The most common indication for orthotopic liver. Liver Transplantation for Severe Intrahepatic Noncirrhotic Portal Hypertension

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1 Liver Transplantation for Severe Intrahepatic Noncirrhotic Portal Hypertension Alyssa M. Krasinskas, 1 Bijan Eghtesad, 2 Patrick S. Kamath, 3 Anthony J. Demetris, 1 and Susan C. Abraham 4 See Editorial on Page 610 Intrahepatic noncirrhotic portal hypertension can be idiopathic or associated with known toxic, developmental, vascular, or biliary tract diseases. Most patients are successfully managed medically or with shunting procedures. The goal of this study was to explore the reasons some patients require orthotopic liver transplantation (OLT). The clinical features, gross and microscopic liver explant pathology, and posttransplantation course in 16 patients who underwent OLT for intrahepatic noncirrhotic portal hypertension were studied. There were 11 men and 5 women with a mean age of 47 years. Clinical manifestations included gastrointestinal varices (n 12), ascites (n 8), encephalopathy (n 3), and hepatopulmonary syndrome (n 3). Cirrhosis was misdiagnosed clinically, radiographically and/or histologically in 13 patients (81%). Grossly, liver explants weighed a mean of 1,100 g, and 12 had a nodular appearance. Histologically, all 16 livers had portal tract vascular abnormalities, 15 had nodular regenerative hyperplasia (NRH), and 9 had incomplete septal cirrhosis. After OLT, mild NRH features were noted in 2 patients, and 1 of these patients developed evidence of portal hypertension. This study demonstrates that a subset of patients with intrahepatic noncirrhotic portal hypertension have severe symptoms requiring OLT. Accurate pre-olt diagnosis is frequently difficult at advanced stages of the disease; 81% of our patients carried a diagnosis of cirrhosis. Morphologically, the explanted livers showed evidence of vascular abnormalities, NRH, and increased fibrosis, but not cirrhosis. Importantly, however, a diagnosis of cirrhosis is not required in this group of patients to qualify them for OLT, and these patients have good long-term graft function after OLT. (Liver Transpl 2005;11: ) The most common indication for orthotopic liver transplantation (OLT) is end-stage liver disease that has failed standard medical and surgical therapy. The vast majority of such patients have cirrhosis. The major clinical manifestations of cirrhosis are the result of portal hypertension and include gastrointestinal varices, portal hypertensive gastropathy, splenomegaly, and ascites. In a minority of cases, portal hypertension is not caused by cirrhosis but results from increased resistance to portal blood flow at the prehepatic (e.g., portal vein thrombosis), intrahepatic, or posthepatic (e.g., Budd-Chiari syndrome) levels. The intrahepatic form is known by different terms, including noncirrhotic portal hypertension (NCPH), idiopathic portal hypertension, and hepatoportal sclerosis. Intrahepatic causes of NCPH can have a variety of morphologic patterns at histologic examination. These include: nodular regenerative hyperplasia (NRH), in which there is parenchymal nodularity caused by alternating hypertrophic and atrophic hepatocyte cords in the absence of significant fibrosis 1-6 ; incomplete septal cirrhosis (ISC), in which there is portal and periportal fibrosis without true cirrhosis 7,8 ; and obliterative portal venopathy (hepatoportal sclerosis), in which there is a reduction in the number of portal vein branches and hypertrophy of the smooth muscle wall of the portal veins. 9,10 These patterns can coexist in any given patient with intrahepatic NCPH. 7,11,12 The etiology of NCPH can be idiopathic or it can occur in association with a variety of developmental, toxic, vascular, collagen vascular, or biliary tract diseases. The complications of NCPH, mainly variceal bleeding and ascites, are managed with medical therapy or with portosystemic shunting. In some patients with NCPH, the complications of portal hypertension are sufficiently severe to warrant liver transplantation. 