Case 1 -

Portal Hypertensive Biliopathy Laura Lamps University of Arkansas Little Rock, AR

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Clinical History The patient was a 60 year old white man with rheumatoid arthritis. He presented to a local physician with new onset jaundice and thrombocytopenia. A liver biopsy was performed, and the pathologist thought the biopsy had features of chronic biliary disease, but could not classify the biliary disease further. He was evaluated in the hospital for a week. He then presented several days after discharge to a hepatologist to whom he had been referred. He had worsening ascites, acute renal failure, and mild encephalopathy. His bilirubin was 43 mg/dl. Review of his complete medical records at that time, which had been previously unavailable, gave a vague history of noncirrhotic portal hypertension. An MRI scan subsequently showed chronic portal vein thrombosis, multiple superior mesenteric vein and splenic vein collaterals, and mild irregularities of the common bile duct. His bilirubin rose to greater than 60 mg/dl, and other labs included an AST of 418 IU/L, ALT 423 IU/L, and alkaline phosphatase of 202 IU/L. A second liver biopsy was performed. Case 1 - Figure 1 The initial liver biopsy in this patient showed a cholestatic hepatitis with portal edema, interlobular bile duct atrophy, and cholangiolar proliferation, suggesting large bile duct obstruction. Case 1 - Figure 2 This higher power view of a portal tract in the patient's first biopsy shows edema, ductal duplication, and cholangiolar proliferation. Cholestasis is prominent. It is difficult to appreciate portal venules as well. Case 1 - Figure 3 Another portal tract from the patient's first biopsy shows interlobular bile duct epithelial disarray. A portal venule is visible in this portal tract. The patient also had increased iron of unknown etiology. Case 1 - Figure 4 A low power view of the second biopsy shows a marked cholestatic hepatitis with worsening cholestasis and lobular inflammation. Case 1 - Figure 5 This portal tract in the second biopsy shows an intact bile duct and relatively sparse inflammation. Portal venules are slit-like but are easily seen. Case 1 - Figure 6 Another portal tract from the second biopsy shows a markedly atrophic interlobular bile duct and cholangiolar proliferation with admixed neutrophils. Portal venules are difficult to appreciate. Note the marked cholestasis. Case 1 - Figure 7 A trichrome stain from the second biopsy highlights a portal tract with irregular periportal fibrosis, and no bile duct. A small slit-like portal venule can be seen. Case 1 - Figure 8 A high power view of a portal tract in the second biopsy shows bile duct epithelial disarray, an apoptotic epithelial cell, and marked cholangiolar proliferation with admixed neutrophils. Introduction: Portal hypertensive biliopathy (PHB) is a rare condition characterized by abnormalities of the biliary tree in patients with portal hypertension. It occurs most often in patients with extrahepatic portal vein thrombosis. The biliary alterations may affect both extra- and intrahepatic bile ducts. These changes occasionally become significant enough to cause signs and symptoms of biliary obstruction, and may also contribute to the development of choledocholithiasis. The natural history of this disease is ill defined, and the clinical spectrum ranges from asymptomatic patients to those with severe biliary obstruction, intractable jaundice, and death, as in the case illustrated here. Pathological/Microscopic Findings and any Immunohistochemical or Other Studies: This condition is rare, and although there is a fair amount in the clinical and radiographic literature describing PHB, there is virtually nothing in the pathology literature detailing the histologic findings. Reportedly, liver biopsy may be normal, especially early in the course of disease. Over time, biopsies may show nonspecific portal inflammation, as well as portal venous changes suggestive of portal vein thrombosis including dilatation of portal veins with "herniation" into the hepatic parenchyma, duplication and capillarization of portal venules, loss of parenchyma between portal and central veins, and ultimately loss of portal venules. The biliary lesions may mimic those seen in primary sclerosing cholangitis, biliary ischemia, and chronic large bile duct obstruction. Findings include variable portal inflammation and edema, interlobular bile duct duplication, marked cholangiolar proliferation, and cholestasis. The cholestasis may be marked, with associated lobular inflammation and hepatocyte dropout. Both canalicular and hepatocellular cholestasis may be prominent. Interlobular bile ducts show features of injury including epithelial disarray, cytoplasmic vacuolization, and apoptosis of individual epithelial cells. Over time, there is atrophy of interlobular bile ducts, and duct dropout. Periportal copper deposition is variably present. The combination of bile duct damage and cholestasis in a patient with portal vein thrombosis should raise the strong possibility of PHB. Unfortunately, however, the presence of a chronic portal vein thrombosis may be unknown at the time of biopsy. Differential Diagnoses: The differential diagnosis primarily includes other causes of chronic obstructive biliary disease, including primary sclerosing cholangitis, biliary ischemia, and chronic large bile duct obstruction from stones or other mechanical causes. Final Diagnosis: Portal Hypertensive Biliopathy Case Discussion: Pathogenesis and Contributing Factors Portal vein thrombosis is present in up to one third of patients with cirrhosis, and occasionally in noncirrhotic patients with predisposing conditions including hematologic diseases, coagulopathy, intra-abdominal infections, trauma, chronic pancreatitis, omphalitis (in infants), or surgical manipulation of the portal vein. The venous drainage of the biliary tree is of particular importance to the development of PHB. The venous drainage of the common bile duct is primarily achieved by veins that ascend along its course, forming the epicholedochal venous plexus and the paracholedochal venous plexus. These plexi form fine reticular venous networks along the common bile duct and hepatic duct, and are in intimate contact with the outer surfaces