythropoietic protoporphyria (EPP) patients is unknown ²⁰⁰, ²⁴⁶. Previous studies suggest that erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP) patients have normal iron absorption and an appropriate hepcidin response ²⁴⁷. The iron deficiency in erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP) patients does not appear to be related to chronic inflammation or iron loss. The cause and mechanism of iron deficiency in these patients remains to be resolved.

Vitamin D deficiency

X-linked protoporphyria (XLP) and erythropoietic protoporphyria (EPP) patients can develop vitamin D deficiency secondary to sun avoidance ²⁴⁸, ²⁴⁹. A recent report showed that the prevalence of osteopenia (low bone mineral density) and osteoporosis is increased in patients in erythropoietic protoporphyria (EPP) ²⁵⁰.

X-linked protoporphyria diagnosis

A diagnosis of X-linked protoporphyria is based upon identification of characteristic symptoms (e.g., non-blistering photosensitivity), a detailed patient history, a thorough clinical evaluation, and a variety of specialized tests ²²⁸, ²⁵¹, ²⁵², ²²².

X-linked protoporphyria (XLP) should be suspected in individuals with the following clinical findings and initial laboratory findings ²²²:

• Clinical findings
  • Skin photosensitivity, usually beginning in childhood
  • Burning, tingling, pain, and itching of the skin (the most common findings); may occur within minutes of sun/light exposure, followed later by erythema and swelling
  • Painful symptoms; may occur without obvious skin damage
  • Absent or sparse blisters and bullae
  • Note: The absence of skin damage (e.g., scarring), vesicles, and bullae often make it difficult to suspect the diagnosis.
  • Liver complications, particularly cholestatic liver disease, may develop in fewer than 5% of affected individuals.

A diagnosis of X-linked protoporphyria may be made through blood tests that can detect markedly increased levels of metal-free and zinc-bound protoporphyrins within red blood cells (erythrocytes). A higher ratio of zinc-bound protoporphyrin to metal-free protoporphyrin can differentiate X-linked protoporphyria from erythropoietic protoporphyria.

Note: It is essential to use an assay for erythrocyte protoporphyrin that distinguishes between free protoporphyrin and zinc-chelated protoporphyrin to differentiate X-linked protoporphyria (XLP) from erythropoietic protoporphyria (EPP) and several other conditions that may lead to elevation of erythrocyte protoporphyrins.

• Initial laboratory findings. Detection of markedly increased free erythrocyte protoporphyrin IX (PPIX) and zinc-chelated erythrocyte protoporphyrin IX (PPIX) is the most sensitive biochemical diagnostic test for X-linked protoporphyria (XLP).
  • Erythroid-specific 5-aminolevulinate synthase 2 (ALAS2) enzyme activity >100% of normal
  • Free protoporphyrin/zinc-chelated protoporphyrin ratio 90:10 to 50:50
  • Urine Protoporphyrins not detectable
  • Stool Protoporphyrin normal or increased
  • Plasma porphyrins increased

Molecular genetic testing can confirm a diagnosis of X-linked protoporphyria (XLP) by detecting mutations in the ALAS2 gene (the only gene known to cause this disorder).

Additional tests may be performed such as blood tests to evaluate anemia and iron stores in the body and vitamin D levels, or an abdominal sonogram to detect and evaluate liver disease potentially associated with X-linked protoporphyria.

Newer imaging modalities such as Fibroscan® may be useful in evaluating liver fibrosis; however, this has not been validated in erythropoietic protoporphyria (EPP) or X-linked protoporphyria (XLP) ²²².

X-linked protoporphyria treatment

The treatment of X-linked protoporphyria is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, hematologists, dermatologists, hepatologists, and other healthcare professionals may need to systematically and comprehensively plan an affected child’s treatment. Genetic counseling may benefit affected individuals and their families.

There is no specific, FDA-approved therapy for individuals with X-linked protoporphyria (XLP). Because the disorder is so rare, most treatment information is based on erythropoietic protoporphyria (EPP), which is clinically similar to X-linked protoporphyria (XLP).

Avoidance of sunlight will benefit affected individuals and can include the use of clothing styles with long sleeves and pant legs, made with double layers of fabric or of light-exclusive fabrics, wide brimmed hats, gloves, and sunglasses. Topical sunscreens are generally ineffective, unless they contain light-reflective ingredients (e.g., zinc oxide). Some tanning products with ingredients that increase pigmentation may be helpful. Affected individuals may also benefit from window tinting and the use of vinyl or films to cover the windows of their homes and cars.

Avoidance of sunlight can potentially cause vitamin D deficiency and some individuals may require supplemental vitamin D.

A high potency form of oral beta-carotene (Lumitene) may be given to improve an affected individual’s tolerance of sunlight. This drug causes skin discoloration and may improve tolerance to sunlight. Oral Lumitene (beta-carotene) (120–180 mg/dL) has been used to improve tolerance to sunlight if the dose is adjusted to maintain serum carotene levels in the range of 10-15 μmol/L (600–800 μg/dL), causing mild skin discoloration due to carotenemia. The beneficial effects of beta-carotene (Lumitene) may involve quenching of singlet oxygen or free radicals. However, a systematic review of about 25 studies showed that the available data are unable to prove efficacy of treatments including beta-carotene, N-acetyl cysteine, and vitamin C ²¹⁰. For more information on oral beta-carotene (Lumitene) treatment, contact the American Porphyria Foundation and the Prophyria Consortium of the Rare Diseases Clinical Research Network.

Another drug sometimes used to improve tolerance to sunlight is cysteine.

In 2019, the Food and Drug Administration (FDA) approved Afamelanotide (Scenesse®) for the treatment of adult patients with erythropoietic protoporphyria (EPP). Afamelanotide (Scenesse) is a controlled-release, long-acting injectable implant, alpha-melanocyte-stimulating hormone (α-MSH) analogue, that increases eumelanin by binding to the melanocortin-1 receptor and provides sun protection and improves sun tolerance by increasing skin pigmentation and antioxidant properties ²³⁵, ²³⁶. Afamelanotide (Scenesse) was available in Europe for a period of time before its approval in the United States. Afamelanotide (Scenesse) was approved for patients with the erythropoietic protoporphyria (EPP) by the European Medicines Agency in 2014, and by the FDA in October 2019. Afamelanotide showed positive results in Phase III clinical trials in the US and Europe ²³⁷. Long-term studies in Europe show good compliance, clinical effectiveness, and improved quality of life ²³⁸.

Other treatment is symptomatic and supportive.

X-linked protoporphyria (XLP) patients should be seen at least yearly to monitor protoporphyrin levels, anemia, liver enzymes, iron and vitamin D levels.

Liver disease treatment

Treatment of liver disease and complications, which may be accompanied by motor neuropathy, is difficult.

• Cholestyramine and other porphyrin absorbents, such as activated charcoal, may interrupt the enterohepatic circulation of protoporphyrin and promote its fecal excretion, leading to some improvement ²¹².
  • Cholestyramine absorbs porphyrin. Cholestyramine may interrupt the recirculation of protoporphyrin secreted into the bile back into the liver and promote its excretion through the feces. Other drugs that absorb porphyrins such as activated charcoal have also been used to treat affected individuals.
  • Cholestyramine and other porphyrin absorbents, such as activated charcoal may lead to improvement of liver disease.
• Plasmapheresis and intravenous hemin have been used to treat people with erythropoietic protoporphyria (EPP) ²¹¹.
• Liver transplantation has been performed as a lifesaving measure in individuals with severe protoporphyric liver disease ²¹³, ²¹⁴. However, many liver transplant recipients experience a recurrence of the protoporphyric liver disease in the transplanted liver. Combined bone marrow and liver transplantation is indicated in patients with liver failure to prevent future damage to the allografts ²¹⁶, and sequential liver and bone marrow transplantation has been successful in curing protoporphyric liver disease ²⁵³.
• Bone marrow transplantation has also been attempted without liver transplantation in some instances. A child age two years with X-linked protoporphyria (XLP) and stage 4 liver fibrosis was treated with a hematopoietic progenitor cell transplantation that stabilized his liver disease, thus avoiding liver transplantation ²⁵⁴.

Individuals with any form of protoporphyria should avoid substances associated with cholestasis including alcohol and certain drugs such as estrogens. 

In patients with cholestatic liver failure, use of protective filters for artificial lights in the operating room to prevent phototoxic damage during procedures such as endoscopy and surgery ²⁵⁵.

Additional treatment

• Vitamin D supplementation is advised as patients are predisposed to vitamin D deficiency resulting from sun avoidance.
• Immunizations for hepatitis A and B are recommended as well.
• Iron supplementation may be attempted in persons with X-linked protoporphyria (XLP) who have anemia and low ferritin levels. Iron supplementation therapy requires strict monitoring by physicians. Whatley et al ²²⁶ reported some evidence of diminished iron stores in males with X-linked protoporphyria (XLP); in one patient with iron deficiency, iron repletion decreased protoporphyrin accumulation and corrected the anemia. Subsequent reports indicate that iron supplementation can improve protoporphyrin levels, liver damage, and anemia in X-linked protoporphyria (XLP) ²⁵⁶. A pilot study using oral iron supplementation in persons with X-linked protoporphyria (XLP) showed a reduction in protoporphyrin levels, but also carries a risk of increased photosensitivity ²⁵⁷.

Pregnancy Management

There is no information on pregnancy management in X-linked protoporphyria (XLP). Based on experience with erythropoietic protoporphyria (EPP), pregnancy is unlikely to be complicated by X-linked protoporphyria (XLP) ²⁵⁸.

Investigational Therapies

A Phase 2 clinical trial with MT-7117, an oral small molecule that works as a melanocortin 1 receptor agonist and increases skin pigmentation in subjects with erythropoietic protoporphyria (EPP) has been completed ²⁵⁹. A Phase 3 clinical trial for adults and children is planned for MT-7117.

X-Linked Protoporphyria prognosis

The natural history of X-linked protoporphyria (XLP) is not as well characterized as that of the autosomal recessive type of erythropoietic protoporphyria (EPP) ²²². A natural history study from the US described 22 individuals with X-linked protoporphyria (XLP) from seven unrelated families ¹⁸⁰.

X-linked protoporphyria (XLP) in Males

While the skin signs and symptoms in males with X-linked protoporphyria (XLP) are similar to those of erythropoietic erythropoietic protoporphyria (EPP), Balwani et al ¹⁸⁰ suggest that males with X-linked protoporphyria (XLP) have significantly higher protoporphyrin levels and increased risk of liver dysfunction.

Photosensitivity

Onset of photosensitivity is typically in infancy or childhood with the first exposure to sun; in most individuals with X-linked protoporphyria (XLP) the photosensitivity is lifelong.

Most males with X-linked protoporphyria (XLP) develop acute cutaneous photosensitivity within five to 30 minutes following exposure to sun or ultraviolet light. Photosensitivity symptoms are provoked mainly by visible blue-violet light in the Soret band, to a lesser degree in the long-wave UV region.

The initial symptoms reported are tingling, burning, and/or itching that may be accompanied by swelling and redness. Symptoms vary based on the intensity and duration of sun exposure; pain may be severe and refractory to narcotic analgesics, persisting for hours or days after the initial phototoxic reaction. Symptoms may seem out of proportion to the visible skin lesions. Blistering lesions are uncommon.

Affected males are also sensitive to sunlight that passes through window glass, which does not block long-wave UVA or visible light.

Skin signs and symptoms

Multiple episodes of acute photosensitivity may lead to chronic changes of sun-exposed skin (lichenification, leathery pseudovesicles, grooving around the lips) and loss of lunulae of the nails. The back of the hands is most notably affected.

Severe scarring is rare, as are hyper- or hypopigmentation, skin friability, and hirsutism.

Unlike in other cutaneous porphyrias, blistering and scarring rarely occur.

Liver problems

Protoporphyrin is not excreted in the urine by the kidneys, but is taken up by the liver and excreted in the bile. Accumulated protoporphyrin in the bile can form stones, reduce bile flow, and damage the liver. Protoporphyric liver disease may cause back pain and severe abdominal pain (especially in the right upper quadrant).

The information on X-linked protoporphyria (XLP) and liver disease is limited ²²². The risk for liver dysfunction in X-linked protoporphyria (XLP) (observed in 5/31 affected individuals) is higher than the risk in erythropoietic protoporphyria (EPP) ²²⁶. A natural history study in the US showed that 40% of males with X-linked protoporphyria (XLP) had a history of abnormal liver enzymes compared to 33% of persons with erythropoietic protoporphyria (EPP). Gallstones were seen in 40% of males with X-linked protoporphyria (XLP) and 33.3% of females with X-linked protoporphyria (XLP) compared to 22.1% of individuals with erythropoietic protoporphyria (EPP).

Note that the information on liver involvement presented below is based on experience with liver disease in autosomal recessive erythropoietic protoporphyria (EPP). Gallstones composed in part of protoporphyrin may be symptomatic in individuals with X-linked protoporphyria (XLP) and need to be excluded as a cause of biliary obstruction in persons with hepatic decompensation.

Life-threatening liver complications are preceded by increased levels of plasma and erythrocyte protoporphyrins, worsening liver function tests, increased photosensitivity, and increased deposition of protoporphyrins in liver cells and bile canaliculi. End-stage liver disease may be accompanied by motor neuropathy, similar to that seen in acute porphyrias. Comorbid conditions, such as viral hepatitis, alcohol abuse, and use of oral contraceptives, which may impair hepatic function or protoporphyrin metabolism, may contribute to hepatic disease in some ²¹³.

