Hereditary hemochromatosis

Definition

Recessive genetic disorder to iron handling that is characterized by elevated iron saturation and high ferritin and that causes progressive end-organ damage, most commonly liver, pancreas, and heart.

Etiology

• Most commonly caused by homozygous C282Y mutation of the HFE gene
  • Only 10% of homozygotes will have iron overload
• Can also present in compound heterozygotes of HFE gene
• Non-HFE-associated iron overload
  • Hemojuvelin (HJV)
  • Transferrin receptor-2 (TfR2)
  • Ferroportin (SLC40A1)
  • Hepcidin (HAMP)
  • African iron overload

Epidemiology

• Most common genetic cause of cirrhosis
• 10% of those homozygous for C282Y develop symptoms

Clinical Presentation

History

• Asymptomatic
  • Abnormal serum iron studies on routine screening chemistry panel
  • Evaluation of abnormal liver tests
  • Identified by family screening
• Nonspecific, systemic symptoms
  • Weakness
  • Fatigue
  • Lethargy
  • Apathy
  • Weight loss
• Specific, organ-related symptoms
  • Abdominal pain (hepatomegaly)
  • Arthralgias (arthritis)
  • Diabetes (pancreas)
  • Amenorrhea (cirrhosis)
  • Loss of libido, impotence (pituitary, cirrhosis)
  • Congestive heart failure
  • Arrhythmias

Physical exam

• Liver
  • Hepatomegaly
  • Cutaneous stigmata of chronic liver disease
  • Splenomegaly
  • Liver failure: ascites, encephalopathy, and associated features
• Joints Arthritis
  • Joint swelling
  • Chondrocalcinosis
• Heart
  • Dilated cardiomyopathy
  • Congestive heart failure
• Skin
  • Increased pigmentation
  • Porphyria cutanea tarda
• Endocrine
  • Testicular atrophy
  • Hypogonadism
  • Hypothyroidism

Investigations

graph TD;

invest["Serum transferrin saturation (TS) and ferritin"]

tsnorm["TS <45% and normal ferritin"]
tsup["TS ≥45% and/or high ferritin"]
fhx["First-degree relative with HH"]
noeval["No further evaluation"]
genotype["HFE genotyping"]

invest --> tsnorm
tsnorm --> noeval

invest --> tsup
tsup --> genotype

fhx --> genotype

• Initial workup is ferritin and serum transferrin saturation
  • If ferritin is above upper limit of normal, or if transferrin saturation is ≥45%, then do HFE mutation analysis
  • Transferrin saturation = serum iron concentration ÷ total iron binding capacity
• HFE mutation analysis
  • Done for all first-degree relatives of an index case
  • Done for all patients with elevated ferriting or TS ≥45%
  • Important results:
    • Homozygous C282Y
    • Compound heterozygous C282Y/H63D
    • Homozygous H63D/H63D generally don't have iron overload
• Iron/transferrin saturation >60% in men or >50% in women
  • Most sensitive and cost-effective test
• If cirrhosis develops, monitor closely for hepatocellular carcinoma

Management

• Phlebotomy to target ferritin of 50-100
  • But need to prevent hematocrit or hemoglobin dropping more than 20% of prior level

Further Reading

• Bacon BR et al. Diagnosis and management of hemochromatosis: 2011 practice guideline by the American Association for the Study of Liver Diseases. Hepatology. 2011;54(1):328-43.