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The Main Liver Disease in Patients with Primary Hypogammaglobulinemia and Hepatic Abnormalitiesq

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The Main Liver Disease in Patients with Primary Hypogammaglobulinemia and Hepatic Abnormalitiesq Journal of Hepatology 48 (2008) 74–82 www.elsevier.com/locate/jhep Nodular regenerative hyperplasia: The main liver disease in patients with primary hypogammaglobulinemia and hepatic abnormalitiesq Georgia Malamut1,*, Marianne Ziol2, Felipe Suarez3, Michel Beaugrand4, Jean Franc¸ois Viallard5, Anne Sophie Lascaux6, Virginie Verkarre7, Dominique Bechade8, Thierry Poynard9, Olivier Hermine3, Christophe Cellier1,* 1Hepatology and Gastroenterology Department, Hoˆpital Europe´en Georges Pompidou, Paris, France 2Pathology Department, AP-HP, Hoˆpital Jean Verdier, Bondy, EA 3406 University Paris 13, France 3CEREDITH (centre de re´fe´rence des de´ficits immunitaires he´re´ditaires, reference centre for inherited immune deficiency), Hoˆpital Necker-Enfants Malades, Paris, France 4Hepatology and Gastroenterology Department, Hoˆpital Jean Verdier, Bondy, France 5Internal Medicine Department, Hoˆpital du Haut Le´veˆque, Pessac, France 6Clinical Immunology Department, Hoˆpital Henri-Mondor,Cre´teil, France 7Pathology Department, Hoˆpital Necker-Enfants Malades, Paris, France 8Hepatology and Gastroenterology Department, Hoˆpital du Val de Graˆce, Paris, France 9Hepatology and Gastroenterology Department, Hoˆpital Pitie´-Salpe´trie`re, Paris, France Background/Aims: Liver lesions associated with primary hypogammaglobulinemia have been poorly described. We aimed to assess the clinical, histological and immune features and outcome of hepatic injury in patients with primary hypogammaglobulinemia. Methods: The medical records of 51 patients (23 patients with liver biopsy) with primary hypogammaglobulinemia and liver abnormalities were retrospectively reviewed. Forty-three controls with primary hypogammaglobulinemia but with no hepatic manifestations were analyzed in parallel. Results: Cholestasis (65%), mainly anicteric, and portal hypertension (50%) were the main hepatic manifestations. His- tological analysis revealed non-fibrosing architectural abnormalities consistent with nodular regenerative hyperplasia (NRH) in 84% of CVID patients and in all HIGM and XLA patients. Intrasinusoidal lymphocytic infiltration, abnormal- ities of portal vessels and epithelioid granulomas were observed in 90%, 43% and 44% of patients, respectively. NRH was associated with portal hypertension in 75% of the cases. These patients more often presented with autoimmune diseases and peripheral lymphocytic abnormalities than control patients (p < 0.05). Conclusions: Liver involvement in primary hypogammaglobulinemia mainly consists of NRH leading to chronic chole- stasis and portal hypertension. Association with intrasinusoidal T cell infiltration, portal vein endotheliitis, autoimmune diseases and peripheral lymphocytic abnormalities suggests an autoimmune mechanism. Ó 2007 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. Keywords: Nodular regenerative hyperplasia; Portal hypertension; Primary hypogammaglobulinemia; Common variable immunodeficiency; Hyper-IgM syndrome; X-linked agammaglobulinemia Received 3 March 2007; received in revised form 4 August 2007; accepted 7 August 2007; available online 17 October 2007 Associate Editor: J. Bosch q The authors declare that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript. * Corresponding authors. Tel.: +33 1 56 09 23 87; fax: +33 1 56 09 35 29. E-mail addresses: [email protected] (G. Malamut), [email protected] (C. Cellier). Abbreviations used: CVID, common variable immunodeficiency; HIGM, hyper-IgM syndrome; ID, immunodeficiency; NRH, nodular regene- rative hyperplasia; XLA, X-linked agammaglobulinemia; PBL, peripheral blood lymphocytes; HVPG, hepatic vein pressure gradient. 0168-8278/$32.00 Ó 2007 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.jhep.2007.08.011 G. Malamut et al. / Journal of Hepatology 48 (2008) 74–82 75 1. Introduction The following data were systematically recorded from the medical files of the 94 patients with confirmed primary hypogammaglobuline- mia: serum Ig levels, peripheral blood lymphocytes (PBL) phenotype, Common variable immunodeficiency (CVID), hyper- aspartate aminotransferase (AST), alanine aminotransferase (ALT), IgM syndrome (HIGM) and Bruton’s disease are the alkaline phosphatases (AP), gamma-glutamyl transferase (GGT), total most common symptomatic primary antibody-deficiency bilirubin, serum albumin level, prothrombin time, platelet count, hep- atitis B virus (HBV) and HCV serologies and polymerase chain reac- syndromes. CVID and HIGM are characterized by tions (PCR), Coomb’s test, Rheumatoid factor, anti-nuclear and decreased levels of at least two serum