Blood problems

Anemia and abnormal iron metabolism can occur in X-linked protoporphyria (XLP). Mild anemia with microcytosis and hypochromia or occasionally reticulocytosis can be seen ²²². However, hemolysis is absent or mild ²²². In a recent series, 30% of males with X-linked protoporphyria (XLP) and 75% of females with X-linked protoporphyria (XLP) were anemic ¹⁸⁰.

Vitamin D deficiency

Individuals with X-linked protoporphyria (XLP) who avoid sun/light are at risk for vitamin D deficiency ²⁴⁸, ²⁴⁹, ¹⁴⁶.

Triggering factors

Unlike the triggering factors for acute hepatic porphyrias, the only known precipitating factor for X-linked protoporphyria (XLP) is sunlight.

X-linked protoporphyria (XLP) in Females

The signs and symptoms of X-linked protoporphyria (XLP) in heterozygous females, the consequence of random X-chromosome inactivation, ranges from as severe as in affected males to asymptomatic. The median age of symptom onset for females with X-linked protoporphyria (XLP) was 11 years. Following sun exposure, symptom onset ranged from within ten minutes to none ¹⁸⁰.

X-Linked Protoporphyria life expectancy

People with X-linked protoporphyria (XLP) generally have a life expectancy similar to those without porphyria, except for those with advanced liver disease ²²².

Congenital erythropoietic porphyria

Congenital erythropoietic porphyria (CEP) also called Gunther’s disease is an extremely rare inherited autosomal recessive disorder that involve defects in heme or ‘haem’ biosynthetic pathway caused by mutations (changes) in the UROS gene which results in low levels of the enzyme uroporphyrinogen III cosynthase or uroporphyrinogen-III synthase (UROS), the fourth enzyme in the heme biosynthetic pathway ²⁶⁰, ²⁶¹, ²⁶², ²⁶³, ²⁶⁴, ²⁶⁵, ²⁶⁶, ²⁶⁷, ²⁶⁸, ²⁶⁹, ²⁷⁰, ²⁷¹, ²⁷², ²⁷³, ²⁷⁴, ²⁷⁵, ²⁷⁶, ²⁷⁷, ²⁷⁸, ²⁷⁹. The UROS (uroporphyrinogen III synthase or uroporphyrinogen III cosynthase) enzyme is involved in the production of a molecule called heme (haem). Heme is vital for all of the body’s organs, although it is most abundant in the blood, bone marrow, and liver. Heme is an essential component of iron-containing proteins called hemoproteins, including hemoglobin (the protein that carries oxygen in the blood). The production of heme is a multi-step process that requires 8 different enzymes. In the presence of insufficient uroporphyrinogen III synthase (UROS) activity, hydroxymethylbilane (HMB), the product of the third step spontaneously closes and forms the non-physiological compound uroporphyrinogen I, which is then acted upon by uroporphyrinogen decarboxylase (UROD) the fifth enzyme in the heme synthetic pathway to form coproporphyrinogen I ²⁸⁰. Coproporphyrinogen I then oxidizes spontaneously to form coproporphyrin I and uroporphyrin I, two harmful and non-physiological compounds associated with abnormalities involving various organs ²⁶⁰. In congenital erythropoietic porphyria (CEP), these toxic porphyrins mostly accumulate in red blood cell precursors (erythroblasts) in your bone marrow, as well as your teeth, bones, urine, and feces. These toxic porphyrins are not significantly elevated in your liver. Your bone marrow, the spongy tissue inside your bones, is essential for producing blood cells and supporting the immune system. Your bone marrow acts as a factory for red blood cells, white blood cells, and platelets, which are vital for oxygen transport, fighting infection, and blood clotting, respectively. Your bone marrow also plays a role in storing fat and supporting bone and cartilage health. As these toxic porphyrins accumulate in your bone marrow, they may be released into your blood and subsequently found in the plasma and mature red blood cells. They then may travel to your skin, and upon exposure to light, generate free radicals that can damage cells and tissues. This leads to disease characterized by severe skin photosensitivity and breakdown of red blood cells (hemolysis) ²⁸¹. The major symptom of congenital erythropoietic porphyria (CEP) is hypersensitivity of your skin to sunlight and some types of artificial light, such as fluorescent lights (photosensitivity). After exposure to light, the photo-activated porphyrins in your skin cause skin friability and blistering (bullae) and the fluid-filled sacs may rupture and the lesions often get infected. These infected lesions can lead to scarring, bone loss, and in severe instances, this can lead to skin mutilation and deformities ²⁸². Your face, ears, neck, arms, forearms and hands are the most commonly affected areas.

Footnotes: An illustration of the heme biosynthesis pathway and congenital erythropoietic porphyria (CEP) pathophysiology. Each number represents the enzyme of the corresponding step: (1) aminolevulinic acid synthase (ALAS), (2) aminolevulinic acid dehydratase (ALAD), (3) hydroxymethylbilane synthase (HMBS), (4) uroporphyrinogen III synthase (UROS), (5) uroporphyrinogen decarboxylase (UROD), (6) coproporphyrinogen-III oxidase (CPOX), (7) protoporphyrinogen oxidase (PPOX), (8) ferrochelatase (FECH). The gray–white rectangle represents the clinical spectrum that narrows by the increase in the age of onset, where the gray beginning expresses the concurrence of black-and-white-indexed involvements.

Figure 23. Congenital erythropoietic porphyria (CEP)

Footnotes: Congenital erythropoietic porphyria (CEP) in a 13-year-old female. (A) a dyspigmented sclerodermatous appearance of the face accompanied with linear and spotted atrophic lesions. (B) Immense areas of ulceration over the dorsum of the hand, with acrolysis of the bones and soft tissues at the ends of the fingers. (C) Healing ulcers on the face and dorsum of the hand after 1 month of treatment; the skin improved in terms of pigmentation and elasticity, with no active ulcers.

Figure 24. Congenital erythropoietic porphyria pathophysiology

Foootnotes: (A) Heme biosynthetic pathway and the porphyrias resulting from the indicated heme biosynthetic enzyme defect. There are 8 enzymatic steps in the conversion of glycine and succinyl-CoA to heme. The heme biosynthetic enzymes are italicized, their substrates and products are indicated, and the resulting porphyrias are shown in boxes. Note that there are two aminolevulinic acid synthase (ALAS) isozymes: a housekeeping enzyme, ALAS1, encoded by a gene that is regulated by negative feedback repression by heme, and an erythroid specific enzyme, ALAS2, that is regulated by the iron response proteins and erythroid transcription binding proteins.

(B) Uroporphyrinogen synthase (UROS) normally converts hydroxymethylbilane (HMB) to uroporphyrinogen III. When the UROS activity is markedly decreased, HMB (hydroxymethylbilane) is non-enzymatically converted to uroporphyrinogen I, which is then enzymatically converted to oproporphyrinogen I by uroporphyrinogen decarboxylase (UROD). The accumulated uroporphyrinogen I and coproporphyrinogen I are oxidized to their respective porphyrins, which are photoactive and cause the sun/light-induced hemolysis and cutaneous manifestations of congenital erythropoietic porphyria (CEP).

Congenital erythropoietic porphyria causes

Congenital erythropoietic porphyria is caused by mutations in the UROS gene located on chromosome 10q26.2 ²⁸⁴. Congenital erythropoietic porphyria (CEP) is rarely inherited in X-linked inheritance pattern due to mutation of the GATA1 gene located on the X chromosome (chromosome Xp11.23) that affected males only while the female heterozygotes were mostly asymptomatic ²⁸⁵, ²⁷⁴, ²⁸⁶, ²⁸¹. Females who are heterozygous for GATA1 gene will be either asymptomatic or have a milder disease with predominantly hematologic abnormalities due to skewed X-chromosome inactivation ²⁷⁴, ²⁸⁶. In a small percentage of congenital erythropoietic porphyria patients (>10%), a disease-causing mutation has not been detected in the UROS or GATA1 genes, raising the possibility that additional gene(s) may play a role in congenital erythropoietic porphyria pathogenesis ²⁸⁷.

Disease-causing mutations in either UROS gene or GATA1 gene result in absent or markedly reduced UROS (uroporphyrinogen III synthase) enzymatic activity. UROS (uroporphyrinogen III synthase) enzyme catalyzes the cyclization of hydroxymethylbilane (HMB) with concomitant inversion of ring D to yield uroporphyrinogen III (URO III) ²⁸⁸. Deficiency of UROS (uroporphyrinogen III synthase) enzyme results in accumulation of HMB (hydroxymethylbilane), most of which is converted nonenzymatically to non-physiological compound uroporphyrinogen I, which is then acted upon by uroporphyrinogen decarboxylase (UROD) the fifth enzyme in the heme synthetic pathway to form coproporphyrinogen I ²⁸⁰. Coproporphyrinogen I then oxidizes spontaneously to form the porphyrins coproporphyrin I and uroporphyrin I. In congenital erythropoietic porphyria (CEP), these toxic porphyrins mostly accumulate in red blood cell precursors in your bone marrow, as well as your teeth, bones, urine, and feces. These toxic porphyrins are not significantly elevated in your liver. Since these toxic porphyrins are photocatalytic compounds, exposure of the skin to sunlight and other sources of long-wave ultraviolet light elicits a phototoxic reaction, resulting in blistering and vesicle formation as well as increased friability of the skin and breakdown of red blood cells (hemolysis) ²⁸¹, ²⁸⁹, ²⁹⁰.

Congenital erythropoietic porphyria inheritance pattern

Congenital erythropoietic porphyria (CEP) is inherited as an autosomal recessive genetic condition. Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. Patients with congenital erythropoietic porphyria (CEP) are either homozygotes or compound heterozygotes for mutations of the UROS gene at 10q25.2-q26.3 that encodes uroporphyrinogen III synthase (UROS), a cytosolic enzyme that converts hydroxymethyl bilane (HMB) to uroporphyrinogen III. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, and usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.

Congenital erythropoietic porphyria (CEP) is rarely inherited in X-linked inheritance pattern due to mutation of the GATA1 gene located on the X chromosome that affected males, while the female heterozygotes were mostly asymptomatic ²⁷⁴, ²⁸⁶, ²⁸¹. Females who are heterozygous for GATA1 gene will be either asymptomatic or have a milder disease with predominantly hematologic abnormalities due to skewed X-chromosome inactivation ²⁷⁴, ²⁸⁶.

Genetic counseling is recommended for affected individuals and their families.

Resources for locating a genetics professional in your community are available online:

• The National Society of Genetic Counselors (https://www.findageneticcounselor.com/) offers a searchable directory of genetic counselors in the United States and Canada. You can search by location, name, area of practice/specialization, and/or ZIP Code.
• The American Board of Genetic Counseling (https://abgc.learningbuilder.com/Search/Public/MemberRole/Verification) provides a searchable directory of certified genetic counselors worldwide. You can search by practice area, name, organization, or location.
• The Canadian Association of Genetic Counselors (https://www.cagc-accg.ca/index.php?page=225) has a searchable directory of genetic counselors in Canada. You can search by name, distance from an address, province, or services.
• The American College of Medical Genetics and Genomics (https://clinics.acmg.net/) has a searchable database of medical genetics clinic services in the United States.

Figure 25. Congenital erythropoietic porphyria (CEP) autosomal recessive inheritance pattern

Congenital erythropoietic porphyria symptoms

Congenital erythropoietic porphyria or Gunther disease severity and age at onset of symptoms are highly variable between individuals. For many, the onset of symptoms and diagnosis are often in infancy. Some do not develop symptoms until adulthood, their symptoms are usually milder and primarily skin related ³⁰⁷.

Congenital erythropoietic porphyria symptoms usually start in infancy or childhood and the diagnosis in most patients is suggested by the reddish color of the urine which stains the diapers and fluoresces with a Wood’s lamp (ultraviolet light). Congenital erythropoietic porphyria (CEP) or Gunther disease major symptoms are sensitivity of the skin to sunlight and some types of artificial light, and anemia which can be very severe. Skin photosensitivity may be extreme, and can lead to blistering, severe scarring and increased hair growth (hypertrichosis). The fluid-filled blisters may rupture and get infected. These infected wound can lead to scarring, bone loss, and deformities. The hands, arms, and face are the most commonly affected areas. Increased hair growth (hypertrichosis) on sun-exposed skin, brownish-colored teeth (erythrodontia), and reddish-colored urine are common. There may be bone fragility and vitamin deficiencies, especially vitamin D deficiency. Vitamin D is a fat-soluble vitamin that essential for bone development and maintenance, as it enhances calcium, magnesium, and phosphate absorption. Vitamin D deficiency due to sunlight avoidance in people with congenital erythropoietic porphyria can lead to a range of health problems, including bone disorders, muscle weakness, and an increased risk of fractures.

Red blood cells have a shortened life-span, and anemia often results. Synthesis of heme and hemoglobin are actually increased to compensate for the shortened red blood cell survival. The spleen can be enlarged due to extramedullary erythropoiesis, particularly in people with severe hemolytic anemia.

