Peliosis hepatis

Peliosis hepatis also called “peliosis hepatitis” is rare benign blood vessel condition characterized by multiple, randomly distributed, blood-filled and cyst-like cavities throughout the liver ¹⁾, ²⁾, ³⁾, ⁴⁾, ⁵⁾. These blood-filled cavities communicate with the hepatic sinusoids and are associated with rupture of the reticulin framework ⁶⁾. The size of the cystic lesions may vary from 1 millimeter to several centimeters ⁷⁾. The cystic lesions are often irregularly shaped and in many cases are incompletely lined with endothelium ⁸⁾. Peliosis hepatis has been described as typically involving the entire liver ⁹⁾.

Peliosis mostly exists without symptoms (asymptomatic) being incidentally found on imaging or during an autopsy ¹⁰⁾. However, with the progress of modern medical imaging technologies such as ultrasound, magnetic resonance imaging (MRI), FDG-PET (fluorodeoxyglucose positron emission tomography) or computed tomography (CT) scan, peliosis hepatis is now more frequently encountered in clinical practice ¹¹⁾. Despite these various medical imaging modalities, imaging may be inadequate for establishing a clear diagnosis of peliosis ¹²⁾, ¹³⁾.

Peliosis hepatis can occur at any age. Although a fetal form exists, peliosis hepatis usually develops in adults without regard to sex ¹⁴⁾.

The cause of peliosis hepatis can be related to drugs including anabolic steroids, oral contraceptives, corticosteroids, tamoxifen, diethylstilbestrol, azathioprine, 6-thioguanine, 6-mercaptopurine, and methotrexate; toxins such as polyvinyl chloride, arsenic, and thorium oxide; chronic wasting diseases (e.g., tuberculosis, leprosy, and various cancers, particularly hepatocellular carcinoma); liver and kidney transplantation; and Bartonella henselae and Bartonella quintana infection in AIDS so-called bacillary peliosis ¹⁵⁾, ¹⁶⁾, ¹⁷⁾, ¹⁸⁾, ¹⁹⁾. In addition, several other conditions are described as associated with peliosis hepatis, including sprue (a disorder in which the intestines are unable to absorb nutrients from food), diabetes mellitus, necrotizing vasculitis, and blood disorders including multiple myeloma, aplastic anemia, Hodgkin disease, and myelofibrosis ²⁰⁾. Moreover, peliosis hepatis may develop after kidney or heart transplantation. In 20 to 50% of patients, no associated condition is identified ²¹⁾.

Peliosis hepatis is very difficult to diagnose. The diagnosis of peliosis hepatis is often missed or delayed because it is usually asymptomatic, and its radiologic appearance closely resembles a benign and malignant/pre-malignant lesions or multiple abscesses ²²⁾, ²³⁾. Radiological imaging shows a broad spectrum of appearances because of its dependence on the blood supply to the lesions. Laparoscopy is a useful examination to sporadically detect dark-blue or dark-red patchy patterns on the liver surface, which is a characteristic finding of peliosis hepatis ²⁴⁾. Pathological findings are considered the gold standard for the diagnosis of peliosis hepatis, being histologically characterized by blood-filled cavities. However, a case has been reported in which repeated biopsies were required to diagnose peliosis hepatis ²⁵⁾.

The correct diagnosis of peliosis hepatis is important because withdrawal of the offending drug or toxin can resolve the disease and prevent serious complications such as hepatic failure or death related to intraabdominal hemorrhage ²⁶⁾. Because of peliosis hepatis potential complications, surgical resection of the involved liver parenchyma should always be considered. In HIV-related peliosis hepatis caused by Bartonella henselae, clinical improvement has been documented with the use of antibiotics (i.e., erythromycin).

Figure 1. Peliosis hepatis

Footnotes: 51-year-old woman with history of benign ovarian tumor and incidentally discovered hepatic mass. On contrast-enhanced CT during hepatic arterial phase, lesion (arrow) shows marked homogeneous contrast enhancement.

[Source ²⁷⁾ ]

Peliosis hepatis cause

The cause of peliosis hepatis can be related to drugs including anabolic steroids, oral contraceptives, corticosteroids, tamoxifen, diethylstilbestrol, azathioprine, 6-thioguanine, 6-mercaptopurine, and methotrexate; toxins such as polyvinyl chloride, arsenic, and thorium oxide; chronic wasting diseases (e.g., tuberculosis, leprosy); cancers, particularly hepatocellular carcinoma; liver and kidney transplantation; and Bartonella henselae and Bartonella quintana infection in AIDS so-called bacillary peliosis ²⁸⁾, ²⁹⁾, ³⁰⁾, ³¹⁾, ³²⁾. In addition, several other conditions are described as associated with peliosis hepatis, including sprue (a disorder in which the intestines are unable to absorb nutrients from food), diabetes mellitus, alcoholic liver disease, necrotizing vasculitis, and blood disorders including multiple myeloma, aplastic anemia, Hodgkin disease, and myelofibrosis ³³⁾, ³⁴⁾, ³⁵⁾, ³⁶⁾. Moreover, peliosis hepatis may develop after kidney or heart transplantation. In 20 to 50% of patients, no associated condition is identified ³⁷⁾.