immunoglobulin anti-tissue antibodies (anti-mitochondria, -smooth muscle, -thyroid), (Ig) isotypes with elevated IgM in HIGM, and Bruton’s the results of abdominal CT-scan or ultrasonography and of upper gastrointestinal endoscopy. disease is an X-linked agammaglobulinemia (XLA) char- Liver abnormalities were defined either through abnormalities of acterized by the absence of B cells. All these syndromes are the liver enzymes (AST > 40 UI/l, ALT > 40 UI/l, AP > 110 UI/l, characterized by recurrent bacterial infections. However, GGT > 45 UI/l, total bilirubin > 17 lmol/l), radiological hepatomeg- aly or signs of portal hypertension. Cytolysis was defined by transam- susceptibility to autoimmune disorders and granuloma- inases AST and/or ALT upper to normal values and cholestasis was tous diseases frequently observed in CVID [1,2] and defined by elevated AP with possibly elevated GGT. Portal hyperten- HIGM [3–5] may be related to T-cell defects. sion was defined by the presence of esophageal varices or portal hyper- tensive gastropathy observed at upper gastrointestinal endoscopy, To date, hepatic diseases associated with primary Doppler ultrasonographic signs (splenomegaly with portal flux inver- hypogammaglobulinemia have not been extensively sion and presence of collateral veins) or a hepatic venous pressure gra- investigated. In the retrospective study of 248 patients dient superior to 6 mmHg. Liver enzymes, serum albumin and Ig levels, prothrombin time, with CVID reviewed by Cunningham et al., 27 patients platelet count and liver imaging (CT-scan or ultrasonography) were (11.9%) had significant liver abnormalities with 15 cases retrieved in all cases. Doppler examination was performed in 11 of hepatitis C [1]. A Norwegian study of 88 patients with patients. Upper gastrointestinal endoscopy was performed in 53 patients (56.4%). primary hypogammaglobulinemia reported 21 cases of Fifty-one patients (forty CVID patients, eight HIGM patients and hepatitis C virus (HCV) RNA-positive patients (24%) three XLA patients) had liver enzyme levels chronically superior to [6]. These studies reported a high incidence and preva- upper normal values, hepatomegaly and/or signs of portal hyperten- sion. In these patients, liver biopsy was performed in 23 patients with lence of HCV infections through contaminated intrave- measurement of the hepatic vein pressure gradient (HVPG) in 7 nous (IV) Ig preparations before 1991. However, little is patients. HCV and HBV were screened by serological tests in 41 known about the hepatic lesions specifically related to (80%) and 42 (84.5%) patients, respectively, and by PCR in 13 patients (25.5%). primary hypogammaglobulinemia. Some cases of pri- Forty-three patients (31 CVID, four HIGM, eight XLA) referred mary biliary cirrhosis [1] and three cases of nodular to the same centres but with no hepatic manifestations (normal hepatic regenerative hyperplasia (NRH) have been described enzymes and normal radiological liver examination) were included as controls. [7–9]. In previous studies [6], liver biopsies were per- Follow-up (mean: 12.3 ± 9.1 years) extended from diagnosis of formed in less than 20% of patients with liver abnormal- immunodeficiency (ID) to the most recent visit until July 1, 2006. ities, precluding a thorough investigation of the spectrum of hepatobiliary diseases in patients with pri- 2.2. Histological evaluation mary hypogammaglobulinemia. We therefore analyzed clinical data and histological Thirty-seven liver biopsies from 23 patients were performed. Nine patients had more than one liver biopsy. Liver biopsy specimens were features in a large series of patients with primary hypo- fixed in formalin or AFA (alcohol, formalin, acetic acid), paraffin gammaglobulinemia, liver abnormalities and liver embedded and stained with hematoxylin–eosin–safran, Masson’s tri- biopsies. chrome, picrosirius red and reticulin. Two pathologists specialized in liver pathology (VV and MZ) re-examined available liver biopsy sec- tions according to the following criteria with no prior knowledge of clinical or biological data. The size of the liver biopsy and the number 2. Patients and methods of portal tracts were recorded. Nodular regenerative hyperplasia was defined on picrosirius red or reticulin staining by the presence of regen- erating liver cell plates (> or = 2 hepatocytes’ width) alternating with 2.1. Patients atrophic areas with no significant portal fibrosis, bridging fibrosis or definite cirrhosis [11,12]. Intrasinusoidal lymphocytic infiltrate was Diagnoses of CVID, HIGM and of Bruton’s disease (XLA) were graded as absent, moderate or marked. Portal fibrosis was graded established by standard criteria [10] including a past history of respira- according to the METAVIR scoring system [13]. Epithelioid cell gran- tory tract infections with
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