The most common symptom of congenital erythropoietic porphyria (CEP) is hypersensitivity of the skin to sunlight and some types of artificial light (photosensitivity), with blistering of the skin occurring after exposure. Affected individuals may also exhibit abnormal accumulations of body fluid under affected areas (edema) and/or persistent redness or inflammation of the skin (erythema). Affected areas of the skin may develop sac-like lesions (vesicles or bullae), scar, and/or become discolored (hyperpigmentation) if exposure to sunlight is prolonged. These affected areas of skin may become abnormally thick. In addition, in some cases, affected individuals may also exhibit malformations of the fingers and nails. The severity and degree of photosensitivity differ depending on the severity of the patient’s gene lesions which correlate with the deficient enzyme activity. In the great majority of congenital erythropoietic porphyria (CEP) cases, photosensitivity is seen from birth; however, in some cases, it may not occur until childhood, adolescence or adulthood. Patients also have brownish discolored teeth (erythrodontia), which fluoresce under ultraviolet light.

In more severe congenital erythropoietic porphyria (CEP) cases, other symptoms can include a low level of red blood cells (anemia), enlargement of the spleen (secondary hypersplenism), and increased hair growth (hypertrichosis) ²⁷⁵. The anemia can be severe and such patients require periodic blood transfusions to quickly increase the amount of red blood cells and iron in the blood. In severely affected patients, anemia may be present in the fetus (non-immune hydrops fetalis). Eye problems also can occur including corneal scarring, eye inflammation, and infections.

Skin involvement

Skin photosensitivity usually begins shortly after birth and is characterized by increased friability and blistering of the epidermis on the hands and face and other sun-exposed areas. Bullae and vesicles containing serous fluid which fluoresces due to their porphyrin content. Blisters are prone to rupture and become infected. Recurrent vesicle formation and secondary infection can lead to cutaneous scarring and deformities, as well as to loss of digits and facial features such as the eyelids, nose and ears. The skin may be thickened, with areas of hypo- and hyper-pigmentation and hypertrichosis of the face and extremities ³⁰⁸. Adult-onset congenital erythropoietic porphyria (CEP) patients have milder clinical symptoms and often exhibit only the skin manifestations of congenital erythropoietic porphyria (CEP) ³⁰⁹, ³¹⁰, ³¹¹, ³¹², ³¹³, ³¹⁴. Photosensitivity symptoms are provoked mainly by visible light (400–410 nm Soret wavelength) and to a lesser degree by wavelengths in the long-wave UV region. Affected individuals are also sensitive to sunlight that passes through window glass that does not filter long-wave UVA or visible light as well as to light from artificial light sources ³¹⁵.

Hemolytic anemia

Mild to severe hemolysis is accompanied by anisocytosis, poikilocytosis, polychromasia, basophilic stippling, reticulocytosis, increased nucleated red cells, absence of haptoglobin, increased unconjugated bilirubin and increased fecal urobilinogen. Plasma iron turnover also is increased ³¹⁶. Hemolysis presumably results from the accumulated uroporphyrin I in erythrocytes. Secondary splenomegaly develops in response to the increased uptake of abnormal erythrocytes from the circulation, which may contribute to the anemia and also may result in leucopenia and thrombocytopenia. The latter is sometimes associated with significant bleeding and splenectomy may be beneficial in such cases. Anemia due to hemolysis can be severe. Erythroid hyperplasia and markedly ineffective erythropoiesis usually accompany hemolytic anemia in transfusion-dependent patients ³¹⁷, ³¹², ³¹⁸.

In the three male patients with congenital erythropoietic porphyria (CEP) due to GATA1 mutations, hematologic abnormalities including dyserythropoietic anemia, beta-thalassemia intermedia, thrombocytopenia, and hereditary persistence of fetal hemoglobin have been described ²⁷⁴, ²⁸⁶.

Other Clinical Features

Deposition of porphyrins can cause corneal ulcers and scarring, which can ultimately can lead to blindness ²⁷⁵. Other eye signs and symptoms can include scleral necrosis, necrotizing scleritis, seborrheic blepharitis, keratoconjunctivitis, sclerokeratitis, and ectropion ³¹⁹, ³²⁰, ³²¹. Porphyrins deposited in the teeth produce a reddish-brown color called erythrodontia. The teeth may fluoresce on exposure to long-wave ultraviolet light.

Deposition of porphyrins in bone causes osteopenia (lower than normal bone density) due to demineralization ²⁹⁶, ³¹⁷, ³²², ³²³. The risk for osteopenia and osteoporosis is further increased by vitamin D deficiency, which individuals with congenital erythropoietic porphyria (CEP) are prone to due to avoidance of sun exposure. Porphyrin accumulation in the bone can also cause expansion of the bone marrow, which can lead to hyperplastic bone marrow observed on biopsy ²⁹⁰, ³⁰⁸.

Congenital erythropoietic porphyria diagnosis

The diagnosis of congenital erythropoietic porphyria may be suspected when the reddish-colored urine is noted at birth or later in life. This finding, or the occurrence of skin blisters on sun or light exposure, should lead to a thorough clinical evaluation and specialized laboratory tests. The biochemical diagnosis of congenital erythropoietic porphyria is established by detection of markedly elevated levels of uroporphyrin I and coproporphyrin I in urine, red blood cells or amniotic fluid as well as high fecal coproporphyrin I concentrations. Diagnostic confirmation requires the demonstration of the specific UROS enzyme activity and/or by identifying the specific mutation(s) in the UROS gene which is/are responsible for the impaired enzyme ²⁸¹.

Congenital erythropoietic porphyria should be considered in the differential diagnosis of non-immune hydrops fetalis, in which case the amniotic fluid surrounding the fetus will be pink, dark-red or brown, and should examined for porphyrins ³²⁴. Newborns with pink to dark-red urine-stained diapers should immediately have diagnostic studies. Congenital erythropoietic porphyria (CEP) also should be considered in children or adults who have porphyrinuria or skin blistering following exposure to sunlight or other sources of long-wave ultraviolet light. In some cases, the disease is less severe and presents in adult life with mild anemia and/or skin lesions.

Congenital erythropoietic porphyria (CEP) should be suspected in individuals with the following clinical and laboratory findings and family history ²⁶⁰.

• Nonimmune hydrops fetalis
• Signs of congenital erythropoietic porphyria
  • Pink-to-dark red discoloration of the urine (pink or dark red urine-stained diapers are often the first sign in infants)
  • Hemolytic anemia
  • Severe cutaneous photosensitivity with onset usually in infancy or early childhood
  • Blisters and vesicles in light-exposed areas, which are prone to rupture and infection
  • Scarring and deformities (photomutilation) of digits and facial features, caused by recurrent blistering, infections, and bone resorption
  • In light-exposed areas: friable skin, skin thickening, hypo- and hyperpigmentation
  • Reddish-brown discoloration of teeth (fluoresce on exposure to long-wave ultraviolet light), also called erythrodontia
  • Corneal ulcers and scarring
  • Hypertrichosis of the face and extremities
• Laboratory findings include markedly increased levels of uroporphyrin I and coproporphyrin I isomers in red blood cells, urine, or amniotic fluid as well as coproporphyrin I in feces

Prenatal and preimplantation genetic diagnoses are available for subsequent pregnancies in congenital erythropoietic porphyria families.

Congenital erythropoietic porphyria treatment

Avoidance of sun and light exposure, including the long-wave ultraviolet light that passes through window glass or is emitted from artificial light sources is essential to prevent the skin lesions in individuals with congenital erythropoietic porphyria (CEP) ²⁶⁰. The use of topical sunscreens containing zinc oxide or titanium oxide, protective clothing, long sleeves, hats, gloves, and wraparound sunglasses are strongly recommended. Individuals with congenital erythropoietic porphyria will benefit from window tinting or using vinyls or films to cover the windows in their car or house and the use of reddish incandescent bulbs, filtering screens for fluorescent lights ²⁶⁰. Before tinting or shading car windows, affected individuals should check with their local Registry of Motor Vehicles to ensure that such measures do not violate any local laws.

Wound care is necessary to prevent infection of opened blisters; surgical intervention may be necessary; blood transfusions with iron chelation are necessary when hemolysis is significant to maintain the hematocrit >35 to decrease reticulocytosis in transfusion-dependent patients ²⁹⁶, ²⁶⁰. Chronic transfusions have been useful in decreasing the bone marrow production of the phototoxic porphyrins.

Blood transfusions and perhaps removing the spleen may reduce porphyrin production by the bone marrow. Activated charcoal given by mouth is sometimes effective.

When successful, bone marrow transplantation (BMT) or hematopoietic stem cell (HSCT) transplantation has cured patients with congenital erythropoietic porphyria, but is accompanied by specific risks of complications and should be considered in children with severe skin and bone marrow involvement ²⁶⁰, ²⁹⁷, ²⁹⁸, ²⁹⁹, ³⁰⁰, ³⁰¹, ³⁰², ³⁰³, ³⁰⁴, ³⁰⁵, ³⁰⁶.

Evaluations Following Initial Diagnosis

To establish the extent of congenital erythropoietic porphyria disease and needs in an individual diagnosed with congenital erythropoietic porphyria (CEP), the evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) are recommended:

• Hematologic indices including reticulocytes and bilirubin (to assess hemolysis) and iron profile (to assess iron storage)
• Serum calcium and vitamin D concentrations; bone densitometry
• Liver function tests, especially in transfusion-dependent individuals given the risk for liver disease due to iron storage
• Skin evaluation to assess photosensitivity, photomutilation, and secondary skin changes (thickening, hyper- or hypopigmentation, hypertrichosis)
• Eye evaluation for corneal ulcers and scarring and other ocular manifestations
• Teeth assessment for erythrodontia (reddish-brown color from porphyrin deposition)
• Consultation with a medical geneticist, certified genetic counselor, or certified advanced genetic nurse to inform affected individuals and their families about the nature, mode of inheritance, and implications of congenital erythropoietic porphyria (CEP) in order to facilitate medical and personal decision making

Monitoring

Monitor blood indices including iron profile, reticulocyte count, and bilirubin to assess hemolysis every six months. In those receiving blood transfusions, monitor for hemolysis more frequently and for iron overload. Monitor liver function and vitamin D 25-OH every six to twelve months in all affected individuals.

Agents to avoid

All affected individuals should avoid sunlight and UV light. To avoid eye complications and damage to the eyelids, wrap-around sun glasses should be worn. Corneal ulcers, scleritis, and blepharitis should be treated with topical antibiotics. In patients with ectropion, corrective surgery of the eyelid to help protect the cornea from injury may be indicated ³⁰⁴. In individuals undergoing surgeries, use of protective filters for artificial lights in the operating room to prevent phototoxic damage ²⁵⁵.

To avoid bone demineralization, vitamin D supplementation is indicated and bisphosphonates can be considered in individuals with osteoporosis ³⁰⁴.

In those with liver dysfunction avoid drugs that may induce cholestasis (e.g., estrogens).

Pregnancy Management

Successful pregnancies in women with congenital erythropoietic porphyria resulting in healthy and unaffected children have been described ³²⁵, ²⁹⁵.

Protective filters for artificial lights should be used in the delivery/operating room to prevent phototoxic damage to the mother during delivery ²⁵⁵.

Congenital erythropoietic porphyria prognosis

Congenital erythropoietic porphyria or Gunther disease severity and age at onset of symptoms are highly variable between individuals. For many, the onset of symptoms and diagnosis are often in infancy. Some do not develop symptoms until adulthood, their symptoms are usually milder and primarily skin related ³⁰⁷. Due to the hematological complications and an increased risk of infection, overall life expectancy may be markedly diminished in more severely affected patients ²⁸¹. In addition, long-term damage, such as loss of fingers or toes and facial cartilage or contractures of the hands, can have a significant impact on patients’ quality of life, psychiatric well-being, and functional status with regard to daily life and ability to work.

Successful bone marrow (BMT) or hematopoietic stem cell (HSCT) transplantation is the only curative approach, but is accompanied by specific risks of complications and should be considered in children with severe skin and bone marrow involvement ²⁶⁰. The age of children with congenital erythropoietic porphyria (CEP) receiving bone marrow transplantation (BMT) ranges from younger than one year to 13 years ²⁹⁵. Some of the first individuals with congenital erythropoietic porphyria (CEP) to successfully undergo bone marrow transplantation in childhood are now in their 20s ²⁹⁸, ³⁰⁵. Although there is limited information available regarding their long-term outcome post receiving bone marrow transplantation (BMT), experts have learned that individuals successfully transplanted have essentially no photosensitivity to artificial light sources or sunlight.

Several cases of late-onset congenital erythropoietic porphyria (CEP) have been reported in patients older than 50 years of age who presented with skin congenital erythropoietic porphyria (CEP) symptoms and increased porphyrin metabolite excretion, though at a lower level than in patients with the classic infantile-onset congenital erythropoietic porphyria (CEP) presentation ²⁷⁵. In several cases, the occurrence of congenital erythropoietic porphyria (CEP) symptoms was associated with the presence of myelodysplastic syndrome (a group of blood cancers where the bone marrow doesn’t produce enough healthy blood cells leading to a deficiency in red blood cells, white blood cells, and platelets, causing symptoms like fatigue, increased risk of infection, and easy bruising or bleeding) and neither germline nor somatic mutations in UROS or GATA1 were detected [39–41]. However, low-level mosaicism in the bone marrow may not be picked up by sequencing methods, but may be sufficient to cause an accumulation of porphyrin metabolites resulting in an attenuated phenotype ³²⁶, ³²², ³²⁷.