2,7,13-17 In other patients with NCPH, the diagnosis is missed, and patients undergo transplantation for a presumptive diagnosis of cirrhosis. In this study, we examine the clinical features, gross and microscopic liver explant pathology, and posttransplantation course Abbreviations: OLT, orthotopic liver transplantation; NCPH, noncirrhotic portal hypertension; NRH, nodular regenerative hyperplasia; ISC, incomplete septal cirrhosis. From the Departments of 1 Pathology and 2 Surgery (Division of Transplant Surgery), University of Pittsburgh, PA; and the 3 Department of Gastroenterology and Hepatology and 4 Division of Anatomic Pathology, Mayo Clinic and Foundation, Rochester, MN. Presented as a poster at the United States and Canadian Academy of Pathology 93rd Annual Meeting in Vancouver, British Columbia, Canada, March 6-12, Address reprint requests to Alyssa M. Krasinskas, MD, Department of Pathology, University of Pittsburgh Medical Center, Presbyterian Hospital, A610, 200 Lothrop St., Pittsburgh, PA Telephone: ; FAX: ; krasinskasam@upmc.edu Copyright 2005 by the American Association for the Study of Liver Diseases Published online in Wiley InterScience ( DOI /lt Liver Transplantation, Vol 11, No 6 (June), 2005: pp

2 628 Krasinskas et al. of 16 patients who underwent OLT because of severe intrahepatic NCPH. We demonstrate that NCPH can mimic cirrhosis clinically, radiographically, and on pretransplantation liver biopsies, and that severe cases of NCPH require OLT. We also show that patients with severe NCPH who undergo OLT do well after transplantation and tend not to develop recurrent symptoms of portal hypertension. Patients and Methods In an attempt to find cases of NCPH, the surgical pathology databases at the Mayo Clinic in Rochester, MN (from 1995 to 2003), and the University of Pittsburgh Medical Center in Pittsburgh, PA (from 1988 to 2003), were searched for liver explants that failed to show cirrhotic morphology. Cases of fulminant hepatic failure and hepatic malignancy were excluded. By definition, cases of postsinusoidal (Budd-Chiari syndrome) and prehepatic (primary occlusive portal vein thrombosis) portal hypertension were excluded. Since a significant minority of patients with known biliary disease (primary biliary cirrhosis, primary sclerosing cholangitis) undergo OLT prior to developing cirrhosis, these patients were also excluded from this study. A total of 16 cases (6 from the Mayo Clinic and 10 from the University of Pittsburgh Medical Center) fulfilled the criteria for inclusion in this study. Pretransplantation and posttransplantation de-identified clinical information was obtained from electronic and paper records. Archived, routine hematoxylin & eosin stained sections from all liver explants were reviewed, as well as at least 1 trichrome stain and often at least 1 reticulin stain on each case. Available pretransplantation and all posttransplantation biopsies were also reviewed. The institutional review boards at both the University of Pittsburgh Medical Center and the Mayo Clinic approved this study. Results Clinical Presentation and Pretransplantation Course Of the 16 cases included in this study, there were 11 men and 5 women, with a mean age at transplantation of 47 years (range: years). The pretransplantation diagnoses (indications for transplantation) were cryptogenic cirrhosis (n 7; 2 had known hepatotoxin exposure), azathioprine-associated liver injury following kidney transplantation (n 2), nonalcoholic and alcoholic fatty liver disease (n 2), nodular regenerative hyperplasia (n 1), methotrexate-associated cirrhosis for rheumatoid arthritis/still s disease (n 1), autoimmune hepatitis (n 1), genetic hemochromatosis (n 1), and viral hepatitis C (n 1). Thirteen patients Table 1. Clinical Sequelae of Portal Hypertension Number of patients (%) Gastrointestinal varices (esophageal in 11, 12 (75) gastric in 1)* Splenomegaly (1 patient was status 12 (75) postsplenectomy) Ascites 8 (50) Encephalopathy 3 (19) Hepatopulmonary syndrome 32 3 (19) Retroperitoneal collateral rupture 1 (6) *3 patients had known bleeding complications of their esophageal varices. (81%) had a pretransplantation diagnosis of cirrhosis; 12 (92%) of the 13 patients were diagnosed clinically with cirrhosis, 11 (85%) of the 13 patients showed radiological evidence of cirrhosis (13 patients had pretransplantation radiographic studies performed), and 4 (36%) of 11 patients had a diagnosis of cirrhosis made on pretransplantation liver biopsies (11 patients had pretransplantation liver biopsies performed). Nine patients had known associations with NCPH: rheumatoid arthritis (2 patients), Raynaud s syndrome (1 patient), azathioprine toxicity (2 patients), myelodysplasia (1 