Intrahepatic portal cavernoma as an indication for liver transplantation

LIVER TRANSPLANTATION 13:1312-1316, 2007

ORIGINAL ARTICLE

Intrahepatic Portal Cavernoma as an Indication for Liver Transplantation Cristina H. Hajdu,1 Takahiro Murakami,2 Thomas Diflo,2 Bachir Taouli,3 Jordan Laser,1 Lewis Teperman,2 and Lydia M. Petrovic1 Department of 1Pathology, 2Department of Surgery, Division of Liver Transplantation, and 3Department of Radiology, New York University School of Medicine, New York, NY

Cavernous transformation of the portal vein (portal cavernoma) consists of a periportal or/and intrahepatic venous collateral network, developed as a result of acute or long-standing portal vein thrombosis. Better control of hemorrhagic and thrombotic complications in the patients with portal cavernoma substantially improves their life span and the clinical outcome. However, biliary complications that occur in the late stages of this disease have been recently recognized as challenging management issues because they recur and are difficult to treat. Because of the relatively small number of the patients with cholangiopathy due to portal cavernoma, there is no current standardized treatment approach. We report the case of a predominantly intrahepatic portal cavernoma occurring in a patient with chronic idiopathic portal vein thrombosis, which led to severe cholangiopathy that mimicked primary sclerosing cholangitis and cholangiocarcinoma, was unresponsive to endoscopic stent placement, and finally required liver transplantation. Liver Transpl 13:1312-1316, 2007. © 2007 AASLD. Received December 23, 2006; accepted May 1, 2007.

Cavernous transformation of the portal vein (portal cavernoma) is a rare condition consisting of portosystemic or portoportal collaterals that substitute for a thrombosed portal vein.1,2 Local factors (omphalitis, umbilical vein catheterization, intra-abdominal inflammatory process, abdominal trauma, malignancy invading or compressing the portal vein) and/or general thrombophilic conditions (myeloproliferative disorders, inherited deficiencies of natural anticoagulants such as antithrombin III, protein C and S, activated protein C resistance, and prothrombin gene G20210A mutation) have all been implicated in the pathogenesis of this condition. However, in up to 50% of the cases, the cause of portal cavernoma remains unexplained.3,4 Cavernous transformation of the portal vein can occur as early as 6-20 days after the thrombotic event, even if a partial recanalization of the thrombus develops.5 To overcome the obstructed portal vein, a hepatopetal collateral network develops within the hepatoduodenal and hepatocolic ligaments, around the common bile duct, hepatic ducts, and gallbladder, draining into midsized intrahepatic portal veins. This results in formation of paracholedochal varices (portal

cavernoma) that may extend into the liver (intrahepatic cavernoma) or that may lead to the formation of gallbladder varices.2,4,5

PATIENT AND METHODS The patient, a 43-year-old Indian man, had a longstanding (17 years) history of portal hypertension. The patient experienced his first episode of hematemesis at the age of 27. At that time, an upper gastrointestinal endoscopy revealed esophageal varices, and abdominal ultrasound documented chronic portal hypertension with periportal enlarged collateral vessels and splenomegaly, suggestive of partial portal venous thrombosis. A baseline liver biopsy was performed. Findings revealed no significant inflammation or fibrosis and no evidence of chronic hepatitis or biliary disease. Between 1989 and 1991, the patient experienced several episodes of hematemesis treated with sclerotherapy and ␤-blockers. A low platelet count prompted blood workup and bone marrow biopsies; findings were within normal limits. In 2000, the patient experienced the first episode of cholangitis, and in 2002, he was

Address reprint requests to Lydia M. Petrovic, MD, Department of Pathology, NYU School of Medicine, 560 First Avenue, TH461 New York, NY, 10016. Telephone: 212-263-7932; FAX: 212-263-7916; E-mail: [email protected] DOI 10.1002/lt.21243 Published online in Wiley InterScience (www.interscience.wiley.com).

© 2007 American Association for the Study of Liver Diseases.

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Figure 1. (a-d): MR images (axial T2-weighted 1a and 1b, coronal MR cholangiogram 1c, and axial post-contrast T1-weighted images 1d) show diffuse intra-hepatic biliary distention (long arrows on 1a-c) with an aneurysmal portal vein containing chronic thrombi (long arrows on 1d). Peribiliary soft tissue is present on T2-weighted images (short arrows on 1a-1b).

diagnosed with non–insulin-dependent diabetes mellitus. Therapy with Prandin was initiated. From 2003 to 2005, a steady increase in liver enzymes was noted, and repeated episodes of cholangitis (jaundice, fever, and hemobilia) prompted further diagnostic and therapeutic evaluations, including endoscopic retrograde cholangiopancreatography and biliary stenting. In 2005, the patient’s condition further deteriorated. His liver function tests were markedly increased (total bilirubin 11.8 mg/dL, aspartate aminotransferase 117 u/L, alanine aminotransferase 65 u/L, alkaline phosphatase 319 u/L), and his symptoms did not improve after bile duct stent insertion and medical treatment, which raised the suspicion of an intrahepatic neoplastic process.