Recently, one 60 year-old male patient was described with late-onset skin porphyria symptoms and a urinary porphyrin metabolite pattern consistent with congenital erythropoietic porphyria (CEP). He was heterozygous for the common UROS gene mutation encoding p.C73R, but a second mutation was not detected. He did not have myelodysplastic syndrome or another underlying hematologic abnormality. While the exact pathophysiology was unclear in the absence of a second disease-causing mutation, acquired mosaicism in the bone marrow affecting the UROS gene was hypothesized to be the underlying cause ³²⁸.

Acute intermittent porphyria

Acute intermittent porphyria also called “AIP” or Swedish Porphyria is one of the acute porphyrias, which are a group of rare inherited metabolic disorders that involve defects in heme or ‘haem’ metabolism (a component of hemoglobin [Hb]) and result in excessive secretion of porphyrins and porphyrin precursors ³²⁹, ³³⁰, ³³¹, ³³², ³³³, ³³⁴, ³³⁵, ³³⁶, ³³⁷ , ⁴⁹, ³³⁸. Heme or haem is a ring-shaped iron (Fe) containing molecule (organic compound containing an iron atom between the structure of the porphyrin ring) that commonly serves as a ligand of various proteins, more notably as a component of hemoglobin (the protein that carries oxygen in the blood), which is necessary to bind oxygen in the bloodstream and transport of oxygen in your body. Heme molecule also helps in respiration, detoxification of drugs, and other different biological functions. In hemoglobin, iron exists as ferrous (Fe2+) iron ion that is located at the center of the porphyrin ring, held in place by the four nitrogen atoms of the pyrrole rings (see Figures 1 to 3 below). Normally, your body makes heme (haem) in a multi-step process. Porphyrins are made during several steps of this process. People with porphyria are lacking certain enzymes needed for this process. This causes abnormal amounts of porphyrins or related chemicals to build up in the body. Porphyria occurs when the body cannot convert naturally occurring compounds called ‘porphyrins’ into heme. Porphyrins are substances that are required for the production of red blood cells. A common feature in all porphyrias is the accumulation in the body of porphyrins or porphyrin precursors. Although these are normal body chemicals, they normally do not accumulate. Precisely which of these chemicals builds up depends on the type of porphyria you have. There are 8 enzymes in the pathway for making heme and at least seven major forms of porphyria ³³⁹. The symptoms associated with the various forms of porphyria differ. It is important to note that people who have one type of porphyria do not develop any of the other types.

Porphyrias are generally classified into 2 groups: the “hepatic” (liver) and “erythropoietic” (red blood cell) types ³³⁹. Porphyrins and porphyrin precursors and related substances originate in excess amounts predominantly from the liver in the hepatic type porphyrias and mostly from the bone marrow in the erythropoietic type porphyrias. Porphyrias with skin manifestations are often referred to as “cutaneous porphyrias”. The term “acute porphyria” is used to describe porphyrias that can be associated with sudden attacks of pain and other neurological symptoms. The “hepatic” (liver) and “erythropoietic” (red blood cell) porphyrias can have cutaneous and acute symptoms, sometimes together. Most forms of porphyria are genetic inborn errors of metabolism.Acute intermittent porphyria (AIP) is an acute, hepatic or liver form of porphyria ³³⁹.

Acute intermittent porphyria (AIP) is caused by a deficiency in the enzyme porphobilinogen deaminase (PBGD) also known as hydroxymethylbilane synthase (HMBS). The porphobilinogen deaminase or hydroxymethylbilane synthase enzyme deficiency leads to a buildup of harmful substances called porphyrin precursors in your body, particularly in your liver. This enzyme deficiency is caused by a mutation in the HMBS gene which is inherited as an autosomal dominant trait (only one HMBS gene copy is affected). However, the enzyme deficiency by itself is not sufficient to produce symptoms of the disease and most individuals with a HMBS gene mutation do not develop symptoms of acute intermittent porphyria (AIP) ³³⁹. Additional factors such hormonal changes associated with puberty, the use of certain prescribed or recreational drugs, excess alcohol consumption, infections, and fasting or dietary changes are required to trigger the appearance of symptoms ³³⁹. Acute intermittent porphyria (AIP) symptoms include attacks of severe abdominal pain, constipation, a rapid heartbeat and increased blood pressure (tachycardia and hypertension), behavioral changes, seizures, and damage of the nerves to muscles (peripheral neuropathy) which can lead to complications like muscle weakness and paralysis. Moreover, unlike some other acute porphyrias, acute intermittent porphyria (AIP) does not manifest as sun sensitivity and skin rashes.

In Europe the prevalence of symptomatic acute intermittent porphyria (AIP) is reported to be 5.9 per million people in the general population ³³⁹. It is likely to be similar elsewhere in the world apart from Sweden where it is higher due to a founder effect. The founder effect is a type of genetic defect that occurs when a small group of individuals establishes a new population, leading to reduced genetic diversity compared to the original population ³⁴⁰. This can happen when a few individuals migrate from a larger population or when a population experiences a significant reduction in size. Over time, the resulting new subpopulation will have genetic and physical traits resembling the initial small, separated group, and these may be very different from the original larger population. Recent population based genetic studies have shown that approximately 1 in 2000 of the population inherit a disease causing (pathogenic) mutation in the HMBS gene. This suggests that only 1% of those who inherit the HMBS gene mutation will ever experience porphyria symptoms. Acute intermittent porphyria (AIP) can occur in individuals of all ethnic backgrounds, although it may be less frequently reported in African-American individuals. Women are affected by symptomatic acute intermittent porphyria (AIP) more often than men. The disorder is most common in young or middle-aged women. A study conducted in Sweden demonstrated an increased risk of schizophrenia or bipolar disorder in patients with acute intermittent porphyria (AIP), as well as in their relatives ³⁴¹.

Clinical findings of an acute porphyria attack ³³⁰:

• Presence of otherwise unexplained severe, acute abdominal pain (without physical signs) in the vast majority (90%) of acute attacks ³⁴². The pain, which occasionally may be more severe in the back or thighs, is usually only relieved with opiate analgesia. Atypical presentations are rare.
• During attacks nausea, vomiting, constipation, tachycardia, and hypertension are common.
• Muscle weakness, seizures, mental changes, and hyponatremia are features that alone or in combination increase the probability of acute porphyria.
• The urine may be reddish brown or red; however, this should not be used as a diagnostic criterion as it is not a constant finding, especially if the sample is fresh. The color is enhanced by exposure to air and light and reflects increased urinary concentrations of porphyrins and porphobilins formed from the porphyrin precursor porphobilinogen (PBG).

A diagnosis of acute intermittent porphyria (AIP) can be difficult because most symptoms are nonspecific and occur episodically. A diagnosis is usually based upon identification of characteristic symptoms from a detailed patient history, a thorough clinical evaluation and certain specialized tests. Acute intermittent porphyria (AIP) should be suspected in individuals with unexplained abdominal pain, especially repeated episodes and when occurring along with psychological symptoms, neurological findings with muscle weakness or unexplained hyponatraemia. Dark or reddish urine in such individuals is also suggestive of acute intermittent porphyria (AIP). However, absence of this feature does not exclude acute intermittent porphyria (AIP). The diagnosis of acute intermittent porphyria (AIP) can be confirmed by finding an elevated level of porphobilinogen (PBG) (> 6 mg/L) on a spot urine test during an acute attack ³⁴³. If the urinary concentration of porphobilinogen (PBG) is increased, molecular genetic testing is performed to confirm the diagnosis and/or to facilitate screening of family members. When a multigene panel or genomic testing has identified an HMBS gene mutation, the diagnosis of an intermittent porphyria (AIP) attack is confirmed when the urinary concentration of PBG is increased.

Acute intermittent porphyria (AIP) treatment is focused on preventing attacks by educating patients to avoid potential triggers (e.g, fasting, unsafe drugs). Acute attacks usually require hospital care and can be effectively treated with intravenous hematin.

Treatment options in acute intermittent porphyria (AIP) may include the following ³⁴³:

• Avoidance of precipitating factors (e.g, fasting, low caloric intake, high-risk porphyrogenic drugs, alcohol, infections and reproductive hormones change)
• High doses of glucose for mild attacks. Intravenous glucose (300 g/d in adults) is used in early acute attacks or when hemin is unavailable, but hemin infusion is more effective ³⁴⁴, ³⁴⁵.
• Hematin for severe attacks, especially those with severe neurologic symptoms. For sporadic acute neurovisceral attacks (i.e., when an individual has experienced one to ≤3 acute porphyria attacks in any 12-month period in the last two years): IV human hemin is the most effective treatment and may be lifesaving if employed early when neuronal damage is reversible. Hemin infusion rapidly downregulates delta-aminolevulinic acid synthase 1 (ALAS1) expression, decreases aminolevulinic acid (ALA) and porphobilinogen (PBG) accumulation, and resolves symptoms in 48–72 hour, although its effectiveness in preventing recurrent attacks is unclear ³⁴⁶, ³⁴⁷. If the criteria for recurrent attacks are met, Givlaari® (givosiran) should be considered, as long-term complications of hemin such as iron overload, phlebitis, and loss of venous access can be avoided. Alternative medical therapies to reduce frequency and/or severity of acute attacks when givosiran is not available include suppression of ovulation and prophylactic hemin infusion.
• During attacks, which generally last for several days, symptomatic treatment for pain and other manifestations (eg, tachycardia, nausea and vomiting, seizures)
• Gonadotropin-releasing hormone analogues for women with attacks related to their menstrual cycles
• Prophylactic hematin infusions
• Givosiran, in patients with acute hepatic porphyria, to decrease the rate of acute attacks ³⁴⁸
• Liver transplantation, as a last resort for patients with intractable recurrent attacks that are life-threatening or severely affect quality of life. Liver transplantation, as reported from several centers, is curative. Indications include repeated life-threatening acute porphyria attacks and poor quality of life when givosiran is not available or has shown insufficient medical efficacy.

Figure 8. Acute intermittent porphyria attack triggers

Figure 9. Acute intermittent porphyria signs and symptoms

Abbreviations: AIP = acute intermittent porphyria; HCC = hepatocellular carcinoma; SIADH = syndrome of inappropriate antidiuretic hormone secretion

Acute intermittent porphyria cause

Acute intermittent porphyria (AIP) is a multifactorial disorder, which means that several different factors such as genetic and environmental factors occurring in combination are necessary for developing symptoms of the disorder ³³⁹. Individuals with acute intermittent porphyria (AIP) have a mutation in the HMBS gene located on the 11q24.1-q24.2 chromosome ³⁵¹, ³²⁹. There are more than 500 mutations of the HMBS gene have been identified in the worldwide ³³⁶, ³⁵². The HMBS gene provides instructions for making an enzyme known as hydroxymethylbilane synthase (HMBS) also known as porphobilinogen deaminase (PBGD) ³⁵³. The porphobilinogen deaminase (PBGD) or hydroxymethylbilane synthase (HMBS) enzyme is involved in the production of a molecule called heme. Heme is vital for all of your body’s organs, although it is most abundant in your blood, bone marrow, and liver. Heme is an essential component of iron-containing proteins called hemoproteins, including hemoglobin (the protein that carries oxygen in the blood). The production of heme is a multi-step process that requires 8 different enzymes. Hydroxymethylbilane synthase (porphobilinogen deaminase) is responsible for the third step in this process, which combines four molecules of porphobilinogen (the product of the second step) to form a compound called hydroxymethylbilane. In subsequent steps, five other enzymes produce and modify compounds that ultimately lead to heme.

Mutations in the HMBS gene lead to deficient levels of hydroxymethylbilane synthase (HMBS) or porphobilinogen deaminase (PBGD) in your body, which in turn can lead to the accumulation and release of porphyrin precursors, delta-aminolevulinic acid (ALA) and porphobilinogen (PBG) from the liver ³⁵⁴, ³⁴⁴.

However, the majority of people with a mutation in this gene do not develop symptoms of acute intermittent porphyria (AIP). Additional endogenous or exogenous factors, often called “triggers” are also required to cause symptomatic acute porphyria ³³⁹. These factors are not necessarily the same for each individual, and susceptibility to specific triggers may vary during a patient’s lifetime. Most of these triggers are believed to stimulate increased heme production (synthesis) in the liver and they include certain porphyrinogenic drugs, alcohol consumption, fasting or dieting (e.g. caloric restriction or low caloric intake), stress, infections or certain hormonal (endocrine) factors, female sex hormones, often in combination ³³⁹.

Acute intermittent porphyria is a low-penetrant genetic metabolic disease with penetrance considered to be around 10% to 20% ³⁵⁵. The penetrance of acute intermittent porphyria (AIP) in the general population has been estimated to be less than 1% ³⁵⁶. Manifest acute intermittent porphyria (MAIP) is considered when carriers develop typical acute neurovisceral attacks with an elevation of porphyrin precursors. In the absence of clinical episodes, it is referred to as latent acute intermittent porphyria (LAIP). Although higher penetrance has links to specific mutations, the overall genetic susceptibility factors underlying penetrance remain unknown.

Acute intermittent porphyria affects women to a greater degree than men, with a ratio of between 1.5 and 2 to 1. Attacks are rare before puberty. The typical age for the appearance of symptoms is between 18 to 40 years.

