Bilirubin is an orange-yellow pigment, a waste product primarily produced by the normal breakdown of heme (ferroprotoporphyrin IX) ¹, ², ³, ⁴, ⁵. Approximately 85 percent of the heme is from the hemoglobin (Hb; an iron-containing protein in red blood cells that transports oxygen from the lungs to the body’s tissues) following the degradation of red blood cells (RBCs), while the remaining heme derives from the ineffective erythropoiesis and the breakdown of other hemoproteins such as cytochromes, myoglobin, and catalase ⁶. Bilirubin is ultimately processed by the liver to allow its elimination from the body.

There are 2 forms of bilirubin in the body: a toxic form called unconjugated bilirubin and a nontoxic form called conjugated bilirubin. Both forms can be measured or estimated by laboratory tests, and a total bilirubin result (a sum of these) may also be reported. Bilirubin is ultimately processed by the liver to allow its elimination from the body.

Red blood cells normally degrade after about 120 days in the blood circulation. As heme is released from hemoglobin, it is converted to bilirubin. The conversion of heme to bilirubin is a 2-step reaction, in the first step the microsomal heme oxygenase enzyme of the reticuloendothelial system (a network of phagocytic cells, including monocytes and macrophages, that is part of the immune system whose function is to engulf and destroy foreign particles, such as bacteria and toxins, and cellular debris, a process known as phagocytosis), converts heme to biliverdin, which in turn is reduced to unconjugated bilirubin (toxic form of bilirubin) by a second enzyme biliverdin reductase ⁷. The unconjugated bilirubin (toxic form of bilirubin) is lipophilic (dissolves readily in fats). Unconjugated bilirubin (toxic form of bilirubin) tightly bound to albumin is transported to the liver. The entry of unconjugated bilirubin into the liver has not been elucidated, and the best candidate appears to be a bilirubin transporter ². In liver cells, unconjugated bilirubin dissociates from albumin and binds to proteins of the glutathione-S-transferases family that present it for conjugation and prevent it from effluxing from the liver ². Next, unconjugated bilirubin gets conjugated (attached) with one or two molecules of glucuronic acid by the enzyme uridine diphospho-glucuronate glucuronosyltransferase (UGT1A1), which forms bilirubin monoglucuronide and bilirubin diglucuronide respectively ⁷, ⁸. Conjugation increases the solubility of bilirubin in plasma and thereby enhances its elimination from the body. The conjugated bilirubin (nontoxic bilirubin) is then pumped into bile via an energy-requiring process requiring the multidrug resistance-associated protein 2 (MRP2) ⁹. This process also reduces the ability of bilirubin to diffuse across the blood-brain barrier. Therefore, unconjugated hyperbilirubinemia can result from dysfunction of any of these conjugation steps. Conjugated bilirubin enters the bile and passes from the liver to the small intestines; there, it is further broken down by bacteria and eventually eliminated in the stool. Therefore, the breakdown products of bilirubin give stool its characteristic brown color. In newborns, inefficient conjugation of bilirubin leads to unconjugated hyperbilirubinemia (physiologic neonatal jaundice).

A small amount (approximately 250 to 350 milligrams) of bilirubin is produced daily in a normal, healthy adult. Most (85%) of bilirubin is derived from damaged or degraded red blood cells, with the remaining amount derived from the bone marrow or liver. Normally, small amounts of unconjugated bilirubin are released into the blood, but virtually no conjugated bilirubin is present.

Bilirubin concentrations tend to be slightly higher in males than females. African Americans routinely show lower bilirubin concentrations than non-African Americans. Strenuous exercise may increase bilirubin levels.

Drugs that can decrease total bilirubin include barbiturates, caffeine, penicillin, and high doses of salicylates. The drug atazanavir increases unconjugated (indirect) bilirubin.

If the bilirubin level increases in the blood, a person may appear jaundiced, with a yellowing of the skin and/or whites of the eyes. The pattern of bilirubin test results can give your doctor information regarding the condition that may be present. For example, unconjugated bilirubin may be increased when there is an unusual amount of red blood cell destruction (hemolysis) or when the liver is unable to process bilirubin (i.e., with liver diseases such as cirrhosis or inherited problems). Conversely, conjugated bilirubin can increase when the liver is able to process bilirubin but is not able to pass the conjugated bilirubin to the bile for removal; when this happens, the cause is often acute hepatitis or blockage of the bile ducts.

Increased total and unconjugated bilirubin levels are relatively common in newborns in the first few days after birth. This finding is called “physiologic jaundice of the newborn” and occurs because the newborn’s liver is not mature enough to process bilirubin yet. Usually, physiologic jaundice of the newborn resolves itself within a few days. However, in hemolytic disease of the newborn, red blood cells may be destroyed because of blood incompatibilities between the baby and the mother; in these cases, treatment may be required because high levels of unconjugated bilirubin can damage the newborn’s brain.

A rare (about 1 in 10,000 births) but life-threatening congenital condition called biliary atresia can cause increased total and conjugated bilirubin levels in newborns. This condition must be quickly detected and treated, usually with surgery, to prevent serious liver damage that may require liver transplantation within the first few years of life. Some children may require liver transplantation despite early surgical treatment.

Rare inherited disorders that cause abnormal bilirubin metabolism such as Rotor, Dubin-Johnson, and Crigler-Najjar syndromes, may also cause increased levels of bilirubin.

Rotor syndrome is a rare, inherited genetic disorder characterized by elevated levels of bilirubin in the blood (hyperbilirubinemia). People with Rotor syndrome have a buildup of both unconjugated and conjugated bilirubin in their blood, but the majority is conjugated bilirubin ¹⁰, ¹¹. Rotor syndrome is caused by SLCO1B1 and SLCO1B3 genes. Mutations in both SLCO1B1 and SLCO1B3 genes are required for Rotor syndrome to occur. The SLCO1B1 and SLCO1B3 genes provide instructions for making similar proteins, called organic anion transporting polypeptide 1B1 (OATP1B1) and organic anion transporting polypeptide 1B3 (OATP1B3), respectively. Both proteins are found in liver cells; they transport bilirubin and other compounds from the blood into the liver so that they can be cleared from the body. In the liver, bilirubin is dissolved in a digestive fluid called bile and then excreted from the body. In people with Rotor syndrome, jaundice is usually evident shortly after birth or in childhood and may come and go; yellowing of the whites of the eyes also called conjunctival icterus is often the only symptom. Rotor syndrome is a benign and harmless condition that typically does not require treatment and does not affect life expectancy. Jaundice may be noticeable shortly after birth or in childhood, but often it’s an incidental finding.
Crigler–Najjar syndrome is a very rare inherited disorder in which bilirubin cannot be broken down. Mutations in the UGT1A1 gene cause Crigler-Najjar syndrome. The UGT1A1 gene provides instructions for making the bilirubin uridine diphosphate glucuronosyl transferase (bilirubin-UGT) enzyme, which is found primarily in liver cells and is necessary for the removal of bilirubin from the body. Mutations in the UGT1A1 gene that cause Crigler-Najjar syndrome result in reduced or absent function of the bilirubin-UGT enzyme. People with Crigler–Najjar Type 1 have no bilirubin uridine diphosphate glucuronosyl transferase (bilirubin-UGT) enzyme function, while people with Crigler–Najjar Type 2 have less than 20 percent of normal function. The loss of bilirubin-UGT function decreases glucuronidation of unconjugated bilirubin. Glucuronidation makes bilirubin dissolvable in water so that it can be removed from the body. This toxic unconjugated bilirubin then builds up in the body, causing unconjugated hyperbilirubinemia and jaundice. Crigler–Najjar Type 1 (CN1) is very severe, and affected individuals can die in childhood due to kernicterus, although with proper treatment, they may survive longer. Crigler–Najjar Type 2 (CN2) is less severe. People with Crigler–Najjar Type 2 are less likely to develop kernicterus, and most affected individuals survive into adulthood.
Dubin-Johnson syndrome is a rare, inherited liver disorder characterized by an increase in conjugated bilirubin, leading to mild, chronic jaundice. Dubin-Johnson syndrome is caused by mutation in ABCC2 gene affecting the liver’s ability to excrete bilirubin, resulting in pigment deposits that make the liver appear black on medical imaging. The ABCC2 gene provides instructions for making a protein that transports certain substances out of cells so they can be released (excreted) from the body. For example, this protein transports bilirubin out of liver cells and into bile (a digestive fluid produced by the liver). Bilirubin is produced during the breakdown of old red blood cells and has an orange-yellow tint. As a result, bilirubin accumulates in the body, causing a condition called hyperbilirubinemia. The buildup of bilirubin in the body causes the yellowing of the skin and whites of the eyes in people with Dubin-Johnson syndrome. Dubin-Johnson syndrome is most often seen in Middle Eastern Jewish and Japanese people. In the Jewish population, about 60% of affected individuals also have an associated blood clotting abnormality, a prolonged prothrombin time (PT), caused by a decrease in factor VII (factor 7). In most affected people jaundice appears during adolescence or early adulthood. Infants with Dubin-Johnson syndrome typically also have enlarged livers (hepatomegaly) and a severely reduced ability to produce and release a digestive fluid called bile (cholestasis). As these children get older, their liver problems go away and they usually do not have any related health problems later in life. Jaundice is typically the only feature of Dubin-Johnson syndrome, but some people can experience weakness, mild abdominal pain, nausea, or vomiting. In most people with Dubin-Johnson syndrome, certain deposits build up in the liver but do not seem to impair liver function. The deposits make the liver appear black when viewed with medical imaging. Dubin-Johnson syndrome is benign, has a normal life expectancy, and usually requires no specific treatment, though precautions like avoiding birth control pills, alcohol, environmental factors that affect the liver, infection, pregnancy, fasting or dehydration and fatigue are recommended.