Peliosis hepatis causes ³⁸⁾:

• Idiopathic: 20 to 50% of cases
• Toxins
  • arsenic
  • polyvinyl chloride (PVC)
  • thorium oxide
• Drugs
  • anabolic steroids
  • azathioprine
  • corticosteroids
  • diethylstilbestrol (DES)
  • immunoglobulin therapy
  • methotrexate
  • oral contraceptives
  • tamoxifen
  • 6-thioguanine (6-TG)
  • 6-mercaptopurine (6-MP)
• Chronic illness
  • malignancy, particularly hepatocellular carcinoma
  • tuberculosis (TB)
  • leprosy
  • celiac sprue
  • diabetes mellitus
  • necrotizing vasculitis
  • hematologic disorders: Hodgkin disease, multiple myeloma
• Infection in AIDS
  • bacillary peliosis caused by Bartonella henselae, Bartonella quintana and Rochalimaea henselae
• Kidney or heart transplantation

Peliosis hepatis pathophysiology

Peliosis hepatis pathogenesis remains poorly understood, with various investigators proposing that the primary event could be obstruction of hepatic outflow at the sinusoidal level, direct breakdown of sinusoidal borders, dilatation of the central vein of the hepatic lobule, or hepatocellular necrosis leading to cavity formation ³⁹⁾. Lastly, post-sinusoidal obstruction from several conditions such as malignant invasion, autoimmune inflammation, and drug injury is also hypothesized to be an alternate mechanism in the formation of peliosis hepatis ⁴⁰⁾.

The anatomy of the sinusoidal capillaries is different than other capillary beds within the body. The fenestrations which are present within the liver allow for passes and filtration of larger molecules such as albumin ⁴¹⁾. Epithelial damage can result from smoking, which can disrupt the architecture through the formation of free radicals. This damage, in turn, impairs vasodilation by inhibiting nitric oxide formation, which allows for normal physiologic relaxation of the arteries ⁴²⁾. Additionally, inflammation, whether it be autoimmune, direct trauma through surgical instrumentation, medication-induced, or invasion by malignancy, can result in the recruitment of inflammatory cytokines and cells, sometimes resulting in further epithelial damage ⁴³⁾. An alternate mechanism may be the depletion of glutathione, a critical regulatory molecule that assists in many biochemical detoxification reactions, which may disrupt the integrity of the epithelial wall and allow toxic metabolites to build up. However, through signal proteins such as vascular endothelial growth factor and others, re-endothelization can occur; thus, that is why using the absence of epithelial lining on imaging studies is not adequate to diagnose patients with peliosis hepatis, though it can raise the concern for it ⁴⁴⁾, ⁴⁵⁾.

Histologically, hepatic peliosis is characterized by multiple mottled blood-filled cyst-like spaces within the liver with associated sinusoidal dilatation ⁴⁶⁾, ⁴⁷⁾. These vary in size from <1 mm to several centimeters in diameter.

Macroscopically, the liver appears dark or even purple, and usually, the entire liver is involved to a greater or lesser degree. Focal lesions may demonstrate central areas of hemorrhage.

Peliosis hepatis symptoms

Peliosis hepatis varies from minimal asymptomatic lesions that is diagnosed incidentally on imaging or during an autopsy to massive lesions that may present with cholestasis, hepatic failure, or spontaneous rupture requiring liver transplantation ⁴⁸⁾, ⁴⁹⁾. In some instances, enlarged liver (hepatomegaly), ascites (accumulation of fluid in the peritoneal cavity), portal hypertension, cholestasis, and hepatic failure may be present ⁵⁰⁾. Severe abdominal pain may result from rupture and intraperitoneal hemorrhage ⁵¹⁾. In the case of bacillary peliosis, enlarged lymph node (lymphadenopathy) with Bartonella henselae and neurologic symptoms with Bartonella quintana are typical findings.

