What is the most likely diagnosis and appropriate workup and treatment for a patient with markedly elevated ferritin, elevated serum iron, mixed hepatocellular‑cholestatic liver enzyme abnormalities (elevated aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase), elevated bilirubin, and a normal alpha‑1 antitrypsin level?

Most Likely Diagnosis: Hereditary Hemochromatosis with Significant Hepatocellular Injury

Based on the markedly elevated ferritin (1675 μg/L), elevated serum iron (179 μg/dL), and mixed hepatocellular-cholestatic pattern with elevated transaminases and bilirubin, the most likely diagnosis is hereditary hemochromatosis with significant liver disease, though secondary causes including NAFLD with iron accumulation must be excluded through immediate transferrin saturation measurement and HFE genetic testing. 1, 2

Immediate Diagnostic Workup Required

Critical First Step: Measure Transferrin Saturation

• Order fasting transferrin saturation (TS) immediately - this is the single most important test to distinguish true iron overload from secondary causes of hyperferritinemia 1, 2
• The combination of elevated ferritin AND elevated serum iron strongly suggests iron overload, but TS ≥45% is required to confirm this diagnosis 1, 2
• Over 90% of elevated ferritin cases are NOT due to iron overload, making TS measurement essential before proceeding 3, 4

If Transferrin Saturation ≥45%: Proceed to HFE Genetic Testing

• Order HFE genotype testing for C282Y and H63D mutations immediately to diagnose hereditary hemochromatosis 1, 2
• C282Y homozygotes or C282Y/H63D compound heterozygotes with elevated iron stores confirm HFE hemochromatosis 1, 3
• This pattern (elevated ferritin, elevated iron, TS ≥45%) indicates primary iron overload requiring genetic confirmation 1, 2

If Transferrin Saturation <45%: Evaluate Secondary Causes

• Consider NAFLD/metabolic syndrome, chronic alcohol consumption, viral hepatitis, or autoimmune hepatitis as primary causes 5, 3, 6
• The mixed hepatocellular-cholestatic pattern with elevated bilirubin suggests significant liver disease regardless of etiology 5, 7
• Check inflammatory markers (CRP, ESR) to assess for occult inflammation 1, 2

Critical Risk Stratification: Ferritin >1000 μg/L

Your patient's ferritin of 1675 μg/L crosses the critical threshold where management changes dramatically. 1, 2

High Risk Features Present

• Ferritin >1000 μg/L carries a 20-45% prevalence of cirrhosis in C282Y homozygotes 1, 2
• Elevated AST (134) and ALT (221) with ferritin >1000 μg/L significantly increases risk of advanced fibrosis or cirrhosis 2
• Elevated bilirubin (total 3.6, direct 2.7) indicates significant hepatocellular dysfunction 5
• Elevated alkaline phosphatase (263) suggests cholestatic component or advanced liver disease 5

Liver Biopsy Decision Algorithm

Strongly consider liver biopsy given the following combination: 1, 2

• Ferritin >1000 μg/L (present: 1675 μg/L)
• Elevated liver enzymes (present: AST 134, ALT 221)
• Elevated bilirubin (present: 3.6 mg/dL)

The combination of ferritin >1000 μg/L with elevated transaminases predicts cirrhosis in 80% of C282Y homozygotes when platelet count <200,000/μL 1, 2

Alternative to Liver Biopsy

• Consider liver elastography or MRI with iron quantification as non-invasive alternatives if available 1, 6
• MRI with T2/T2* relaxometry can quantify hepatic iron concentration with 84-91% sensitivity and 80-100% specificity 1

Differential Diagnosis Beyond Hemochromatosis

Secondary Causes to Exclude

NAFLD/Metabolic Syndrome: 5, 3

• Mildly elevated ferritin is common in NAFLD and does not necessarily indicate increased iron stores 5
• Ferritin elevation in NAFLD reflects hepatocellular injury and insulin resistance rather than true iron overload 1, 3
• However, your patient's serum iron of 179 μg/dL argues against pure NAFLD

Alcoholic Liver Disease: 3, 6

• Chronic alcohol consumption increases iron absorption and causes hepatocellular injury 3
• Detailed alcohol history is essential 3

