What is the most likely diagnosis for an adult patient with elevated liver enzymes, specifically Aspartate Aminotransferase (AST) of 35 and Alanine Aminotransferase (ALT) of 75, hyperferritinemia (ferritin level of 600), and a negative workup for other causes of liver disease?

Diagnosis: Nonalcoholic Steatohepatitis (NASH)

With ferritin 600, AST 35, ALT 75, and negative workup for other causes, the most likely diagnosis is nonalcoholic fatty liver disease (NAFLD), specifically nonalcoholic steatohepatitis (NASH), particularly if metabolic risk factors are present. 1

Diagnostic Reasoning

AST/ALT Pattern Analysis

• The AST:ALT ratio of 0.47 (<1) is characteristic of NAFLD, distinguishing it from alcoholic liver disease which typically shows AST:ALT ≥2 2, 1
• ALT elevation is more pronounced than AST, which is the typical hepatocellular injury pattern seen in NAFLD 2, 1
• This pattern indicates hepatocellular injury rather than cholestatic disease 3

Hyperferritinemia in NAFLD Context

• Mildly elevated serum ferritin is common in patients with NAFLD and does not necessarily indicate increased iron stores 2
• Ferritin of 600 with normal transferrin saturation is frequently found in NAFLD patients and reflects metabolic dysregulation rather than true hemochromatosis 4, 5
• Hyperferritinemia in NAFLD correlates with more severe metabolic dysfunction, insulin resistance, and hepatic steatosis 4, 5
• The simultaneous disorder of iron and glucose/lipid metabolism, often associated with insulin resistance, is responsible for persistent hyperferritinemia in NASH patients 5

When to Consider Hemochromatosis Testing

Elevated serum ferritin and transferrin saturation in patients with suspected NAFLD should lead to testing for genetic hemochromatosis 2

• If transferrin saturation is also elevated (not mentioned in your case), test for HFE gene mutations (C282Y and H63D) 2
• Consider liver biopsy to assess hepatic iron concentration if homozygote or compound heterozygote C282Y mutation is present 2
• However, in NAFLD patients with hyperferritinemia, HFE mutations are present in 65% but do not necessarily indicate clinically significant hemochromatosis 5

Risk Stratification for Advanced Fibrosis

Calculate the FIB-4 score using age, ALT, AST, and platelet count to determine risk of advanced fibrosis 2, 1:

• FIB-4 <1.3 (<2.0 if age >65): Low risk for advanced fibrosis (NPV ≥90%)
• FIB-4 >2.67: High risk for advanced fibrosis, warrants hepatology referral

Clinical Significance and Prognosis

• NAFLD patients with hyperferritinemia demonstrate more severe metabolic dysfunction, higher aminotransferases, and worse hepatic steatosis 4
• Independent risk factors for hyperferritinemia in NAFLD include insulin resistance, elevated ALT, and positive hepatic iron staining 4
• Survival is reduced in patients with NASH compared to simple steatosis, with increased cardiovascular and liver-related mortality 6
• Progression to end-stage liver disease occurs in 5.4% of NAFLD patients with elevated liver enzymes 6

Management Approach

Immediate Assessment

• Evaluate for metabolic syndrome components: obesity, type 2 diabetes, hypertension, dyslipidemia 2, 1
• Measure transferrin saturation to determine if hemochromatosis workup is needed 2
• Obtain fasting glucose/HbA1c and lipid panel 3
• Perform abdominal ultrasound (sensitivity 84.8%, specificity 93.6% for moderate-severe steatosis) 2, 3

Lifestyle Modifications (Cornerstone of Treatment)

• Target 7-10% body weight loss through caloric restriction 2, 3
• Low-carbohydrate, low-fructose diet 2, 3
• 150-300 minutes of moderate-intensity aerobic exercise weekly 2, 3

Monitoring Strategy

• Repeat liver enzymes in 2-4 weeks to establish trend 3
• If ALT increases to >5× ULN (>235 IU/L males, >125 IU/L females) or remains elevated ≥6 months, refer to hepatology 2, 1
• Monitor for progression of fibrosis, which is associated with weight gain >5 kg and worsening insulin resistance 6

Critical Pitfalls to Avoid

• Do not assume hyperferritinemia automatically indicates hemochromatosis in NAFLD patients—it usually reflects metabolic dysregulation 2, 4, 5
• Do not overlook autoimmune hepatitis if autoantibodies are elevated (ANA >1:160 or ASMA >1:40), though these are present in 21% of NAFLD patients as an epiphenomenon 2
• Do not attribute ALT ≥5× ULN to NAFLD alone—this warrants investigation for viral hepatitis, autoimmune hepatitis, or drug-induced liver injury 3
• Most NAFLD patients will develop diabetes or impaired glucose tolerance long-term (78% in one study), necessitating aggressive metabolic management 6