What is the diagnosis for a patient with elevated iron levels, hyperferritinemia, and increased iron saturation?

Diagnosis: Hereditary Hemochromatosis (HFE-Related Iron Overload)

This 52-year-old woman has biochemical evidence of iron overload consistent with hereditary hemochromatosis, based on her markedly elevated transferrin saturation of 61% (threshold >45% for women) combined with elevated serum iron (183 mg/dL) and ferritin (141 ng/mL). 1

Diagnostic Interpretation

Iron Studies Analysis

• Transferrin saturation of 61% is the critical diagnostic finding that indicates inappropriate iron absorption and disturbed plasma iron homeostasis characteristic of hemochromatosis 1
• The 2022 EASL guidelines specify that transferrin saturation >45% in women warrants genetic testing for HFE mutations 1
• Her ferritin of 141 ng/mL, while mildly elevated above the 200 ng/mL threshold for women, is relatively modest and indicates she is likely in an earlier stage of iron accumulation 1
• The elevated serum iron (183 mg/dL) with normal-range TIBC (300 mg/dL) confirms true iron overload rather than secondary hyperferritinemia 1

Why This is Hemochromatosis and Not Secondary Hyperferritinemia

The key distinguishing feature is the elevated transferrin saturation >55-60%, which specifically indicates primary iron overload disorders rather than the >90% of hyperferritinemia cases caused by inflammation, liver disease, metabolic syndrome, or malignancy. 2, 3

• When transferrin saturation is <45%, iron overload is effectively ruled out and secondary causes predominate 2, 3
• In secondary hyperferritinemia (inflammation, NAFLD, alcohol, malignancy), ferritin rises as an acute phase reactant while transferrin saturation typically remains normal or even decreases 2, 4
• This patient's pattern—high transferrin saturation with moderately elevated ferritin—is the biochemical signature of hereditary hemochromatosis 1

Immediate Next Steps

Mandatory Genetic Testing

HFE genetic testing for C282Y and H63D mutations must be performed immediately in this patient. 1

• C282Y homozygosity is the most common genetic cause of hereditary hemochromatosis in individuals of European descent 1
• C282Y/H63D compound heterozygosity can also cause clinically significant iron overload 1
• If genetic testing is negative for these common mutations, consider non-HFE hemochromatosis (mutations in TFR2, SLC40A1, HAMP, HJV genes) 2

Risk Stratification for Liver Disease

This patient is at low risk for advanced liver fibrosis based on her ferritin <1,000 μg/L. 1

• The 2011 AASLD guidelines state that C282Y homozygotes with ferritin <1,000 μg/L, normal liver enzymes, and no hepatomegaly can proceed directly to phlebotomy without liver biopsy 1
• Ferritin <1,000 μg/L has a 94% negative predictive value for cirrhosis in hemochromatosis patients 2
• Liver biopsy should be considered only if ferritin exceeds 1,000 μg/L or if liver enzymes are elevated 1

Assessment for Organ Damage

Evaluate for early organ involvement before initiating treatment: 1

• Check liver enzymes (AST, ALT) and assess for hepatomegaly clinically
• Screen for diabetes mellitus with fasting glucose or HbA1c
• Evaluate for cardiac involvement if any symptoms of heart failure or arrhythmias are present
• Consider joint examination for arthropathy, particularly metacarpophalangeal joints

Treatment Initiation

Therapeutic phlebotomy should be initiated immediately once genetic testing confirms HFE hemochromatosis. 1

• Weekly phlebotomy (500 mL per session as tolerated) until ferritin reaches 50-100 μg/L 1
• Monitor hemoglobin/hematocrit before each phlebotomy; do not allow >20% decrease from baseline 1
• Check ferritin every 10-12 phlebotomies during intensive phase 1
• After reaching target ferritin of 50-100 μg/L, transition to maintenance phlebotomy at intervals needed to keep ferritin in this range 1

Family Screening

All first-degree relatives (siblings, children) must be screened with ferritin, transferrin saturation, and HFE genetic testing. 1, 3

• Siblings have a 25% chance of being C282Y homozygotes if both parents are carriers 3
• Early detection in relatives prevents progression to organ damage and normalizes life expectancy 1

Critical Pitfalls to Avoid

• Do not dismiss this as "just elevated ferritin" because the level is only 141 ng/mL—the elevated transferrin saturation is the diagnostic key 1, 2
• Do not attribute hyperferritinemia to metabolic syndrome or NAFLD without checking transferrin saturation first—these conditions typically have normal or low transferrin saturation 2, 4
• Do not delay genetic testing—early diagnosis before age 40 and before ferritin exceeds 1,000 μg/L is associated with normal life expectancy 1
• Avoid vitamin C supplements, which enhance iron absorption and can accelerate organ damage 1
• Do not order liver biopsy in this patient unless genetic testing reveals an unexpected result or liver enzymes are elevated—her ferritin <1,000 μg/L makes advanced fibrosis extremely unlikely 1

Prognosis

If treatment is initiated now, before development of cirrhosis or diabetes, this patient should have normal life expectancy. 1

• Survival is normal in hemochromatosis patients when phlebotomy begins before cirrhosis or diabetes develops 1
• The major causes of death in untreated hemochromatosis—cirrhosis, hepatocellular carcinoma, diabetes, and cardiomyopathy—are preventable with early iron removal 1