In a patient with elevated ALT and ferritin, normal hemoglobin, normal serum iron and transferrin saturation, should hereditary hemochromatosis or Wilson disease still be considered, and which specific tests (hepatitis B and C serologies, HFE genotype, ceruloplasmin, urinary copper) should be ordered?

Diagnostic Approach to Elevated ALT and Ferritin with Normal Iron Studies

With normal iron saturation and serum iron, hereditary hemochromatosis is highly unlikely, but you should still order hepatitis B and C serologies, and consider Wilson disease screening with ceruloplasmin and 24-hour urinary copper if the patient is under 40 years old with unexplained liver disease.

Understanding Your Laboratory Pattern

Your combination of elevated ALT and ferritin with normal transferrin saturation and normal serum iron makes hereditary hemochromatosis extremely improbable. Transferrin saturation ≥45% is the most sensitive early marker for hemochromatosis, and its absence effectively excludes primary iron overload in over 90% of cases 1, 2. The elevated ferritin in your scenario reflects hepatocellular injury, inflammation, or metabolic dysfunction—not iron accumulation 1, 2.

Ferritin is an acute-phase reactant that rises during inflammation, liver disease, malignancy, and tissue necrosis independent of actual iron stores 1, 2. Never diagnose iron overload based on ferritin alone without confirming transferrin saturation ≥45% 1, 2.

Algorithmic Diagnostic Workup

Step 1: Viral Hepatitis Screening (Highest Priority)

Order hepatitis B and C serologies immediately, as chronic viral hepatitis is among the most common causes of elevated ALT with hyperferritinemia 2. Specifically obtain:

• Hepatitis B surface antigen (HBsAg) to detect active infection 2
• Hepatitis B core antibody (anti-HBc) to identify past or chronic infection 2
• Hepatitis C antibody (anti-HCV) with reflex to HCV RNA if positive 2

Chronic hepatitis C causes ferritin elevation through hepatocellular injury and systemic inflammation rather than iron overload, and viral eradication with direct-acting antivirals frequently normalizes ferritin levels 2.

Step 2: Wilson Disease Evaluation (If Age <40 Years)

If the patient is under 40 years old with unexplained liver disease, screen for Wilson disease by ordering 3:

• Serum ceruloplasmin: Levels <20 mg/dL are highly suggestive of Wilson disease
• 24-hour urinary copper: Levels >100 μg/24 hours indicate excessive copper excretion
• Slit-lamp examination for Kayser-Fleischer rings if ceruloplasmin is low

Wilson disease typically presents before age 40 with hepatic dysfunction, neuropsychiatric symptoms, or hemolytic anemia. Although less common than viral hepatitis or metabolic liver disease, missing this diagnosis has devastating consequences because chelation therapy is highly effective 3.

Step 3: Assess for Metabolic Liver Disease

The combination of elevated ALT and ferritin with normal transferrin saturation strongly suggests non-alcoholic fatty liver disease (NAFLD) or metabolic syndrome 2. Evaluate:

• Abdominal ultrasound to detect hepatic steatosis—nearly 40% of patients with abnormal liver enzymes show fatty liver on imaging 2
• Metabolic risk factors: obesity (BMI >30), type 2 diabetes, dyslipidemia, hypertension 2
• Alcohol consumption history: >14 drinks/week in women or >21 drinks/week in men suggests alcoholic liver disease 2

In NAFLD, ferritin elevation reflects hepatocellular injury and insulin resistance rather than iron overload, and management focuses on weight loss and metabolic control, not iron reduction 2.

Step 4: Inflammatory and Autoimmune Causes

Check inflammatory markers and autoimmune serologies 2:

• C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) to detect systemic inflammation 2
• Antinuclear antibody (ANA) and smooth muscle antibody if autoimmune hepatitis is suspected 2
• Rheumatoid factor and anti-CCP if joint symptoms suggest rheumatologic disease 2

If ferritin exceeds 4,000–5,000 ng/mL with persistent fever, measure glycosylated ferritin fraction (<20% is 93% specific for adult-onset Still's disease) 2.

When to Reconsider Hemochromatosis

Only proceed to HFE genetic testing if repeat transferrin saturation is ≥45% 1, 3. The diagnostic thresholds are 4, 1:

• Transferrin saturation ≥45% (most sensitive early marker)
• Ferritin >300 μg/L in men or >200 μg/L in women

If both criteria are met, order HFE gene mutation analysis for C282Y and H63D 1, 3. C282Y homozygosity confirms HFE-related hemochromatosis and accounts for 85–90% of clinically affected patients 1, 5, 6.

A single normal transferrin saturation does not absolutely exclude hemochromatosis, as biological variability means up to 33% of C282Y homozygotes may have one normal result 2. However, with both normal serum iron and normal transferrin saturation, the probability of hemochromatosis is extremely low 1, 2.

Critical Pitfalls to Avoid

• Do not order HFE genetic testing when transferrin saturation is <45%—this leads to false-positive diagnoses and unnecessary phlebotomy 1, 2
• Do not assume iron overload causes elevated ferritin when transferrin saturation is normal—in the general population, iron overload is NOT the most common cause of hyperferritinemia 1, 2
• Do not overlook viral hepatitis screening—chronic hepatitis B and C are treatable causes of elevated ALT and ferritin 2
• Do not miss Wilson disease in young patients—it is rare but catastrophic if untreated, and chelation therapy is highly effective 3

Risk Stratification by Ferritin Level

Your ferritin level determines urgency 1, 2:

Ferritin Level	Clinical Significance	Action Required
<1,000 μg/L	Low risk of organ damage; 94% negative predictive value for advanced fibrosis	Outpatient workup acceptable
1,000–10,000 μg/L	Increased risk of cirrhosis if iron overload present (80% in C282Y homozygotes with elevated ALT and platelets <200,000/μL)	Consider liver biopsy if transferrin saturation ≥45%
>10,000 μg/L	Rarely simple iron overload; suggests life-threatening conditions (hemophagocytic lymphohistiocytosis, severe inflammation)	Urgent specialist referral

Summary Algorithm

1. Confirm transferrin saturation is truly normal (<45%) by repeating fasting morning sample 1, 2
2. Order hepatitis B and C serologies (HBsAg, anti-HBc, anti-HCV) 2
3. If age <40 years: Check ceruloplasmin and 24-hour urinary copper for Wilson disease 3
4. Obtain abdominal ultrasound to assess for fatty liver 2
5. Check CRP, ESR, and consider autoimmune serologies if inflammatory disease suspected 2
6. Only order HFE genetic testing if repeat transferrin saturation ≥45% 1, 3

The treatment target is the underlying liver disease (likely viral hepatitis, NAFLD, or Wilson disease), not the elevated ferritin itself 2.