Symptomatic acute intermittent porphyria (AIP) is always accompanied by increased production and excretion of porphyrin precursors. However, for reasons that are unknown, some affected individuals have elevated porphyrin precursors without symptoms of acute intermittent porphyria (AIP). As discussed above, triggering factors are required for symptom development. The exact, underlying reasons why symptoms develop in some individuals with acute intermittent porphyria (AIP) are not fully understood. There are several theories as to the underlying pathogenesis of acute intermittent porphyria (AIP). One theory states that a specific porphyrin precursor (most likely 5-aminolevulinic acid [ALA]) is a neurotoxin that damages nerve tissue ³³⁹. This theory is supported by the information obtained from patients who have had liver transplant, which corrects both the clinical and biochemical features of the condition ³³⁹. A second theory suggests that heme deficiency in nerve cells (neurons) contributes to the development of symptoms ³³⁹. More research is necessary to determine the exact underlying mechanisms that are involved in the development of symptomatic episodes in individuals with acute intermittent porphyria (AIP).

Acute intermittent porphyria inheritance pattern

The HMBS gene mutation that predisposes individuals to developing acute intermittent porphyria (AIP) is inherited in an autosomal dominant pattern. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Dominant genetic disorders occur when only a single copy of an abnormal gene is sufficient for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy. The risk is the same for males and females.

People with specific questions about genetic risks or genetic testing for themselves or family members should speak with a genetics professional.

Resources for locating a genetics professional in your community are available online:

• The National Society of Genetic Counselors (https://www.findageneticcounselor.com/) offers a searchable directory of genetic counselors in the United States and Canada. You can search by location, name, area of practice/specialization, and/or ZIP Code.
• The American Board of Genetic Counseling (https://abgc.learningbuilder.com/Search/Public/MemberRole/Verification) provides a searchable directory of certified genetic counselors worldwide. You can search by practice area, name, organization, or location.
• The Canadian Association of Genetic Counselors (https://www.cagc-accg.ca/index.php?page=225) has a searchable directory of genetic counselors in Canada. You can search by name, distance from an address, province, or services.
• The American College of Medical Genetics and Genomics (https://clinics.acmg.net/) has a searchable database of medical genetics clinic services in the United States.

Figure 10. Acute intermittent porphyria autosomal dominant inheritance pattern

Acute intermittent porphyria pathophysiology

Acute intermittent porphyria (AIP) results from defects in the enzyme porphobilinogen deaminase (PBGD) also known as hydroxymethylbilane synthase (HMBS), which catalyzes the conversion of porphobilinogen (PBG) to hydroxymethylbilane. Impaired function of porphobilinogen deaminase (PBGD) leads to the accumulation of the porphyrin precursors porphobilinogen (PBG) and amino-levulinic acid (ALA). The predominant clinical problem appears to be neurologic damage that leads to peripheral and autonomic neuropathies and psychiatric manifestations ³⁵⁷.

Although levels of porphobilinogen (PBG) and amino-levulinic acid (ALA) are always elevated during acute attacks, how this leads to symptomatic acute intermittent porphyria is still unclear because most patients with the HMBS genetic defect have excessive porphyrin secretion but no symptoms.

In patients with acute intermittent porphyria (AIP), the function of porphobilinogen deaminase (PBGD) is only 40-60% of normal ³²⁹. With the advent of molecular technique, it has become clear that carriage of the HMBS genetic defect is much more common than symptomatic acute intermittent porphyria (AIP) ³²⁹. On average, out of 100 patients with the HMBS genetic defect, perhaps 10-20 secrete excess porphyrin precursors and only 1 to 2 have symptoms ³²⁹.

In acute intermittent porphyria (AIP), the neurologic damage occurs due to the accumulation of the porphyrin precursors, porphobilinogen (PBG) and aminolevulinic acid (ALA). The acute intermittent porphyria (AIP)-associated neurological damage manifests as peripheral and autonomic neuropathies and psychiatric manifestations.

A 2017 case-control study in 50 patients reported the association of acute intermittent porphyria (AIP) with systemic inflammation. Storjord et al. ³⁵⁸ found that the levels of insulin, C-peptide, prealbumin, and markers of kidney function, were decreased in symptomatic patients only, but not in asymptomatic ones. They postulated that in symptomatic patients of acute intermittent porphyria (AIP), the decrease in C-peptide levels in symptomatic acute intermittent porphyria (AIP) cases indicates that reduced insulin release is associated with enhanced disease activity and compromised kidney function ³⁵⁸.

Acute intermittent porphyria types

There 5 types of acute intermittent porphyria (AIP), caused by a heterozygous HMBS gene mutation and are based on the urine porphobilinogen (PBG)-to-creatinine ratio and occurrence of acute attacks ³³⁰, ³⁵⁹:

1. Active (symptomatic) acute intermittent porphyria: An individual who has experienced at least one acute attack within the last two years.
   • Sporadic AIP: 1-3 acute porphyria attacks in any 12-month period within the last 2 years
   • Recurrent AIP: ≥4 acute porphyria attacks in a maximum period of 12 months within the last 2 years
2. Symptomatic high excreter: Urine porphobilinogen (PBG)-to-creatinine ratio ≥4 times upper limit of normal (ULN) and no acute attacks in the last 2 years but has chronic long-standing manifestations of acute porphyria (e.g., pain or other porphyria-related manifestations in the absence of other likely explanations).
3. Asymptomatic high excreter: Urine porphobilinogen (PBG)-to-creatinine ratio ≥4 times upper limit of normal (ULN) and no acute attacks in the last 2 years and no porphyria-related manifestations.
4. Asymptomatic acute intermittent porphyria: Urine porphobilinogen (PBG)-to-creatinine ratio <4 times upper limit of normal (ULN) and no acute attacks in the last 2 years but has had ≥1 acute attack in the past.
5. Latent (inactive) acute intermittent porphyria: Urine porphobilinogen (PBG)-to-creatinine ratio <4 times upper limit of normal (ULN) and no acute porphyria-related manifestations to date.
   • Latent at-risk individual: An asymptomatic individual with a positive family history of acute intermittent porphyria (AIP) in whom an HMBS pathogenic variant was identified during screening of family members
   • Latent low-risk individual: An asymptomatic individual with no known family history of acute intermittent porphyria (AIP) in whom the identification of an HMBS pathogenic variant was an incidental finding (the identification of a pathogenic variant in a gene that does not account for the phenotype that prompted the diagnostic testing).

Active (Symptomatic) acute intermittent porphyria

Active symptomatic acute intermittent porphyria, which are more common in women than men, are very rare before puberty ³³⁰. Onset typically occurs in the second or third decade ³⁶⁰.

The visceral, peripheral, autonomic, and/or central nervous systems (brain and spinal cord) may be affected, leading to a range of findings that are usually intermittent and sometimes life-threatening ³³⁰. The course of acute porphyria attacks is highly variable in an individual and between individuals ³³⁰.

Affected individuals may recover from acute porphyria attacks within days, but recovery from severe attacks that are not promptly recognized and treated may take weeks or months ³³⁰. Although attacks in most individuals are typically caused by exposure to certain endogenous or exogenous factors, it is not uncommon for individuals to have acute attacks in which no precipitating factor can be identified ³³⁰.

Acute porphyria attacks

An acute porphyria attack is defined as an episode that includes significantly increased urinary porphobilinogen (PBG) concentration and two or more of the clinical manifestations of an acute porphyria attack that typically persist for more than 24 hours in the absence of other likely explanations ³⁶¹.

Severe abdominal pain, which may be generalized or localized and not accompanied by muscle guarding, is the most common symptom and is often the initial sign of an acute attack. Back, buttock, or limb pain may be a feature. Gastrointestinal features including nausea, vomiting, constipation or diarrhea, and abdominal distention are common, and ileus can occur. Tachycardia and hypertension are frequent, while fever, sweating, restlessness, and tremor are seen less frequently. Urinary retention, incontinence, and dysuria may be present.

Approximately 3%-8% of individuals with acute intermittent porphyria (AIP), mainly women, experience recurrent acute intermittent porphyria (AIP) (defined as ≥4 attacks in one year) for a prolonged period, often many years ³⁶¹, ³⁴².

Acute porphyria triggers

Acute porphyria attacks may be precipitated or triggered by endogenous or exogenous factors. These include the following ³⁶²:

• Prescribed and recreational drugs that are detoxified in the liver by cytochrome P450 and/or result in induction of 5-aminolevulinic acid (ALA) synthase and heme biosynthesis. Prescription drugs that can precipitate an attack include, for example, barbiturates, sulfa-containing antibiotics and antibiotics for urinary tract infections, some anti-seizure medications, progestogens, and synthetic estrogens (see a list of medications that clinicians must avoid using in porphyria patients (https://drugsporphyria.net/).
• Endocrine factors. Reproductive hormones play an important role in the clinical expression of acute intermittent porphyria (AIP). In women, acute neurovisceral attacks related to the menstrual cycle, usually the luteal phase, are common ³⁶². Pregnancy in women with acute intermittent porphyria (AIP) is usually uncomplicated, and although urinary PBG concentration may increase during pregnancy, this does not lead to a higher frequency of clinical porphyria manifestations ³⁶³. However, there is a higher risk for pregnancy-induced hypertensive disorder, gestational diabetes, and infants with intrauterine growth restriction. In general, risk ratios are higher among women with acute intermittent porphyria (AIP) who have high lifetime urinary porphobilinogen (PBG) concentrations ³⁶⁴.
• Fasting. A recognized precipitating factor is inadequate caloric intake in connection with, for example, dieting or heavy exercise schedules ³⁶².
• Stress. Psychosocial and other stresses, including intercurrent illnesses, infections, alcoholic excess, and surgery, can precipitate an attack ³⁶⁵

Peripheral neuropathy

Peripheral neuropathy is predominantly motor and is less common now than in the past, due to the availability of better treatments that reduce the risk of long duration of untreated acute porphyria attacks, the main risk factor for neurologic manifestations and long-term neurologic complications ³³⁰. Muscle weakness often begins proximally in the legs but may involve the arms or legs distally and can progress to include respiratory muscles, resulting in complete paralysis with respiratory failure ³³⁰. Bilateral axonal motor neuropathy may also involve the distal radial nerves. Motor neuropathy may also affect the cranial nerves or lead to bulbar paralysis.

Patchy sensory neuropathy may also occur ³³⁰.

Central nervous system signs

Mild mental changes such as anxiety, insomnia, irritability, and even mild cognitive impairment occur in up to 80% of symptomatic individuals and often in the initial stages of an acute porphyria attack ³⁴².

Severe mental symptoms attributed to acute encephalopathy characterize the severe acute porphyria attack, manifesting as aberrant behavior, hallucinations, confusion, impaired consciousness, or seizures ³⁶⁶, ³⁶¹.

Brain MRI changes can be detected in 47% of individuals with severe mental changes, usually in the form of posterior reversible encephalopathy syndrome, but normal MRI examination despite acute encephalopathy also occurs ³⁶⁶.

Hyponatremia is present in 25%-61% of acute porphyria attacks due to sodium loss, overhydration, hypothalamic involvement (i.e., syndrome of inappropriate antidiuretic hormone [SIADH]), or a combination of these conditions ³⁶⁶, ³⁶⁷.

Seizures occur in 1%-20% of acute porphyria attacks, with or without hyponatremia. They are transient and only present in severe attacks with acute encephalopathy; they do not occur in remission ³⁶⁶.

High Urine Porphobilinogen (PBG) Excreter

• Symptomatic high excreter. An individual with permanently high urinary porphobilinogen (PBG) concentration is considered symptomatic (i.e., a symptomatic high excreter) when having porphyria-related manifestations, usually pain, peripheral neuropathy, and psychiatric symptoms. Management of these manifestations is based on the need for supportive drugs, all of which should be evaluated for safety in acute intermittent porphyria (AIP). The condition usually occurs after an acute porphyria attack and can persist for many years ³⁶⁸. In a Swedish acute intermittent porphyria (AIP) cohort approximately 10% of adults with acute intermittent porphyria (AIP) are high urinary porphobilinogen (PBG) excreters ³⁶⁹.
• Asymptomatic high excreter. An asymptomatic HMBS heterozygote with permanently high urinary porphobilinogen (PBG) concentration (urine PBG-to-creatinine ratio ≥4 times the upper limit of normal) and has had no porphyria-related manifestations during the last two years.

Asymptomatic acute intermittent porphyria

Asymptomatic acute intermittent porphyria also called acute porphyria in remission refers to a person has had one or more acute porphyria attacks in the past but has had no acute porphyria-related manifestations during the last two years and has a urine porphobilinogen (PBG)-to-creatinine ratio is less than four times the upper limit of normal.

Latent acute intermittent porphyria

Latent acute intermittent porphyria refers to a person who is heterozygous for an HMBS pathogenic variant associated with acute intermittent porphyria who has never experienced acute porphyria-related manifestations and does not have significantly elevated urinary porphobilinogen (PBG) concentration.

The risk of becoming symptomatic depends on age, sex, and exposure to provoking agents, and is higher if the individual belongs to a family with other symptomatic individuals ³⁷⁰.

Acute intermittent porphyria signs and symptoms

Most people who inherit the HMBS gene for acute intermittent porphyria (AIP) never develop symptoms. However, experts recommend that all relatives of someone with acute intermittent porphyria obtain testing, to determine who has the genetic trait and who does not. Those who test positive for the trait should be educated as to measures that will help avoid attacks. Prevention is essential to good management.

