Peliosis hepatis

INTRODUCTION — Peliosis hepatis is a rare vascular condition of the liver characterized by a proliferation of the sinusoidal hepatic capillaries that results in cystic blood-filled cavities distributed randomly throughout the liver [1,2]. The term originates from the Greek "pelios," which means blue/black or discolored extravasated blood [3]. Peliosis is most commonly found in the liver but can also involve the spleen, bone marrow, lungs, abdominal lymph nodes, and other organs [2,4].

EPIDEMIOLOGY — The epidemiology of peliosis hepatis is incompletely understood since many patients are asymptomatic and remain undiagnosed. Peliosis hepatis is often an incidental finding on abdominal imaging or autopsy. The incidence does not differ by patient sex [5].

The reported prevalence of peliosis hepatis in patients with associated conditions ranges from 0.2 percent of patients with pulmonary tuberculosis to as high as 22 percent in patients following renal transplant [2,6,7].

ETIOLOGY — First described in patients with advanced cancer and tuberculosis and in users of anabolic steroids [2,8,9], peliosis hepatis is now associated with a variety of conditions (table 1) [10-13]. The mechanisms by which these lead to peliosis hepatis is unknown. Risk factors can be divided into three categories:

●Drug–related factors (ie, steroids, oral contraceptives, azathioprine, chemotherapeutic agents).

●Immune disorders (ie, diseases associated with secondary immunodeficiency such as hematologic disorders or immunosuppression following transplantation) [10,14].

●Infectious causes (ie, tuberculosis, HIV, syphilis and Bartonella henselae) [15-17]. Bartonella-associated or bacillary peliosis hepatis is described separately. (See "Bartonella infections in people with HIV".)

In the renal transplant setting, peliosis hepatis appears to be acquired after transplantation, rather than as a manifestation of chronic kidney disease [3,7,18]. In one report, 22 percent of renal transplant recipients had peliosis hepatis compared with only 2 percent of those awaiting transplant [7]. Possible explanations include use of azathioprine, cyclosporine, or development of opportunistic infections after transplantation [15,18,19].

In 20 to 50 percent of patients with peliosis hepatis, no risk factor is identified [5].

PATHOGENESIS — The pathogenesis of peliosis hepatis is unclear, but probably involves hepatocellular necrosis and injury to the sinusoidal endothelium. One theory suggests that focal areas of hepatocellular necrosis destroy the reticulum framework thereby leading to central or peripheral hemorrhage [2]. The area of necrosis can either heal or form a cyst, which can eventually develop an endothelial lining. This mechanism has been demonstrated in a mouse model where chemically-induced hepatocyte necrosis resulted in the development of peliotic changes [20,21].

Direct endothelial cell injury may also have a role in the development of peliosis hepatis [8,22,23]. An experimental study of cadmium toxicity in a rat model suggested that the initial damage to hepatocytes and sinusoidal cells leads to disruption of the sinusoidal endothelial cell lining followed by sinusoidal dilatation and ultimately formation of peliotic cavities [24-26]. Studies involving electron microscopy of peliotic lesions from patients with AIDS have demonstrated Bartonella within sinusoidal epithelial cells, leading to microcirculatory damage [13,24].

In addition, some patients with azathioprine-induced peliosis hepatis have evidence of sinusoidal injury [27], while others have concomitant idiopathic noncirrhotic portal hypertension or veno-occlusive liver disease, both of which are known to be caused by drug-induced vascular injury [28]. Other drugs known to cause sinusoidal endothelial cell damage include 6-thioguanine and urethane [25,27]. Conversely, certain drugs (eg, anabolic steroids, glucocorticoids, methotrexate, vitamin A, oral contraceptives) associated with peliosis hepatis do not cause sinusoidal endothelial cell injury and thus the mechanisms by which they lead to peliosis hepatis remain unclear [25].

