IgG4-related autoimmune hepatitis: A case report

Abstract

IgG-4-related autoimmune hepatitis (IgG4-AIH) is a rare disease. We report here a case of IgG4-AIH in an elderly male patient who was admitted to hospital because of unexplained hepatic insufficiency. After excluding viral hepatitis, alcoholic liver disease, drug-induced liver disease, parasitic infection, hepatolenticular degeneration and other diseases, and observing elevated levels of IgG-4, humoral immunity index, abnormal liver disease antibody spectrum and liver biopsy results, we made a diagnosis of IgG4-AIH. Following treatment with prednisone and ursodeoxycholic acid, the patient's liver function improved significantly and the patient was discharged from hospital.

Introduction

Immunoglobin G4 (IgG4)-related disease is a systemic fibroinflammatory disease that can involve many organs including biliary tract and liver. ¹ Biliary tract involvement is known as IgG4 sclerosing cholangitis (IgG4-SC) and liver involvement includes IgG4-hepatopathy and IgG4-related autoimmune hepatitis (IgG4-AIH)^1,2 IgG4-AIH is an immune-mediated inflammatory liver disease that is chronic and progressive and can result in liver failure and cirrhosis. ²

IgG4 antibodies have unique structural and functional properties suggesting anti-inflammatory and immune tolerance effects.^3,4 While concentrations of IgG4 in serum can vary more than 100-fold (normal range, 10–1350 mg/l), concentrations are generally stable per individual.^3,4 The pathology of IgG4-related disease involves an inflammatory process and fibrogenic pathway, the combination of which damages affected organs. ⁵ Fibroinflammatory injury is characterized by three histopathological findings: dense lymphoplasmacytic infiltrate rich in IgG4-positive plasma cells; obliterative phlebitis; fibrosis arranged, at least focally, in a storiform pattern. ⁵ Although the characteristic pathological change of IgG4-related disease is the massive infiltration of IgG4-positive plasma cells in tissues and multiple organs, diagnosing patients using biopsy specimens remains challenging.^6,7 Diagnosis should be based on a combination of histopathological findings, clinical manifestations, laboratory tests, and imaging results.^1,8

We report here a case of IgG4-AIH in an elderly male patient who was admitted to hospital because of unexplained hepatic insufficiency.

Case presentation

A man in his 50s was admitted to our hospital in April 2021. Two months previously he had been admitted to a local hospital and had been experiencing ‘poor’ abdominal distension and a bitter mouth for four months. His hepatic function was evaluated in February 2021 and was as follows: alanine aminotransferase (ALT), 716 IU/l; aspartate aminotransferase (AST), 570 IU/l; total bilirubin (TB), 52 μmol/l; direct bilirubin (DB), 42 μmol/l. All these values were higher than the normal range. Following symptomatic treatment, the patient was discharged from hospital. However, a month after discharge, the patient developed progressive oedema in both lower extremities. Consequently, he was admitted to our hospital for further diagnosis and treatment.

The patient had no history of chronic liver disease, alcohol abuse, metabolic syndrome, blood transfusions, recent surgery, or any risk factors for viral hepatitis. In addition, he had not taken any contraindicated medications or herbal products. On physical examination, the lower border of the liver was found to be 2 cm below his right rib cage. The liver was firm in texture, with clear borders and a smooth surface. No nodules or masses were palpated.

Laboratory tests on April 8, 2021 were as follows: TB, 37 μmol/l; DB, 27 μmol/l; albumin, 29 g/l; ALT, 193 IU/l, AST, 157 IU/l; gamma-glutamyl transferase (GGT), 517 IU/l; alkaline phosphatase, 253 IU/l. All these values were higher than the normal range. Serum tests for hepatitis A, B, C, and E were negative. Serum ceruloplasmin was 0.19 g/l. Autoantibody titres (i.e., antinuclear antibodies [ANA] and anti-smooth muscle antibodies [ASMA]) were positive. Humoral immune indices were as follows: kappa-light chain, 8.5 g/l; lambda-light chain, 2.4 g/l; complement C3, 0.6 g/l; complement C4, 0.1 g/l; Ig G, 29 g/l; IgE, 120 kU/l. Kappa- and lambda-light chains and Ig G and IgE were higher than the normal range; complement C3 and C4 were lower than the normal range. The serum IgG4 level was significantly higher than the normal range (2930 mg/l; normal range, 10–1350mg/l).

An abdominal computed tomography (CT) scan showed liver cirrhosis with a small amount of fluid around the liver and splenomegaly (Figure 1). An upper abdominal magnetic resonance image (MRI) scan (3.0T) and magnetic resonance cholangiopancreatography (MRCP) further confirmed liver cirrhosis, splenomegaly, and a small amount of fluid around the liver, and MRCP showed no significant abnormalities (Figure 2).

Figure 1.

Upper abdominal computed tomography (CT) scan showing liver cirrhosis with perihepatic effusion, splenomegaly, and small stones in the left kidney.

Figure 2.

Magnetic resonance image (MRI) scan (3.0T) of the upper abdomen and magnetic resonance cholangiopancreatography (MRCP) showed liver cirrhosis with splenomegaly and a small amount of perihepatic effusion.

Based on the above findings, we considered a high possibility of liver cirrhosis caused by autoimmune hepatitis. To further confirm our diagnosis, we performed an ultrasound-guided liver biopsy on April 16, 2021. Postoperative histopathological examination (i.e., light microscopy, immunohistochemistry, special staining, and electron microscopy) showed autoimmune liver disease, severe inflammation, localized cirrhosis, and IgG4-AIH (Figure 3).

