Introduction
Khat (Catha edulis), a plant chewed for its stimulant effects by millions in East Africa and the Arabian Peninsula, is increasingly recognized for its hepatotoxic potential. Its primary active alkaloids, cathinone and cathine, are sympathomimetics with amphetamine-like properties. Beyond its established links to acute and chronic liver injury, emerging evidence strongly associates khat use with the development of autoimmune hepatitis (AIH). This review synthesizes the current knowledge on khat-associated AIH, analyzing published cases through the validated Roussel Uclaf Causality Assessment Method (RUCAM) and the simplified AIH score to establish a causal link and guide clinical management.
Epidemiology and Diagnostic Challenges
Khat use is deeply entrenched in the cultures of Yemen, Somalia, and Ethiopia, with prevalence among men as high as 90% in some regions. Consequently, khat-associated liver injury predominantly affects young men, a demographic distinct from the typical middle-aged female population of classic AIH. Diagnosis is often hindered by the plant's legal status in many endemic areas, cultural acceptance, and the short detection window of cathinones in urine. With global migration, cases of khat-induced hepatotoxicity are now reported in the UK, US, and Australia, necessitating increased awareness among clinicians worldwide.
Pharmacokinetics and Metabolic Interactions
The liver bears the primary metabolic burden for khat's alkaloids. Cathinone is extensively metabolized by cytochrome P450 enzymes, particularly CYP2D6, which khat itself significantly inhibits. This inhibition poses a substantial risk for drug-drug interactions with common medications metabolized by CYP2D6, such as antidepressants, beta-blockers, and opioids. Genetic polymorphisms in CYP2D6 and UGT enzymes, which handle phase II glucuronidation, contribute to individual susceptibility to khat's hepatotoxicity, underscoring the need for personalized risk assessment.
Proposed Pathogenetic Mechanisms
Khat is not a mere hepatotoxin; it acts as an immunomodulator. The primary mechanism driving khat-associated AIH appears to be the stimulation of a pro-inflammatory immune response. Cathinones induce the release of cytokines such as IL-2, IL-6, and TNF-α, promoting a T-helper cell (Th1 and Th17) mediated response. This leads to hepatic inflammation, characterized by elevated CD4+ and CD8+ T lymphocytes. Animal and human studies confirm that khat chewing creates a chronic inflammatory state, which can trigger a loss of immune tolerance and the development of an AIH-like phenotype in susceptible individuals. The liver injury is predominantly idiosyncratic (non-dose-dependent), suggesting an adaptive immune-mediated mechanism.
Clinical Spectrum: Acute and Chronic Khat-Associated AIH
The review meticulously analyzes 18 cases of acute and 14 cases of chronic khat-associated AIH.
Acute AIH: Patients typically present with a severe hepatocellular injury pattern, significantly elevated transaminases, hypergammaglobulinemia, and positive autoantibodies (ANA in 58.8%, ASMA in 44.4%). Histology reveals interface hepatitis, lymphoplasmacytic infiltration, and liver cell rosetting. A key diagnostic feature is the prompt response to corticosteroid therapy or complete resolution upon khat cessation.
Chronic AIH: These cases often show evidence of established liver disease, with fibrosis being a common histological finding (present in 70% of cases). The prognosis is worse than in acute AIH, with a subset of patients progressing to cirrhosis, liver failure, or death despite immunosuppressive therapy.
The Critical Role of Causality Assessment
This review strengthens the causal association by systematically applying RUCAM. Scores of ≥5 (probable or highly probable) were found in one-third of acute and over half of chronic cases with sufficient data. The integration of high RUCAM scores with elevated AIH scores, characteristic histology, and a positive response to immunosuppression allows for a confident diagnosis of Herb-Induced Autoimmune Hepatitis (HIAIH), a specific subtype of drug-induced liver injury.
Management and Outcomes
The cornerstone of management is immediate and permanent cessation of khat use. For most patients, this must be combined with immunosuppressive therapy, typically starting with prednisolone. Azathioprine is often required for steroid-sparing purposes or for treating recurrent episodes. Outcomes are generally favorable with early diagnosis and intervention, preventing progression to fibrosis and cirrhosis. However, delayed diagnosis can lead to fulminant liver failure requiring transplantation or death from complications of chronic liver disease.
Conclusion
The evidence compiled in this review, supported by calculated RUCAM and AIH scores, strongly affirms a causal link between khat use and the development of both acute and chronic autoimmune hepatitis. The pathogenesis is rooted in khat's immunomodulatory effects, which disrupt immune tolerance. Clinicians must maintain a high index of suspicion for khat-associated AIH in young male patients from endemic regions presenting with hepatitis and autoimmune features. A definitive diagnosis requires a thorough workup, including autoimmune serology, liver biopsy, and the application of validated causality assessment methods. Successful management hinges on khat abstinence and timely initiation of immunosuppressive therapy to prevent severe, irreversible liver damage.
Full text
https://www.xiahepublishing.com/2310-8819/JCTH-2025-00180
The study was recently published in the Journal of Clinical and Translational Hepatology .
The Journal of Clinical and Translational Hepatology (JCTH) is owned by the Second Affiliated Hospital of Chongqing Medical University and published by XIA & HE Publishing Inc. JCTH publishes high quality, peer reviewed studies in the translational and clinical human health sciences of liver diseases. JCTH has established high standards for publication of original research, which are characterized by a study's novelty, quality, and ethical conduct in the scientific process as well as in the communication of the research findings. Each issue includes articles by leading authorities on topics in hepatology that are germane to the most current challenges in the field. Special features include reports on the latest advances in drug development and technology that are relevant to liver diseases. Regular features of JCTH also include editorials, correspondences and invited commentaries on rapidly progressing areas in hepatology. All articles published by JCTH, both solicited and unsolicited, must pass our rigorous peer review process.
