1 Springer ORIGINAL ARTICLE

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1 ORIGINAL ARTICLE Idiopathic non-cirrhotic intrahepatic portal hypertension: common cause of cryptogenic intrahepatic portal hypertension in a Southern Indian tertiary hospital Kadiyala Madhu Balekuduru Avinash Banumathi Ramakrishna C E Eapen Shyamkumar N K Uday Zachariah George Chandy George Kurian Abstract Background and aim Patients with intrahepatic portal hypertension and negative etiological work-up for liver disease are often labeled as having cryptogenic cirrhosis. The aim of this study was to evaluate causes of liver disease in patients with unexplained intrahepatic portal hypertension. Methods We retrospectively analyzed cause of liver disease in all patients with cryptogenic intrahepatic portal hypertension who underwent liver biopsies between June 2005 to June 2007 in our center. Results Five hundred and seventeen patients underwent liver biopsies of whom 227 had portal hypertension. Of these, the cause of liver disease could not be detected prior to liver biopsy in 62 patients. Causes of liver disease identified after liver biopsy in these 62 patients were: idiopathic non-cirrhotic intrahepatic portal hypertension (NCIPH) (30 patients, 48 ), cirrhosis (14), fatty liver disease (7) and other causes (11). Initial presentations in idiopathic NCIPH patients were splenomegaly and anemia (18 patients), variceal bleed (9) and ascites (3). Median age (range) of patients at first presentation was 32 (15-57) years, and 19 were male. Majority (90 ) were in Child s class A. Hepatic vein pressure gradient was <5 mmhg in 2 of 7 NCIPH patients tested. K Madhu 1 B Avinash 1 B Ramakrishna 2 CE Eapen 1 Shyamkumar NK 3 U Zachariah 1 G Chandy 1 G Kurian 1 Departments of 1 Gastrointestinal Sciences, 2 Pathology and 3 Radiology, Christian Medical College, Vellore , India C Eapen ( ) eapen@cmcvellore.ac.in Received: 22 November 2008 / Revised: 15 March 2009 / Accepted: 20 April 2009 Indian Society of Gastroenterology 2009 Conclusions We identified 30 patients with idiopathic NCIPH at our center over the 2 year study period. The clinical presentation and investigations of NCIPH closely mimic cryptogenic cirrhosis. Idiopathic NCIPH should be considered as a differential diagnosis of cryptogenic cirrhosis in India. Keywords Cryptogenic cirrhosis hepatic vein pressure gradient liver biopsy Introduction Patients with portal hypertension, in whom no cause for liver disease is found, are often labeled as having cryptogenic cirrhosis. Occult hepatitis B infection, 1,2 end-stage nonalcoholic fatty liver disease 3 and autoimmune liver disease 4 are potential causes of cryptogenic cirrhosis in India. In this study, we document idiopathic non-cirrhotic intrahepatic portal hypertension (NCIPH) as a common cause of cryptogenic intrahepatic portal hypertension among patients who underwent liver biopsy over a 2-year period at our center. Methods We retrospectively analyzed case records of all patients aged 15 years who had undergone liver biopsy in our unit between June 2005 and June From these patients, we selected those with evidence of portal hypertension at either endoscopy (esophageal or gastric varices) or imaging. Those with evidence of extrahepatic portal vein obstruction or hepatic outflow obstruction on imaging, or with a detectable cause of parenchymal liver disease prior to liver biopsy (all patients had been asked about intake of alcohol and hepatotoxic drugs, and tested for HBsAg, anti-hcv antibody, anti-nuclear antibody, serum ceruloplasmin and serum ferritin) were excluded. In the remaining patients with cryptogenic intrahepatic portal hypertension, the causes of portal hypertension were analyzed. Clinical and investigation data were retrieved, as were those on hepatic vein pressure gradient (HVPG), if available. We defined idiopathic NCIPH as: 5 (i) evidence of portal hypertension (esophageal or gastric varices on endoscopy or features of portal hypertension on ultrasound or computed