It is important to note the highly variable nature of acute intermittent porphyria (AIP) and that affected individuals may not have all of the symptoms discussed below. Acute intermittent porphyria (AIP) can be associated with a range of symptoms and physical findings that can potentially involve multiple organ systems of the body. The course and severity of attacks is highly variable from one person to another. In some cases, particularly those without proper diagnosis and treatment, acute intermittent porphyria (AIP) can potentially cause life-threatening complications. Affected individuals and parents of affected children should talk to their physician and medical team about their specific case, associated symptoms and overall prognosis.

Acute intermittent porphyria (AIP) rarely attacks before puberty, with typical symptoms occurring between the ages of 20 and 40, more in females than males due to female sex hormones ³³². Symptoms usually come as discrete attacks that develop over two or more days.

The abdominal pain is typically severe, epigastric, and colicky and can be severe and occurs in most cases. It tends to last for several days. The abdominal pain can be associated with constipation, nausea and vomiting ³³⁰.

Other symptoms may include:

• nausea
• vomiting
• constipation
• pain in the back, arms and legs
• muscle weakness (due to effects on nerves supplying the muscles)
• urinary retention
• palpitation (due to a rapid heart rate and often accompanied by increased blood pressure)
• Sometimes red or brown urine due to elevated porphobilinogen (PBG) in urine, which are the immediate precursors proximal to the hydroxymethylbilane synthase (HMBS), may be observed, which darkens on exposure to air, light, and warmth ³⁷¹.

Central nervous system signs may include delirium, confusion, hallucinations, weakness with progression to quadriplegia and respiratory failure, cortical blindness, and even coma. In 5% of cases, patients can develop seizures, with partial seizures being the most common subtype ³⁷²

Sometimes the level of salt (sodium and chloride) in the blood decreases markedly and contributes to some of these symptoms. The skin is not affected.

The symptoms of acute intermittent porphyria (AIP) usually occur as episodes or “attacks” that develop over course of several hours or a few days. Affected individuals usually recover from an attack within days. However, if an acute attack is not diagnosed and treated promptly recovery can take much longer, even weeks or months. Most affected individuals do not exhibit any symptoms in between episodes. Onset of attacks usually occurs in the 20s or 30s, but may rarely occur at or just after puberty. Onset before puberty is extremely rare. Attacks are much more common in women than men, probably because of the menstrual cycle hormones. Approximately 3%-5% of affected individuals, predominately women, experience recurrent attacks, which are defined as more than 4 per year, for a period of many years.

Abdominal pain, which is usually severe, is the most common symptom associated with acute intermittent porphyria (AIP) and often the initial sign of an attack. Abdominal pain is usually severe, steady (unremitting) and widespread (diffuse). Less often, abdominal pain is described as cramping. Pain may also occur in the neck, lower back, buttocks, or arms and legs.

Gastrointestinal symptoms are also common during an attack and can include nausea, vomiting, constipation or diarrhea, and abdominal swelling (distention). A painful blockage or obstruction (ileus) of part of the small intestines may also occur. Difficulty passing urine (urinary retention) can also occur.

Neurological symptoms may also develop including damage to the nerves outside the central nervous system (peripheral neuropathy). Peripheral neuropathy is characterized by numbness or tingling and burning sensations that usually begin in the feet and sometimes the arms. Affected individuals may develop muscle weakness in the legs that may progress to affect the arms and the trunk of the body, eventually causing partial loss or impairment of motor function (motor paralysis). In rare cases, the muscles used to breathe can become involved and potentially cause life-threatening respiratory failure which requires mechanical ventilation.

During attacks some individuals develop psychological symptoms including irritability, depression, anxiety, insomnia, hallucinations, paranoia, disorientation, and altered consciousness ranging from excessive drowsiness (somnolence) to agitation or, in severe cases, coma.

Affected individuals may also experience a faster than normal heart rate (tachycardia) , high blood pressure (hypertension) and irregular heartbeats (cardiac arrhythmias). Seizures have also been reported. Abnormally low sodium levels (hyponatremia) may develop rapidly during an attack and contribute to the onset of seizures.

Patients have been reported to be completely free of symptoms in between the attacks. However, it is also suggested that 20% to 64% of patients may suffer from disabling chronic signs and symptoms such as pain, nausea, fatigue, and neuropathic features, including numbness and tingling sensations ³⁷³.

Individuals with chronic acute intermittent porphyria (AIP) may also develop complications that occur after many years (long-term complications) such as high blood pressure (hypertension), kidney damage potentially resulting in kidney failure, and liver cancers such as hepatocellular carcinoma (liver cancer) or cholangiocarcinoma (bile duct cancer).

A study conducted in Sweden demonstrated an increased risk of schizophrenia or bipolar disorder in patients with acute intermittent porphyria (AIP), as well as in their relatives ³⁴¹.

Acute intermittent porphyria complications

Acute intermittent porphyria complications include:

• Systemic arterial hypertension and chronic kidney disease – Reports exist of the prevalence of up to 30% of these closely linked disorders in patients with acute intermittent porphyria (AIP) ³⁷⁴. End-stage renal disease (ESRD) is a life-threatening complication in acute intermittent porphyria (AIP) patients with chronic active disease ³⁷⁵
• Muscle denervation is another major pathologic complication ³⁷⁶. Some patients after acute attacks have residual deficits such as foot/wrist drop or wasting of the intrinsic muscles of hands ³⁷⁷.
• Hepatocellular carcinoma (liver cancer): This is the most deadly long-term complication of acute intermittent porphyria (AIP). Results of studies performed over the last 3 to 4 decades have shown a remarkably increased incidence of hepatocellular carcinoma (liver cancer) in acute intermittent porphyria (AIP) patients compared with the general population ³⁷⁸. A Swedish study showed that the risk for hepatocellular carcinoma (liver cancer) in AIP is increased 80 times after the age of 50 years ³⁷⁹, ³³⁰. It is worthwhile to know that acute intermittent porphyria (AIP) -associated hepatocellular carcinoma (liver cancer) is typically free from the usual preceding comorbidities such as Hepatitis B or C infection.

Acute intermittent porphyria diagnosis

A diagnosis of acute intermittent porphyria (AIP) can be difficult because most symptoms are nonspecific and occur episodically. A diagnosis is usually based upon identification of characteristic symptoms from a detailed patient history, a thorough clinical evaluation and certain specialized tests. Acute intermittent porphyria (AIP) should be suspected in individuals with unexplained abdominal pain, especially repeated episodes and when occurring along with psychological symptoms, neurological findings with muscle weakness or unexplained hyponatraemia. Dark or reddish urine in such individuals is also suggestive of acute intermittent porphyria (AIP). However, absence of this feature does not exclude acute intermittent porphyria (AIP). The diagnosis of acute intermittent porphyria (AIP) can be confirmed by finding an elevated level of porphobilinogen (PBG) (> 6 mg/L) on a spot urine test during an acute attack ³⁴³. If the urinary concentration of porphobilinogen (PBG) is increased, molecular genetic testing is performed to confirm the diagnosis and/or to facilitate screening of family members. When a multigene panel or genomic testing has identified an HMBS gene mutation, the diagnosis of an intermittent porphyria (AIP) attack is confirmed when the urinary concentration of PBG is increased.

Clinical Testing and Workup

Screening tests to measure the levels of the porphyrin precursor porphobilinogen (PBG) in urine are essential to confirm a diagnosis of acute porphyria. Acute attacks are always accompanied by increased production and excretion of porphyrin precursor porphobilinogen (PBG) in acute intermittent porphyria (AIP). If urinary porphobilinogen (PBG) excretion is increased, then further testing (fecal and blood porphyrin measurement) is necessary to distinguish acute intermittent porphyria (AIP) from variegate porphyria or hereditary coproporphyria. This should not delay treatment of acutely unwell patients. Delta-aminolevulinic acid (ALA) excretion will also be elevated in urine samples from individuals with acute intermittent porphyria (AIP), but measurement is less widely available and is not essential. These tests can be performed on a random (spot) urine sample that should be protected from light after collection and during transport to the laboratory. There is now good evidence that once urine porphobilinogen (PBG) excretion is increased in acute intermittent porphyria (AIP) it takes many years to return to normal. Increased urine porphobilinogen (PBG) excretion in a known acute intermittent porphyria (AIP) patient does not therefore prove that a patient is having an acute attack.

Family Testing

Molecular genetic testing is not essential to confirm a diagnosis as the porphyrin biochemical findings are characteristic. However molecular genetic testing to detect a mutation in the HMBS gene is usually required so that family members can be offered testing for this mutation. Genetic testing is available mainly from laboratories specializing in porphyria diagnosis.

Patients and family members who have inherited acute intermittent porphyria (AIP) should be advised on how to limit their risk of any future acute attacks. This should include information about acute intermittent porphyria (AIP) and what causes attacks, how to check if a prescribed medication is safe or unsafe and details of relevant patient support groups.

Resources for locating a genetics professional in your community are available online:

• The National Society of Genetic Counselors (https://www.findageneticcounselor.com/) offers a searchable directory of genetic counselors in the United States and Canada. You can search by location, name, area of practice/specialization, and/or ZIP Code.
• The American Board of Genetic Counseling (https://abgc.learningbuilder.com/Search/Public/MemberRole/Verification) provides a searchable directory of certified genetic counselors worldwide. You can search by practice area, name, organization, or location.
• The Canadian Association of Genetic Counselors (https://www.cagc-accg.ca/index.php?page=225) has a searchable directory of genetic counselors in Canada. You can search by name, distance from an address, province, or services.
• The American College of Medical Genetics and Genomics (https://clinics.acmg.net/) has a searchable database of medical genetics clinic services in the United States.

Evaluations Following Initial Diagnosis of Acute Intermittent Porphyria (AIP) Attack

To establish the extent of disease and needs in an individual diagnosed with acute intermittent porphyria (AIP) who is experiencing acute signs and symptoms, the following evaluations (if not performed as part of the evaluation that led to the diagnosis) are recommended:

• Consider other causes of abdominal pain in addition to porphyria.
• Review all medications and discontinue any that can exacerbate acute porphyria ³⁸⁰.
• Initial investigations should include the following:
  • Complete blood count
  • Measurement of serum/plasma concentrations of urea, creatinine, and electrolytes
  • If there is hyponatremia, measure serum and urine osmolality, and urine sodium concentration
  • Other blood tests as indicated by the individual’s condition and possible cause of the attack (e.g., C-reactive protein, blood cultures, serum creatine kinase, and plasma magnesium concentration)
  • Brain MRI when central nervous system manifestations are present
• Refer individual to a porphyria specialist for more detailed clinical advice on acute intermittent porphyria (AIP).
• Affected individuals should be advised to register with an organization that provides warning jewelry in case of an accident (e.g., MedicAlert® or similar).
• Consultation with a medical geneticist, certified genetic counselor, or certified advanced genetic nurse is recommended to inform affected individuals and their families about the nature, mode of inheritance, and implications of AIP to facilitate medical and personal decision making.
• Assess need for family support and resources including community or online resources and home nursing referral.

Acute intermittent porphyria differential diagnosis

Symptoms of the following disorders can be similar to those of acute intermittent porphyria (AIP). Comparisons may be useful for a differential diagnosis.

The acute attacks that characterize acute intermittent porphyria (AIP) are similar to those seen in 3 other forms of porphyria specifically variegate porphyria, hereditary coproporphyria, and ALA-Dehydratase deficiency porphyria. Collectively, these four forms of the porphyria are classified as the acute porphyrias.

Variegate porphyria causes

As in hereditary coproporphyria, acute attacks of variegate porphyria are unusual except in the presence of environmental activating factors, such as drugs, hormones, and dietary changes.

Variegate porphyria is caused by mutations of the protoporphyrinogen oxidase gene. A protoporphyrinogen oxidase mutation is inherited as an autosomal dominant trait within a family. The pattern of inheritance is autosomal dominant, which means that a single mutation is inherited from one parent and, in the presence of other triggering factors, is sufficient to cause the disease. The abnormal gene can be inherited from either parent, or on rare occasions can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50 percent for each pregnancy regardless of the sex of the resulting child.

The protoporphyrinogen oxidase gene is located on the long arm (q) of chromosome 1 (1q22). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 1q22” refers to band 22 on the long arm of chromosome 1. The numbered bands specify the location of the thousands of genes that are present on each chromosome.

The protoporphyrinogen oxidase gene contains instructions for creating protoporphyrinogen oxidase, one of the eight enzymes necessary for the production of heme. Heme is an iron-containing porphyrin (iron protoporphyrin) and is a part of many heme-containing proteins (hemoproteins) in the body. Hemoproteins interact with oxygen and some are involved in electron transport and energy metabolism. The best known hemoprotein is hemoglobin, which is made in the bone marrow, makes red blood cells red, and transports oxygen from the lungs to other tissues. However, the bone marrow and hemoglobin are not affected in variegate porphyria. In this condition the heme pathway in the liver, which makes heme for other important hemoproteins, is affected.

Mutations of the protoporphyrinogen oxidase gene result in deficient levels of protoporphyrinogen oxidase, which, in turn, disrupts the biochemical process to create heme in the liver. This disruption causes porphyrins and porphyrin precursors to accumulate in the liver and these are then transported to other parts of the body to affect the nervous system and skin.