RESULTS Magnetic Resonance Imaging Findings A magnetic resonance (MR) cholangiogram showed diffuse intrahepatic biliary distension and aneurysmal dilatation of the portal vein with intraluminal-filling defects compatible with old thrombi (Fig. 1). The

intrahepatic right and left portal vein branches were patent. There was extensive peribiliary soft tissue showing enhancement at the portal venous phase, compatible with extensive peribiliary varices extending from the hilum and around the intrahepatic biliary tree (Figs. 1 and 2). No filling defects were noted in the biliary system. There was a small rim-enhancing lesion in the right lobe, compatible with an abscess, but no other intrahepatic masses were noted. Manifestations of portal hypertension included splenomegaly, GammaGandy bodies, mild ascites, and varices (gastroesophageal, perisplenic, and periportal). The patient was listed for a liver transplant and underwent orthotopic liver transplantation in January 2006.

Liver Transplantation Some technical difficulties were encountered at the time of hilar dissection as a result of inflammation and fibrosis around the common hepatic duct. In particular, the separation of the bile duct from the large portal vein and the dissection of hepatic arteries were exceedingly laborious. After dissection and ligation of the hepatic

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merous vascular channels in the porta hepatis that extended into the posterior and middle part of the right lobe. The tortuous, closely packed veins and venules formed a spongelike mass lesion in the middle of the right lobe that measured approximately 4.5 by 2.5 cm (Fig. 3). Some of the dilated veins contained old, partially organized thrombi. Hilar fibrosis was also noted, and the branches of the hepatic ducts showed segmental dilatation of the lumen and inspissated bile. In addition, 2 areas of abscess formation were seen in the right lobe that were associated with the dilated bile ducts. The largest measured 1.3 by 1.2 cm.

Microscopic Findings

Figure 2. (a-b): MR images (axial post-contrast T1-weighted images at the arterial phase 2a, portal venous phase 2b) show extensive peribiliary enhancement at the portal venous phase, compatible with a portal cavernoma (arrows).

arteries, the portal vein and bile duct were clamped en masse, and after division of these structures, the bile duct was identified by the presence of an indwelling stent. The cold ischemic time was 7 1/2 hours. The immediate postoperative course was unremarkable. One year after transplantation, the patient is doing well.

Macroscopic Findings The explanted liver measured 22 by 18 by 10 cm and weighed 1,620 g. Although the overall liver shape was preserved, the right lobe appeared dominant and globular, and the left lobe appeared somewhat atrophic. The liver was not cirrhotic. The liver hilum was remarkable for an enlarged irregularly dilated portal vein measuring approximately 5.0 cm in its greatest diameter. The portal vein was patent; however, the stented common hepatic duct appeared to emerge from the aneurysmal portal vein (Fig. 3). Serially sectioned (0.5-cm intervals) liver samples revealed nu-

Histologic examination revealed an irregularly thickened portal vein wall with partially organized thrombosis at porta hepatis. A complex network of tortuous, closely packed veins and venules, some with thrombosed lumen, was seen in the right lobe of the liver parenchyma. The adjacent large and medium size bile ducts encased by or adjacent to the portal cavernoma showed a spectrum of changes, including dilated or compressed irregular lumens with reactive biliary epithelium, bile lakes, focally acute cholangitis with an abscess formation, and periductal fibrosis. In some areas, it was evident that the dilated and thrombosed veins were directly compressing bile ducts (Fig. 4). A mild mixed inflammatory infiltrate was present in most of the portal tracts, associated with portal, periportal, and in some areas early portal-portal bridging fibrosis, with mild to moderate bile duct damage and focal ductular reaction (proliferation). The changes were similar to those seen in primary sclerosing cholangitis (Fig. 5). There was no evidence of dysplasia or malignancy. These findings were interpreted as sclerosing cholangitis, stage II/IV, which resulted from cavernous transformation (portal cavernoma) of the portal vein.

DISCUSSION Balfour and Stewart first described portal cavernoma in 1869 as thrombosis and varicose dilatation of the portal vein leading to splenomegaly and ascites. Kobrich coined the term “cavernoma” to describe the peculiar spongy appearance of the portal vein and the phrase “cavernomatous transformation of the portal vein” to imply that this condition followed thrombosis of the portal vein.5 The difficulties encountered during the surgical treatment of this entity were first recognized in 1944. The patient was a 31-year-old woman, diagnosed on the basis of clinical findings (jaundice, progressive alteration of general status, and unexplained splenomegaly) and radiologic findings with an adenocarcinoma of the head of the pancreas. During the laparotomy, instead of intrapancreatic bile duct obstruction, a vascular mass in the porta hepatis encasing and compressing the biliary tree was discovered. To release the pressure on the

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Figure 3. (a-b): a) Cut section of the explanted liver showing intrahepatic cavernoma. b) Dilated portal vein encasing the stented common hepatic duct.