CLINICAL FEATURES

Symptoms and signs — The clinical presentation of peliosis is variable. Many patients are asymptomatic, and peliosis hepatis is discovered during the work up of abnormal liver function tests or incidentally on abdominal imaging [3].

Some patients present with abdominal pain [29], jaundice [30], hepatomegaly [3,6], portal hypertension [4,27,31,32], or liver failure [27,33,34]. Complications of portal hypertension are discussed separately. (See "Portal hypertension in adults", section on 'Clinical manifestations'.)

Other patients present with ruptured or infarcted peliotic cysts resulting in significant and sometimes fatal intrahepatic or intraperitoneal hemorrhage [33,35-40].

The size of the peliotic cavities and extent of liver involvement are associated with the severity the clinical manifestations. Patients with minor microscopic forms of peliosis usually remain asymptomatic. Clinical manifestations are more common in patients with major or macroscopic forms of peliosis hepatis, characterized by large cysts that occupy a significant portion of the liver [3,11,18]. One study of 12 patients with biopsy-confirmed peliosis hepatis reported hepatomegaly, portal hypertension, esophageal varices, and ascites in five out of six patients with major peliosis hepatis, while the other six patients with minor peliosis hepatis were asymptomatic [3].

Bartonella-associated or bacillary peliosis hepatis may be associated with splenic peliosis and cutaneous bacillary angiomatosis [41,42]. (See "Bartonella infections in people with HIV", section on 'General clinical issues'.)

Laboratory findings — Liver function tests may be abnormal but no specific cholestatic or hepatocellular pattern exists.

Imaging studies — The pattern of peliosis hepatis on various imaging modalities depends upon the pathologic type of the disease, size of the lesion, extent of communication with sinusoids, and presence of a thrombus or hemorrhage.

The microscopic (minor) form of peliosis hepatis tends to have no specific characteristics on imaging while the macroscopic (major) form of peliosis hepatis is characterized by large hepatic vascular lesions that can be visualized by various imaging techniques. Imaging studies may reveal a single lesion or multiple, diffuse lesions that appear infiltrating or that resemble abscesses (image 1) [5,16,17,35,43]. Specific imaging characteristics can help to differentiate these lesions from other space occupying structures [44,45]. (See "Approach to the adult patient with an incidental solid liver lesion".)

●On ultrasound, lesions may appear as pseudocystic areas in the hepatic parenchyma. These lesions can be hypoechoic in an otherwise normal liver or they may appear hyperechoic in the setting of hepatic steatosis. Doppler studies can demonstrate the vascular nature of the lesion [5,46].

●On contrast-enhanced computed tomography (CT), the lesions can appear as heterogeneous densities that become hypodense on the late arterial and venous phase. Peripheral ring-like enhancement is occasionally seen. A characteristic finding is the absence of mass effect on the adjacent vasculature. In the case of hemorrhage, peliosis hepatis lesions appear as hyperattenuating structures on unenhanced CT [44,45].

●On magnetic resonance imaging (MRI), peliosis hepatis lesions are typically of low signal intensity on T1-weighted images and of high signal on T2-weighted images, with late and slow but intense enhancement on contrast-enhanced T1-weighted images [47]. Fresh and actively circulating blood within the dilated sinusoids can cause hypervascular enhancement on the arterial phase of triphasic CT or MRI, whereas old and stagnated blood can lead to persistently low or slow enhancement on portal or delayed phase images [45,48,49]. (See "Approach to the adult patient with an incidental solid liver lesion".).

●Hepatic angiography of the lesions shows accumulation of contrast in the late arterial or parenchymal phase and retention of contrast through the early venous phase [35,44,50]. Noninvasive diagnostic tests such as CT angiography are now preferred for the evaluation of hepatic lesions with vascular features.