Peliosis hepatis complications

Peliosis hepatis complications may include:

• hepatic failure
• portal hypertension
• rupture and hemorrhage

There is no current consensus on whether patients with asymptomatic peliosis hepatis warrant routine imaging studies to monitor disease burden or progression. However, some experts believe annual or more frequent evaluation with ultrasound is adequate ⁵²⁾.

Although the incidence of intraperitoneal and intrahepatic hemorrhage do not seem to be common complications, the risk does exist ⁵³⁾. Thus surgical resection appears to assist in the avoidance of such complications, especially if imaging studies have demonstrated worsening of the cavitary lesions ⁵⁴⁾.

Peliosis hepatis diagnosis

Peliosis hepatis is very difficult to diagnose. The diagnosis of peliosis hepatis is often missed or delayed because it is usually asymptomatic, and its radiologic appearance closely resembles a benign and malignant/pre-malignant lesions or multiple abscesses ⁵⁵⁾, ⁵⁶⁾. Radiological imaging shows a broad spectrum of appearances because of its dependence on the blood supply to the lesions. In reality, the imaging findings of peliosis hepatis vary depending on the pathologic patterns of disease, various stages of the blood component of the lesions, and concomitant hepatic steatosis ⁵⁷⁾.

Laparoscopy is a useful examination to sporadically detect dark-blue or dark-red patchy patterns on the liver surface, which is a characteristic finding of peliosis hepatis ⁵⁸⁾. Pathological findings are considered the gold standard for the diagnosis of peliosis hepatis, being histologically characterized by blood-filled cavities. However, a case has been reported in which repeated biopsies were required to diagnose peliosis hepatis ⁵⁹⁾.

Ultrasound findings

Conventional gray-scale sonography appearances are non-specific, usually demonstrating an irregular hypoechoic region/mass ⁶⁰⁾

Doppler studies can show evidence of both perinodular and intranodular vascularity ⁶¹⁾. Recently, the use of a sonographic contrast agent (Levovist [Schering], a galactose and palmitic acid compound) has been shown to provide a “fast surge” central-echo enhancement in peliotic lesions ⁶²⁾.

CT findings

Peliosis lesions appearance on pre-contrast CT (unenhanced CT) is variable, depending on liver density, but is usually of multiple hypoattenuating lesions of variable size ⁶³⁾. Central hemorrhage may lead to areas of hyperattenuation and even dystrophic calcification ⁶⁴⁾. CT findings vary with the size of lesions, presence or absence of thrombus within the cavities, and presence of hemorrhage. In particular, peliosis lesions may be spontaneously hyperattenuating to liver parenchyma in certain patients (probably related to intralesional hemorrhage). In addition, if peliotic cavities are smaller than 1 cm in diameter, CT findings may be normal ⁶⁵⁾. Calcifications within peliosis lesions have also been described.

On contrast-enhanced CT, peliosis lesions typically show early globular enhancement and multiple small, central accumulations of contrast material during the arterial phase, with a centrifugal progression of enhancement during the portal venous phase ⁶⁶⁾. In addition, some lesions can also show areas of increased attenuation. Notably, larger cavities communicating with sinusoids display the same attenuation of blood vessels, whereas thrombosed cavities have the same appearance as nonenhancing nodules ⁶⁷⁾. More often, during the arterial phase of contrast enhancement, peliosis lesions typically show early globular enhancement (vessel-like enhancement) and multiple small accumulations of contrast material in the center of the lesions the so-called target sign ⁶⁸⁾. During the portal venous phase, a centrifugal progression of enhancement without a mass effect on hepatic vessels is usually observed ⁶⁹⁾; however, a centripetal progression of enhancement can also be seen ⁷⁰⁾. On the delayed phase, late diffuse homogeneous hyperattenuation can also be seen in the phlebectatic type of peliosis hepatis because of the lack of hemorrhagic parenchymal necrosis ⁷¹⁾. This accumulation of contrast material in the delayed phase can be useful in the differential diagnosis with other focal hepatic lesions that do not show blood pooling. In some instances, small (< 2 cm) peliotic lesions may also show hyperattenuation on both arterial and portal venous phase images.

MRI findings

On MRI, the signal intensities of peliosis lesions largely depend on the stage and the status of the blood components ⁷²⁾. On T1-weighted images, lesions are hypointense or heterogeneously hypointense if complicated by hemorrhage. On T2-weighted images, they are usually hyperintense compared to the liver parenchyma. Hemorrhagic parenchymal necrosis and thrombosed cavities manifest as non-enhancing areas. The differential diagnosis of peliosis hepatis may differ according to the actual imaging findings. On T2-weighted images, high signal together with early lesion enhancement can mimic hepatocellular carcinoma or hypervascular metastasis ⁷³⁾, while a bright T2-weighted signal and persistent delayed-phase CT or MRI may help distinguish peliosis hepatis.

