Autoimmune hepatitis and HIV infection

HIV infection, in the absence of treatment, causes a severe immunodeficiency, exposing the patient to life-threatening opportunistic infections. In this context, the occurrence of autoimmune diseases such as systemic lupus erythematosus, immune thrombocytopenic purpura and autoimmune hepatitis (AIH) have been rarely described [1–2]. AIH is an uncommon liver disease [3] characterized by hypergammaglobulinemia, typical histological features (i.e. interface hepatitis, plasmacytic infiltrates and regenerative liver-cell rosettes, despite no findings being specific for AIH by itself) and the presence of circulating autoantibodies such as antinuclear (ANA), antismooth muscle (ASMA) and antiliver kidney microsomal antibodies [4]. We report on two HIV-1-infected patients who were diagnosed with AIH and successfully treated with steroids (with or without azathioprine) and we review the published cases. A 38-year-old white man tested positive for HIV in 2007. He had no previous opportunistic infections. His medical history was unremarkable and he reported no current or past use of alcohol, tobacco or illicit drugs. In March 2009, the patient was admitted to hospital for acute hepatitis: alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were 3800 and 4600 IU/l, respectively. Prothrombin time decreased to 40% and gamma-globulin was 2.28 g/dl (29.5%). Serologies for hepatitis A (HAV), hepatitis B (HBV) and hepatitis C (HCV) viruses were negative. At that time, his CD4+ cell count was 762 cells/μl and HIV RNA was 8072 copies/ml, in the absence of HIV therapy. He was not overweight and his abdominal ultrasound revealed only hepatosplenomegaly. ANA was positive (1 : 640) with speckled pattern, as well as ASMA (1 : 160). The liver biopsy showed mild-to-moderate interface hepatitis, regenerative liver-cell rosettes and numerous plasma cells, as well as sinusoidal eosinophilic globules. Mild periportal fibrosis, hepatocyte swelling and pycnotic necrosis were present. The pretreatment score using the system of the International AIH Group (IAIHG) [5] was 20 points, consistent with definite AIH. The patient was started on oral prednisone (75 mg/die, tapering dose to 10 mg in the following 12 weeks) and liver enzymes were normalized. After 6 months, azathioprine was added to his regimen and prednisone was successfully discontinued. In October 2014, his CD4+ cell count was 632 cells/μl (33%) with a viral load of 21 000 copies/ml. He was started on rilpivirine/tenofovir/emtricitabine with virological response, while continuing azathioprine (75 mg/day) with persistent normal transaminases during the following 25 months of follow-up. A 70-year-old white woman was diagnosed with HIV in 1984. Her medical history included fibrocalcified aortic valve with moderate stenosis and dyslipidemia in a normal weight woman. The patient had a history of moderate alcohol use (between 25 and 60 g/day), with gamma-glutamiltransferase of 176 IU/ml (normal value <55 IU/ml). Since 1991, she had been put on HIV therapy which, in 2012, was switched to atazanavir/ritonavir/raltegravir, when HIV RNA was less than 50 copies/μl and her CD4+ cell count was 938 cells/μl. She was also on rosuvastatin (10 mg/day). Her abdominal ultrasound revealed only hepatomegaly without steatosis. In November 2014, AST and ALT levels started to be persistently elevated (2.5-fold). She tested negative for HAV, HBV, HCV, as well for hepatitis E-RNA, cytomegalovirus-DNA and herpes simplex 1/2-DNA. Antigliadin antibodies were also negative, whereas ANA were 1 : 640 (normal value <1 : 160). The patient remained asymptomatic until February 2016, when she was admitted to our unit for liver decompensation with ascites. The liver biopsy showed features of cirrhosis, with portal tract infiltrates of lymphocytes, clusters of plasma cells and focal interface hepatitis. There were also numerous intrasinusoidal eosinophilic globules within the endothelial cells. The patient's pretreatment score [5] was 16, meeting criteria for definite AIH. She was put on methylprednisolone (40 mg/day for 1 week, then tapered down to prednisone 25 mg). The patient's liver enzymes normalized and she was discharged home. Her HIV RNA remained undetectable, with CD4+ cell count of 1016 cells/μl. After 6 weeks, she was put on maintenance dose of prednisone (12.5 mg/day) with persistent remission of AIH. Table 1 shows the 31 cases of AIH in HIV patients reported in 14 articles over the last 13 years [6–19]. In the HIV setting, AIH appears to involve all ages, with a predominance of female patients. All of them had a CD4+ cell count more than 150 cells/μl at AIH presentation. Rarely, AIH can present as a fulminant hepatic failure leading to orthotopic liver transplantation [6,9]. In one case, about 1 week after starting steroids, the patient died of sepsis and multisystem organ failure [15]. At AIH presentation, HIV-RNA was below the limit of detection in most patients. These patients were successfully treated with corticosteroids, with