patient), lymphoproliferative disease (plasma cell dyscrasia, 1 patient), and hepatotoxin exposure (arsenic in 1 patient, unknown in 1 patient). All patients had complications of portal hypertension (Table 1). In 4 patients, portal hypertension was complicated by significant gastrointestinal bleeding (3 patients had esophageal variceal bleeds, and 1 patient had a hematoma form due to a retroperitoneal collateral bleed). Pretransplantation liver function tests were available in 15 patients. At least 1 liver function test (aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase and serum bilirubin) was elevated 1.5-fold or more in 8 (53%) of the 15 patients. Low platelet counts and albumin levels were present in 11 (73%) of 15 and 10 (67%) of 15 patients, respectively. All Model End-stage Liver Disease scores were less than 24 at the time of transplantation (mean: 15; range: 8-23). Pretransplantation workup revealed 1 patient with positive viral hepatitis C serology and 2 patients with positive antinuclear antibodies (1 patient had autoimmune hepatitis, and 1 patient had rheumatoid arthritis); no patients had positive tests for viral hepatitis B. Radiographically, 3 patients had nonocclusive portal vein thrombi (in 1 patient, the thrombus was associated

3 Intrahepatic Noncirrhotic Portal Hypertension 629 Table 2. Pathologic Features of Severe Noncirrhotic Portal Hypertension Observed in the Explanted Livers Feature Value Gross Pathology Explant weight 1100 g (range: g) Parenchymal nodularity, n (%) 12 (75) Nonocclusive extrahepatic portal vein thrombi and/or webs, n (%) 4 (25) Histopathology Portal tract vascular abnormalities, n (%) 16 (100) Portal tract venopathy, n (%) Portal vein sclerosis 13 (81) Aberrant portal venous branches 11 (69) Portal arteriopathy, n (%) 4 (25) Nodular regenerative hyperplasia, n (%) 15 (94) Incomplete septal fibrosis, n (%) 9 (56) Other findings, n (%) Focal/mild lymphocytic portal inflammation 10 (62) Focal/mild bile ductular proliferation 10 (62) Focal nodular hyperplasia 2 (12) with a mesocaval shunt). Two patients underwent pretransplantation portosystemic shunting procedures, including 1 transjugular intrahepatic portosystemic shunt and 1 mesocaval shunt; these patients did not have encephalopathy. The time between presentation with portal hypertension and liver transplantation ranged from 1 to 11 years, with a mean of 4.3 years. Pathology Gross Pathology The macroscopic findings are summarized in Table 2. Explanted livers were atrophic, weighing a mean of 1,100 g (range: 600-1,550 g). Gross nodularity was described in 12 livers (75%) (typically a diffuse pattern of vague or fine nodularity was noted) (Fig. 1). There were nonocclusive extrahepatic portal vein thrombi and/or webs in 4 cases (25%). Histopathology The histologic findings are summarized in Table 2. All 16 explanted livers showed evidence of portal tract vascular abnormalities (Fig. 2A-2B), including portal tract venopathy characterized by portal vein sclerosis in 13 cases (in 3 cases, this finding was focal) and/or aberrant portal venous branches in 11 cases (in 3 cases, this finding was focal), and arteriopathy in 4 cases, characterized by hypertrophic or increased number (branching) of small-caliber hepatic arteries in 3 cases and focal arterial amyloid deposition in 1 case (the patient with the clinical history of myelodysplasia). Fifteen livers showed NRH (in 4 cases, the features of NRH were focal or mild) (Fig. 2C-2D), and 9 livers had ISC (in 5 cases, the ISC was focal, usually located within the perihilar area) (Fig. 2E). Additional findings included focal/mild lymphocytic portal inflammation (without interface activity) in 10 explants, and focal/ mild bile ductular proliferation in 10 explants. Two livers had 3 foci of focal nodular hyperplasia. Interlobular bile ducts were intact in all cases. One patient, who received a kidney transplant 11 years prior for polycystic kidney disease, showed scattered foci of inspissated bile and focal biliary ectasia, likely related to her polycystic kidney disease. One liver showed focal, random, well-formed, noncaseating granulomas (clinical history of sarcoidosis). None of the liver explants had cholesta- Figure 1. Macroscopic features of severe noncirrhotic portal hypertension. Representative photograph of a cut section though an explanted liver showing vague nodules without obvious fibrosis throughout the liver parenchyma.

