Gut 2000;47:429–435 429 Pathological and virological findings in patients with persistent hypertransaminasaemia of Gut: first published as 10.1136/gut.47.3.429 on 1 September 2000. Downloaded from unknown aetiology C Berasain, M Betés, A Panizo, J Ruiz, J I Herrero, M-P Civeira, J Prieto Abstract In most patients with persistent abnormal liver Background—The histopathological spec- biochemistry, clinical data and serological tests trum and role of hepatitis viruses in cases allow identification of the causative factor or of hypertransaminasaemia of unknown disease entity responsible for liver damage. The aetiology have not been correctly analysed aetiological search includes investigation of inasuYciently large number of patients. alcohol abuse or exposure to drugs or other Methods—We studied 1075 consecutive toxins, detection of hepatitis B virus (HBV) patients referred for liver biopsy because surface antigen (HBsAg) or antibodies against of elevation of alanine aminotransferase hepatitis C virus (HCV), assays for autoanti- (ALT) levels for more than six months. bodies, ceruloplasmin, alpha1 antitrypsin, From this population we selected those serum ferritin, and transferrin saturation, and cases in whom the aetiology could not be study of other metabolic disorders or systemic defined from clinical, biochemical, and diseases (such as morbid obesity, diabetes with serological data obtained before biopsy. In deficient glycaemic control, or thyroid dysfunc- these patients liver biopsies were re- tion) which can aVect the liver. However, in viewed, and hepatitis B virus (HBV)-DNA some subjects with persistent alteration of liver and hepatitis C virus (HCV)-RNA were enzymes the cause of the disturbance cannot be assayed in serum by polymerase chain established on the basis of these clinical and reaction (PCR). Serum hepatitis G virus analytical data. These cases are referred to as (HGV)-RNA was determined by PCR in cryptogenic chronic liver disease. The preva- 74 patients. lence and histopathological spectrum of this Results—Of 1075 patients studied, the entity have not been analysed in detail. In our cause of the increased serum ALT levels study, we investigated the histological findings remained elusive after appropriate testing and implication of hepatitis viruses in cases in 109 patients (10.1%). Liver biopsies referred for liver biopsy as a result of persistent from these patients showed non-specific elevation of transaminases in whom clinical, http://gut.bmj.com/ changes in 32.7% of cases, non-alcoholic biochemical, and serological testing prior to steatohepatitis (NASH) in 15.8%, and histological sampling could not define the aeti- Department of chronic hepatitis or cirrhosis in 51.5%. ology of the disease. Medicine and Liver HBV-DNA and/or HCV-RNA was detected The advent of the polymerase chain reaction Unit, Medical School more frequently in cryptogenic liver dis- (PCR) allowed detection of HBV-DNA or and Clínica ease than in healthy blood donors (26.7% v HCV-RNA in patients who lacked HBsAg or Universitaria, 1–4 3.4%; p<0.001). HGV-RNA was found in anti-HCV antibodies. However, the signifi- University of Navarra, on September 26, 2021 by guest. Protected copyright. Pamplona, Spain only one patient. The proportion of cases cance and prevalence of occult viral infections C Berasain* with detectable HBV-DNA or HCV-RNA in cryptogenic liver disease remains controver- M Betés* was 14.3% in patients with non-specific sial. Thus while some studies have found 67% J Ruiz changes or NASH, 30.7% in patients with of HCV-RNA in whole blood from subjects J I Herrero 3 chronic hepatitis, and 61.5% in patients with cryptogenic chronic hepatitis or cirrhosis, M-P Civeira other investigators failed to detect HCV-RNA J Prieto with cirrhosis. Cirrhosis was found more 5 6 frequently in patients with positive HBV- in the liver or serum from these patients. In Department of DNA and/or HCV-RNA in serum than in contrast, while in some series HBV-DNA could Pathology, Medical not be detected in the serum of HBV seroneg- those who tested negatively (p=0.005). 