Human immunodeficiency virus-associated obliterative portopathy underlies unexplained aminotransferase elevations under antiretrovirals
Authors: Vincent O. Mallet, Anaïs Vallet‐Pichard, Stanislas Pol
Journal: Hepatology (2009)

Ingiliz et al.1 reported a series of human immunodeficiency virus (HIV)–infected patients with unexplained chronic liver disease (CLD) under highly active antiretroviral therapy (HAART). We agree that steatosis, nonalcoholic steatohepatitis (NASH), and metabolic syndrome are causes of persistent serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) elevations in HIV-infected patients.2 In Ingiliz et al.'s case series, 16 of 30 patients (53%) had unexplained CLD because of occult NASH, and some of them had significant fibrosis. Therefore, 14 of their 30 patients (47%) had a persistent AST/ALT elevation with all common causes of CLD, including NASH, ruled out. The authors chose to exclude from their analysis one case of unexplained nodular regenerative hyperplasia (NRH) of the liver. Consequently, the prevalence of truly unexplained abnormal AST/ALT levels was 13/31 (42%). More specifically, the prevalence of NRH in their series was 1/31 (3%). Soriano's group in Madrid, Spain, was the first to report unexplained CLD in a cohort of HIV-monoinfected patients.3 The mechanism of this syndrome is, to date, unknown. An involvement of the liver vasculature presenting as NRH, hepatoportal sclerosis, or sinusoidal dilatation seems to account for some of these cases.4, 5 To date, seven teams worldwide have reported 39 cases of vascular disorders of the liver linked to HIV infection. Our group currently follows 21 patients with biopsy-proven NRH, 13 of them having been either previously published or presented. The mode of presentation was stereotypical: long-lasting HIV infection, exposure to HAART (especially didanosine), adequate immune restoration, and unexplained CLD and/or portal hypertension. Complications related to portal hypertension occurred in about half of them, and four required liver transplantation over the last 2 years. The pathological examination of the explants and computed tomography portography of the explant of the last transplanted patient showed diffuse obliterative portal venopathy, and we prefer today the term HIV-OP for HIV-associated obliterative portopathy to describe this new syndrome.6, 7 In view of these findings, we screened all our patients for coagulation abnormalities and found in an unexpected proportion of patients protein S activity and antigen below physiological levels.8 We designed a case-control study and found that protein S activity was significantly lower in patients with HIV-OP in comparison with matched HIV-positive controls without NRH and in HIV-negative patients with biopsy-proven NRH. Interestingly, we documented increased levels of anti–protein S immunoglobulin G (IgG) in the plasma from patients with HIV-OP in comparison with controls, and these anti–protein S IgGs were able to inhibit the cofactor activity of protein S toward activated protein C. Altogether, our data suggest that acquired anti–protein S IgGs participates in the pathogenesis of HIV-OP. In conclusion, in parallel with steatosis and NASH, HIV-OP appears to be a new and perhaps emerging cause of CLD under HAART. A possible mechanism could be acquired thrombophilia secondary to autoimmune protein S deficiency. As our data implicate a prothrombotic state, use of anticoagulants is an important question to be addressed because oral anticoagulants are effective in preventing thrombosis in congenital protein S deficiencies. Vincent O. Mallet* , Anaïs Vallet-Pichard* , Stanislas Pol* , * Université Paris-Descartes, France, Assistance Publique—Hôpitaux de Paris, Unité d'Hépatologie, Hôpital Cochin, France, Unité 567, Institut National de la Santé et de la Recherche Médicale; all in Paris, France.