Figure 1. Bilirubin metabolism

Unconjugated bilirubin

Unconjugated bilirubin is a fat-soluble form of bilirubin that is formed during the initial chemical breakdown of hemoglobin and while being transported in the blood, is mostly bound to albumin.

Though unconjugated bilirubin may be toxic to brain development in newborns (up to 2-4 weeks of age), it does not pose the same threat to older children and adults. In older children and adults, the “blood-brain barrier” is more developed and prevents bilirubin from gaining access to brain cells. Nevertheless, elevated bilirubin strongly suggests that a medical condition is present that must be evaluated and treated.

Table 1. Causes of Unconjugated Hyperbilirubinemia

[Source ¹² ]

Unconjugated hyperbilirubinemia

Increased bilirubin production

Unconjugated hyperbilirubinemia is usually a result of too much bilirubin presented to the conjugating machinery (from increased red blood cell destruction). Increased red blood cell breakdown may be caused by red blood cell membrane disorders, red blood cell enzyme disorders, hemoglobin disorders (Thalassemias), autoimmune red blood cell destruction (autoimmune hemolytic anemia), or some cancers ¹³, ¹⁴, ¹⁵, ¹⁶. The excess turnover of red blood cells results in increased heme metabolism, producing large amounts of bilirubin that overwhelm the conjugating machinery, leading to decreased excretion and clinical jaundice.

Impaired bilirubin conjugation

Deficiencies in the same conjugating machinery may also lead to jaundice in individuals with normal red blood cell turnover. Gilbert syndrome involves a deficiency in uridine diphosphate-glucuronosyltransferase, and it affects 10% of the white population ¹⁷. This is a benign condition that may be exacerbated by physical or emotional stress such as illness, strenuous exercise, or fasting. Crigler-Najjar syndrome is a more severe variant of the same uridine diphosphate-glucuronosyltransferase enzyme deficiency ¹⁷. Patients with impaired conjugation due to low levels of the bilirubin-UGT enzyme are particularly susceptible to jaundice from medications that inhibit this enzyme, such as protease inhibitors ¹⁸. Table 1 lists the causes of unconjugated hyperbilirubinemia.

Conjugated bilirubin

Conjugated bilirubin is a water-soluble form of bilirubin formed in the liver by the chemical addition of sugar molecules to unconjugated bilirubin; when present in the blood, conjugated bilirubin can become chemically bound to albumin, forming delta-bilirubin also known as biliprotein.

Table 2. Causes of Conjugated Hyperbilirubinemia

[Source ¹² ]

Conjugated hyperbilirubinemia

Intrahepatic disorders and intrahepatic cholestasis

The largest worldwide contributor to liver disease is viral hepatitis, mostly from hepatitis C ¹⁹. Viral hepatitis causes increased oxidative stress within liver cells (hepatocytes), leading to cell death, scarring, and diminished liver mass available for normal function ²⁰, ²¹. Chronic alcohol consumption can cause various hepatic disorders, including fatty liver disease (steatosis) with minimal symptoms and often no jaundice; alcoholic hepatitis with acute onset jaundice and more severe symptoms; and cirrhosis, which is often associated with decompensation and liver failure in the setting of jaundice ²². Jaundice in persons with alcoholic liver disease can occur via multiple mechanisms, such as direct hepatocellular damage caused by ethanol metabolites or from alcohol’s effect on bile acid uptake and secretion contributing to cholestasis (reduced or stopped bile flow) ²², ²³.

Approximately 30% to 40% of patients with nonalcoholic fatty liver disease (NAFLD) progress to nonalcoholic steatohepatitis (NASH), and approximately 40% to 50% of these patients develop fibrosis or cirrhosis that may lead to hyperbilirubinemia ²⁴. Although the exact mechanism is poorly understood, liver lipid deposition may trigger inflammation and fibrosis, particularly when coupled with type 2 diabetes ²⁴. Sepsis may also induce hyperbilirubinemia as circulating acute phase reactants and bacterial endotoxins disrupt bilirubin transport, leading to cholestasis and elevated bile salt levels ²⁵, ²⁶.

Drug-induced liver injury has multiple potential mechanisms, including direct hepatocellular toxicity and activation of an immune response that advances the inflammatory cascade, inhibiting bilirubin transport into canaliculi, which causes cholestasis ²⁷. Wilson disease, a rare genetic disorder, is associated with a loss of function of a cellular transporter responsible for moving dietary copper into liver canaliculi. Elevated liver copper levels affect hepatic lipid metabolism, which leads to steatosis and cholestasis ²⁸. Additional causes of intrahepatic hyperbilirubinemia include autoimmune disorders, such as autoimmune hepatitis and the rare autoimmune condition primary biliary cirrhosis, which occurs most commonly in middle-aged women. Both conditions are associated with inflammation, which disrupts the transport of bilirubin within the liver ²².

Extrahepatic disorders

Conjugated hyperbilirubinemia may also arise from extrahepatic obstruction. Patients with biliary obstruction may present with multiple signs and symptoms, including fever, itch (pruritus), abdominal pain, weight loss, muscle wasting, dark urine, and pale stools. Choledocholithiasis or the presence of gallstones within the common bile duct, is the most common non-neoplastic cause of biliary obstruction, accounting for 14% of all new cases of jaundice ²⁹. An estimated 20 million Americans have gallstones, and risk factors for gallstones within the common bile duct (choledocholithiasis) include female sex, older age, increasing body mass index, and rapid weight loss ³⁰.

Gallstones may cause jaundice by obstructing the biliary tree (typically the common bile duct) or by inducing a biliary stricture ³¹. Less commonly, stones in the gallbladder or cystic duct may mechanically compress the common hepatic duct causing jaundice, and, rarely, stones may cause the formation of a biliary-vascular fistula with accompanying jaundice ³². Biliary stricture causing postoperative jaundice is a rare complication of cholecystectomy (0.6% of cases) ³¹, ³³.

