Although metabolic, viral, and drug- and alcohol-related etiologies are a familiar part of the evaluation of elevated liver enzymes, less common causes include autoimmune hepatitis, Wilson disease, and hereditary hemochromatosis. Each has a progressive course to end-organ damage underscoring the importance of early recognition, as effective therapies are available. Autoimmune hepatitis is an immune-mediated liver disease, with a female predominance and autoantibodies present in about 80% of cases. It can progress rapidly without treatment. Liver biopsy featuring lymphoplasmacytic hepatitis is needed for diagnosis and to determine the intensity of immunosuppression. Wilson disease is caused by biallelic variants in the ATP7B gene resulting in copper accumulation in the liver, brain, kidneys, and corneas. Diagnosis relies on clinical findings, laboratory data, and genetic testing results. Lifelong chelation therapy is required. Hereditary hemochromatosis is characterized by iron overload, usually due to a common variant in the HFE gene with variable disease penetrance; it is prevalent in people of Northern European ancestry. Untreated hemochromatosis leads to cirrhosis and hepatocellular carcinoma. Early diagnosis and initiation of phlebotomy can result in normal life expectancy. To facilitate early diagnosis, genetic testing of first-degree relatives is recommended for those with Wilson disease or hemochromatosis.
Darling JM. Hepatitis Overview: Less Common Causes of Hepatitis. FP Essent. 2026;566:37-46.
Case 4. EH is a 25-year-old White man reporting 6 months of intermittent nausea, fatigue, and difficulty concentrating. He reports stress with his current graduate coursework. He has been more sedentary than usual and gained about 11.3 kg (25 lb). He has no significant medical history. He occasionally takes a multivitamin. He drinks two or three beers twice a week. His body mass index is 28 kg/m2. The liver edge is palpable 6 cm (2.4 in) below the costal margin and is nontender. Physical examination findings are otherwise normal. Laboratory results are normal except for an elevated aspartate transferase (AST) level of 88 U/L (1.47 μkat/L) and an elevated alanine transferase (ALT) level of 96 U/L (1.60 μkat/L).
Overview
Autoimmune hepatitis, Wilson disease, and hereditary hemochromatosis are rare disorders and account for less than 10% of chronic liver disease cases in the United States.1,2 Each has a progressive course to end-organ damage, which underscores the importance of early recognition, as effective therapies are available. Development of formal diagnostic criteria has improved identification of these conditions. Presentations are heterogeneous but usually include transferase elevations with fatigue. Diagnosis and management of autoimmune hepatitis, Wilson disease, and hereditary hemochromatosis are summarized in Table 1.3–18
Table 1 Less Common Causes of Hepatitis
| Liver disease, genetic association, prevalence | Demographics | Extrahepatic manifestations | Presentations | Lifestyle management |
|---|---|---|---|---|
| Autoimmune hepatitis HLA and non-HLA genes; HLA-DR3 and/or HLA-DR4 genetic predisposition in White individuals 1 in 3,800 | Female to male ratio of 4:1 Any age but peak adult incidence is 50-59 years of age Any race or ethnicity; more prevalent in White people but notable increase in Black and Hispanic people in United States | Thyroid disorders Rheumatoid arthritis Skin conditions (vitiligo, alopecia) Inflammatory bowel disease Celiac disease | Asymptomatic, elevated transferase level (> upper limit of normal to 250 U/L [4.17 μkat/L]) with or without cirrhosis Acute, severe transferase elevations (> 500 U/L [8.35 μkat/L]) with or without jaundice or cirrhosis Acute liver failure with transferase level > 500 U/L, jaundice, high International Normalized Ratio, and encephalopathy Decompensated cirrhosis with normal or mild transferase elevations | Given prevalence of metabolic dysfunction–associated steatotic liver disease overlap and need for steroid therapy, a healthy, low-glycemic, low-sodium diet with moderate exercise is recommended Vitamin D, calcium supplementation Strict sun protection when receiving azathioprine and mycophenolate mofetil |
| Wilson disease Autosomal recessive ATP7B gene: biallelic variants Consider genetics consultation 1 in 30,000 | Female to male ratio of 1:1 overall, but 4:1 for acute liver failure Typically ages 3 to 55 years (but up to 70 years) Any race or ethnicity | Neurologic: motor* (dysarthria, gait abnormality, dystonia, parkinsonism, postural tremor, dysphagia, chorea) or cognitive (memory, concentration) Psychological: mood, personality, or behavior changes Nonimmune hemolytic anemia | Unexplained transferase elevation or cirrhosis regardless of age Unexplained liver disease with neurologic or psychiatric disorders Acute liver failure with nonimmune hemolytic anemia Recurrent, self-limited nonimmune hemolysis | No strict guidelines, but avoiding high-copper foods (eg, beef liver, shellfish, nuts, seeds, chocolate) during first year of therapy is helpful Copper level in drinking water ideally < 100 ng/mL Copper from pipes mitigated by allowing faucet to run for 30 seconds Consider nutrition consultation |
| Hemochromatosis Autosomal recessive HFE gene: C282Y and H63D variants 1 in 300 for C282Y/C282Y homozygosity (but variable penetrance) Consider genetics consultation | Morbidity in those with C282Y/C282Y homozygosity occurs in a male to female ratio of 2:1 Male prevalence higher after age 18 years Female prevalence higher after menopause Non-Hispanic White, Northern European | Joint disease (hemochromatosis arthropathy, pseudogout) Cardiac disease (diastolic dysfunction, conduction abnormalities) Pancreatic disease (diabetes) Pituitary gland (hypogonadism, hypothyroidism) Skin (hypermelanotic changes, porphyria cutanea tarda) | Elevated liver enzymes or cirrhosis No acute liver failure Symptoms associated with extrahepatic disease | Decrease red meat intake Avoid alcohol Avoid supplemental vitamin C and iron With copresent metabolic risks, Mediterranean diet and exercise encouraged Avoid raw shellfish when iron overload is present because of risk of Vibrio vulnificus and other siderophilic bacteria |
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