Viral Hepatitis: 5, 3

• Approximately 50% of hepatitis B and C patients have abnormal serum iron studies 1
• Check hepatitis B surface antigen and hepatitis C antibody 5

Autoimmune Hepatitis: 5, 8

• High serum titers of autoantibodies (ANA >1:160 or ASMA >1:40) with very high aminotransferases and high globulin should prompt complete autoimmune workup 5
• Autoimmune hepatitis can present with markedly elevated transferrin saturation, mimicking iron overload syndrome 8
• Check ANA, ASMA, immunoglobulin levels 5

Management Algorithm Based on Transferrin Saturation

Scenario A: If TS ≥45% and C282Y Homozygote Confirmed

Initiate therapeutic phlebotomy immediately: 1, 2

• Remove 500 mL blood weekly or biweekly as tolerated 1
• Target ferritin 50-100 μg/L for induction phase endpoint 1
• Check hemoglobin/hematocrit before each phlebotomy 1
• Allow hemoglobin to fall no more than 20% from baseline 1
• Check ferritin every 10-12 phlebotomies 1

Critical considerations with ferritin >1000 μg/L: 1, 2

• Liver biopsy should be performed BEFORE or early in phlebotomy therapy to stage disease 1, 2
• Therapeutic phlebotomy prevents hepatic cirrhosis, primary liver cancer, diabetes, and cardiomyopathy when initiated before severe iron overload develops 1
• Does NOT reverse established cirrhosis but prevents progression 1

Screen first-degree relatives: 1, 2

• All first-degree relatives require HFE genotype testing and phenotype (ferritin and TS) 1
• Penetrance is higher in family members than general population 1

Scenario B: If TS <45% - Treat Underlying Liver Disease

The treatment target is the underlying liver disease, NOT the elevated ferritin itself: 2

• Phlebotomy is ONLY indicated for confirmed iron overload with elevated TS 2
• Address NAFLD with weight loss and metabolic syndrome management if present 2
• Treat viral hepatitis or autoimmune hepatitis if confirmed 5
• Abstinence from alcohol if alcoholic liver disease 3

Additional Workup to Complete

Imaging Studies

• Abdominal ultrasound to evaluate for fatty liver, hepatomegaly, cirrhotic features, or bile duct abnormalities 3
• Nearly 40% of adults with abnormal liver tests have fatty liver on ultrasound 3

Laboratory Tests Not Yet Mentioned

• Complete blood count with differential and platelet count (platelet count <200,000/μL predicts cirrhosis) 1, 2
• Complete metabolic panel including albumin (decreased in cirrhosis) 9
• Prothrombin time/INR (synthetic liver function) 5
• Hepatitis B surface antigen, hepatitis C antibody 5
• ANA, ASMA, immunoglobulin levels 5
• Fasting glucose and lipid panel (metabolic syndrome assessment) 5

Critical Pitfalls to Avoid

Never use ferritin alone to diagnose iron overload: 1, 2, 3

• Ferritin is an acute phase reactant elevated in inflammation, liver disease, malignancy, and tissue necrosis independent of iron stores 1, 3
• Transferrin saturation is ESSENTIAL for diagnosis 1, 2

Do not overlook liver biopsy with ferritin >1000 μg/L and abnormal liver tests: 1, 2

• This combination has 100% sensitivity for cirrhosis in hemochromatosis patients 2
• No patient with ferritin <1000 μg/L had cirrhosis in validation studies 2

Do not assume iron overload when TS <45%: 1, 2

• In the general population, iron overload is NOT the most common cause of elevated ferritin 3, 4

Do not fail to screen first-degree relatives if HFE-related hemochromatosis confirmed: 1, 2

• This is a Grade 1A recommendation 1

Prognosis and Urgency

With early diagnosis and treatment before cirrhosis develops, prognosis is excellent: 2

• Therapeutic phlebotomy can prevent cirrhosis, hepatocellular carcinoma, and other complications 2
• However, your patient's elevated bilirubin and mixed enzyme pattern suggest significant liver disease may already be present 5, 7

Refer to gastroenterology/hepatology if: 1, 4

• Ferritin >1000 μg/L (present in your patient) 4
• Evidence of significant liver dysfunction (elevated bilirubin present) 5
• TS ≥45% on testing 1
• Cause of elevated ferritin remains unclear after initial workup 4