A man in his 60s with immunodeficiency and hepatitis

An overweight man in his sixties with hypogammaglobulinaemia and bone marrow failure was admitted to hospital for investigation of hepatitis. He had recently been hospitalised with an uncomplicated respiratory infection. At that time, elevated liver enzymes were noted: alanine aminotransferase (ALT) 160 U/L (reference range 10–70), alkaline phosphatase (ALP) 220 U/L (35–105) and gamma-glutamyl transferase (γ-GT) 330 U/L (15–115). Ultrasound of the liver and biliary tract showed no abnormal findings, although visualisation was suboptimal. Following discharge, liver enzymes were monitored by the patient's general practitioner and remained stably elevated at levels similar to those during hospitalisation. Six weeks later, a rapid rise in ALT to 954 U/L and γ-GT to 449 U/L occurred, prompting acute re-admission for further evaluation.

On admission, the patient reported some fatigue but was otherwise in good general condition, with no organ-specific symptoms. He did not appear jaundiced, although he had recently noticed darker urine. On examination, he was afebrile; the liver was not enlarged on abdominal palpation, and there were no clinical signs of advanced liver disease. The patient reported a modest alcohol intake of 1–2 units per month. Three weeks prior to admission, treatment with semaglutide for obesity had been initiated, but he had not started any other new medications in recent months. His medical history included prostate cancer surgery, diet-controlled type 2 diabetes, and established coronary artery disease (previously treated with percutaneous coronary intervention), for which he was taking acetylsalicylic acid, atorvastatin, diltiazem and isosorbide mononitrate. He also used pregabalin and methadone for neuropathic pain, mirtazapine for depression, pantoprazole for gastroesophageal reflux, valaciclovir for prophylaxis against reactivation of herpes simplex and varicella zoster virus, and trimethoprim-sulfamethoxazole prophylactically for Pneumocystis jirovecii. Additionally, he received intravenous immunoglobulin every four weeks for hypogammaglobulinaemia and once weekly granulocyte colony-stimulating factor (G-CSF) for long-term bone marrow failure.

Blood tests on admission showed C-reactive protein (CRP) 5 mg/L (< 5), leukocytes 1.7 × 10⁹/L (3.5–11.0 × 10⁹/L), platelets 57 × 10⁹/L (145–390 × 10⁹/L), ALT 940 U/L, aspartate aminotransferase (AST) 611 U/L (15–45), γ-GT 440 U/L, ALP 221 U/L, ferritin 4 850 µg/L (30–400), bilirubin 28 µmol/L (< 26), international normalised ratio (INR) 1.2 (0.8–1.2), albumin 37 g/L (34–45), IgA < 0.1 g/L (0.7–4.3), IgG 5.3 g/L (6.1–14.9), IgM < 0.1 g/L (0.4–2.1).

Ten years earlier, the patient had been diagnosed with IgG-kappa multiple myeloma, which relapsed after high-dose chemotherapy with autologous stem cell support. Subsequent lines of therapy had limited effect, and he developed bone marrow failure. Blood tests eight months prior to admission showed neutropenia (neutrophils 0.85 × 10⁹/L [1.6–8.3 × 10⁹/L]), lymphopenia (lymphocytes 0.39 × 10⁹/L [0.8–3.7 × 10⁹/L]) and thrombocytopenia (platelets 71 × 10⁹/L [145–390 × 10⁹/L]). In addition, he had hypogammaglobulinaemia, with IgA and IgM both < 0.1 g/L and IgG 46.5 g/L (6.1–14.9). The M-protein was estimated at 43 g/L. Having exhausted all treatment options available in Norway at that time, he was enrolled in a clinical trial in Southern Europe six months prior to admission. In this trial, he received chimeric antigen receptor T-cell (CAR-T) therapy targeting B-cell maturation antigen (BCMA), resulting in a subsequent fall in M-protein from 43 g/L to 1.5 g/L.

Serological tests for viral hepatitis were performed, which provided no evidence of active infection with hepatitis A, B or C viruses. Both IgM and IgG for hepatitis E virus (HEV) were also negative. For cytomegalovirus and Epstein-Barr virus, IgG was positive and IgM negative, consistent with past infection. No viral DNA was detected in the blood for these two viruses or hepatitis B virus. Combined antibody/antigen testing for HIV was negative.

CT imaging of the liver in the arterial, portal venous and venous phases demonstrated patent vessels, no evidence of cholestasis or focal lesions, but mild inflammatory changes with periportal oedema and contrast enhancement of the bile ducts. Blood tests for autoimmune hepatitis, including anti-F-actin antibodies (anti-smooth muscle antibodies), were negative.

As imaging, autoantibodies and microbiological tests did not reveal the cause of the patient's hepatitis, an ultrasound-guided liver biopsy was performed. Liver enzymes were now improving spontaneously, and the patient was discharged while awaiting the biopsy result, which came one week later. Histology demonstrated chronic active portal and lobular inflammation, scattered single-cell necroses and mild iron deposition in hepatocytes. Inflammation was graded as 3 (0–4) with fibrosis stage 0 (0–4). The absence of plasma cells and interface activity was inconsistent with autoimmune hepatitis, and the histological picture was most consistent with drug-induced or viral hepatitis.

The findings were discussed with a hepatologist at a university hospital, and it was considered that the overall picture could be consistent with autoimmune hepatitis, even though no anti-F-actin antibodies were detected. Prednisolone 40 mg daily was therefore initiated. Given the diagnostic uncertainty, the patient was to be closely monitored for treatment response. Two weeks after discharge, the patient attended a planned follow-up for multiple myeloma at the study centre in Southern Europe. Much of the hepatitis work-up was repeated there, with the same findings as in Norway, but additional analysis of HEV ribonucleic acid (RNA) in the blood was performed, resulting in 183 million IU/mL. Prednisolone was therefore discontinued, and oral ribavirin 800 mg daily was initiated.

While receiving ribavirin therapy, viral load and liver enzymes gradually declined. A treatment interruption due to medicine supply issues led to a rapid flare-up of hepatitis and a rise in viral load to several million IU/mL. Due to adverse effects, including nausea and psychiatric symptoms (low mood, racing thoughts and sleep disturbance), ribavirin was reintroduced at a reduced dose of 600 mg daily, which was better tolerated.

After three months of continuous ribavirin therapy, liver enzymes had normalised, while HEV RNA remained at 30,000 IU/mL. Treatment was therefore extended for an additional three months. Liver stiffness measurement showed a median stiffness of 7.8 kPa, consistent with the absence of significant fibrosis. After a total of six months of continuous ribavirin therapy, HEV RNA was 9,000 IU/mL.

At follow-up ten months after discharge, HEV RNA was no longer detectable in blood samples. This was confirmed six weeks later in blood and stool samples. Ribavirin was therefore discontinued. At a subsequent follow-up three months later, viral RNA remained undetectable.