7 School and Clínica Conclusions—In our series, patients in ative patients with cryptogenic hepatitis or cir- Universitaria, rhosis, in other series it was found in whom biochemical and serological data University of Navarra, 14–85%4 8–12 of such cases. The low number of did not determine the aetiology of the dis- Pamplona, Spain cases analysed in most reports, variability of A Panizo ease represented 10% of all cases referred criteria used to categorise patients, together for liver biopsy for persistent elevation of *Both authors have with diVerences in techniques and material serum transaminases. Approximately 50% contributed equally to this tested, and the diversity in geographic origin of of patients had chronic hepatitis or cir- work. the reported series, have contributed to our rhosis and the remainder had NASH or lack of knowledge of the pathogenic role of Correspondence to: non-specific changes. Occult viral infec- Professor J Prieto, Department of Medicine and tions were found in a high proportion of Liver Unit, Clínica cases in the first group and in a low Abbreviations used in this paper: HBV, hepatitis B Universitaria, Universidad de percentage of patients in the second. virus; HCV, hepatitis C virus; HGV, hepatitis G virus; Navarra, Avda, Pio XII s/n, 31080 Pamplona, Spain. (Gut 2000;47:429–435) ALT, alanine aminotransferase; NASH, non-alcoholic Email: [email protected] steatohepatitis; HBsAg, hepatitis B virus surface Keywords: cryptogenic liver disease; cryptogenic antigen; PCR, polymerase chain reaction; RT-PCR, Accepted for publication hepatitis; hepatitis B virus; hepatitis C virus; hepatitis reverse transcription-PCR; HIV, human 7 March 2000 G virus; non-alcoholic steatohepatitis immunodeficiency virus. www.gutjnl.com 430 Berasain, Betés, Panizo, et al known hepatitis viruses in cryptogenic liver evaluated including fibrosis, portal inflamma- diseases. In addition, most studies on chronic tion, piecemeal necrosis, lobular inflammation, liver disease of unknown aetiology have fo- lobular necrosis, steatosis, cholestasis, bile duct Gut: first published as 10.1136/gut.47.3.429 on 1 September 2000. Downloaded from cused on specific histopathological entities damage, sinusoidal dilation, and iron deposi- (chronic hepatitis and/or cirrhosis) and not on tion. These histological features were graded as the broader spectrum of patients with hepatic absent, sparse-mild, or moderate-severe. Fibro- disease of unknown causes who are referred for sis was graded on a scale of absent, sparse- liver biopsy because of persistent abnormalities mild, or severe bridging-cirrhosis. According to of liver biochemistry. these data, liver biopsies were classified into In this study we analysed 1075 consecutive three groups: (1) chronic hepatitis and cirrho- patients who underwent liver biopsy because of sis according to international criteria13; chronic persistent abnormalities in liver enzymes. From hepatitis in turn was subclassified into mild this group we selected those cases in whom (lymphocytic inflammation in more than one clinical, biochemical, and serological screening third of portal tracts, leaving the parenchymal before biopsy did not identify the aetiology of limiting plate preserved, with minimal intra- the liver lesion. In these cases the biopsy was acinous changes), moderate (dense inflamma- reviewed blindly, and the role of occult tory portal infiltration with piecemeal necrosis infection by HBV, HCV, and hepatitis G virus involving less than 50% of the circumference of (HGV) was established by determining HBV- most portal tracts but still restricted to DNA, HCV-RNA, and HGV-RNA in serum periportal areas), or severe (piecemeal necrosis using PCR. in the periportal region involving more than 50% of the circumference of most portal tracts, Material and methods and along fibrous septa); (2) non-alcoholic PATIENTS steatohepatitis (NASH): moderate-gross mac- Patients with liver disease of unknown cause rovesicular fatty changes with hepatocyte were identified among 1075 consecutive pa- degeneration and ballooning (with or without tients who underwent liver biopsy in our liver Mallory hyaline bodies) or fibrosis in zone unit between 1991 and 1997. They were iden- 314 15; and (3) non-specific/minimal changes: a tified as cases with a persistent increase in variety of mild abnormalities including intra- alanine aminotransferase (ALT) (>1.5 times hepatocytic cholestasis, steatosis, sinusoidal the upper limit of normal on at least two diVer- dilation, and mild lobular inflammation or ent occasions over a minimum period of six necrosis. months) and who met the following criteria: Immunoperoxidase staining for HBV surface (1) absence of HBsAg and anti-HCV antibod- and core proteins was performed in liver sam- ies in serum; (2) ferritin, alpha1 antitrypsin, and ples of all PCR-B positive cases. ceruloplasmin levels within the normal range; (3) antinuclear, antimitochondrial, and anti- SEROLOGY http://gut.bmj.com/ smooth muscle antibodies at a titre of <1/80; HBsAg, anti-HBc (IgG), and anti-HBs were (4) ethanol intake less than 80 g/day; (5) tested by standard ELISA kits (Cobas Core, absence of treatment with potentially hepato- Roche, Madrid). Anti-HCV antibodies were toxic drugs; (6) negative human immuno- detected using the ELISA 3 test (Ortho- deficiency virus (HIV) serology; (7) absence of Clinical Diagnostics GmbH, Germany). Anti- decompensated diabetes, thyroid dysfunction, HIV antibodies were tested by ELISA (Cobas