2 84 Madhu, et al. tomography); (ii) imaging showing patent portal and hepatic veins; (iii) liver biopsy showing no cirrhosis; (iv) exclusion of common conditions that cause cirrhosis (chronic viral hepatitis, alcoholic liver disease, Wilson s disease, autoimmune hepatitis or hemochromatosis), using conventional diagnostic criteria. For patients with idiopathic NCIPH, demographic and clinical features were reviewed, and liver biopsies were reviewed by a histopathologist (BR). Results Of the 517 patients aged 15 years who had undergone liver biopsy during the study period, 290 lacked features of portal hypertension and none had portal vein or hepatic venous outflow obstruction. Of the remaining 227 patients with intrahepatic portal hypertension, 165 had an identifiable cause of parenchymal liver disease (hepatitis B-58, probable autoimmune liver disease-54, hepatitis C-36, Wilson s disease-12, alcohol-related liver disease-5). Data from the remaining 62 patients with intrahepatic portal hypertension and no known cause for liver disease were analyzed. Analysis of liver biopsies in cryptogenic intrahepatic portal hypertension patients (n=62) Following liver biopsy, the causes of liver disease in these patients was identified as: idiopathic NCIPH (30 patients), cirrhosis (14), fatty liver disease (7), probable autoimmune hepatitis (2), copper related non-wilsonian liver disease (3), granulomatous liver disease (2), amyloidosis (2), biliary type of bridging fibrosis (1) and intrahepatic cholestatic disorder (1). Liver histology in 30 idiopathic NCIPH patients In the patients, liver biopsies had been done through the transjugular route in 21 patients, percutaneous route in 6 and per-operatively (both trucut and wedge biopsies) in 3 patients. The median (range) size of the largest liver tissue cores was 1.3 ( ) cm for percutaneous biopsies, 1.7 ( ) cm for operative biopsies and 1.5 ( ) cm for transjugular biopsies. While one liver biopsy core was obtained from each patient at percutaneous biopsy and per-operative biopsy (1 wedge and 1 needle biopsy each), multiple cores of biopsy were obtained at transjugular liver biopsy (median number of biopsy cores was 3 [2-5]). In patients with transjugular biopsy, the length of the largest biopsy core was cm in 2 patients, cm in 4 patients, cm in 12 patients and >1.5 cm in 3 patients. The median aggregate core length in transjugular category was 2 cm ( ). The number of portal tracts present in the liver biopsies was between 5-9 in 6 patients and 10 in 24 patients. Histological features seen in idiopathic NCIPH patients were mild portal fibrosis with or without formation of short thin fibrous septa in 19 patients, abnormal dilatation of portal venules protruding into the parenchyma in 15 patients with focal angiomatosis in 3 (Fig. 1), focal mild perisinusoidal fibrosis in 5, focal approximation of portal tracts in 2, few hypoplastic portal tracts in 2 and no specific histological changes in 6. Some patients had more than one of these histological features. None had evidence of cirrhosis. Of the 3 patients with operative liver biopsies, 2 had subcapsular nodular formation mimicking cirrhosis in wedge biopsies (Fig. 2); trucut biopsy in one of these patients showed preserved architecture with no fibrosis (Fig. 2) and that in the other patient showed portal fibrosis with formation of septa but no evidence of cirrhosis. In the 3rd patient, both trucut and wedge biopsies showed only mild portal fibrosis and no nodule formation. Other histological features seen in idiopathic NCIPH were focal mild portal inflammation in 13 patients, extramedullary hemopoiesis in 4, focal mild steatosis in 3 and moderate steatosis in 2. One patient had grade III iron overload, probably due to multiple transfusions. Clinical features and investigations in idiopathic NCIPH patients (Table 1) Of the 30 idiopathic NCIPH patients, 19 were male. Their median age at presentation was 32 (15-61) years, and states of origin were: West Bengal 10 patients, Tamil Nadu 8, Jharkhand 6, Andhra Pradesh 3, and Bihar, Chattisgarh and Karnataka one each. Their clinical presentation was: anemia and splenomegaly in 18 (60 ), variceal bleeding in 9 (30 ) and ascites in 3 (10 ) patients. Hypersplenism was present in 26 (87 ) patients. Gum bleeding was present in 3 patients, epistaxis in 1, menorrhagia in 1 and intracerebral bleeding in 1. Fig. 1 Needle liver biopsy from a patient with idiopathic noncirrhotic portal hypetension showing portal angiomatosis (arrow) (H&E, 200)