Jaundice may be caused by surgeries such as liver transplantation and the Whipple and Billroth procedures, which both involve the creation of a choledochojejunostomy. Chronic pancreatitis may cause biliary strictures and jaundice, as may different forms of cholangitis ³³, ³⁴. In children, biliary atresia and choledochal cysts are the main causes of extrahepatic biliary obstruction ³⁵.

Tumors are associated with 6.2% of new-onset cases of jaundice ²⁹. Cholangiocarcinoma may affect the proximal or distal portions of the biliary tree by causing biliary strictures. Five-year survival for persons who have resection is 20% to 40%; survival in unresectable disease is less than one year ³⁶, ³⁷. Primary sclerosing cholangitis confers a 1,500-fold increased risk of cholangiocarcinoma, but more than 80% of cases have no risk factors for cholangiocarcinoma ³⁶.

Gallbladder cancer, although rare, is the most common biliary tract malignancy; risk factors include gallstones, infection (Salmonella typhi), and female sex. Median survival is six to 12 months, depending on the stage at diagnosis ³⁸. Ampullary cancers and bile duct compression from lymphadenopathy, or external tumors such as pancreatic cancer, may also cause bile duct obstruction.

Normal bilirubin levels

Direct (conjugated) Bilirubin

> or =12 months: 0.0-0.3 mg/dL (less than 5.1 µmol/L)

Reference values have not been established for patients who are <12 months of age.

Total Bilirubin

0-6 days: Refer to www.bilitool.org for information on age-specific (postnatal hour of life) serum bilirubin values.
7-14 days: <15.0 mg/dL
15 days to 17 years: < or =1.0 mg/dL
> or =18 years: 0.1 to 1.2 mg/dL (1.71 to 20.5 µmol/L)

Normal value ranges may vary slightly among different laboratories. Some labs use different measurements or may test different samples. Talk to your provider about the meaning of your specific test results.

Bilirubin in urine

Bilirubin is not normally present in the urine. However, conjugated bilirubin is water-soluble and may be eliminated from the body through the urine if it cannot pass into the bile. Measurable bilirubin in the urine usually indicates blockage of liver or bile ducts, hepatitis, or some other form of liver damage and may be detectable early in disease; for this reason, bilirubin testing is integrated into common dipstick testing used for routine urinalysis.

Are some people more at genetic risk of abnormal bilirubin levels?

Several inherited chronic conditions increase bilirubin levels in the blood and include Gilbert syndrome, Dubin-Johnson syndrome, Rotor syndrome, and Crigler-Najjar syndrome. The first three are usually mild, chronic conditions that can be aggravated under certain conditions but in general cause no significant health problems. For example, Gilbert syndrome is very common; about 1 in every 6 people has this genetic abnormality, but usually people with Gilbert syndrome do not have elevated bilirubin. Crigler-Najjar syndrome is the most serious inherited condition listed; this disorder is relatively rare, and some people with it may die.

How do you treat abnormal bilirubin levels and/or jaundice?

Treatment depends on the cause of the jaundice. In newborns, phototherapy (special light therapy), blood exchange transfusion, and/or certain drugs may be used to reduce the bilirubin level. In Gilbert, Rotor, and Dubin-Johnson syndromes, no treatment is usually necessary. Crigler-Najjar syndrome may respond to certain enzyme drug therapy or may require a liver transplant. Jaundice caused by an obstruction is often resolved by surgery. Jaundice due to cirrhosis is a result of long-term liver damage and does not respond well to any type of therapy other than liver transplantation.

Bilirubin test

Bilirubin test measures the amount of bilirubin in your blood to evaluate your liver function or to help diagnose anemias caused by red blood cell destruction (hemolytic anemia).

A bilirubin test is used to detect an elevated bilirubin level in the blood. Bilirubin test may be used to help determine the cause of jaundice and/or help diagnose conditions such as liver disease, hemolytic anemia, and blockage of the bile ducts.

Bilirubin is an orange-yellow pigment, a waste product primarily produced by the normal breakdown of heme. Heme is a component of hemoglobin, which is found in red blood cells. Bilirubin is ultimately processed by the liver to allow its elimination from the body. Any condition that accelerates the breakdown of red blood cells or affects the processing and elimination of bilirubin may cause an elevated blood level.

Two forms of bilirubin can be measured or estimated by laboratory tests:

Unconjugated bilirubin—when heme is released from hemoglobin, it is converted to unconjugated bilirubin. It is carried by proteins to the liver. Small amounts may be present in the blood.
Conjugated bilirubin—formed in the liver when sugars are attached (conjugated) to bilirubin. It enters the bile and passes from the liver to the small intestines and is eventually eliminated in the stool. Normally, no conjugated bilirubin is present in the blood.

Usually, a chemical test is used to first measure the total bilirubin level (unconjugated plus conjugated bilirubin). If the total bilirubin level is increased, the laboratory can use a second chemical test to detect water-soluble forms of bilirubin, called “direct” bilirubin. The direct bilirubin test provides an estimate of the amount of conjugated bilirubin present. Subtracting direct bilirubin level from the total bilirubin level helps estimate the “indirect” level of unconjugated bilirubin. The pattern of bilirubin test results can give your healthcare provider information regarding the condition that may be present.

In adults and older children, bilirubin is measured to:

Diagnose and/or monitor diseases of the liver and bile duct (e.g., cirrhosis, hepatitis, or gallstones)
Evaluate people with sickle cell disease or other causes of hemolytic anemia; these people may have episodes called crises when excessive red blood cell destruction increases bilirubin levels.

In newborns with jaundice, bilirubin is used to distinguish the causes of jaundice.

In both physiologic jaundice of the newborn and hemolytic disease of the newborn, only unconjugated (indirect) bilirubin is increased.
In much less common cases, damage to the newborn’s liver from neonatal hepatitis and biliary atresia will increase conjugated (direct) bilirubin concentrations as well, often providing the first evidence that one of these less common conditions is present.

It is important that an elevated level of bilirubin in a newborn be identified and quickly treated because excessive unconjugated bilirubin damages developing brain cells. The consequences of this damage include mental retardation, learning and developmental disabilities, hearing loss, eye movement problems, and death.

When is bilirubin test ordered?

A healthcare practitioner usually orders a bilirubin test in conjunction with other liver function tests (alkaline phosphatase [ALP], aspartate aminotransferase [AST], alanine aminotransferase [ALT]) when someone shows signs of abnormal liver function.

A bilirubin level may be ordered when a person:

Shows evidence of jaundice
Has a history of drinking excessive amounts of alcohol
Has suspected drug toxicity
Has been exposed to hepatitis-causing viruses

Other symptoms that may be present include:

Dark, amber-colored urine
Nausea/vomiting
Abdominal pain and/or swelling
Fatigue and general malaise that often accompany chronic liver disease

Measuring and monitoring bilirubin in newborns with jaundice is considered standard medical care.

Tests for bilirubin may also be ordered when someone is suspected of having (or known to have) hemolytic anemia as a cause of anemia. In this case, it is often ordered along with other tests used to evaluate hemolysis, such as complete blood count, reticulocyte count, haptoglobin, and lactate dehydrogenase (LDH).

What does high bilirubin levels mean?