DIAGNOSIS — The diagnosis of peliosis hepatis is suspected based on imaging findings particularly when an associated condition is present (eg, history of renal transplant or corticosteroid therapy). A definitive diagnosis of peliosis hepatis requires histologic examination acquired through liver biopsy [16,51,52]. Patients with suspected bacillary peliosis may have skin lesions which can be biopsied, thereby avoiding a liver biopsy.

A definitive diagnosis is not always required. For patients with incidental imaging findings consistent with peliosis, it may be reasonable to defer biopsy which may be dangerous and to follow with serial imaging studies and liver function tests. (See 'Monitoring' below.)

In contrast, when imaging findings suggest possible malignancy, a liver biopsy is indicated.

Liver biopsy — When a definitive diagnosis is required, histologic examination of liver tissue along with compatible clinical presentation and imaging findings establishes the diagnosis.

Successful percutaneous needle biopsies of a suspected peliotic lesion are described, but carry a significant risk of bleeding given the vascular nature of peliosis hepatis [53]. In some case reports an intraoperative approach to liver biopsy with or without ultrasound guidance was used to reduce the risk of severe hemorrhage [5,54,55]. Visualization of the liver surface at the time of surgery can also reveal findings suggestive of peliosis hepatis.

Pathologic findings — Microscopic examination of peliosis hepatis reveals round or oval cavities that are randomly distributed between areas of normal hepatic parenchyma. The cavities communicate with sinusoids that are sometimes dilated. Dilation of space of Disse may be seen. Red blood cells can be seen in the peliotic cysts, dilated sinusoids, and space of Disse (picture 1A-B) [4,56].

Microscopically, there are two types of peliosis:

●Parenchymal peliosis, characterized by cavities that are not lined by sinusoidal cells or fibrous tissue

●Phlebectatic peliosis, characterized by cavities that are lined by endothelium or fibrosis

Both microscopic forms can be seen in the same liver and likely represent different stages of the disease [9].

The microscopic appearance of peliosis hepatis may resemble secondary hepatic congestion due to sinusoidal obstruction syndrome (formerly known as hepatic veno-occlusive disease) or Budd-Chiari syndrome except that the lesions of peliosis hepatis are randomly distributed in the liver parenchyma while the other disorders are associated with sinusoidal dilation in the centrilobular areas (zone 3) [3].

When bacillary peliosis is suspected (eg, in a patient with HIV), special diagnostic studies are ordered to identify the pathogen. (See "Microbiologic diagnosis of Bartonella infections", section on 'Approach to diagnosis'.).

DIFFERENTIAL DIAGNOSIS — The radiographic appearance of the hepatic vascular lesion is not specific for peliosis hepatis and alternative diagnoses should be considered. The differential diagnosis includes hypervascular tumors such as hepatocellular carcinoma and hepatic abscess [57]. On imaging studies, the differential diagnosis includes other focal liver lesions including adenoma, hemangioma, focal nodular hyperplasia, abscess, hypervascular metastatic lesions, and hepatocellular carcinoma. When malignancy is suggested by imaging studies, a biopsy is usually performed and distinguishes tumor from peliosis [58]. (See "Approach to the adult patient with an incidental solid liver lesion".)

As noted above, the differential diagnosis on microscopic examination of liver specimens includes sinusoidal obstruction syndrome, heart failure, and Budd-Chiari syndrome. The clinical setting (ie, bone marrow transplant) and findings on imaging studies (ie, hepatic vein thrombosis) can help distinguish among these entities. (See "Budd-Chiari syndrome: Epidemiology, clinical manifestations, and diagnosis", section on 'Diagnosis' and "Hepatic sinusoidal obstruction syndrome (veno-occlusive disease) in adults", section on 'Diagnosis/Differential diagnosis'.).

TREATMENT — There is no specific treatment of peliosis hepatis except for the bacillary form. This is discussed separately. (See "Bartonella infections in people with HIV".)

Monitoring — There are no clear guidelines for monitoring patients with peliosis hepatis. We monitor liver function tests and obtain a repeat ultrasound every 12 months to ensure stability of the lesion. For larger lesions at risk for hemorrhage or rupture, we suggest monitoring with ultrasound on a more frequent basis than annually.