Angiographic findings

On angiography, peliosis lesions appear as multiple vascular nodules (i.e., accumulations of contrast material) during the late arterial phase. The enhancement of peliotic lesions typically is more distinct during the parenchymal phase and persists during the portal venous phase ⁷⁴⁾.

Biopsy findings

A percutaneous needle biopsy can be used to obtain a specimen to further elucidate imaging findings and confirm the diagnosis. However, a percutaneous liver biopsy carries a risk of bleeding and hepatic hemangioma formation ⁷⁵⁾. Some authors claim that, due to the high risk of bleeding, an open biopsy is essential in order to realize the differential diagnosis under intraoperative ultrasound supervision ⁷⁶⁾, ⁷⁷⁾, ⁷⁸⁾, ⁷⁹⁾, ⁸⁰⁾, ⁸¹⁾.

The gross pathologic appearance of peliosis hepatis is that of multiple, irregularly shaped blood-filled hepatic cavities ⁸²⁾. The lesions typically involve the entire liver, but focal peliosis hepatis has been described. At microscopic examination, cystic dilated sinusoids filled with red blood cells and bound by cords of liver cells can be seen (see Figure 1).

Macroscopic examinations show that peliotic lesions in the cutting section present hemorrhagic cyst cavities of various sizes (from < 1 mm to several centimeters) with features of “Swiss cheese”⁸³⁾, ⁸⁴⁾. From the histopathologic point of view, the differential diagnosis is used in order to diversify the sinusoids’ dilatation from Budd-Chiari syndrome, which determines a venous congestion of the liver due to a vascular occlusion ⁸⁵⁾, ⁸⁶⁾, ⁸⁷⁾.

Pathologists originally classified peliotic lesions by the presence or absence of endothelium (inner cellular lining of the blood vessels) ⁸⁸⁾. However, even though the blood-filled cavities do not always have endothelial lining , it has been observed that reendothelialization occurs rapidly ⁸⁹⁾, ⁹⁰⁾, ⁹¹⁾. Therefore, the continuity or rupture of the endothelial lining of hepatic sinusoids is not a reliable criterion to define peliosis hepatis ⁹²⁾. To distinguish peliosis hepatis from hepatic sinusoidal dilatation, lesions should show evidence of rupture of the reticulin fibers that support the hepatocytes and sinusoids ⁹³⁾. This rupture may follow the intrinsic weakness of the fibers of the endothelial wall (peliosis hepatis of the phlebectatic type) or may be associated with focal hepatocyte necrosis (peliosis hepatis of the parenchymal type) ⁹⁴⁾.

Yanoff et al ⁹⁵⁾ described microscopically two different types of peliosis hepatis:

• “parenchymal peliosis,” which consists of irregular cavities that are surrounded neither by the sinusoidal cells nor by fibrous tissue, and
• “peliosis flebectasica” which is characterized by spherical regular cavities coated by endothelium and/or fibrosis ⁹⁶⁾, ⁹⁷⁾, ⁹⁸⁾

Peliotic lesions in bacillary peliosis contain clumps of organisms (i.e., Bartonella henselae and Bartonella quintana) that stain with the Warthin-Starry technique ⁹⁹⁾. Patients with bacillary peliosis often have peliosis of the spleen and lymph nodes and cutaneous angiomatous lesions ¹⁰⁰⁾.

Peliosis hepatis differential diagnosis

Peliosis hepatis differential diagnosis may include:

