Portal Hypertension and Unexplained Diarrhea in an 80-Year-Old Man

Abstract

Question: An 80-year-old man was referred for evaluation of cirrhosis and chronic diarrhea of unknown etiologies. In the past year he had been diagnosed with ascites, esophageal varices, and splenomegaly. His history was notable for four loose, non-bloody stools per day, intermittent abdominal cramping, and thirty pound weight loss. He denied fever, night sweats, rash, itching, or flushing. Physical examination revealed cachexia, no jugular venous distension, and a distended abdomen with shifting dullness. There were no skin lesions. His only medications were loperamide and propranolol. Laboratory studies showed a white blood cell count 5.5 x 109/L [3.5-10.5 x 109/L], hemoglobin 11 g/dL [13.5-17.5 g/dL], platelets 93 x 109/L [150-450 x 109/L], ALT 111 U/L [7-55 U/L], AST 67 U/L [8-48 U/L], alkaline phosphatase 601 U/L [46-118 U/L], total bilirubin 0.9 mg/dL [0.1-1.0mg/dL], and INR of 3.3. An abdomen/pelvis CT demonstrated hepatosplenomegaly, ascites (Figure A), and punctate sclerotic bone lesions. Diagnostic paracentesis revealed a SAAG of 2.6 and total protein of 1.6 g/dL. Gram stain, bacterial culture, and cytology of the ascitic fluid were negative. Liver biopsy with hematoxylin and eosin staining showed nodules without surrounding fibrosis (Figure B). Serum tryptase was elevated at 243 ng/dL [<11.5 ng/dL]. What is the most likely cause of his diarrhea and portal hypertension?A.Congestive heart failureB.Felty’s syndromeC.Systemic mastocytosisD.Cirrhosis Look on page 819 for the answer and see the Gastroenterology web site (www.gastrojournal.org) for more information on submitting your favorite image(s) to Practical Teaching Cases. The correct answer is C. The liver biopsy (Figure B) shows hepatocellular nodules less than 3 mm in diameter with hypertrophic hepatocytes (arrows). These nodules are not surrounded by fibrosis but rather compressed hepatocytes (arrowheads). A reticulin stain (Figure C) highlights the changes of nodular hyperplasia (arrows) and atrophic hepatocytes (arrowheads) which are diagnostic of nodular regenerative hyperplasia (NRH). Given the history of chronic diarrhea, sclerotic bone lesions, and elevated serum tryptase, a bone marrow biopsy was performed. This revealed a hypercellular marrow with 20% involvement by atypical mast cells. Together these findings support a diagnosis of SM and secondary NRH. Congestive heart failure (Answer A) has been associated with NRH but the lack of jugular venous distension on physical exam makes this unlikely. NRH was first described in a patient with rheumatoid arthritis, neutropenia, and splenomegaly (Felty’s syndrome); however, in this case, there is no personal history of rheumatoid arthritis and neutropenia which excludes Felty’s syndrome (Answer B). While cirrhosis (Answer D) may present with esophageal varices, portal hypertension and hypersplenism; liver biopsy would demonstrate fibrosis rather than nodular regenerative hyperplasia. Occasionally, NRH and cirrhosis may be difficult to distinguish, particularly on clinical grounds and radiographic imaging. The diagnosis of NRH is made by liver biopsy. SM is characterized by excessive mast cell accumulation in multiple tissues, most commonly the skin, central nervous system, musculoskeletal system and gastrointestinal tract. Gastrointestinal manifestations such as diarrhea and malabsorption are likely a result of GI mucosal infiltration by mast cells with concomitant release of prostaglandin mediators.1Capron J.-P. Lebrec D. Degott C. et al.Portal hypertension in systemic mastocytosis.Gastroenterology. 1978; 74: 595-597Abstract Full Text PDF PubMed Scopus (28) Google Scholar SM is a rare cause of portal hypertension which may develop from arteriovenous shunting secondary to histamine release, increased intrahepatic resistance due to mast cell infiltration of sinusoids, and the development of NRH.2Grundfest S. Cooperman A.M. Ferguson R. Benjamin S. Portal hypertension associated with systemic mastocytosis and splenomegaly.Gastroenterology. 1980; 78: 370-373Abstract Full Text PDF PubMed Scopus (35) Google Scholar In this case, portal hypertension was caused by the development of NRH. NRH of the liver is an uncommon condition characterized by the diffuse transformation of normal hepatic parenchyma into small, regenerative nodules with no fibrosis. It is associated with systemic diseases including rheumatologic disorders, vascular disorders, myeloproliferative disorders, and certain medications.3Reshamwala P.A. Kleiner D.E. Heller T. Nodular Regenerative Hyperplasia: Not All Nodules Are Created Equal.Hepatology. 2006; 44: 7-14Crossref PubMed Scopus (189) Google Scholar NRH develops as a consequence of portal venopathy and altered hepatic circulation. The nodular areas are believed to develop as hyperperfused hepatocytes become hypertrophic while hypoperfused hepatocytes become atrophic.3Reshamwala P.A. Kleiner D.E. Heller T. Nodular Regenerative Hyperplasia: Not All Nodules Are Created Equal.Hepatology. 2006; 44: 7-14Crossref PubMed Scopus (189) Google Scholar Portal hypertension and its complications are the predominant clinical manifestations of NRH. Occasionally, as in this case, NRH and cirrhosis may be difficult to distinguish on clinical grounds and radiographic imaging. This case illustrates the importance of the gastroenterologist having knowledge of systemic diseases known to be associated with NRH and how liver biopsy is essential for diagnosis. Exam 2: Portal Hypertension and Unexplained Diarrhea in an 80-Year-Old ManGastroenterologyVol. 154Issue 4Preview Full-Text PDF