Unconjugated hyperbilirubinemia arises in one of the 3 major pathophysiologic conditions or a combination of them ³⁹, ¹², ⁴⁰ ⁴¹:

Increased bilirubin production. Increased bilirubin production and consequential unconjugated hyperbilirubinemia can result from increased catabolic degradation of hemoglobin and other heme proteins, typically due to accelerated hemolysis, a large hematoma, dyserythropoiesis (e.g., megaloblastic and sideroblastic anemias), or sometimes due to destruction of transfused erythrocytes. In these conditions, patients with normal liver function efficiently conjugate and excrete the excess bilirubin. As a result, the serum levels of unconjugated bilirubin remain modest (1 to 4 mg/dL) and rarely exceed 4 mg/dL. Prolonged hemolysis can lead to severe unconjugated hyperbilirubinemia in patients with concurrent hepatic dysfunction.
Impaired bilirubin uptake. The impaired hepatic uptake of bilirubin can be the result of decreased bilirubin delivery to the liver and inefficient uptake of bilirubin by hepatocytes, usually resulting from reduced hepatic blood flow (congestive heart failure and portosystemic shunts) and drugs/contrast administration. The unconjugated hyperbilirubinemia induced by several drugs (rifampin, flavaspidic acid, novobiocin, and various cholecystographic contrast agents), generally resolves within 48 hours of drug discontinuation ⁴².
Impaired bilirubin conjugation. Impaired bilirubin conjugation can result from hereditary defects, including Gilbert syndrome and the Crigler-Najjar syndrome type 1 and 2, that cause a decrease or loss of UDP-glucuronosyltransferase (UGT1A1) activity, an enzyme responsible for conjugation of bilirubin with glucuronic acid ⁴³. Lucy-Driscoll syndrome, also known as maternal serum jaundice, a form of transient familial neonatal unconjugated hyperbilirubinemia, is a rare metabolic disorder caused by a UGT1A1 inhibitor usually present in the maternal serum ⁴⁴. Most newborns develop unconjugated hyperbilirubinemia (neonatal jaundice) because of hepatic immaturity and low activity of UGT1A1 during days 2 to 5. Breast milk feeding increases bilirubin levels in infants which results in maternal milk jaundice ⁴⁵, ⁴⁶. Lactation failure also results in hyperbilirubinemia due to insufficient caloric intake, which results in decreased bilirubin clearance, and increased enterohepatic circulation ⁴⁷. Drugs such as novobiocin, pregnanediol, chloramphenicol, gentamycin, and several HIV protease inhibitors can induce hyperbilirubinemia by inhibiting the UGT1A1 enzyme ⁴⁸. In newborns, ABO incompatibility or Rh incompatibility may lead to hyperbilirubinemia and consequently, neonatal jaundice ⁴¹.

Adults and children

Increased total bilirubin that is mainly unconjugated (indirect) bilirubin may be a result of:

Hemolytic anemia or pernicious anemia
Megaloblastic anemia
A blood disorder called erythroblastosis fetalis
Transfusion reaction in which red blood cells that were given in a transfusion are destroyed by the person’s immune system
Cirrhosis (scarring of the liver)
A relatively common inherited condition called Gilbert syndrome, due to low levels of the enzyme that produces conjugated bilirubin

If conjugated (direct) bilirubin is elevated more than unconjugated (indirect) bilirubin, there typically is a problem associated with decreased elimination of bilirubin by the liver cells. Some conditions that may cause this include:

Conjugated (direct) bilirubin is also elevated more than unconjugated (indirect) bilirubin when there is blockage of the bile ducts. This may occur, for example, with:

Gallstones present in the bile ducts
Tumors
Scarring of the bile ducts or abnormal narrowing of the common bile duct (biliary stricture)
Cancer of the pancreas or gallbladder cancer

In hepatobiliary diseases of various causes, bilirubin uptake, storage, and excretion are impaired to varying degrees. Thus, both conjugated and unconjugated bilirubin are retained and a wide range of abnormal serum concentrations of each form of bilirubin may be observed. Both conjugated and unconjugated bilirubins are increased in hepatitis and space-occupying lesions of the liver; and obstructive lesions such as carcinoma of the head of the pancreas, common bile duct, or ampulla of Vater.

Newborns

An elevated bilirubin level in a newborn may be temporary and resolve itself within a few days to two weeks. However, if the bilirubin level is above a critical threshold or increases rapidly, an investigation of the cause is needed so appropriate treatment can be initiated. Increased bilirubin concentrations may result from the accelerated breakdown of red blood cells due to:

Blood type incompatibility between the mother and her newborn
Certain congenital infections
Lack of oxygen (hypoxia)
Diseases that can affect the liver

In most of these conditions, only unconjugated (indirect) bilirubin is increased. An elevated conjugated (direct) bilirubin is seen in the rare conditions of biliary atresia and neonatal hepatitis. Biliary atresia requires surgical intervention to prevent liver damage.

Physiologic jaundice should resolve in 5 to 10 days in full-term infants and by 14 days in preterm infants.

Neonatal jaundice

Neonatal jaundice or infant jaundice is the yellow coloring of a newborn baby’s skin and eyes. Neonatal jaundice is caused by a buildup of pigment called bilirubin in the baby’s blood. Infant jaundice is a common condition, especially in babies born before 37 weeks’ gestation (preterm babies) and some breastfed babies. It usually happens because a baby’s liver isn’t mature enough to get rid of bilirubin in the bloodstream. In some babies, an underlying disease may cause infant jaundice. Most infants born between 35 weeks’ gestation and full term need no treatment for jaundice. Rarely, an unusually high blood level of bilirubin can place a newborn at risk of brain damage, particularly in the presence of certain risk factors for serious jaundice.

Hyperbilirubinemia in newborn also called neonatal hyperbilirubinemia, is a medical condition in which there is a build up of bilirubin in the blood, defined as a total serum bilirubin level above 5 mg per dL (86 μmol per L), causing yellow discoloration of the eyes and skin, called jaundice. Jaundice typically results from the deposition of unconjugated bilirubin pigment in the skin and mucus membranes. Depending on the underlying cause, this condition may present throughout the neonatal period. Approximately 60% of term babies and 80% of preterm newborns develop jaundice in the first week of life, and about 10% of breastfed babies are still jaundiced at 1 month of age ⁴⁹, ⁵⁰, ⁵¹, ⁵², ⁵³. In most babies with jaundice there is no underlying disease, and this early jaundice termed ‘physiological jaundice’ is generally harmless and does not cause any trouble and will resolve on its own in the first week of life ⁵⁴. However, there are pathological causes of hyperbilirubinemia in the newborn period, which, although rare, need to be detected. Such pathological jaundice may co-exist with physiological jaundice. Hyperbilirubinemia in the newborn period can be associated with severe illnesses such as premature infants (babies born before 37 weeks’ gestation), certain blood disorders, metabolic and endocrine disorders, anatomic abnormalities of the liver, and infections ⁵⁵. Although low levels of bilirubin are not usually a concern, large amounts of bilirubin can circulate to tissues in the brain and may cause seizures and brain damage. This condition is called kernicterus or bilirubin encephalopathy, which refers to the ‘yellow staining of the basal nuclei of the brain’ caused by bilirubin ⁵⁶. This is seen in parts of the brain on autopsy. Poor-quality studies have shown a link between kernicterus (acute and chronic brain effects of severe hyperbilirubinemia) and both high serum bilirubin levels and free bilirubin levels in all babies.

Physiological jaundice is mild, unconjugated bilirubinemia, and affects nearly all newborns. Physiological jaundice levels typically peak at 5 to 6 mg/dL (86 to 103 micromol/L) at 72 to 96 hours of age, and do not exceed 17 to 18 mg/dL (291 to 308 micromol/L) ⁵⁷. The level of bilirubinemia that results in kernicterus in a given infant is unknown. The level of bilirubinemia that causes kernicterus varies by infant, but risk increases significantly when unconjugated bilirubin levels exceed 25 to 30 mg/dL (428 to 513 micromol/L) in term or near-term infants ⁵⁸, ⁵⁹, ⁵⁶, ⁶⁰. Factors like prematurity, hypoxia, acidosis, and certain infections can lower this threshold, making some infants more vulnerable at lower bilirubin levels

Depending on the cause of the hyperbilirubinemia, jaundice may appear at birth or at any time afterward. Factors significantly associated with hyperbilirubinemia are gestational age < 38 weeks, visible jaundice within 24 hours of birth, mother’s intention to breastfeed exclusively and family history of neonatal jaundice requiring treatment with phototherapy.