or without azathioprine. Only one patient was switched to mycophenolate mofetil because of relapse during azathioprine treatment [16]. In two patients, HIV-RNA was detectable at AIH presentation: the first improved spontaneously (he was treated with HIV therapy only) [19], the second responded to corticosteroid therapy [8]. A spontaneous remission without therapy was also described [16] and, in at least 18 cases, AIH was interpreted by clinicians as being related to immune reconstitution in the course of HIV therapy [6,7,10,12,17,18].Table 1: Overview of reported cases of autoimmune hepatitis in HIV-infected patients.The current diagnosis of AIH is based on a scoring system according to laboratory abnormalities, serological data and histological findings [4]. It is noteworthy that this score also includes the response to corticosteroid treatment, so that the liver biopsy is not mandatory, the histological features are not specific and up to 10% of patients may lack circulating autoantibodies [5]. According to the above mentioned scoring system, the diagnosis of AIH may be classified as probable (if the post-treatment score is between 12 and 17 points) or definite (with a posttreatment score higher than 17 points). According to the autoantibody patterns, AIH may be classified as type 1 or type 2 [3]. Appropriate tests are required to rule out the alternative causes of AST/ALT abnormalities such as viral hepatitis, drug-induced or alcoholic-induced toxicities, metabolic abnormalities (such as nonalcoholic fatty liver disease or obesity), immune-mediated cholestatic diseases and hereditary factors (such as Wilson disease, hereditary hemochromatosis). AIH can present as a life-threatening acute liver failure leading to transplantation, or as mild aminotransferase elevations of unknown cause [6]. Its activity may fluctuate over time and spontaneous remission may occur [3]. Immunosuppressive treatment frequently induces remission, but long-term maintenance therapy is often required [3]. The prevalence of AIH in the general population is uncertain. The majority of the few epidemiological studies were performed prior to the introduction of the IAIHG scoring system [5], and so the diagnostic criteria are inconsistent. The first study to use the IAIHG scoring system reported a prevalence of definite AIH in 34.5 cases per 100 000 in Alaskan natives [20]. However, in another study carried out in New Zealand, the prevalence described was estimated as 24.5 cases per 100 000, with an annual incidence of 2.0 cases of AIH per 100 000 [21]. Alternatively, most reports from Japan showed that AIH is considerably less frequent with an estimated incidence of between 0.08 and 0.15 cases per 100 000 people per year [22,23]. The AIH in HIV-infected patients has been rarely described. A recent retrospective French study investigated the clinical manifestations, treatments, prognosis and prevalence of autoimmune diseases in HIV-infected individuals: only one case of AIH was identified in a cohort of 5186 patients [24]. We reviewed the English literature over the last 13 years and a total of 14 reports, describing 31 cases, were identified (Table 1; [6–19]). Indeed, multiple factors causing abnormal liver enzymes may be coexisting in this population, such as HCV or HBV, opportunistic infections, neoplasms, antiretroviral drugs, liver steatosis, overweight, alcohol or illicit drug use [25]. The occurrence of an autoimmune disorder in the context of a viral disease, whose hallmark is the immune depression, is intriguing. HCV coinfection is frequent in the HIV setting, and there is an association between AIH and HCV. Up to 38% of patients with HCV have ANA [14]. In contrast, nearly one-third of patients with AIH have positive HCV antibodies [26]. An array of autoimmune phenomena and autoantibodies has been described during the course of HIV disease, potentially due to the high level of immune activation [27]. In addition, the immune reconstitution inflammatory syndrome, typically seen in patients with immune depletion and starting antiretroviral therapy, may unmask an autoimmune liver disease, as described in several reports [6,7,10,12,17,18]. The review of the literature underlines the potential connection between autoimmune diseases and HIV infection, as polymyositis and Sjögren's syndrome [8], primary biliary cirrhosis [10], systemic lupus erythematosus [12], Graves’ disease history [17] and vitiligo [19] are reported in patients with AIH and HIV infection. Clinicians should be aware of this uncommon clinical entity in the course of HIV infection, irrespective of the degree of immunosuppression. The differential diagnosis of the serum ALT/AST increase should include this uncommon, but potentially treatable condition, which may be masked by multiple confounders in the HIV population. Acknowledgements We thank Guido Colloredo, MD, for his collaboration in the description of the first case report. Conflicts of interest There are no conflicts of interest.

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