Autoimmune hepatitis in young Somalian men – experience from a German tertiary care center

Introduction

Autoimmune hepatitis (AIH) is a rare disease characterized by increased alanine aminotransferase (ALT) and aspartate aminotransferase (AST), hypergammaglobulinemia (elevated immunoglobulin G, IgG) and interface hepatitis or/and lobular necroinflammation in liver biopsy.¹ The diagnosis of AIH is based on circulating antibodies (antinuclear antibodies (ANA), smooth muscle antibodies (SMA), liver kidney muscle antibodies (LKM)) and exclusion of other causes of liver disease including viral hepatitis. Diagnostic scoring systems from the International Autoimmune Hepatitis Group (IAIHG) have been created to established the diagnosis of AIH.²

AIH mainly affects women and is often diagnosed between the age of 40 to 70. Genome wide association studies (GWAS) associate HLA A1, B8, Cw7 and DR3 haplotype with AIH in European patients.^1,3 Significant diversity in disease severity has been identified for autoimmune disorders in general and AIH before.³ Yet, data on AIH in non-European/non-Asian patients is very limited, especially for African patients. Compared to European AIH patients, non-European patients present at younger age, with a cholestatic laboratory pattern and a poorer response to standard therapy.⁴ A recent study from England reported a small cohort of six Somalian men with an unusual form of AIH with cholestatic features.³ These patients responded poorly to standard immunosuppressive therapy. In this context, we recently treated two Somalian patients with AIH in our tertiary care center. The aim of this study was to identify additional Somalian patients with liver disease in our electronic hospital database and analyze the cause of liver disease, the clinical course and outcome of these patients.

Material and methods

Results

All three male patients were referred from other hospitals to our Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology for further diagnostic and therapy. Two of the three patients presented with acute onset of hepatitis, while one patient had a history of autoimmune hepatitis and a recent episode of variceal bleeding. Detailed patients’ characteristics are presented in Table 1.

Case 1

A 38-year-old Somalian man was admitted to our hospital shortly after acute variceal bleeding that required transfusion of packed red blood cells. The initial diagnosis of AIH type 1 was made in another hospital five years prior to presentation. At this time, antibody screening revealed an ANA of 1:80 and a SMA 1:80 with an elevated IgG (17.2 g/l) and liver biopsy showed fibrosis but no cirrhosis and typical features of AIH including lymphoplasmacellular inflammation (Figure 1A). Immunosuppressive treatment with azathioprine (1.5 mg/kg per os once a day) was initiated. The patient denied any herbal drugs or hepatotoxic medication history and there was no family history of liver diseases or alcohol abuse.

Figure 1. Liver biopsies show typical findings compatible with the diagnosis of AIH.

A. Liver biopsy of case no 1 shows fibrosis with incomplete cirrhosis, ductular reaction and lymphoplasmacellular inflammation. B. Liver biopsy of case no 2 shows subacute subtotal necrosis of the liver parenchyma (95%) with fibrosis, ductular reaction, hepatocyte rosettes and lymphoplasmacellular inflammation. C. Liver biopsy of case no 3 shows ballooning of hepatocytes, apoptosis and portal plasmacellular inflammation. No modifications have been made to the images.

At the current admission the patient was treated with azathioprine and showed no relevant elevation of transaminases while cholestasis parameters were slightly elevated (Table 1). Liver function corresponded to Child Pugh Score B. Total IgG was within normal range under immunosuppressive therapy. Abdominal ultrasound and computed tomography revealed signs of liver cirrhosis and a thrombosis of the mesenteric and portal vein and therapeutic anticoagulation was initiated. As the patient suffered from recurrent episodes of variceal bleeding, we implanted a transjugular intrahepatic portosystemic shunt (TIPS). During the clinical course the patient developed an increase of transaminases (AST 284 U/l, ALT 131 U/l, AP 154 U/l, GGT 95 U/l, total bilirubin 18 μmol/l) and we intensified immunosuppression by adding prednisolone at a dose of 20 mg/day (per os once a day) with good response. After TIPS placement the patient developed recurrent pleural effusion which could not be managed by diuretics alone. A pleurodesis was performed followed by the placement of a long-term indwelling pleural catheter.

In the following months the patient was readmitted several times for complications of liver cirrhosis including infection (spontaneous bacterial peritonitis, infection of pleural effusion) and hepatic encephalopathy. Esophageal varices improved after TIPS insertion. IgG was within normal range under immunosuppressive therapy. However, the general condition of the patient worsened over time. While the patient presented with another episode of acute-on-chronic liver failure and a Model of End Stage Liver Disease (MELD)-Score of 32 he was evaluated for liver transplantation. There were no contraindications for solid organ transplantation. He was listed for liver transplantation and successfully transplanted (extended right lobe) six months after he presented to our hospital for the first time.