of the ducts. Portal venous thrombosis leads to the development of portal hypertension, which in turn leads to the development of venous collaterals in many sites. The development of varices in association with the venous plexi that drain the common bile duct and hepatic ducts can be particularly problematic. Because the bile duct walls are thin and pliable, the varices can easily protrude into the lumen, altering the normal smooth intraluminal surface and producing irregular mural changes. Ultimately, PHB is believed to be caused by compression of the common bile duct by these peribiliary varices, by the thrombus itself, or by a portal cavernoma (portal vein thrombosis with cavernous transformation, or tortuous collateral veins around and inside the thrombus that appear as a compensatory mechanism bypassing the obstructed vein). The situation may be further complicated by the development of biliary stones, which occurs in approximately 17% of patients. The final common pathway of injury is the development of biliary strictures, either from ischemia, prolonged compression of the biliary tree, or both. Clinical Findings Approximately 80-100% of patients with portal vein thrombosis have evidence of PHB on biliary imaging studies, and reportedly 5-20% become symptomatic due to biliary obstruction, infection, or choledocholithiasis. Symptomatic PHB is most commonly found in adults, although it has been described in children. As above, many patients are asymptomatic even though they have characteristic imaging findings. The predominant signs and symptoms of PHB are related to partial or complete bile duct obstruction. Jaundice is by far the most common finding at presentation. Jaundice may be accompanied by abdominal pain and fever, particularly late in the course of disease, when bacterial cholangitis may develop due to chronic biliary obstruction. Alterations of liver tests most commonly include elevated alkaline phosphatase, GGT, and bilirubin. Patients may show evidence of portal hypertension as well, including varices at other sites with associated gastrointestinal bleeding, and ascites. Imaging Studies Although PHB is most often a sequel of longstanding portal vein thrombosis, imaging findings have been detected as early as one year after acute portal vein thrombosis. Cholangiography is essential to diagnosis (either ERCP or MRCP). The imaging findings are very variable, and include biliary stenosis, an irregular or wavy appearance of the bile duct walls, "pruning" of the biliary tree, and proximal dilatation of the bile ducts. Many of these radiographic findings mimic primary sclerosing cholangitis, and some findings may mimic Caroli's disease, especially in children. Transabadominal ultrasonography is helpful in detecting portal cavernomas and the presence of venous collaterals. Pathologic Evaluation and Differential Diagnosis Ultimately, for the pathologist, the diagnosis of PHB relies upon recognition of the correct clinical context and the exclusion of other causes of biliary disease. This may be difficult, as in this case, when the presence of a chronic portal vein thrombosis is only found late in the course of disease. As above, the differential diagnosis primarily includes other causes of biliary disease, including primary sclerosing cholangitis, biliary ischemia, and chronic large bile duct obstruction from stones or other mechanical causes. The most helpful way to distinguish PSC from PHB is the clinical history of portal vein thrombosis in the latter. The presence of chronic idiopathic inflammatory bowel disease in the former may be helpful as well. In addition, patients with PHB usually present with jaundice, which is not usually the presenting finding in PSC. However, this may be a very difficult differential diagnosis to resolve without the history of portal vein thrombosis. Ischemic bile duct injury is almost always seen in the context of previous liver transplantation or hepatobiliary surgery, and this information ( as well as the history of portal vein thrombosis in PHB) can be very helpful in distinguishing between ischemic bile duct injury and PHB. Imaging studies are critical in distinguishing mechanical large bile duct obstruction from PHB, as is (again) the presence of a portal vein thrombus in the latter. The portal edema and neutrophilic infiltrate associated with large bile duct obstruction may be prominent in cases of PHB, especially in patients with superimposed cholangitis. Hepatic venous outflow obstruction (HVOO) may also produce histologic changes that mimic biliary obstruction, including portal expansion of bile ductular proliferation, reactive interlobular bile duct changes, lymphocytic cholangitis, and portal/periportal fibrosis. The presence of zone 3 sinusoidal dilatation with extravasation of red blood cells into the hepatic plates should alert the pathologist to the presence of HVOO. These patients often have elevated serum alkaline phosphatase, and GGT, but imaging of the biliary tree is normal. In children, the imaging findings of Caroli's disease or syndrome can occasionally mimic PHB. The absence of congenital hepatic fibrosis and the involvement of the entire liver or most of a lobe by the lesions of Caroli's can help distinguish between the two. In addition, portal vein thrombosis is very rare in children. Review of the Literature/Treatment Options (if applicable): Effective therapy depends on both decompression of the biliary tree and treatment of the portal hypertension. Short-term biliary decompression may be achieved by ERCP with balloon dilatation and stent placement. Ultimately, some form of portal-systemic shunt surgery is usually required for long-term resolution. However, extensive vascular thrombosis may preclude surgery in some cases. Conclusion(s): Patients with portal hypertension and features of biliary obstruction (clinical, radiographic, and/or histologic) should provoke a high index of suspicion for PHB. Alternatively, although fortunately this is only a rare occurrence, patients with unexplained biliary obstruction should be evaluated for the possibility of occult portal vein thrombosis. A high index of suspicion for PHB and early intervention are critical in symptomatic patients. References: Abdalian R, Heathcote EJ. 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