4 630 Krasinskas et al. Figure 2. Histologic features of severe intrahepatic noncirrhotic portal hypertension. (A-B) All explanted livers showed evidence of obliterative portal venopathy (portal tract venopathy). (A) This portal tract contains a diminished-caliber, almost sclerotic, portal vein radical (arrow); H&E stain, 200. (B) This portal tract shows fragmentation of the portal vein radical (*) with focal extension into the adjacent parenchyma ( S shunt vessels ); H&E stain, 200. (C-D) Nodular regenerative hyperplasia was noted in 15 of the 16 liver explants. (C) Parenchymal nodularity created by areas of hypertrophic hepatocytes in periportal areas (PT portal tract) alternating with areas of cord atrophy (center to top right of image) without fibrosis (H&E stain, 100 ). (D) Hypertrophic hepatocytes alternate with atrophic cords (center of image); PT portal tract (reticulin stain, 100 ). (E) Nine explanted livers had increased fibrosis characterized by incomplete septal cirrhosis. Here, delicate fibrous bands extend from the portal tract and end blindly in the liver parenchyma (arrows); trichrome stain, 100.

5 Intrahepatic Noncirrhotic Portal Hypertension 631 Recurrent Disease Recurrent NRH-like features were observed in the allograft biopsies of 2 patients at 3.5 and 11 months (Fig. 3). The patient with NRH-like features in his allograft biopsy 3.5 months after transplantation developed anemia 1 year after transplantation and was found to have evidence of portal hypertension (portal hypertensive gastropathy and mild [1 ] esophageal varices). The other patient with NRH-like features in his allograft biopsy did not have symptoms to indicate portal hypertension. Figure 3. Histologic features of nodular regenerative hyperplasia in a protocol allograft biopsy at 11 months after transplantation. This trichrome stain (100 ) highlights an absence of fibrosis and apparent parenchymal nodularity created by centrilobular hepatic plate atrophy (arrowheads) with adjoining periportal hypertrophy (PT portal tract). sis. There was no evidence of dysplasia or neoplasia in any of the explants. 2,4 Posttransplantation Course Mortality/Survival Clinical follow-up ranged from 6 months to 10 years (mean: 54 months). Thirteen of the 16 patients received tacrolimus-based immunosuppression; 2 received cyclosporine-based therapy and one received sirolimus. One patient died of pneumonia at 5 months after transplantation. One patient underwent retransplantation 11 weeks after transplantation for primary graft nonfunction (severe ischemic/preservation injury). Rejection Seven patients were lost to follow-up with a mean time to loss of 66 months. A total of 36 allograft biopsies were performed in 14 patients. Eight patients (50%) experienced acute cellular rejection in the early posttransplantation period (6 patients had mild or moderate rejection within 2.5 months, and 2 patients had central venulitis (centrilobular necrosis) at 3 months and 5 years after transplantation). Two patients showed bile duct injury and focal bile duct loss suggestive of early/evolving chronic rejection at 2 and 6 years after transplantation. Liver function tests at last follow-up were normal in all patients tested (n 15). Discussion We identified 16 patients who underwent OLT for symptomatic end-stage liver disease unrelated to biliary tract disease whose liver explants were not cirrhotic. Only 3 patients (19%) did not carry a pretransplantation diagnosis of cirrhosis, and 2 of these patients had a known association with NCPH (exposure to azathioprine for kidney transplantation). The remaining 13 patients (81%) were clinically believed to have cirrhosis. Seven (54%) of these 13 patients carried the diagnosis of cryptogenic cirrhosis, but 2 of these patients had known exposure to hepatotoxins in the workplace, including 1 case of exposure to arsenic. The remaining 6 patients carried pretransplantation diagnoses that more typically resulted in cirrhosis, including fatty liver disease, viral hepatitis C infection, autoimmune hepatitis, and methotrexate toxicity. However, they did not have cirrhosis and, in fact, 3 of the 6 patients had diseases that are associated with NCPH, including rheumatoid arthritis (the patient with methotrexate exposure), collagen vascular disease (the patient with autoimmune hepatitis) and myelodysplasia (the patient with nonalcoholic steatohepatitis). NCPH is a clinicopathologic entity with a variety of etiologies. It is typically characterized by splenomegaly with or without esophageal varices in the absence of cirrhosis. 