Bilirubin is a natural byproduct produced when red blood cells breakdown. The adult liver converts unconjugated bilirubin into a conjugated form, that be excreted. During pregnancy, the placenta excretes bilirubin but when the baby is born, the baby’s immature liver must assume that role. There are several causes of hyperbilirubinemia and jaundice in newborn, including the following:

Physiologic jaundice. Physiologic jaundice occurs as a “normal” response to the baby’s limited ability to excrete bilirubin in the first days of life due to the immaturity of the liver. This will usually resolve by the first week of life.
Breastfeeding failure jaundice. During the first few days of breastfeeding when the maternal breast milk supply is low and the baby is having trouble latching and feeding, the baby may become dehydrated. Since bilirubin is eliminated in the urine and stool, decreased urination and infrequent stools result in a buildup of bilirubin. While common in full term infants, premature infants and late preterm infants are more susceptible to breastfeeding failure jaundice because they may have uncoordinated suck as well as easy fatigability. Once effective breastfeeding is established, this problem will resolve.
Breast milk jaundice. About 2 percent of breastfed babies develop jaundice after the first week. It peaks about two weeks of age and can persist up to three to twelve weeks. Breast milk jaundice is thought to be caused by glucuronidase enzyme in the breast milk that deconjugates bilirubin into unconjugated bilirubin ⁶¹. Breastfeeding can usually continue or only be interrupted briefly.
Jaundice from breakdown of red blood cells (hemolysis). Jaundice may occur if there is an increase of red blood cell breakdown (hemolysis) such as that seen when there is a mismatch of maternal and fetal blood type, resulting in ABO incompatibility (a condition where a mother’s antibodies attack a baby’s red blood cells due to a difference in blood type, with most common type when a mother is blood type O and her baby is blood type A or B), hemolytic disease of the newborn (Rh disease) or abnormalities of the red cell itself such as hereditary spherocytosis, elliptocytosis, glucose-6-phosphate dehydrogenase deficiency (G6PD deficiency), pyruvate kinase deficiency; and hemoglobinopathies, such as alpha and beta thalassemias ⁶². Increased hemolysis (red blood cell breakdown) can also occur if the baby is bruised or develops a hematoma during delivery.
Birth Trauma such as cephalohematoma (a collection of blood under the scalp that forms on a newborn’s skull, usually caused by ruptured blood vessels during childbirth), subgaleal hemorrhage (a serious, potentially life-threatening condition in newborns caused by bleeding into the space between the skull’s periosteum and the galea aponeurosis [the scalp’s tough, fibrous tissue layer]), or peripheral bruises from birth trauma ⁶³.
Jaundice related to inadequate liver function. Jaundice may be related to prolonged liver dysfunction due to infection and other factors.
- Disruption or Obstruction in the Biliary System.
- Hereditary Bilirubin Conjugation Defects – Crigler-Najjar syndrome and Gilbert syndrome are due to the deficiency of the enzyme uridine 5′-diphospho-glucuronosyltransferase (UDGPT), which conjugates the bilirubin in the liver cells ⁶⁴.
  - Rotor syndrome is a rare, inherited genetic disorder characterized by elevated levels of bilirubin in the blood (hyperbilirubinemia). People with Rotor syndrome have a buildup of both unconjugated and conjugated bilirubin in their blood, but the majority is conjugated bilirubin ¹⁰, ¹¹. Rotor syndrome is caused by SLCO1B1 and SLCO1B3 genes. Mutations in both SLCO1B1 and SLCO1B3 genes are required for Rotor syndrome to occur. The SLCO1B1 and SLCO1B3 genes provide instructions for making similar proteins, called organic anion transporting polypeptide 1B1 (OATP1B1) and organic anion transporting polypeptide 1B3 (OATP1B3), respectively. Both proteins are found in liver cells; they transport bilirubin and other compounds from the blood into the liver so that they can be cleared from the body. In the liver, bilirubin is dissolved in a digestive fluid called bile and then excreted from the body. In people with Rotor syndrome, jaundice is usually evident shortly after birth or in childhood and may come and go; yellowing of the whites of the eyes also called conjunctival icterus is often the only symptom. Rotor syndrome is a benign and harmless condition that typically does not require treatment and does not affect life expectancy. Jaundice may be noticeable shortly after birth or in childhood, but often it’s an incidental finding.
  - Crigler–Najjar syndrome is a very rare inherited disorder in which bilirubin cannot be broken down. Mutations in the UGT1A1 gene cause Crigler-Najjar syndrome. The UGT1A1 gene provides instructions for making the bilirubin uridine diphosphate glucuronosyl transferase (bilirubin-UGT) enzyme, which is found primarily in liver cells and is necessary for the removal of bilirubin from the body. Mutations in the UGT1A1 gene that cause Crigler-Najjar syndrome result in reduced or absent function of the bilirubin-UGT enzyme. People with Crigler–Najjar Type 1 have no bilirubin uridine diphosphate glucuronosyl transferase (bilirubin-UGT) enzyme function, while people with Crigler–Najjar Type 2 have less than 20 percent of normal function. The loss of bilirubin-UGT function decreases glucuronidation of unconjugated bilirubin. Glucuronidation makes bilirubin dissolvable in water so that it can be removed from the body. This toxic unconjugated bilirubin then builds up in the body, causing unconjugated hyperbilirubinemia and jaundice. Crigler–Najjar Type 1 (CN1) is very severe, and affected individuals can die in childhood due to kernicterus, although with proper treatment, they may survive longer. Crigler–Najjar Type 2 (CN2) is less severe. People with Crigler–Najjar Type 2 are less likely to develop kernicterus, and most affected individuals survive into adulthood.
  - Dubin-Johnson syndrome is a rare, inherited liver disorder characterized by an increase in conjugated bilirubin, leading to mild, chronic jaundice. Dubin-Johnson syndrome is caused by mutation in ABCC2 gene affecting the liver’s ability to excrete bilirubin, resulting in pigment deposits that make the liver appear black on medical imaging. The ABCC2 gene provides instructions for making a protein that transports certain substances out of cells so they can be released (excreted) from the body. For example, this protein transports bilirubin out of liver cells and into bile (a digestive fluid produced by the liver). Bilirubin is produced during the breakdown of old red blood cells and has an orange-yellow tint. As a result, bilirubin accumulates in the body, causing a condition called hyperbilirubinemia. The buildup of bilirubin in the body causes the yellowing of the skin and whites of the eyes in people with Dubin-Johnson syndrome. Dubin-Johnson syndrome is most often seen in Middle Eastern Jewish and Japanese people. In the Jewish population, about 60% of affected individuals also have an associated blood clotting abnormality, a prolonged prothrombin time (PT), caused by a decrease in factor VII (factor 7). In most affected people jaundice appears during adolescence or early adulthood. Infants with Dubin-Johnson syndrome typically also have enlarged livers (hepatomegaly) and a severely reduced ability to produce and release a digestive fluid called bile (cholestasis). As these children get older, their liver problems go away and they usually do not have any related health problems later in life. Jaundice is typically the only feature of Dubin-Johnson syndrome, but some people can experience weakness, mild abdominal pain, nausea, or vomiting. In most people with Dubin-Johnson syndrome, certain deposits build up in the liver but do not seem to impair liver function. The deposits make the liver appear black when viewed with medical imaging. Dubin-Johnson syndrome is benign, has a normal life expectancy, and usually requires no specific treatment, though precautions like avoiding birth control pills, alcohol, environmental factors that affect the liver, infection, pregnancy, fasting or dehydration and fatigue are recommended.
Neonatal polycythemia also called polycythemia in newborns is a condition where there are too many red blood cells, defined by a venous hematocrit greater than 65% ⁶⁵, ⁶⁶, ⁶⁷. Polycythemia means there are too many red blood cells (RBCs) in an infant’s blood. Polycythemia in newborn can lead to increased blood viscosity and decreased blood flow, causing symptoms like lethargy, poor feeding, and respiratory distress. Causes of polycythemia in newborn include delayed cord clamping, twin-to-twin transfusion, and intrauterine hypoxia. Treatment may involve fluid administration for mild cases or a partial exchange transfusion for more severe cases.
Hypoalbuminemia is a condition where the level of albumin, a protein in the blood, is abnormally low. Unconjugated bilirubin is lipid-soluble and is normally bound to albumin; a decrease in the albumin level leads to an increase in free unconjugated bilirubin level ⁶⁸