A variety of different triggers are known to lead to attacks in individuals with variegate porphyria. Many of these triggers act by increasing heme synthesis in the liver, which makes the protoporphyrinogen oxidase deficiency more significant and increases the accumulation of porphyrins and porphyrin precursors. As noted above, triggers include a variety of drugs, hormones (especially progesterone), reduced intake of calories and carbohydrate, alcohol, and stress induced by infection or other illness.

Variegate porphyria diagnosis

Urine aminolevulinic acid and porphobilinogen are increased during attacks, but as in hereditary coproporphyria, these may increase less and decrease more rapidly than in acute intermittent porphyria. Plasma porphyrins are frequently increased in variegate porphyria, in contrast to acute intermittent porphyria and hereditary coproporphyria, and the plasma of variegate porphyria patients displays a distinctive fluorescence peak, which is diagnostic. Fecal porphyrins are also elevated and are predominantly coproporphyrin III and protoporphyrin.

Molecular genetic testing to identify a protoporphyrinogen oxidase mutation is recommended for all biochemically confirmed cases of variegate porphyria. Molecular testing is sometimes useful when symptoms have been absent for months or years and biochemical abnormalities are no longer present. Knowing the protoporphyrinogen oxidase mutation is a family enables other family members to be tested reliably for the same mutation.

Variegate porphyria treatments

Management and prevention are the same as in acute intermittent porphyria and hereditary coproporphyria. Hospitalization is usually indicated for pain control and treatment of other severe symptoms such as nausea and vomiting, electrolyte imbalances and convulsions. Monitoring for these manifestations as well and muscle weakness and respiratory embarrassment is also indicated in severe attacks. A narcotic analgesic is generally required for pain, and a phenothiazine or ondansetron for nausea and vomiting. Triggering factors should be identified and discontinued when possible. Specific therapies are hemin for injection, which is available in the U.S. as lyophilized hematin (Panhematin®,), and glucose loading. Hemin represses the heme pathway in the liver and lowers aminolevulinic acid, porphobilinogen and porphyrins, and is associated with more rapid recovery from an attack. Glucose given intravenously has a similar effect, but because it is less potent is used only for mild attacks, or until hemin can be obtained from the manufacturer. Blistering skin lesions are much more common than in hereditary coproporphyria and are not readily treated. The only effective preventive measure is use of protective clothing.

Variegate porphyria prognosis

The prognosis is usually good if the disease is recognized and treated promptly, before nerve damage develops. Although symptoms usually resolve after an attack, recovery of neuromuscular function (in a severe case) may require several months. Mental symptoms may occur during attacks but are not chronic. Premenstrual attacks often resolve quickly with the onset of menses.

Can attacks be prevented?

Yes, particularly with regard to drugs and diet. Genetic Variegate Porphyria carriers should become informed on medications to avoid and should be prepared to point their healthcare providers to on-line drug lists that are regularly updated.

A Medic Alert bracelet is useful for a situation in which the patient is incapacitated. Very frequent premenstrual attacks can be prevented by a gonadotropin-releasing hormone (GnRH) analogue (Lupron, Zoladex, others) administered with expert guidance. In selected cases, frequent noncyclic attacks can be prevented by once- or twice-weekly infusions of hemin.

Individuals who are prone to attacks should consume a normal balanced diet. Despite on-line discussion, there is no evidence that pushing carbohydrate prevents attacks, and it has the side effect of weight gain, which is undesirable for most people. Fasting, fad diets (for example, high protein) and gastric reduction surgery should be avoided. If weight loss is desired, it is advisable to consult a physician and a dietitian about an individualized diet with modest caloric restriction (ca. 10%), which will produce gradual weight loss without increasing the risk of an attack of porphyria. Exercise is safe in porphyria, and recommended.

Hereditary coproporphyria

Hereditary coproporphyria is due to a mutation in coproporphyinogen oxidase, which is part of the pathway that produces porphyrins and heme. It is an autosomal dominant disorder, meaning that a mutation is present in only one of the pair of coproporphyinogen oxidase genes. The incidence of active hereditary coproporphyria appears to be at most 2 per 1,000,000. The prevalence of the genetic carrier state is unknown.

Hereditary coproporphyria is termed a disease with low penetrance, meaning that many genetic carriers (defined by having a coproporphyinogen oxidase mutation) never have signs or symptoms of active porphyria. Active disease in general requires the presence of environmental factors such as certain drugs, hormones, and dietary changes, as in acute intermittent porphyria. Lists are available of drugs that are risky for hereditary coproporphyria genetic carriers as well as drugs that are safe (see the full list here: http://www.porphyriafoundation.com/drug_database/). The worst offenders are barbiturates, sulfonamide antibiotics, anti-seizure drugs, rifampin, and oral contraceptives (progesterone, in particular). Attacks in women may occur after ovulation and during the last part of the menstrual cycle when progesterone levels are high. Reduced food intake, often in an effort to lose weight, as well as infections, surgery, and stressful situations may also precipitate attacks. Alcohol has been implicated in some attacks. People with repeated attacks are at risk for developing chronic renal disease and liver cancer (hepatocellular carcinoma)

Hereditary coproporphyria diagnosis

The initial test for people with symptoms is quantitative urinary aminolevulinic acid, porphobilinogen and porphyrins. Elevation of aminolevulinic acid, porphobilinogen and coproporphyrin (predominantly isomer III) is highly suggestive of Hereditary coproporphyria. For asymptomatic individuals, the urine studies may be normal, but a fecal porphyrin analysis will show elevation of coproporphyrin III. Screening tests of this kind should be confirmed by DNA analysis to confirm a coproporphyinogen oxidase mutation.

Hereditary coproporphyria treatment

Treatment, complications, and preventive measures are the same as in acute intermittent porphyria. Hospitalization is often necessary for acute attacks. Medications for pain, nausea, and vomiting and close observation are generally required. During treatment of an attack, attention should be given to sodium (salt) and water balance. Harmful drugs should be stopped. Attacks are treated with either glucose loading or hemin (Panhematin®, Recordati). These are specific treatments that lower the production of heme pathway intermediates by the liver. Glucose or other carbohydrates are given by mouth if possible, otherwise by vein. However, unless an attack is mild, it is now common practice to give hemin as soon as it is available, because it works more quickly than glucose loading, preventing the neurological complications of prolonged attacks.

Patients with severe renal disease tolerate hemodialysis or kidney transplantation. Liver transplantation has been very effective for patients who have repeated attacks and who are resistant to other treatments. However, experience with transplantation as a treatment is still limited.

Hereditary coproporphyria prognosis

The prognosis is usually good if the disease is recognized and treated promptly, before nerve damage develops. Although symptoms usually resolve after an attack, recovery of neuromuscular function (in a severe case) may require several months or longer. Mental symptoms may occur during attacks but are not chronic. Premenstrual attacks often resolve quickly with the onset of menses.

Can attacks be prevented?

Yes, particularly with regard to drugs and diet. Genetic hereditary coproporphyria carriers should become informed on drugs and other factors that can lead to symptoms (see above). They should be prepared to point their healthcare providers to drugs and medications to avoid. A Medic Alert bracelet is useful for a situation in which the patient is incapacitated. Very frequent premenstrual attacks can be prevented by a gonadotropin-releasing hormone (GnRH) analogue administered with expert guidance. In selected cases, frequent noncyclic attacks can be prevented by once- or twice-weekly infusions of hemin.

Individuals who are prone to attacks should consume a normal balanced diet. Despite online discussion, there is no evidence that pushing carbohydrate prevents attacks, and it has the side effect of weight gain, which is undesirable for most people. Fasting, fad diets (for example, high protein) and gastric reduction surgery should be avoided. If weight loss is desired, it is advisable to consult a physician and a dietitian about an individualized diet with modest caloric restriction, which will produce gradual weight loss without increasing the risk of an attack of porphyria. Exercise is safe in porphyria, and recommended.

ALA dehydratase deficiency porphyria

ALA dehydratase deficiency porphyria is a severe disorder caused by a deficiency of the enzyme δ-aminolevulinic acid dehydratase which results in an increase of 5’-aminolevulinic acid (ALA) in the liver, other tissues, blood plasma, and urine. In addition, urine coproporphyrin and erythrocyte protoporphyrin are increased. ALA dehydratase deficiency porphyria generally presents with sudden attacks of severe stomach pain that last for several days.

All of the reported cases of ALA dehydratase deficiency porphyria have been males, in contrast to the other acute porphyrias. ALA dehydratase deficiency porphyria is the least common of all the porphyrias with less than 10 cases documented to date. This is an autosomal recessive disease, whereas the other three acute porphyrias are autosomal dominant. Each parent of an affected individual must have a mutation in one of their δ-aminolevulinic acid dehydratase genes and both must pass their mutation on to their child.

ALA-dehydratase porphyria causes

ALA dehydratase deficiency porphyria is caused by a deficiency of the enzyme δ-aminolevulinic acid dehydratase (ALAD).

ALA dehydratase deficiency porphyria is caused by mutations in the ALA dehydratase deficiency gene, and the disease is inherited as an autosomal recessive disorder. This means that both copies of the ALA dehydratase deficiency gene have a mutation. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother.

Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual inherits one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the altered gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.

The ALA dehydratase deficiency gene contains instructions for creating the enzyme aminolevulinate dehydratase, which is necessary for the production of heme. Heme is part of hemoglobin, which is the oxygen-carrying component of red blood cells. Heme is mainly produced in the bone marrow and the liver. Eight different enzymes are necessary for the creation of heme.

Mutations of the ALA dehydratase deficiency gene result in deficient levels ofporphobilinogen in the body, with accumulation of ALA, which causes the symptoms associated with ALA dehydratase deficiency porphyria.

A variety of different triggers have been identified that can precipitatean acute attack in individuals with ALA dehydratase deficiency porphyria. These triggers include alcohol, certain drugs, physical and psychological stress, infection, fasting (reduced caloric intake) and dehydration. The use of estrogen or progesterone is also suspect of triggering an acute attack.

ALA dehydratase deficiency porphyria diagnosis

There are many laboratory tests available for the porphyrias, and it is often difficult to decide which should be chosen. Many of these tests are expensive and the results are often difficult to interpret. When abdominal and neurological symptoms suggest an acute porphyria, the best screening tests are urinary aminolevulinic acid (ALA) and porphobilinogen (PBG). DNA testing to identify the specific mutation in an individual’s porphyria-causing gene is the most specific and sensitive test to confirm the diagnosis of a specific porphyria. Before requesting DNA testing, it is recommended that patients have biochemical testing (urinary, stool and/or plasma porphyrins and porphyrin precursors (ALA and PBG) and/or enzyme assays). However, biochemical testing may be inconclusive.

ALA dehydratase deficiency porphyria treatment

Treatment is the same as in the other acute porphyrias. For the acute porphyrias, hospitalization is often necessary for acute attacks. Medications for pain, nausea and vomiting, and close observation are generally required with monitoring of salt and water balance. Harmful drugs should be stopped. Attacks are treated with either glucose loading or intravenous administration of hemin (Panhematin®). Attacks can be prevented in many cases by avoiding harmful drugs and adverse dietary practices.

Porphyria complications

Possible complications depend on the form of porphyria:

• Acute porphyrias can be life-threatening if an attack isn’t promptly treated. During an attack, you may experience dehydration, breathing problems, seizures and high blood pressure. Episodes often require hospitalization for treatment. Long-term complications with recurrent acute attacks may include chronic pain, chronic kidney failure and liver damage.
• Cutaneous porphyrias can result in permanent skin damage. Also, the skin blisters can become infected. When your skin heals after cutaneous porphyria, it may have an abnormal appearance and coloring, be fragile, or leave scars.

Without medical treatment, complications of porphyria may include:

• Permanent hair loss
• Skin scarring
• Permanent skin pigmentation changes
• Dehydration
• Breathing problems
• High blood pressure (hypertension)
• Low salt levels in the blood (hyponatremia)
• Kidney failure
• Liver problems, which may require a liver transplant in severe cases. Several types of porphyrias can cause liver problems. Acute porphyria increases the chance of developing liver cancer (hepatocellular carcinoma [HCC]). Porphyria cutanea tarda can damage the liver and increase the chance of developing cirrhosis (scarring of the liver) and liver cancer. Some people with protoporphyria also develop liver damage and cirrhosis, and up to 5 percent of people with protoporphyria develop liver failure ³⁹⁹. In people with protoporphyria, bile carries extra porphyrins from the liver to the gallbladder, which may lead to gallstones that are made of porphyrins.
• Anemia. People with congenital erythropoietic porphyria or hepatoerythropoietic porphyria who develop severe anemia may require treatment with blood transfusions. In some cases, doctors may also recommend surgery to remove an enlarged spleen, which can help treat anemia.

Porphyria causes

The substance heme (or haem) is used in various metabolic processes. The body makes heme from porphyrins, which are metallic compounds found naturally in the tissues of animals and plants. The conversion of porphyrins into heme requires the action of special proteins called enzymes. Genes control the action of enzymes. A flawed gene (or genes) can stop the body from making one or more of these enzymes. This creates a lack of heme and a build-up of porphyrins, which causes the signs and symptoms of porphyria.