3 Non cirrhotic-portal hypertension 85 Fig. 2 Operative liver biopsies from a patient with idiopathic non-cirrhotic portal hypertension: wedge biopsy showing subcapsular nodularity (reticulin, 50) (left), and needle biopsy showing preserved architecture (reticulin, 50) (right) Table 1 Baseline parameters in idiopathic NCIPH patients Parameter Value (n=30) Hemoglobin (g/dl) 9.5 ( ) White blood cell count (/ L) 3000 ( ) Platelet count (/L) 5.2 ( ) Prothrombin time (INR) 1.11 ( ) Serum total bilirubin (mg/dl) 1.4 ( ) Serum protein (g/dl) 7.4 ( ) Serum albumin (g/dl) 3.8 ( ) Aspartate aminotransferase (IU/L) 40 (22-168) Alanine aminotransferase (IU/L) 33 (16-97) Alkaline phosphatase (U/L) 96 (50-220) Child-Pugh class (A:B:C) 27:3:0 MELD score 9.5 (6-14) Data for quantitative parameters are shown as median (range) Liver function tests were completely normal in 8 patients and prothrombin time was normal in 22 patients. Majority (27 patients, 90 ) of these patients were in Child s class A (Table 1). On ultrasound scan, liver was normal sized in 20 patients (67 ) and shrunken with evidence of volume redistribution in 10 patients (33 ). Platelet count <80,000/cumm. (n=26) or prolonged prothrombin time (n=4) were the main reasons for selecting transjugular route for liver biopsy. HVPG was measured in 7 patients, this was >5 mmhg in 5 patients and <5 mmhg in 2. Of the 5 patients with HVPG >5 mmhg (median 12.5, range 6-17 mmhg), none had ascites. Of 13 patients who had variceal bleed, 10 had undergone endoscopic therapy for gastro-esophageal varices (band ligation 6, sclerotherapy 4), 2 had undergone splenorenal shunt surgery and 1 had both endoscopic therapy and shunt surgery. Discussion Idiopathic NCIPH was identified in 30 patients during this 2-year study period. In the absence of liver biopsy, it is possible to mislabel idiopathic NCIPH as cryptogenic cirrhosis 6 this point is borne out in our report. Though different terms-like non-cirrhotic portal fibrosis, benign intrahepatic portal hypertension, idiopathic portal hypertension, hepatoportal sclerosis, incomplete septal cirrhosis, nodular regenerative hyperplasia and partial nodular transformation of the liver-are used to describe idiopathic NCIPH, 5 these may be viewed as histological spectrum of different stages of a single clinical entity (idiopathic NCIPH). 5,7 We classified idiopathic NCIPH as a single entity for our study. Our finding is in contrast to the APASL consensus document reporting declining incidence of non-cirrhotic portal fibrosis in different centers in India. 8 Non-cirrhotic portal hypertension was previously common in India. 9 Why is the incidence of idiopathic NCIPH falling in India? Essential criteria to diagnose non-cirrhotic portal fibrosis/ idiopathic portal hypertension on needle liver biopsy are absence of regenerative nodules with features of possible/ definite cirrhosis in an adequate-sized biopsy. 8 All 3 reports from in the APASL consensus document were personal communications, while of 4 studies from , only one was a full length article (others being personal communication, abstract and text book chapter). 8 Most centers in this APASL document do not mention if liver biopsy was done to confirm non-cirrhotic portal fibrosis. 8 Change in route of liver biopsy maybe one reason why NCIPH is often not diagnosed now. With change in preferred treatment of variceal bleed in idiopathic NCIPH from shunt surgery to endoscopic treatment, 10,11 liver biopsies have