Treating associated condition — Discontinuation of the causative agent or treatment of the underlying condition (table 1) may result in regression of the hepatic lesions.

Case reports have documented regression of peliosis hepatis after discontinuation of an implicated drug [30,36,59]. Such patients have had complete resolution of the clinical, laboratory, and radiographic abnormalities. By contrast, the disease tended to progress in patients in whom an implicated drug was continued [60,61].

Bacillary peliosis hepatis responds to treatment with antibiotics, but untreated cases are associated with a high mortality rate. Hepatic lesions frequently recur even with the appropriate course of treatment [62]. (See "Bartonella infections in people with HIV".)

Managing complications — For patients whose lesions progress and are associated with moderate to severe symptoms or are judged to be at risk for rupture, surgical therapy can be considered [5,16,17].

Patients with portal hypertension should be managed similarly to those with portal hypertension caused by other conditions. (See "Portal hypertension in adults", section on 'Treatment'.)

Portal hypertension in the setting of peliosis hepatis may be complicated by ascites, portopulmonary hypertension, or hepatopulmonary syndrome [31,34,63]. (See "Portal hypertension in adults", section on 'Clinical manifestations'.)

Rare cases of liver failure from peliosis hepatis have required liver transplantation [6,34].

Patients presenting with hepatic rupture or intraperitoneal hemorrhage due to peliosis hepatis have required emergent surgery for hepatic resection but successful angiographic intervention for transcatheter embolization has also been described [50,64]. (See "Management of hepatic trauma in adults", section on 'Hepatic embolization'.)

PROGNOSIS — The natural history of peliosis hepatis is not well defined. There have been several outcomes described:

●Lesions discovered incidentally on imaging remain asymptomatic.

●Peliosis hepatis may progress to complications including cholestasis, portal hypertension, liver failure, and hepatic rupture [33]. Case reports have documented progression of disease in patients in whom an implicated drug was continued [60,61].

●Lesions regress after drug withdrawal or treatment of underlying infection.

SUMMARY AND RECOMMENDATIONS

●Peliosis hepatis is a rare vascular condition of the liver characterized by the presence of cystic blood-filled cavities distributed randomly throughout the liver parenchyma. (See 'Clinical features' above.)

●Peliosis hepatis has been associated with multiple drugs and chemicals, infections, hematologic disorders, malignancies, renal transplantation, HIV infection, and a variety of other conditions (table 1). A bacillary form is caused by Bartonella henselae. An etiology remains unclear in 20 to 50 percent of patients. (See 'Etiology' above.)

●Peliosis hepatis may be discovered incidentally during evaluation of abnormal liver function tests or on abdominal imaging. A subset of patients develops clinical features attributable to peliosis hepatis, which may include abdominal pain, jaundice, hepatomegaly, portal hypertension, liver failure, and rupture of the cyst with intraperitoneal hemorrhage. (See 'Clinical features' above.)

●The diagnosis of peliosis hepatis requires a high degree of clinical suspicion. Various imaging modalities may help in establishing the diagnosis in the appropriate clinical setting. (See 'Imaging studies' above.)

●Liver biopsy of a peliotic lesion for histologic examination confirms the diagnosis, but percutaneous liver biopsy carries significant risk of hemorrhage due to the vascular nature of the lesion. Intraoperative liver biopsy may be a safer alternative if histologic confirmation is needed, particularly in the setting of a larger lesion at greater risk for hemorrhage. (See 'Liver biopsy' above.)

●Withdrawal of the offending drug (ie, corticosteroids, oral contraceptives, azathioprine) or treatment of the underlying condition may lead to regression of the liver lesions. (See 'Treatment' above.)

●There is no specific treatment for peliosis hepatis except for the bacillary form. (See "Bartonella infections in people with HIV".)