Genetic forms

Most forms of porphyria are inherited, which means the genetic predisposition is passed from one generation to the next. The faulty gene interferes with the body’s ability to create one or more enzymes necessary in the conversion of porphyrins into heme. The pattern of inheritance may include:

• Autosomal dominant inheritance – the faulty gene is inherited from one parent. This faulty gene overrides the healthy gene inherited from the other parent.
• Autosomal recessive inheritance – the faulty gene is inherited from both parents.

However, about nine in every 10 people with the faulty gene or genes don’t have porphyria. It appears that an environmental trigger is needed to allow porphyria to develop. You might have what’s called latent porphyria, and never have symptoms. This is the case for most carriers of the abnormal genes.

Acquired forms

Porphyria cutanea tarda typically is acquired rather than inherited, although the enzyme deficiency may be inherited. Certain triggers that impact enzyme production — such as too much iron in the body, liver disease, estrogen medication, smoking or excessive alcohol use — can cause symptoms.

Porphyria cutanea tarda is usually an acquired disorder, meaning factors other than genes cause the enzyme deficiency. This type of porphyria can be triggered by

• too much iron
• use of alcohol or estrogen
• smoking
• chronic hepatitis C—a long-lasting liver disease that causes inflammation, or swelling, of the liver
• HIV—the virus that causes AIDS
• abnormal genes associated with hemochromatosis—the most common form of iron overload disease, which causes the body to absorb too much iron

Risk factors for porphyria

In addition to genetic risks, environmental factors may trigger the development of signs and symptoms in porphyria. When exposed to the trigger, your body’s demand for heme production increases. This overwhelms the deficient enzyme, setting in motion a process that causes a buildup of porphyrins.

Examples of triggers include:

• Exposure to sunlight
• Certain medications, including hormone drugs
• Recreational drugs
• Dieting or fasting
• Smoking
• Physical stress, such as infections or other illnesses
• Emotional stress
• Alcohol use
• Menstrual hormones ― acute porphyria attacks are rare before puberty and after menopause in women.

Porphyria symptoms

The signs and symptoms of porphyria can vary, depending on the type and severity. Some people have no symptoms. Some go for long periods without any symptoms. Some people have quite a bit of trouble with symptoms.

The most common symptoms are:

• skin problems like sensitivity to the sun, blistering, discoloration and scarring
• abdominal pain
• muscle weakness
• numbness in the arms and legs
• confusion and seizures.

Symptoms vary from one type of porphyria to the next. Cases are generally classified into one of three groups, which include:

• Acute porphyrias – the condition mostly affects the nervous system. The skin is occasionally affected. Symptoms may include muscle pain or paralysis, seizures, disorientation, hallucination, bloody (red) urine, hypertension and gastrointestinal problems such as vomiting, abdominal pain and constipation. Acute porphyrias generally occur during adulthood and are rare before puberty or after menopause. Different types of acute porphyria include ‘acute intermittent porphyria’ and ‘erythropoietic protoporphyria’.
  • Signs and symptoms of acute porphyria may include:
    • Severe abdominal pain
    • Pain in your chest, legs or back
    • Constipation or diarrhea
    • Nausea and vomiting
    • Muscle pain, tingling, numbness, weakness or paralysis
    • Red or brown urine
    • Mental changes, such as anxiety, confusion, hallucinations, disorientation or paranoia
    • Breathing problems
    • Urination problems
    • Rapid or irregular heartbeats you can feel (palpitations)
    • High blood pressure
    • Seizures
• Cutaneous porphyrias – the condition affects the skin but not the nervous system. The skin is highly sensitive to sunlight and exposure tends to trigger symptoms within minutes. Symptoms may include red, itchy, blistered, painful and swollen skin and bloody (red) urine. The condition may develop during childhood. Different types of cutaneous porphyria include ‘porphyria cutanea tarda’ and ‘hepatoerythropoietic porphyria’.
  • As a result of sun exposure, you may experience:
    • Sensitivity to the sun and sometimes artificial light, causing burning pain
    • Sudden painful skin redness (erythema) and swelling (edema
    • Blisters on exposed skin, usually the hands, arms and face
    • Fragile thin skin with changes in skin color (pigment)
    • Itching
    • Excessive hair growth in affected areas
    • Red or brown urine
• Neurocutaneous porphyrias – the condition affects both the skin and the nervous system. Sunlight exposure tends to rapidly trigger symptoms. Different types of neurocutaneous porphyria include ‘variegate porphyria’ and ‘hereditary coproporphyria’.

Porphyria diagnosis

Because porphyria can cause so many different symptoms, it can be hard to diagnose. Your doctor can talk to you and examine you, and will probably want to arrange urine or blood tests as well.

Genetic tests can be useful, too.

Since porphyria is rare, most doctors are unfamiliar with it and may not recognise the symptoms. Diagnosis can be delayed because porphyria mimics the symptoms and signs of various other medical conditions such as Guillain-Barre syndrome, eczema, multiple sclerosis and irritable bowel syndrome. Diagnostic tests may include:

• Physical examination
• Medical history
• Urine tests to check for elevated substances including porphyrins
• Blood tests to check for high levels of porphyrins in the plasma
• Stool sample to check for excreted porphyrins
• Genetic test.

Porphyria treatment

Treatment for porphyria will depend on what type of porphyria you have and how severe your symptoms are.

Some of the medicines used to treat a sudden (acute) attack of porphyria may include:

• Hematin given through a vein (intravenously)
• Pain medicine
• Propranolol to control the heartbeat
• Sedatives to help you feel calm and less anxious

Other treatments may include:

• Beta-carotene supplements to lessen photosensitivity
• Chloroquine in low doses to reduce levels of porphyrins
• Fluids and glucose to boost carbohydrate levels, which helps limit the production of porphyrins
• Removal of blood (phlebotomy) to reduce levels of porphyrins

Depending on the type of porphyria you have, your doctor may tell you to:

• Avoid all alcohol
• Avoid certain drugs that may trigger an attack
• Avoid injuring the skin
• Avoid sunlight as much as possible and use sunscreen when outside
• Eat a high-carbohydrate diet

If a question of drug safety arises, a physician or medical center specializing in porphyria should be contacted. A list of these institutions may be obtained from the American Porphyria Foundation. The Foundation also maintains an Acute Porphyria Drug Database (https://porphyriafoundation.org/for-healthcare-professionals/ahp-drug-safety-database/). The EPNET/NAPOS Database should also be consulted. The Norwegian Porphyria Centre (NAPOS), with the European Porphyria Network (EPNET), has created a list of medications that clinicians must avoid using in porphyria patients (https://drugsporphyria.net/). These drugs include ketamine, thiopental, chloramphenicol, erythromycin, nitrofurantoin, rifampicin, trimethoprim/sulfamethoxazole, spironolactone, methyldopa, valproic acid, carbamazepine, phenytoin, phenobarbital, primidone, and risperidone ³⁸⁶. For information on prescribing medication in the context of certain conditions (e.g., HIV, epilepsy, malaria), see https://porphyria.uct.ac.za/porphyria-professionals/prescribing-porphyria-treatment-specific-disorders-poprhyria/therapy-epilepsy.

During treatment of an attack, attention should be given to salt and water balance. For example, if individuals develop hyponatremia, which can induce seizures, they should be treated by saline infusion. Harmful drugs should be stopped. These include barbiturates, sulfonamides, and many others (see the full list here: https://porphyriafoundation.org/for-healthcare-professionals/ahp-drug-safety-database/).

Acute porphyria

Doctors most often treat acute porphyria attacks in a hospital. A doctor treats acute porphyrias with heme or glucose loading to decrease the liver’s production of porphyrins and porphyrin precursors. A patient receives heme intravenously once a day for 4 days. Glucose loading involves giving a patient a glucose solution by mouth or intravenously. Heme is usually more effective and is the treatment of choice unless symptoms are mild. In rare instances, if symptoms are severe, a doctor will recommend liver transplantation to treat acute porphyria. In liver transplantation, a surgeon removes a diseased or an injured liver and replaces it with a healthy, whole liver or a segment of a liver from another person, called a donor. A patient has liver transplantation surgery in a hospital under general anesthesia. Liver transplantation can cure liver failure.

Treatment of acute porphyria attacks focuses on providing rapid treatment of symptoms and preventing complications. Treatment may include:

• Pain medication
• Addressing the underlying cause – for example, prescribing antibiotics to treat an infection or ceasing a particular medication
• Medication called ‘hematin’, which is a type of heme the body can use
• Intravenous fluids and glucose
• Admission to hospital in severe cases.

There are plenty of ways to prevent future porphyria attacks.

To prevent future attacks, your doctor may recommend:

• Avoiding any drugs that may trigger an attack in people who have porphyria. Talk with your doctor before you take any over-the-counter or prescription medicines, dietary supplements or complementary or alternative medicines, such as herbal or botanical medicines.
• Avoiding alcohol. Experts recommend no more than one drink per day for women and no more than two drinks per day for men ⁴⁰⁰.
• Protecting your skin from the sun as much as possible
• Eating carbohydrates frequently
• Eating a balanced diet and avoiding fasting or extreme diets.
• Avoiding smoking

Avoiding triggers may include:

• Not using medications known to trigger acute attacks. Ask your doctor for a list of safe and unsafe drugs.
• Not using alcohol or recreational drugs.
• Avoiding fasting and dieting that involves severe calorie restriction.
• Not smoking.
• Taking certain hormones to prevent premenstrual attacks.
• Minimizing sun exposure. When you’re outdoors, wear protective clothing, and use an opaque blocking sunscreen, such as one with zinc oxide. When
• indoors, use window filters.
• Treating infections and other illnesses promptly.
• Taking steps to reduce emotional stress.

Your doctor may also advise you about:

• medication to control pain, or any nausea or vomiting
• other medication to reduce the amount of porphyrin in the blood
• regular blood donation or blood-letting to reduce the amount of porphyrin in the blood.

Cutaneous porphyria

Treatment may include:

• Oral administration of activated charcoal, which helps to absorb excess porphyrins
• Daily supplementation with beta-carotene (vitamin A) as part of long-term treatment.
• A dietary supplement to replace vitamin D deficiency caused by avoidance of sunlight.
• Periodically drawing blood (phlebotomy) to reduce the iron in your body, which decreases porphyrins.
• Taking a drug used to treat malaria — hydroxychloroquine (Plaquenil) or, less often, chloroquine (Aralen) — to absorb excess porphyrins and help your body get rid of them more quickly than usual. These medications are generally used only in people who can’t tolerate a phlebotomy.

The most important step a person can take to treat a cutaneous porphyria is to avoid sunlight as much as possible. Other cutaneous porphyrias are treated as follows:

• Porphyria cutanea tarda. A health care provider treats porphyria cutanea tarda by removing factors that tend to activate the disease and by performing repeated therapeutic phlebotomies to reduce iron in the liver. Therapeutic phlebotomy is the removal of about a pint of blood from a vein in the arm. A technician performs the procedure at a blood donation center, such as a hospital, clinic, or bloodmobile. A patient does not require anesthesia. Another treatment approach is low-dose hydroxychloroquine tablets to reduce porphyrins in the liver.
• Erythropoietic protoporphyria. People with erythropoietic protoporphyria may be given beta-carotene or cysteine to improve sunlight tolerance, though these medications do not lower porphyrin levels. Experts recommend hepatitis A and hepatitis B vaccines and avoiding alcohol to prevent protoporphyric liver failure. A health care provider may use liver transplantation or a combination of medications to treat people who develop liver failure. Unfortunately, liver transplantation does not correct the primary defect, which is the continuous overproduction of protoporphyria by bone marrow. Successful bone marrow transplantations may successfully cure erythropoietic protoporphyria. A health care provider only considers bone marrow transplantation if the disease is severe and leading to secondary liver disease.
• Congenital erythropoietic porphyria and hepatoerythropoietic porphyria. People with congenital erythropoietic porphyria or hepatoerythropoietic porphyria may need surgery to remove the spleen or blood transfusions to treat anemia. A surgeon removes the spleen in a hospital, and a patient receives general anesthesia. With a blood transfusion, a patient receives blood through an intravenous (IV) line inserted into a vein. A technician performs the procedure at a blood donation center, and a patient does not need anesthesia.

Eating, Diet, and Nutrition

People with an acute porphyria should eat a diet with an average-to-high level of carbohydrates. The recommended dietary allowance for carbohydrates is 130 g per day for adults and children 1 year of age or older; pregnant and breastfeeding women need higher intakes ⁴⁰⁰. People should avoid limiting intake of carbohydrates and calories, even for short periods of time, as this type of dieting or fasting can trigger symptoms. People with an acute porphyria who want to lose weight should talk with their doctor and dietitian about diets they can follow to lose weight gradually.

People undergoing therapeutic phlebotomies should drink plenty of milk, water, or juice before and after each procedure.

A health care provider may recommend vitamin and mineral supplements for people with a cutaneous porphyria.

Home remedies

Be guided by your doctor, but general suggestions include:

• In all cases avoid known triggers – for example, don’t smoke.
• When out in the sun, wear sunglasses, a brimmed hat, a long-sleeved top and long pants. Apply SPF 30+ sunscreen to exposed skin areas.
• Protect your skin every day. For example, wear rubber gloves when handling chemicals or very hot water. Avoid perfumed soaps. Regularly apply barrier cream to the hands.
• Eat regular meals and avoid alcohol.
• You may like to consider wearing a medical alert bracelet or pendant, since surgery and some drugs can provoke symptoms.

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