11,14,18 All of the etiologies of NCPH result in increased resistance to portal blood flow at 1 of 3 levels; the impediment to blood flow can occur at the extrahepatic presinusoidal level (i.e., portal vein thrombosis), at the intrahepatic (presinusoidal, sinusoidal, or postsinusoidal level, Table 3) or at the extrahepatic postsinusoidal level (i.e., Budd-Chiari syndrome). 18 Several different terms have been used to describe the clinicopathologic features of the intrahepatic disorders, including idiopathic portal hypertension, noncirrhotic portal fibrosis, 14 NRH, 1-6 ISC, 7,8 and hepatoportal sclerosis. 9,10 Regardless of the level of resistance,

6 632 Krasinskas et al. Table 3. Intrahepatic Causes of Noncirrhotic Portal Hypertension Intrahepatic portal venous thrombosis/sclerosis or aberrant portal venous branches Toxins (including arsenic, vinyl chloride) Hypercoagulability Primary biliary cirrhosis, primary sclerosing cholangitis Schistosomiasis Nodular regenerative hyperplasia Collagen vascular disease Myeloproliferative disorders Primary biliary cirrhosis Drugs (including azathioprine) Noncirrhotic portal fibrosis ( idiopathic portal hypertension / hepatoportal sclerosis ) Sarcoidosis Chronic biliary obstruction Perisinusoidal fibrosis Hypervitaminosis A Noncirrhotic alcoholic liver disease Hemochromatosis Peliosis hepatis Infiltrative disorders Amyloidosis Myeloproliferative disorders Systemic mastocytosis Malignancy Veno-occlusive disease most patients develop gastric and esophageal varices; ascites and encephalopathy tend to develop in patients with sinusoidal or intrahepatic postsinusoidal disease. 18 However, patients with decompensated liver disease can also develop ascites and encephalopathy, which could have occurred in our patients with those symptoms. With appropriate management of the symptoms of portal hypertension, patients with NCPH have a much better prognosis than patients with portal hypertension related to cirrhosis. 20 Only very few patients have progressive disease that results in liver failure and the need for OLT. 2,7,13-17 Histopathologically, whole livers from patients with NCPH can show heterogeneous morphology, 7,11,12 and they cannot always be categorized into the published disease entities of idiopathic portal hypertension, hepatoportal sclerosis, NRH, or ISC. Our liver explants showed a mixture of pathologic features. All of the liver explants in our study showed some form of vascular abnormality, including portal tract venopathy (aberrant portal venous branches and/or portal vein sclerosis) and portal tract arteriopathy (hypertrophic and/or branching hepatic arteries). Most livers also showed NRH and ISC, but in many cases, these findings were focal or mild and appeared most pronounced in perihilar areas. Since the histologic features are so heterogenous within this group of patients, the different morphologic patterns should be kept in mind when evaluating pathologic specimens, either core biopsies or hepatectomy specimens. Furthermore, it is our opinion that NCPH should be viewed as a single clinical entity with various pathologic features rather than separate clinicopathologic entities. The patients in our study represent the small percentage of patients with NCPH who have severe clinical manifestations of the disease with a progressive clinical course that requires OLT. Several small studies and case reports in the English literature have addressed the efficacy of OLT for severe NCPH. 7,13-16,26 These reports include a total of 19 patients, 8 who had a pretransplantation diagnosis of cirrhosis and 9 who had pretransplantation diagnoses of NRH, idiopathic portal hypertension, or ISC. Most of the patients with severe NCPH in the literature did well following OLT; 3 died in the early posttransplantation period from complications unrelated to the underlying liver disease, including sepsis, 26 splenic artery rupture, 15 and suicide. 