Prematurity, hemolytic disease of the newborn and glucose-6-phosphate dehydrogenase (G6PD) deficiency are the most common risk factors ⁶⁰, ⁶⁹. Newborns who develop neurological complications of hyperbilirubinemia usually have at least two neurotoxicity risk factors ⁷⁰. There is no clear correlation between bilirubin level alone and the risk of developing brain toxicity ⁷¹, ⁶².

The timing of when your child’s jaundice first starts matters. It may help their your baby’s doctor make a diagnosis.

First 24 hours. This type of jaundice is often serious. Your child will likely need treatment right away.
Second or third day. This is often physiologic jaundice. Sometimes it can be a more serious type of jaundice. It’s important to be sure the baby is getting enough milk at this point.
Toward the end of the first week. This type of jaundice may be from breastmilk jaundice but may be due to an infection or other rare, serious problems.
In the second week. This is often caused by breastmilk jaundice but may be caused by rare liver problems.

In the United States Kernicterus Registry, 56% had abnormalities known to increase the bilirubin concentration in the blood. Glucose-6-phosphate dehydrogenase deficiency (G6PD deficiency) was diagnosed in 21.3%, severe hemolytic processes were recognized in 20.5%, birth trauma was identified in 15%, and other causes such as galactosemia, Crigler-Najjar syndrome, and sepsis were diagnosed in 7% ⁵⁶. However, no cause was identified in 43.4% of the infants ⁷².

Severe jaundice requiring exchange transfusion (bilirubin > 340 micromol/liter) and early onset of jaundice (within 24 hours) are statistically significant risk factors for hearing loss ⁴⁹, ⁷³. Hemolytic disorders such as G6PD deficiency and ABO incompatibility (ABO incompatible blood) may cause a rapid increase in bilirubin level, and these disorders have been over-represented in international kernicterus registries and population studies of significant hyperbilirubinemia. A study of low-birthweight babies found a weak association between high serum bilirubin levels (> 340 micromol/L) and neurodevelopmental impairment, hearing impairment and psychomotor impairment.

Rarely, bilirubin crosses the blood-brain barrier (BBB) and can cause serious consequences ⁷⁴. One study performed in Canada found that acute bilirubin encephalopathy occurs in approximately 1 out of 10,000 infants ⁷⁵. Symptoms include lethargy, hypotonia or hypertonia, back and neck arching, irritability, and high-pitched crying ⁷⁵, ⁷⁶. Acute bilirubin encephalopathy fully resolves in most cases but can progress to kernicterus ⁶², ⁷⁷.

Kernicterus describes the irreversible, chronic effects of bilirubin toxicity ⁵⁴. Kernicterus occurs in approximately 1 out of 100,000 infants in high-income countries and presents as cerebral palsy, hearing loss, gaze paralysis, dental dysplasia, and developmental disability ⁷⁸, ⁶⁰, ⁶⁹.

Complications of kernicterus include ⁷⁹, ⁸⁰, ⁸¹:

Hearing loss – most common abnormality
Extrapyramidal symptoms like athetosis and chorea
Visual abnormalities including gaze palsies
Abnormalities in dentition

Because of the serious and irreversible complications of kernicterus, it is important to be aware of risk factors for neurotoxicity and routinely examine newborns for jaundice.

Bilirubin encephalopathy

Bilirubin encephalopathy is a rare neurological condition that occurs in some newborns with severe jaundice. Bilirubin encephalopathy is a serious condition. Many infants with late-stage nervous system complications die.

Bilirubin encephalopathy most often develops in the first week of life, but may be seen up until the third week. Some newborns with Rh hemolytic disease are at high risk for severe jaundice that can lead to this condition. Rarely, bilirubin encephalopathy can develop in seemingly healthy babies.

Acute bilirubin encephalopathy

Bilirubin is toxic to cells of the brain. If a baby has severe jaundice, there’s a risk of bilirubin passing into the brain, a condition called acute bilirubin encephalopathy ⁸². Prompt treatment may prevent significant lasting damage.

Bilirubin encephalopathy is a rare neurological condition that occurs in some newborns with severe jaundice due to severe unconjugated hyperbilirubinemia ⁸². Bilirubin encephalopathy is a serious condition. Many infants with late-stage nervous system complications die.

Signs of acute bilirubin encephalopathy in a baby with jaundice include:

Listlessness.
Difficulty waking.
High-pitched crying.
Poor sucking or feeding.
Backward arching of the neck and body.
Fever.

The signs and symptoms of bilirubin encephalopathy in neonates with severe unconjugated hyperbilirubinemia depend on when the symptoms appear. The level at which unconjugated bilirubin becomes neurotoxic is unclear, and kernicterus has been reported in infants without markedly elevated bilirubin levels on autopsy. There are 3 phases of acute bilirubin encephalopathy, including:

Phase 1: The symptoms of phase 1 appear during the first 1 to 2 days of illness and are notable for poor feeding, lethargy, hypotonia, irritability, or frank seizures.

Early stage symptoms:

Extreme jaundice
Absent startle reflex
Poor feeding or sucking
Extreme sleepiness (lethargy) and low muscle tone (hypotonia)

Phase 2: If infants continue to deteriorate, they progress to phase 2, characterized by increased extensor muscle tone, exhibiting opisthotonus and retrocollis. This typically occurs during the middle of the first week of illness.

Middle stage:

High-pitched cry
Irritability
May have arched back with neck hyperextended backwards, high muscle tone (hypertonia)
Poor feeding

Phase 3: After the first week, muscle rigidity, stupor or coma, apnea, or seizures may occur.

Late stage:

Stupor or coma
No feeding
Shrill cry
Muscle rigidity, markedly arched back with neck hyperextended backwards
Seizures.

Kernicterus

Kernicterus is the syndrome that happens if acute bilirubin encephalopathy causes permanent damage to the brain ⁸³. Extreme hyperbilirubinemia (total bilirubin of 25 to 30 mg/dL) can cause kernicterus. Kernicterus is usually characterized by the deposition of unconjugated bilirubin (yellow stain) in brain cells. Neuronal necrosis or damage occurs in the basal ganglia, hippocampus, hypothalamic nuclei, diencephalon, midbrain responsible for neurohumoral and electrolyte control, brainstem nuclei accounting for oculomotor and auditory function, and in the cerebellum depositing as a bilirubin-phosphatidylcholine precipitate. Vision, hearing, speech, cognition, gait, and language are typically affected ⁸⁴, ⁸⁵, ⁸⁶, ⁸⁷. Kernicterus clinical features include cerebral palsy, deafness, seizures, abnormalities of the gaze, and hypoplasia of the dental enamel ⁸³.

The symptoms depend on the stage of bilirubin encephalopathy. Not all babies with kernicterus on autopsy have had definite symptoms.

