What is the most likely diagnosis and initial work‑up for a patient with normal serum iron, elevated ferritin, low total iron‑binding capacity (TIBC), low‑normal hemoglobin, elevated transaminases (AST/ALT), low albumin, and normal creatinine?

Likely Diagnosis: Hepatocellular Injury with Secondary Hyperferritinemia

The most likely diagnosis is chronic liver disease—specifically non-alcoholic fatty liver disease (NAFLD), alcoholic liver disease, or viral hepatitis—causing secondary hyperferritinemia through hepatocellular injury and inflammation, not iron overload. 1

Diagnostic Reasoning

Why This Is NOT Iron Overload

• Transferrin saturation must be calculated immediately using the formula (serum iron × 100) ÷ TIBC to differentiate true iron overload from secondary causes. 1
• If transferrin saturation is <45%, iron overload is excluded with >90% certainty, and the elevated ferritin reflects inflammation, liver injury, or metabolic dysfunction—not iron accumulation. 1
• Over 90% of elevated ferritin cases are caused by chronic alcohol consumption, inflammation, cell necrosis, tumors, or NAFLD/metabolic syndrome, not hereditary hemochromatosis. 1
• Normal serum iron with low TIBC strongly argues against primary iron overload, which characteristically shows elevated transferrin saturation (≥45%) and elevated serum iron. 1

Why This Pattern Suggests Liver Disease

• Elevated transaminases (AST/ALT) indicate active hepatocellular injury, which releases ferritin from damaged hepatocytes independent of iron stores. 1, 2
• Low serum albumin reflects impaired hepatic synthetic function, pointing to chronic liver disease rather than acute inflammation alone. 1
• In liver disease, serum ferritin correlates with both the degree of hepatocellular injury (transaminases) and liver iron concentration, creating this exact laboratory pattern. 2
• Low TIBC in the setting of liver disease reflects decreased hepatic transferrin synthesis, not iron overload. 3

Initial Work-Up Algorithm

Step 1: Calculate Transferrin Saturation (IMMEDIATE)

• Formula: (Serum iron × 100) ÷ TIBC 1
• If TS ≥45%: Suspect primary iron overload → proceed to HFE genetic testing for C282Y and H63D mutations 1
• If TS <45%: Iron overload excluded → evaluate secondary causes below 1

Step 2: Assess Inflammatory Markers

• Order CRP and ESR to quantify systemic inflammation 1
• Elevated inflammatory markers support anemia of chronic disease or inflammatory liver disease 1

Step 3: Evaluate Liver Disease Etiology

Imaging

• Abdominal ultrasound is mandatory to assess for fatty liver, chronic liver disease, hepatomegaly, or cirrhotic features 1
• Nearly 40% of patients with abnormal liver tests have fatty liver on ultrasound 1

Serologic Testing

• Hepatitis B surface antigen and hepatitis C antibody to screen for viral hepatitis 1
• Detailed alcohol history (chronic alcohol consumption is a leading cause of this pattern) 1
• Fasting glucose, lipid panel, and hemoglobin A1c to assess for metabolic syndrome/NAFLD 1

Additional Liver Testing

• Prothrombin time/INR and bilirubin to assess hepatic synthetic function and severity 1
• Platelet count (if <200,000/µL with ferritin >1000 µg/L and elevated transaminases, this predicts cirrhosis in 80% of cases) 1

Step 4: Rule Out Other Secondary Causes

• Complete blood count with differential to assess for hematologic malignancy or polycythemia 1
• Creatine kinase (CK) to evaluate for muscle necrosis as a source of ferritin elevation 1
• Consider malignancy screening if ferritin is extremely elevated (>10,000 µg/L) or if constitutional symptoms are present 1

Risk Stratification by Ferritin Level

Ferritin Level	Clinical Implication	Action Required
<1,000 µg/L	Low risk of organ damage; 94% negative predictive value for advanced fibrosis [1]	No liver biopsy needed if TS <45% and liver enzymes mildly elevated [1]
1,000–10,000 µg/L	Higher risk of advanced fibrosis/cirrhosis if iron overload present [1]	Consider liver biopsy if TS ≥45% with elevated transaminases or platelets <200,000/µL [1]
>10,000 µg/L	Rarely simple iron overload; urgent specialist referral needed [1]	Evaluate for life-threatening conditions (hemophagocytic lymphohistiocytosis, severe inflammation) [1]

Management Strategy

If Transferrin Saturation <45% (Most Likely Scenario)

• Treat the underlying liver disease, not the elevated ferritin itself 1
• For NAFLD: weight loss, metabolic syndrome management, and lifestyle modification 1
• For alcoholic liver disease: alcohol cessation and nutritional support 1
• For viral hepatitis: antiviral therapy as indicated 1
• Phlebotomy is contraindicated unless TS ≥45% with confirmed iron overload 1

If Transferrin Saturation ≥45%

• Order HFE genetic testing immediately for C282Y and H63D mutations 1
• If C282Y homozygote or C282Y/H63D compound heterozygote confirmed: initiate therapeutic phlebotomy and screen first-degree relatives 1
• Consider liver biopsy if ferritin >1,000 µg/L with elevated transaminases or platelets <200,000/µL to assess for cirrhosis 1

Critical Pitfalls to Avoid

• Never diagnose iron overload based on elevated ferritin alone—transferrin saturation ≥45% is mandatory for this diagnosis 1
• Do not assume hereditary hemochromatosis when TS <45%; conditions like alcoholic hepatitis or acute liver injury produce identical ferritin elevations 1
• Do not overlook liver biopsy in patients with ferritin >1,000 µg/L and abnormal liver tests, as this combination warrants histologic assessment for cirrhosis 1
• Recognize that ferritin is an acute-phase reactant that rises in inflammation, liver disease, malignancy, and tissue necrosis independent of iron stores 1, 4
• Low TIBC with normal iron does NOT indicate iron overload—it reflects decreased hepatic transferrin synthesis from liver disease 3

When to Refer to Hepatology

• Ferritin >1,000 µg/L with elevated bilirubin 1
• Ferritin >10,000 µg/L regardless of other findings 1
• Confirmed TS ≥45% on repeat testing 1
• Clinical evidence of cirrhosis (platelet count <200,000/µL, elevated bilirubin, hepatomegaly) 1
• Confirmed C282Y homozygosity requiring therapeutic phlebotomy 1