Double Trouble: Drug-Induced AIH-PBC Overlap Syndrome Triggered by Hydralazine

Abstract

Introduction

Autoimmune liver disease comprises a spectrum of conditions, notably autoimmune hepatitis (AIH) and primary biliary cholangitis (PBC). When features of multiple autoimmune diseases overlap, the condition is termed overlap syndrome with AIH-PBC being the most common. However, its etiology remains complex and not fully understood. This case highlights drug-induced liver injury (DILI) as a potential trigger for AIH-PBC overlap syndrome in a patient with initially elevated liver function tests (LFTs) attributed to hydralazine use.

Case description

A 51-year-old male with a medical history of hypertension (HTN), type 2 diabetes mellitus, and a prior cerebrovascular accident presented with elevated LFTs after starting hydralazine. Initial labs showed aspartate aminotransferase (AST) 456 U/L, alanine aminotransferase (ALT) 779 U/L, alkaline phosphatase 250 U/L, and total bilirubin 1.4 mg/dL. Additional workup included testing for antimitochondrial antibody (AMA), antinuclear antibody (ANA), anti-smooth muscle antibody (ASMA) and an iron profile. While AMA, ANA, and ASMA were elevated, a diagnosis of AIH or PBC was not made due to the absence of diagnostic histologic findings. Liver biopsy showed mixed portal and lobular inflammation with lymphocytes, plasma cells, and eosinophils, without interface hepatitis or bile duct lesions.

Despite discontinuing hydralazine, the patient returned one month later with persistently elevated LFTs. Further workup was notable for an antimitochondrial antibody (AMA) titer greater than 1:320 and an anti-smooth muscle antibody (ASMA) level of 39, indicating an autoimmune etiology, specifically pointing toward AIH-PBC overlap syndrome. A repeat liver biopsy showed florid duct lesions and interface hepatitis, supporting the diagnosis of AIH-PBC overlap syndrome.

The patient was treated with prednisone and ursodiol (13 mg/kg/day in two divided doses). Statin therapy was discontinued, and a 30- day prednisone course at 40 mg daily was initiated. Follow-up LFTs demonstrated marked improvement, with AST 26 U/L, ALT 77 U/L, and alkaline phosphatase 89 U/L. A steroid taper was initiated in response to the significant improvement.

Discussion

The clinical presentation of AIH-PBC overlap syndrome is often non-specific, including symptoms such as fatigue, abdominal pain, myalgias, and arthralgias. Diagnosis is based on the Paris criteria: Patients with PBC must have two of the following (1) ALP ≥ 2x the upper limit or GGT ≥ 5x the upper limit; (2) positive anti-mitochrondrial antibody; and (3) floral duct lesion on biopsy [1]. A comprehensive history is essential to assess the multifactorial etiologies commonly underlying AIH-PBC overlap syndrome. When the etiology remains uncertain, our case suggests evaluating the patient’s medication history, as DILI may trigger AIH-PBC overlap syndrome. Common drugs associated with DILI include hydralazine, acetaminophen, amiodarone, and methotrexate [2]. Additionally, medications known to induce autoimmune hepatitis include statins, NSAIDs, nitrofurantoin, and anti-tumor necrosis factor agents [3]. Once AIH-PBC overlap syndrome is diagnosed, treatment typically involves ursodeoxycholic acid in combination with an immunosuppressive regime [4]. In our case, the patient was treated with ursodiol and corticosteroids, resulting in near-normalization of liver enzymes and improvement of symptoms.