4 86 Madhu, et al. changed from operative biopsies to percutaneous/transjugular needle biopsies. In an earlier study on NCIPH from Chandigarh, of 109 patients had operative wedge biopsy of liver, while 54 had needle liver biopsies (route of needle biopsies not mentioned). In contrast, we performed transjugular liver biopsy in 70 of NCIPH patients in our study. Increasing use of transjugular liver biopsy 12 may be one reason why idiopathic NCIPH is now being diagnosed more often at our center. Sampling error is a limitation in using needle liver biopsy to diagnose idiopathic NCIPH - in particular, macronodular cirrhosis can be mistaken for the former. As multiple cores of liver tissue were obtained in most patients, the possibility of missing macronodular cirrhosis is less likely. Selection bias is another limitation of our study. The indication for liver biopsy was decided on a case-to-case basis, depending on the clinical scenario. Despite these limitations, our study indicates that idiopathic NCIPH is a relatively common cause of unexplained intra-hepatic portal hypertension in India (15 new cases per year over 2 years). This compares well with 83 noncirrhotic portal fibrosis patients seen over 10 year period (ie: 8 per year) at a center in New Delhi 13 and 151 patients seen over 15 years (ie. 10 per year) in Chandigarh. 10 Some of the histological changes in the liver seen in NCIPH patients in our study - like hypoplastic portal tracts, focal approximation of portal tracts and abnormal dilatation of portal venules protruding into the parenchyma - can be attributed to portal venous insufficiency. 14,15 Both wedge and needle biopsies are advisable during operative liver biopsies to confirm idiopathic NCIPH. 16 In 2 of our patients, subcapsular nodules mimicking cirrhosis were seen in wedge biopsies while the needle biopsies showed preserved liver architecture. Hepatic vein pressure studies are an adjunct to the diagnostic evaluation. Normal HVPG (<5 mmhg) reflects pre-sinusoidal portal hypertension in NCIPH. Elevated HVPG also occurs in NCIPH, probably due to additional peri-sinusoidal resistance 17 (seen in 5 of 7 patients in our study). Though idiopathic NCIPH patients typically have well - preserved liver function, 3 patients in our study had ascites. Progression to liver failure (ascites, hepatic encephalopathy) can occur in idiopathic NCIPH patients. 5-7,10,18 On imaging, 67 of NCIPH patients in our study had normal sized liver while 33 had shrunken liver or volume redistribution of the liver. Thus, clinically and on imaging, idiopathic NCIPH is a differential diagnosis for compensated cirrhosis as well as for decompensated cirrhosis. In conclusion, we documented idiopathic NCIPH as a common cause of cryptogenic intrahepatic portal hypertension in our center. Increasing availability of transjugular liver biopsy and hepatic vein pressure studies are likely to lead to increased recognition of this disease. Acknowledgements We express our gratitude to Professor Elwyn Elias, Liver Unit, Queen Elizabeth Hospital, Birmingham, UK for his kind review of the manuscript and constructive suggestions. References 1. Radhakrishnan S, Abraham P, Raghuraman S, et al. Infrequent occurrence of silent HBV infection among Indian patients with chronic liver disease. Indian J Gastroenterol 2001;20: Agarwal N, Naik S, Aggarwal R, et al. Occult hepatitis B virus infection as a cause of cirrhosis of liver in a region with intermediate endemicity. Indian J Gastroenterol 2003;22: Duseja A, Das A, Das R, et al. The clinicopathological profile of Indian patients with nonalcoholic fatty liver disease (NAFLD) is different from that in the West. Dig Dis Sci 2007;52: Gupta R, Agarwal SR, Jain M, Malhotra V, Sarin SK. Autoimmune hepatitis in the Indian subcontinent: 7 years experience. J Gastroenterol Hepatol 2001;16: Hillaire S, Bonte E, Denninger MH, et al. Idiopathic noncirrhotic intrahepatic portal hypertension in the West: a re-evaluation in 28 patients. Gut 2002;51: Madhu K, Ramakrishna B, Zachariah U, Eapen CE, Kurian G. Non-cirrhotic intrahepatic portal hypertension. Gut 2008;57: Krasinskas AM, Eghtesad B, Kamath PS, Demetris AJ, Abraham SC. Liver transplantation for severe intrahepatic non-cirrhotic portal hypertension. Liver Transpl 2005;11: Sarin SK, Kumar A, Chawla YK, et al. Non-cirrhotic portal fibrosis/idiopathic portal hypertension: APASL recommendations for diagnosis and treatment. Hepatol Int 2007;1: Okuda K. Non-cirrhotic portal hypertension: why is it so common in India? J Gastroenterol Hepatol 2002; 17: Dhiman RK, Chawla Y, Vasishta RK, et al. Non-cirrhotic portal fibrosis (idiopathic portal hypertension): experience with 151 patients and a review of the literature. J Gastroenterol