Figure 4. (a-b): a) Intrahepatic dilated and tortuous portal veins compressing midsize bile ducts (Hematoxylin and Eosin, original magnification ⴛ200). b) Periductal acute and chronic inflammation, fibrosis and biliary lake formation secondary to portal cavernoma (Hematoxylin and Eosin, original magnification ⴛ100).

Figure 5. Portal, periportal and focal portal to portal bridging fibrosis consistent with stage II/IV sclerosing cholangitis secondary to portal cavernoma (Trichrome stain, original magnification ⴛ100).

biliary tree, cavernoma vessels were ligated that temporarily resolved the biliary obstruction.3 The pathogenesis of this condition remains elusive. The results of several autopsies6-8 and imaging studies5,9,10,11 favor a mechanical-obstructive hypothesis in the formation of portal cavernoma over the congenital (malformation that replaces a nondeveloped portal vein) or neoplastic (hemangioma) hypotheses. In the acute phase of portal vein thrombosis, immediate vasodilatation of the hepatic arterial bed and a patent mesenteric collateral circulation compensates for the portal flow obstruction. However, the extension

of the thrombus in the mesenteric venous arches in association with reflex arteriolar vasoconstriction may result in bowel ischemia of varying severity and duration. The patient may be asymptomatic or may experience acute abdominal pain and fever, although rarely ascites. Within a few days, even with partial recanalization of the thrombus, a hepatopetal collateral venous system (portal cavernoma) will develop as a second compensatory mechanism. However, in time, slow blood flow through tortuous veins, new thromboses, permanent redistribution of the blood, and periportal fibrosis work together to increase the blood pressure and lead to hepatofugal circulation. Common clinical manifestations of the portal hypertension are esophageal or gastric varices and splenomegaly. The occurrence of ascites and encephalopathy in patients with pure portal cavernoma is uncommon, and liver function tests are essentially normal.4,5,12,13 With long-standing portal cavernoma, the venous collateral network may compress or encase the biliary tree, resulting in extrahepatic and intrahepatic bile duct damage. Imaging studies that are sensitive in detection of bile duct injury (ultrasound, endoscopic retrograde cholangiopancreatography, MR cholangiography) permit systematic follow-up and a better characterization of the progressive bile duct damage in patients with portal cavernoma. Two theories of biliary abnormalities that result from portal cavernoma are postulated: mechanical compression and ischemic injury. The proponents of the latter hypothesis believe that vascular injury at the time of portal vein thrombosis may cause ischemic necrosis of the bile ducts. Vascular injury can also occur as a result of thrombosis of the veins drain-

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ing the bile ducts or extension of thrombosis to the arterial network supplying the bile ducts.15 Condat et al.9 studied 25 patients with portal cavernoma by MR cholangiography coupled with MR portography and showed that in all cases, biliary abnormalities were the result of long-standing pressure caused by dilated veins. Moreover, they showed that none of the patients developed bile duct stenosis before the development of cavernoma. Although mechanical obstruction seems plausible and biliary tree indentation or caliber irregularities appear to vanish after shunt surgery, biliary tree angulations and ectasias do not reverse after this procedure, indicating fixed obstruction due to ongoing ischemia and/or fibrous scarring. The 2 hypotheses are not mutually exclusive and they can each explain, in part, the biliary involvement in patients with portal cavernoma.10,11 Cholangiographic abnormalities are noted in up to 90% of patients with portal cavernoma. Surprisingly, clinically important manifestations of biliary obstruction occur in only 25% of cases, and when present, they are severe and can include complications like ascending cholangitis, acute cholecystitis, and chronic obstructive jaundice potentially progressing to secondary biliary cirrhosis and requiring prompt treatment.9 Although there is no standardized treatment approach, the following algorithm is generally accepted. The first line of surgical treatment includes endoscopic stone extraction or endoscopic dilatation of the biliary tree strictures with or without stent insertion. As the second line, a portosystemic shunt is recommended, although this is not often feasible because of the poor quality of the splanchnic veins. Biliary intestinal bypass may be considered as the third line of therapy, although it is known to be associated with a high mortality rate as a result of hemorrhage and biliary infection.1,4,9,11,14,15 In conclusion, we present the case of a young patient with a long (17 year) history of noncirrhotic portal hypertension and cavernous transformation of the portal vein (predominantly intrahepatic portal cavernoma). Ultimately, the patient developed portal cavernoma–associated cholangiopathy not alleviated by repeated endoscopic stent insertion, clinically mimicking cholangiocarcinoma. To our knowledge, this is the first case reported in the English-language literature of a tumorlike, predominantly intrahepatic portal cavernoma complicated with chronic cholangiopathy and treated with liver transplantation. Although portal cavernoma is a rare condition, it should be recognized as one of the indications for liver transplantation.

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