• Hepatic adenoma: Similar to peliosis, hepatic adenoma might also be associated with the long-term use of estrogens. In the case of diffuse peliosis hepatis, the differential diagnosis is relatively easy. In addition, the presence of fat in some adenomas is a useful sign to make a differential diagnosis. In certain instances, however, focal peliosis can be difficult to differentiate from adenomas. In these patients, biopsy is often required to reach a definitive diagnosis.
• Cavernous hemangioma: The typical enhancement pattern of hemangiomas (i.e., globular discontinuous contrast enhancement tends to be centripetal (periphery first) rather than centrifugal (center first)) is opposite of peliosis hepatis, and therefore differential diagnosis can be achieved in most patients. In addition, hemangiomas may be rather large lesions with a mass effect on the hepatic vessels, whereas peliotic lesions usually show no mass effect on hepatic vessels.
• Hepatocellular carcinoma (liver cancer): Hepatocellular carcinoma is usually hyperattenuating in the arterial phase with rapid washout in the portal venous phase and iso- or hypoattenuation in the delayed phase. Although rare, the possibility that peliosis hepatis may mimic the presence of hypervascular hepatocellular carcinoma has been reported in the literature. In these patients, biopsy is often necessary to reach a definitive diagnosis.
• Hepatic abscess (liver abscess): The differential diagnosis between peliosis hepatis and hepatic abscess is extremely important to avoid the percutaneous drainage of peliotic lesions, which can be dangerous and even fatal ¹⁰¹⁾. With regard to imaging criteria, a hepatic abscess usually presents as a mass with a multiseptated or cluster-of-grapes appearance with nonenhancing contents.
• Focal nodular hyperplasia (benign tumor that forms in the liver): Focal nodular hyperplasias are typically homogeneously hyperattenuating masses on the arterial phase and isoattenuating on the portal venous and delayed phases. These lesions often have a central scar with low attenuation on the arterial and portal venous phases and enhancement on the delayed phase images. When such typical imaging characteristics of focal nodular hyperplasia are present, the differential diagnosis with peliosis hepatis can be achieved easily. Atypical forms of focal nodular hyperplasia may not show the characteristic enhancement patterns and the central scar just described, however, and thus pose some problems in the differential diagnosis with peliosis hepatis.
• Hepatic adenoma (an uncommon solid, benign liver lesion that develops in an otherwise normal-appearing liver) may contain fat
• Hypervascular metastases: Although some hypervascular metastases with fibrotic change can show mild hyperattenuation in the delayed phase, hypervascular metastases are usually totally hypoattenuating or isoattenuating in the delayed phase of contrast enhancement because of the rapid washout of contrast material. Thus, in general, peliotic lesions are rarely confused with hypervascular metastases.
  
• Hepatic sinusoidal dilation: usually the enhancement pattern is different on CT/MRI ¹⁰²⁾

Peliosis hepatis treatment

Peliosis hepatis treatment depends on the cause. When a causative drug or toxin is suspected, withdrawal of that agent may result in resolution. If peliosis hepatis seen in the setting of HIV/AIDS, antibiotic treatment may be effective in eradicating B. henselae. If focal and hemorrhagic, surgical resection may also be beneficial ¹⁰³⁾.

It is important not to drain peliosis, having mistaken it for a hepatic abscess, as bleeding can be life threatening ¹⁰⁴⁾.

Peliosis hepatis prognosis

The progression of peliosis hepatis is still largely uncertain ¹⁰⁵⁾. Researchers have not observed any apparent patterns of peliosis hepatis disease progression. The natural course of peliosis hepatis is regression after drug withdrawal, cessation of steroid therapy, or resolution of an associated infectious disease ¹⁰⁶⁾. However, peliosis hepatis can become worse asymptomatically and present as an accidental finding that occurs during investigations of other diseases or on the autopsy table ¹⁰⁷⁾, ¹⁰⁸⁾. A pseudotumoral and hemorrhagic evolution has also been described ¹⁰⁹⁾, ¹¹⁰⁾.

Some authors claim that peliosis hepatis could be associated to liver failure with clinical features of hepatomegaly, portal hypertension, cholestasis, liver rupture leading to intraperitoneal hemorrhage (internal bleeding in which blood gathers in your peritoneal cavity) or shock and, more rarely, in cirrhotic patients positive for hepatitis C virus ¹¹¹⁾, ¹¹²⁾, ¹¹³⁾ or in cases of rupture of peliosis hepatis lesions with hemoperitoneum and hemodynamic decompensation with lethargy and abdominal pain ¹¹⁴⁾, ¹¹⁵⁾, ¹¹⁶⁾, ¹¹⁷⁾. In general, if untreated, ruptured peliosis hepatis may be rapidly fatal ¹¹⁸⁾.

In other cases, especially when peliosis hepatis occurs at very young age, the disease shows important effects of compression with stenosis of the vena cava ¹¹⁹⁾.

In still other cases, after the interruption of the steroid therapy or the resolution of the subsequent infections, a total regression was noticed ¹²⁰⁾, ¹²¹⁾, ¹²²⁾. Peliosis hepatis regression can also occur without any connection with the past medical history, especially in those cases (20% to 50%) that do not allow association of peliosis hepatis to any kind of etiology ¹²³⁾.

Even though some authors support possible transplantation in acute liver failure cases or to use hepatectomy for the diagnosis and treatment of peliosis hepatis, surgery is more and more often used in urgent cases as treatment for the bleeding that may occur. At the same time, for the same issue, some authors proposed embolization that may be performed by an interventional radiologist or during the operation or the laparoscopic biopsy ¹²⁴⁾, ¹²⁵⁾.