Hepatol 2002;17: Sarin SK, Kapoor D. Non-cirrhotic portal fibrosis: current concepts and management. J Gastroenterol Hepatol 2002;17: Mammen T, Keshava SN, Eapen CE, et al. Transjugular liver biopsy: a retrospective analysis of 601 cases. J Vasc Interv Radiol 2008;19: Bhargava DK, Dasarathy S, Sundaram KR, Ahuja RK. Efficacy of endoscopic sclerotherapy on long-term management of oesophageal varices: a comparative study of results in patients with cirrhosis of the liver, noncirrhotic portal fibrosis (NCPF) and extrahepatic portal venous obstruction (EHO). J Gastroenterol Hepatol 1991;6: Nakanuma Y, Hoso M, Sasaki M, et al. Histopathology of the liver in non-cirrhotic portal hypertension of unknown aetiology. Histopathology 1996;28:

5 Non cirrhotic-portal hypertension Roskams T, Baptista A, Bianchi L, et al. Histopathology of portal hypertension: a practical guideline. Histopathology 2003;42: Smith PM, Crossley IR, Williams DM. Portal hypertension in vinyl-chloride production workers. Lancet 1976;2: Sarin SK, Sethi KK, Nanda R. Measurement and correlation of wedged hepatic, intrahepatic, intrasplenic and intravariceal pressures in patients with cirrhosis of liver and non-cirrhotic portal fibrosis. Gut 1987;28: Sawada S, Sato Y, Aoyama H, Harada K, Nakanuma Y. Pathological study of idiopathic portal hypertension with an emphasis on cause of death based on records of Annuals of Pathological Autopsy Cases in Japan. J Gastroenterol Hepatol 2007;22: IMAGE Spontaneous air in the main pancreatic duct A 34-year-old lady was referred to us after an episode of acute biliary pancreatitis which was diagnosed three months back, and resolved on conservative treatment. She again became symptomatic with abdominal discomfort after one month. There was no history of vomiting, dyspnea, jaundice, fever, weight loss or anorexia. Her laboratory parameters were: Hb 12 gm, leukocyte count 8600/cmm, S. amylase 350, bilirubin 1.2 mg, and alkaline phosphatase 428 IU/dL; serum protein and transaminase values were normal. CECT of the abdomen revealed air in the main pancreatic duct (PD) (Fig. 1); the duct was normal in caliber. CT also showed multiple fluid collections suggestive of pseudocyst, stone in gall bladder and dilated common bile duct (CBD). She underwent ERCP which showed large periampullary diverticula with normal CBD and normal PD without any extravasations of contrast from PD. She was kept on conservative management for the pancreatic pseudocyst. At six month follow-up, she was asymptomatic; follow-up ultrasound did not reveal air in pancreatic duct but showed the decrease in pseudocyst size to 2.5 cm. Air in the pancreas is frequently reported to be associated with an abscess or a pancreatic fistula but has also been demonstrated in normal pancreatic glands. It has been shown to occur with duodenal obstruction, biliary and pancreatic ascariasis with liver abscesses, pancreatic pseudocyst and acute or chronic pancreatic. 1-4 Our patient was a follow-up case of acute pancreatitis who had presented with pseudocyst and was found to have air in pancreatic duct. In the majority of cases reported in the literature, the air was visualized by US and only in three cases was the air seen at CT abdomen. In our case no air was detected in the biliary tree as had been reported in some of the previously described patients. Pankaj Tyagi A S Puri S Sachdeva Department of Gastroenterology, G B Pant Hospital, Delhi , India. P Tyagi ( ) drpankajtyagi@rediffmail.com References Fig. 1 CT scan of patient showing air in the main pancreatic duct (white arrow). pseudocyst (arrow head) and well enhancing pancreatic gland 1. Peer S, Kiechl-Kohlendorfer U, Gassner I. Air in the main pancreatic duct revealed by abdominal ultrasound: an additional diagnostic sign in paediatric patients with duodenal obstruction. Clin Radiol 2002;57: Itai Y, Ohtomo K, Kokubo T, Nagai H, Atomi Y, Kuroda A. CT demonstration of gas in dilated pancreatic duct. J Comput Assist Tomogr 1986;10: Costa PL, Righetti G. Air in the main pancreatic duct: demonstration with US. Radiology 1991;181: Brindisi C, Calculli L, Casadei R, Pezzilli R. Air in the Wirsung duct. An unusual finding. J Pancreas 2008;9:534-7.