Kernicterus usually present in 2 forms, depending on the timing of symptoms ⁴¹:

In the first year: These patients present with hypotonia, exaggerated deep tendon reflexes, obligatory tonic neck reflexes, and delayed motor milestones.
Beyond the first year: Patients exhibit movement disorders, most commonly choreo-athetoid cerebral palsy, dental enamel hypoplasia, upward gaze abnormality, and sensorineural hearing loss.

Kernicterus may result in:

Permanent brain damage
Movements that are not controlled or intended, known as athetoid cerebral palsy.
Permanent upward gaze.
Hearing loss.
Improper development of tooth enamel.
Death.

Bilirubin encephalopathy Prevention

Pregnant women should be screened with Rhesus factor (Rh factor) and treated appropriately. Rhesus factor (Rh factor) is a type of protein on the outside or surface of your red blood cells. You inherit the Rh protein, which means you get your Rh factor from your biological parents. If you have the Rh protein, you’re Rh-positive (Rh+). If you don’t have the Rh protein, you’re Rh-negative. The majority of people, about 85%, are Rh-positive (Rh+). During pregnancy, complications may occur if a mother is Rh-negative and the fetus is Rh-positive (Rh+). This is called Rh factor incompatibility. With Rh incompatibility, a mother who is Rh-negative reacts to this difference known as incompatibility and creates antibodies. These antibodies drive an immune system attack against the fetus’s red blood cells that are Rh-positive (Rh+), which a mother who is Rh-negative thinks are foreign objects. This is called Rh sensitization. Obstetricians (physicians who specialize in delivering babies) can prevent this from happening by giving you a shot (injection) of immune globulin called Rh immune globulin (RhIg or RhoGAM®). Rh immune globulin (RhIg or RhoGAM®) is a medication that stops a mother who is Rh-negative from making Rh antibodies. It’s only helpful if your body hasn’t already made Rh antibodies. You receive it as a shot (injection). Rh immunoglobulin shots are usually very successful in treating Rh-incompatibility during pregnancy. Detecting Rh incompatibility early in pregnancy is the best way to prevent serious complications.

If a mother who is Rh-negative already has Rh antibodies, the fetus is at risk for Rh disease. Since Rh immune globulin won’t be helpful, the best treatment is close monitoring for the remainder of your pregnancy. There’s a small chance your obstetrician will want to deliver early, but this depends on how severe the fetus’s Rh disease is.

During pregnancy, a mother don’t share blood with the fetus she’s carrying. However, a small amount of blood from the fetus can mix with a mother’s blood during labor and delivery (either vaginal or cesarean). It can also happen during:

Tests like amniocentesis and chorionic villus sampling (CVS).
Any type of vaginal bleeding during pregnancy.
Injury or trauma to your abdomen.
Early pregnancy complications like miscarriage or ectopic pregnancy.
After external cephalic version, a maneuver to turn a breech baby.

Rh incompatibility doesn’t affect the pregnant woman. In a fetus, Rh disease can cause hemolytic anemia. Hemolytic anemia destroys the fetus’s red blood cells faster than it can replace them.

The effects of Rh incompatibility can range from mild to severe. These effects may also include:

Jaundice.
Liver failure.
Heart failure.
Stillbirth.

For mild Rh disease, the fetus may not need any treatment. Most fetuses recover fully if they have a mild case of Rh disease.

For severe Rh disease cases, the fetus may receive a blood transfusion. This procedure helps replace its red blood cells. Doctors can use special lights to help reduce bilirubin levels in fetuses that have jaundice. You may need to give birth early to avoid serious complications of hemolytic anemia.

Since the development of Rh immune globulin injections, Rh disease occurs infrequently.

Because suboptimal feeding plays a role in developing hyperbilirubinemia, all breastfeeding mothers should receive support to promote adequate feeding. Breastfeeding within the first hour of life is recommended, followed by on-demand nursing at least 8 times daily. Furthermore, staff should visually assess all hospitalized neonates for jaundice at least every 12 hours. The AAP guidelines recommend universal bilirubin screening before discharge with total serum bilirubin ⁸⁸.

For all babies, diagnosing jaundice early and getting treatment right away are key. This can stop your baby’s bilirubin levels from rising to dangerous levels.

Treating jaundice or conditions that may lead to it can help prevent neonatal hyperbilirubinemia. Infants with the first signs of jaundice have bilirubin level measured within 24 hours. If the level is high, the infant should be screened for diseases that involve the destruction of red blood cells (hemolysis).

The best preventive of infant jaundice is adequate feeding. Feedings should start within the first hour of life and continue at least every 2 or 3 hours, or sooner if the baby shows signs of wanting to eat. The more premature the baby, the more likely they are to need supplements of expressed milk or formula at first. Make sure you feed your baby early and often. Breastfed infants should have 8 to 12 feedings a day for the first several days of life.

All newborns have a follow-up appointment within 2 to 3 days after leaving the hospital. This is very important for late preterm or early term babies (born more than 2 to 3 weeks before their due date).

Bilirubin encephalopathy treatment

Treatment depends on how old the baby is (in hours) and whether the baby has any risk factors (such as prematurity). It may include:

Light therapy (phototherapy)
Exchange transfusions (removing the child’s blood and replacing it with fresh donor blood or plasma)

In preterm infants, the risk of a handicap increases by 30% for each 2.9 mg/dL increase of maximal total bilirubin concentration. While central nervous system damage is rare when total serum bilirubin is less than 20 mg/dL, premature infants may be affected at lower levels. The decision to institute therapy is based on a number of factors including total serum bilirubin, age, clinical history, physical examination, and coexisting conditions. Phototherapy typically is discontinued when total serum bilirubin level reaches 14 to 15 mg/dL.

How to manage hyperbilirubinemia in newborn babies

Treatment will depend on your child’s symptoms, age, and general health. It will also depend on how bad the condition is. Mild infant jaundice often disappears on its own within two or three weeks. For moderate or severe jaundice, a baby may need to stay longer in the newborn nursery or be readmitted to the hospital. Use the bilirubin level to determine the management of hyperbilirubinemia in all babies, see threshold table (see Table 1) and treatment threshold graphs (Figures 4 and 5).

Treatment depends on how old the baby is (in hours) and whether the baby has any risk factors (such as prematurity). It may include:

Light therapy also called phototherapy. Your baby may be placed under a special lamp that emits light in the blue-green spectrum. The light changes the shape and structure of bilirubin molecules in such a way that they can be excreted in both the urine and stool. During treatment, your baby will wear only a diaper and protective eye patches. Light therapy may be supplemented with the use of a light-emitting pad or mattress.
Fiber optic blanket is another form of phototherapy. The blanket is usually put under your baby. It may be used alone or with regular phototherapy.
Exchange transfusions (removing the child’s blood and replacing it with fresh donor blood or plasma). Rarely, when severe jaundice doesn’t respond to other treatments, a baby may need an exchange transfusion of blood. This involves repeatedly withdrawing small amounts of blood and replacing it with donor blood. The procedure dilutes the bilirubin and maternal antibodies and is done in a newborn intensive care unit.
Enhanced nutrition. To prevent weight loss, your baby’s doctor may recommend more-frequent feeding or supplementation to ensure that your baby receives enough nutrition.
Intravenous immunoglobulin (IVIg). Jaundice may be related to blood type differences between mother and baby. This condition results in the baby carrying antibodies from the mother that contribute to the rapid breakdown of the baby’s red blood cells. Intravenous transfusion of an immunoglobulin (IVIg), a blood protein that can reduce levels of antibodies, may decrease jaundice and lessen the need for an exchange transfusion, although results are not conclusive.
Treating any underlying cause of the hyperbilirubinemia.

Use the bilirubin level to determine the management of hyperbilirubinemia in all babies see threshold table (see Table 3) and treatment threshold graphs (Figures 2 and 3).