Figure 3.

Histopathological examination using light microscopy, immunochemistry and special staining showed autoimmune liver disease, severe inflammation, localized cirrhosis, and IgG4-AIH. Extensive infiltration of plasma cells was observed in portal area and hepatic lobule. Severe interfacial inflammation was seen. Some interlobular bile ducts were damaged, and regional bile capillaries showed hyperplasia. The staining for multiple myeloma oncogene 1 (MUM-1) showed a significant infiltration of lymphocytes and plasma cells in the portal vein area: IgG plasma cells (>50/high power field [HPF]); IgG4 plasma cells (25/HPF); cytokeratin (CK) 7, and CK19 showed regional bile capillary hyperplasia.

The patient was diagnosed with IgG4-AIH and on April 25, 2021, was given prednisone (25 mg qd), ursodeoxycholic acid (250 mg bd), and silymarin (140 mg tds). Two days later, on April 27, 2021, the patient was discharged from the hospital because his clinical symptoms had abated and his liver function had improved. The reporting of this study conforms to CARE guidelines. ⁹ Written informed consent was obtained from the patient before publishing his anonymised data.

Discussion

Currently, the diagnosis of IgG4-AIH must meet the following three criteria: serum IgG4 level >1350 mg/l; infiltration of plasma cells (>10 per high power field [HPF]) especially in the area of the portal vein area; autoimmune hepatitis according to the diagnostic criteria of the simplified International Autoimmune Hepatitis Group (IAIHG) scoring system.^10–12 These criteria were met in our patient: he had an elevated serum IgG4 level (2930 mg/l), his histopathological results showed >10 IgG4-positive plasma cells/HMF and had simplified IAIHG score of 7 (i.e., exclusion of viral hepatitis [score 2]; positive ANA and SMA [score 2]; serum IgG > 1 [score 2]; liver histology were consistent with AIH [score 1]).

Glucocorticoids are the preferred first-line of treatment for active IgG4-AIH. ¹³ To induce remission, treatment should be initiated weight-based at a dose of prednisone 0.6–0.8 mg/kg body weight/day orally for one month. Thereafter, the dose should be reduced by 5 mg every 1–2 weeks, depending on the patient's symptoms, serological indicators, and imaging manifestations. Maintenance treatment of 2.5–5 mg/day can be administered to prevent a recurrence. While steroids are the drug of choice for the initial response, azathioprine is more appropriate for maintenance therapy, and it also aids treatment response and helps to reduce steroid side effects. ¹⁴ Azathioprine should be started at a low dose (50 mg/day) with monitoring for side effects including full blood counts undertaken every one to two weeks; the dose should then be increased to 1–2 mg/kg body weight. ¹⁴ For patients who relapse or cannot tolerate azathioprine, B-cell depleting biologics (e.g., rituximab) may be considered in addition to ursodeoxycholic acid and reduced glutathione supplementation. ¹⁵ Regular follow-up is required and clinical and laboratory evaluations (including complete blood count, blood biochemistry, concentrations of IgG subclasses, IgE levels [if elevated from baseline] and complement C3 and C4 levels) should be conducted every six months. Patients should be instructed to report any new symptoms. In some cases, periodic imaging studies may be necessary if the patient’s history, physical examination, and/or laboratory tests cannot easily assess the condition.

Despite the highly characteristic histological presentation of IgG4-associated disease, immunostaining with IgG4 is required to confirm the disease and distinguish IgG4 related disease from autoimmune hepatitis because they are similar both clinically and pathologically.^11,12 However, patients with IgG4-AIH have significantly more advanced portal inflammation, interface hepatitis, fibrosis, and rosette formation at the time of diagnosis than patients with classical autoimmune hepatitis. ¹⁶

In this present case we eliminated the possibility of liver cirrhosis from the following: Hepatitis B or C infection; alcoholic liver disease; non-alcoholic fatty liver disease; genetic/metabolic diseases (including hepatolenticular degeneration, hemochromatosis, hepatic amyloidosis, hereditary hyperbilirubinemia, α1-antitrypsin deficiency, hepatic porphyria, etc.); drugs or chemical toxins; parasitic infections (primarily schistosomiasis and Clonorchis sinensis). Drug-induced liver injury (DILI) can be divided into intrinsic (i.e., dose-dependent) and idiosyncratic (dose-independent). ¹⁷ The latter has a wider range of clinical presentations and is more likely to affect susceptible individuals who may have comorbidities. Antibiotics and antiepileptic medications are among the leading causes of DILI.^17,18 Amoxicillin has been reported to be the most common cause of DILI in Europe, whereas, antituberculosis drugs have been cited as the most common cause of DILI in India.^17,18 To rule out DILI, we scrutinised our patient’s medication history and determined that he had not previously received any antibiotics or antiepileptic drugs. It was also necessary to exclude other autoimmune hepatobiliary diseases including primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC). After these were excluded, IgG4-AIH was highly suspected, and an ultrasound-guided liver biopsy was used to confirm the diagnosis.

Reports of IgG4-AIH are rare and so there are few related guidelines and established treatment protocols. Therefore, this present case may provide interesting diagnosis and treatment ideas for physicians. As more cases are identified, the aetiology of the disease will become clearer and the criteria for diagnosis will become established. In our case, IgG4-AIH had a good prognosis. An important issue that needs to be addressed in future studies is if IgG4-AIH is a subtype of autoimmune hepatitis or a hepatic manifestation of IgG4 related disease.