15 It also appears from the literature that NCPH tends not to recur after OLT. Only 1 patient showed evidence suggesting recurrent disease when asymptomatic NRH was noted on a posttransplantation biopsy. 15 Similar to the literature, our patients with severe intrahepatic NCPH who underwent OLT did well after OLT. In our series of 16 patients, there was only 1 death in the early post-olt period (due to pneumonia), resulting in a survival rate of 94% over a mean time to follow-up of 54 months (4 years, 7 months). Compared to the University of Pittsburgh Medical Center s overall 5-year survival rate of 72% for females and 63% for males (based on 4,000 liver transplants), 27 the survival rate for the subset of patients with NCPH is higher, although the numbers are too small to determine statistical significance. Regarding possible recurrence of disease, 2 of our patients were diagnosed with NRH after OLT. One patient was asymptomatic, and the other patient developed symptomatic NRH 1 year after transplantation. Interestingly, although a subset of patients who undergo transplantation for cryptogenic cirrhosis are found to have nonalcoholic steatohepatitis or autoimmune hepatitis before or after transplantation, 28 neither of these diseases was seen in the posttransplantation biopsies of our patients, 9 of whom had pretransplantation diagnoses of cryptogenic cirrhosis, nonalcoholic steatohepatitis, or autoimmune hepatitis. The finding of NRH in post-olt biopsies is interesting because it has been our personal experience that

7 Intrahepatic Noncirrhotic Portal Hypertension 633 NRH-like features can be seen in a minority of posttransplantation biopsies, possibly related to altered blood flow after surgery and/or altered graft size; this finding has also been associated with azathioprine use. 29 We cannot, therefore, be certain that NCPH has truly recurred in these 3 patients (our 2 and the 1 from the literature), although if it has, the incidence appears to be low. Making a pretransplantation diagnosis of NCPH can be difficult, as noted above, especially if patients have severe manifestations of the disease. 2,7,13-15 But even patients without end-stage liver disease can be misdiagnosed with cirrhosis when in fact they have NCPH. 3 While OLT is the treatment of choice for patients with severe portal hypertension and/or hepatic insufficiency regardless of the etiology, it is important to distinguish cirrhosis from NCPH at earlier stages, since patients with NCPH and intact liver function are managed differently and tend to do much better than patients with cirrhosis. 3,18,20,30 Liver biopsies can be helpful 3,8,16,30,31 but must be interpreted with caution, since many livers with NCPH will have increased fibrosis. In summary, patients with severe NCPH can successfully undergo liver transplantation and they tend to do well after transplantation. Very few patients have recurrent symptoms of portal hypertension. We found that many patients with NCPH were clinically believed to have cirrhosis, either based on the clinical presentation or misleading pretransplantation biopsy or radiographic evidence. Clinicians, radiologists, and pathologists should be aware that NCPH can mimic cirrhosis, but that OLT is reasonable management of patients with end-stage liver disease with both cirrhosis and severe NCPH. References 1. Wanless IR. Micronodular transformation (nodular regenerative hyperplasia) of the liver: A report of 64 cases among 2,500 autopsies and a new classification of benign hepatocellular nodules. Hepatology 1990;11: Stromeyer FW, Ishak KG. Nodular transformation (nodular regenerative hyperplasia) of the liver. A clinicopathologic study of 30 cases. Hum Pathol 1981;12: Arvanitaki M, Adler M. Nodular regenerative hyperplasia of the liver. A review of 14 cases. Hepatogastroenterology 2001;48: Colina F, Alberti N, Solis JA, Martinez-Tello FJ. 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