Discussion

AIH is a differential diagnosis in every new onset hepatopathy. The diagnosis is based on several circulating autoantibodies, hypergammaglobulinemia, the exclusion of other causes of liver disease and liver biopsy showing typical histological findings. Two scores are used in clinical practice to determine the likelihood of AIH. While the revised AIH score includes female gender in the scoring system, the simplified AIH score does not consider gender at all.^2,5 In addition, the prevalence of AIH is higher in western Europe and north America and significantly lower in Asia and Africa.^1,3 Therefore, AIH is often not considered as a likely differential diagnosis in African patients with elevated liver enzymes. However, at first presentation African American patients have more advanced stages of liver fibrosis than white American patients.⁶ In line with this observation, data from the UK found that Black patients presented at younger age and with higher IgG levels than white patients.⁷ A retrospective study from a hospital in the US which serves indigent and under-resourced communities identified race/ethnicity as an independent risk factor for AIH.⁸ Taken together, AIH needs to be considered as a differential diagnosis not only in White women but also in patients of African origin.

In this context, D’Souza et al. published a case series that analyzed the clinical, histological and immunological features of AIH in young Somalian men.³ The authors identified six patients (all male) from Somalia (all immigrants who had lived in the UK for the last six years) by scanning their histopathology database. Similar to the aforementioned studies and our three individuals, these patients were younger at presentation (median age 37 years) than the European control group (median age 55 years). There was a trend toward more advanced liver disease at presentation in Somalian patients (median ISHAK fibrosis 2.5 compared to 2 in Europeans). Biochemical cholestasis (AP greater than twice the upper normal limit) was observed in 66% of the Somalian patients and histopathological findings consistent with cholestasis were detected in 50% of patients, in contrast there was only one European patient with evidence of biochemical cholestasis. While initial therapy with prednisolone and azathioprine was effective in 8/10 European AIH patients, only 1/6 Somalian patients had a treatment response. HLA typing in this study revealed classical autoimmune associated allotypes in the European patients (HLA A1, B8, Cw7, DR3 or DR4).^1,3 In contrast, Somalian patients shared different HLA allotypes (HLA B7, DR8, DQ2 and DQ4).

Another study by Zolfino et al. identified twelve patients from Africa (six patients), Asia (five patients) and Arabia (one patient) with AIH from an AIH-patient database with a median age of 30 years at presentation.⁴ Of those nine (75%) had a cholestatic serum biochemistry and three had histological findings comparable to PBC or a cholangiographic evidence of PSC. Complete biochemical response to standard immunosuppressive therapy was detectable in only four patients (33%), while five patients (42%) had no response to standard therapy. Overall, four of the 12 patients underwent liver transplantation for intractable disease. Zolfino et al. compared the twelve patients to a group of 130 European patients with AIH. In contrast to Yang et al.¹ the non-European patients were younger at presentation, presented with cholestatic biochemistry and morphological biliary features more frequently. In addition, they showed poorer response to standard immunosuppressive therapy.

The patients that were identified in our tertiary care hospital are comparable to the cases series mentioned before. Our Somalian patients also suffered from advanced liver disease (one required liver transplantation, another patient had progression towards decompensated liver cirrhosis in less than two years) at a young age (median age of 37). No Somalian women with AIH were identified in our tertiary care center and no relevant overlap syndrome was observed in our patients. In line with the previous report by D`Souza et al, one of our patients (no 2) showed also elevated cholestatic enzymes. The typical HLA genotypes were not detected in our cohort. The treatment response in our patients was different. Although patient 1 had a biochemical response, he subsequently developed hepatic decompensation with variceal bleeding and ascites requiring TIPS insertion and subsequently liver transplantation. Both, patients 2 and 3 had a biochemical response to standard immunosuppressive therapy. However, patient 3 was not compliant resulting in several flares of AIH with progression to liver cirrhosis in less than two years. While all three patients had possible AIH according to the revised/simplified AIH score, autoimmune hepatitis can be also be associated with the intake of certain drugs or herbal medicine.⁹ In this context, there are reports that Khat chewing is associated with liver disease in Somalian men,¹⁰ while others question this observation.¹¹ Khat is a herbal product, and a study from Ethiopia observed a significant association between chewing khat and the risk for developing chronic liver disease. Unfortunately, our retrospective study could not rule out khat intake by all three patients.

An obvious limitation of this retrospective study is that there is no systematic follow up and that some patients may have been missed when the country of birth was not documented.

In summary, AIH should be considered in every new onset hepatopathy, especially when viral hepatitis is excluded. AIH in non-European patients is different. Somalian patients with AIH are younger at presentation and show a severe disease that may poorly respond to standard immunosuppressive therapy. AIH treatment of non-European patients requires a more aggressive and maybe alternative treatment. The different clinical features and treatment regimens should be considered in our multicultural society.

Consent

Written informed consent for publication of their clinical details and histological images was obtained from the patients.