Table 3. Bilirubin threshold table for the management of babies of 38 weeks or more gestational age with hyperbilirubinemia

Age (hours)	Bilirubin measurement (micromol/liter)
0	>100	>100
6	>125	>150
12	>150	>200
18	>175	>250
24	>200	>300
30	>212	>350
36	>225	>400
42	>237	>450
48	>250	>450
54	>262	>450
60	>275	>450
66	>287	>450
72	>300	>450
78	>312	>450
84	>325	>450
90	>337	>450
96	>350	>450
Action	Start phototherapy	Perform an exchange transfusion unless the bilirubin level falls below threshold while the treatment is being prepared

Footnotes: Note that there is variability between assays from different manufacturers in reported bilirubin measurement. Healthcare professionals should consult their local pathology laboratory when interpreting threshold tables.

[Source ⁸⁹ ]

Figure 2. Hyperbilirubinemia threshold graph for babies

[Source ⁹⁰ ]

Figure 3. Hyperbilirubinemia treatment threshold graph for babies with neonatal jaundice: >=38 weeks gestation

[Source ⁴⁹ ]

Phototherapy

Bilirubin absorbs light. High bilirubin levels often decrease when a baby is put under special blue spectrum lights. This is called phototherapy ⁹¹, ⁸², ⁹². Your child may get this treatment in the day and night. It may take several hours for it to start working. During light treatment, your baby’s eyes will be protected. Your baby’s doctor will check your baby’s temperature. They will also test your baby’s bilirubin levels. This will tell if phototherapy is working.

Bilirubin optimally absorbs light in the blue-green range (ie, 460-490 nm). The underlying mechanism of phototherapy involves inducing photoisomerization and converting bilirubin into lumirubin, which is readily excreted into bile and urine ⁹³. During phototherapy, the neonate’s maximum body surface area should be exposed to the light source while keeping the eyes covered to avoid retinal injury, and interruptions should be minimized. The maintenance of hydration is necessary to ensure adequate urine output, as most bilirubin is excreted in the urine as lumirubin, a structural isomer of bilirubin formed during phototherapy. Therefore, breastfeeding support should be offered to all nursing mothers as early initiation of breastfeeding and frequent, on-demand feeding decreases the likelihood of dehydration. Although supplemental oral water and dextrose water are not recommended, supplemental pumped breastmilk or infant formula can be considered for feeding issues, including infants with ineffective sucking or latching or inadequate maternal milk production ⁸⁸.

After phototherapy is discontinued, there may be an increase in the total serum bilirubin level, known as the rebound bilirubin. This level is usually lower than the pretreatment level and rarely requires reinitiation of phototherapy ⁹⁴. Phototherapy is considered safe, but recent evidence suggests a possible association with long-term complications, including a small risk of childhood seizures. However, no studies have proven causation ⁹⁵. A few studies also have reported a possible association between solid organ tumors and nonlymphocytic leukemias and children treated with phototherapy ⁹⁶, ⁹⁷. Adverse effects of phototherapy include rashes, dehydration, hypocalcemia, retinal damage, hemolysis due to oxidative damage, delay in patent ductus arteriosis closure in preterm infants, and allergic reactions ⁹⁸. Bronze baby syndrome is a self-limited condition associated with elevated levels of conjugated bilirubin that rarely occurs with phototherapy, resulting in irregular, bronze-gray pigmentation of the skin, mucous membranes, and urine. The Bronze baby syndrome’s mechanism is unclear but appears to be related to the accumulation of bilirubin and biliverdin photoisomers. Bronze baby syndrome usually resolves within a few days of discontinuing phototherapy; however, the prognosis depends upon the underlying cause of the conjugated hyperbilirubinemia ⁹⁹, ¹⁰⁰.

Fiber optic blanket

A fiber optic blanket is another form of phototherapy. The blanket is usually put under your baby. It may be used alone or with regular phototherapy.

Exchange transfusion

Exchange transfusion is the treatment that involves removing your baby’s blood that has a high bilirubin level and replacing it with fresh donor blood or plasma ¹⁰¹. This raises your baby’s red blood cell count. It also lowers their bilirubin level. During the procedure, your baby will switch between giving and getting small amounts of blood. This will be done through a vein or artery in the baby’s umbilical cord. It is only done in an intensive care nursery when bilirubin levels are extremely high. Your baby may need to have this procedure again if their bilirubin levels stay high.

Exchange transfusion is now the second-line treatment for severe unconjugated hyperbilirubinemia since phototherapy was developed in the 1950s ¹⁰², ¹⁰³. Indications for exchange transfusion include neonatal failure to respond to phototherapy or a total serum bilirubin level at the exchange transfusion threshold. The threshold to initiate exchange transfusion is calculated based on several factors, including the total serum bilirubin level and rate of rise, neonatal age (ie, hours or days since birth), and risk factors for neurologic complications ⁸⁸. Exchange transfusion rapidly removes bilirubin and hemolysis-causing antibodies from the infant’s circulation. A double-volume exchange blood transfusion (160-180 ml/kg) is performed, replacing aliquots of the neonate’s blood with crossed-matched donor blood. Since most of the total body bilirubin is extravascular, the total serum bilirubin level immediately following exchange transfusion is approximately 60% of the pre-exchange level, but that later increases to 70% to 80% of the pretreatment level as a result of equilibrium. During exchange transfusion, the neonate’s vital signs should be monitored closely. Following the procedure, total serum bilirubin, complete blood count, serum calcium, glucose, and electrolytes should be rechecked due to potential complications, including electrolyte abnormalities (eg, hypocalcemia and hyperkalemia), cardiac arrhythmias, thrombocytopenia, blood-borne infections, portal vein thrombosis, graft versus host disease, and necrotizing enterocolitis (NEC) ¹⁰⁴, ¹⁰⁵. Phototherapy should resume after exchange transfusion until the bilirubin reaches a level where phototherapy can be safely discontinued.

Intravenous immunoglobulin (IVIg)

Jaundice may be related to blood type differences between mother and baby. This condition results in the baby carrying antibodies from the mother that contribute to the rapid breakdown of the baby’s red blood cells. Intravenous transfusion of an immunoglobulin (IVIg), a blood protein that can reduce levels of antibodies, may decrease jaundice and lessen the need for an exchange transfusion, although results are not conclusive. The American Academy of Pediatrics recommends intravenous immunoglobulin (IVIg) infusion in immune-mediated hemolysis if total serum bilirubin remains within 2 to 3 mg/dL of the exchange threshold despite intensive phototherapy ¹⁰⁶, ¹⁰⁷. However, the evidence that intravenous immunoglobulin (IVIg) reduces the need for exchange transfusion is unclear. Nonetheless, intravenous immunoglobulin (IVIg) is often used in clinical practice to manage severe unconjugated hyperbilirubinemia ⁸².

Feeding with breastmilk

The American Academy of Pediatrics says that you should keep breastfeeding a baby with jaundice. If your baby has not been getting enough milk at the breast, you may need to supplement with pumped breastmilk or formula.

Feeding more frequently will provide your baby with more milk and cause more bowel movements, increasing the amount of bilirubin eliminated in your baby’s stool. Infants who are breastfed should have 8 to 12 feedings a day for the first several days of life. Formula-fed infants usually should have 1 to 2 ounces (about 30 to 60 milliliters) of formula every 2 to 3 hours for the first week.

Supplemental feedings

If your baby is having trouble breastfeeding, is losing weight or is dehydrated, your baby’s doctor may suggest giving your baby formula or expressed milk to supplement breastfeeding. Depending on the situation, your baby’s doctor may recommend using formula alone for a couple of days and then resuming breastfeeding. Ask your baby’s doctor what feeding options are right for your baby.

Treating any underlying cause of the hyperbilirubinemia

This may include treating an infection.

What does low bilirubin levels mean?

Low levels of bilirubin are generally not of any concern and are not monitored.

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Bilirubin

What is bilirubin