What is Hemochromatosis?

Hemochromatosis: Definition, Diagnosis, and Management

Hemochromatosis is a genetic disorder of iron metabolism characterized by increased transferrin saturation and progressive iron accumulation in organs, primarily the liver, which can lead to serious complications including cirrhosis, hepatocellular carcinoma, diabetes, arthropathy, and heart failure if left untreated. 1

Definition and Pathophysiology

Hemochromatosis is caused by a deficiency or impairment in hepcidin synthesis or function due to pathogenic variants in genes regulating hepcidin production. This leads to:

• Increased intestinal iron absorption
• Increased iron release from macrophages
• Expanded circulating iron pool (reflected by increased transferrin saturation)
• Progressive body iron accumulation, primarily in the liver 1

The disease evolves in stages:

1. Clinically insignificant iron accumulation (0-20 years of age, 0-5g parenchymal iron storage)
2. Iron overload without disease (approximately 20-40 years of age, 10-20g parenchymal iron storage)
3. Iron overload with organ damage (usually more than 20g parenchymal iron storage) 1

Genetics

• Homozygosity for the p.Cys282Tyr variant in the HFE gene is the most common genetic variant in individuals of European origin, present in almost 90% of affected individuals 1
• Most patients are homozygous with autosomal recessive transmission 1
• Compound heterozygotes (C282Y/H63D) can develop iron overload in a small proportion of cases 1
• In non-European individuals or those not homozygous for p.Cys282Tyr, hemochromatosis may be caused by rarer variants in HFE or non-HFE genes 1

Clinical Manifestations

Common symptoms and signs include:

• Weakness and fatigue
• Greyish-brown skin discoloration
• Liver fibrosis, cirrhosis, and hepatocellular carcinoma
• Diabetes mellitus
• Osteoporosis and arthropathy
• Hypogonadotropic hypogonadism (in severe cases)
• Hypothyroidism (in severe cases)
• Heart failure (in severe cases) 1

Males are affected significantly more frequently than females, and disease prevalence increases with age 1.

Diagnosis

Diagnosis is based on:

1. Laboratory findings:

   • Elevated transferrin saturation (>45% in females, >50% in males and post-menopausal women)
   • Elevated serum ferritin (>200 μg/L in females, >300 μg/L in males) 1

2. Genetic testing:

   • Testing for HFE gene mutations (C282Y and H63D) after obtaining informed consent 1

3. Imaging or biopsy (when needed):

   • MRI to detect hepatic iron overload
   • Liver biopsy (historically the gold standard but less commonly used with advent of genetic testing) 1

Diagnostic algorithm:

• In patients homozygous for p.Cys282Tyr in HFE with elevated transferrin saturation and ferritin: diagnosis can be established without further testing
• In patients with high transferrin saturation and elevated ferritin but other HFE genotypes: diagnosis requires confirmation of hepatic iron overload on MRI or liver biopsy 1

Target Populations for Screening

Priority groups for screening include:

• First-degree relatives of confirmed hemochromatosis cases
• Individuals with unexplained liver disease or elevated liver enzymes
• Patients with type 2 diabetes mellitus, particularly with hepatomegaly or elevated liver enzymes
• Individuals with early-onset atypical arthropathy, cardiac disease, or male sexual dysfunction
• Individuals with unexplained elevation of transferrin saturation or ferritin 1

Management

The primary treatment is phlebotomy to remove excess iron and prevent organ damage:

• Induction phase: Regular phlebotomies until ferritin <50 μg/L
• Maintenance phase: Ongoing phlebotomies to maintain ferritin <100 μg/L 1

Early diagnosis and treatment significantly improve prognosis. Survival is normal in patients in whom treatment is initiated before the development of cirrhosis or diabetes, confirming the importance of early diagnosis and treatment 1.

Monitoring and Follow-up

• Regular monitoring of serum ferritin levels to guide phlebotomy frequency
• Assessment of liver fibrosis and other end-organ damage at diagnosis
• Patients with advanced fibrosis should be included in a screening program for hepatocellular carcinoma 1

Prognosis

The degree of iron overload directly impacts life expectancy. Major causes of death include:

• Decompensated cirrhosis
• Hepatocellular carcinoma
• Diabetes mellitus
• Cardiomyopathy 1

These complications occur 10-119 times more frequently than in the general population, but early treatment before cirrhosis or diabetes develops normalizes survival rates 1.

Key Pitfalls and Caveats

• Transferrin saturation can be falsely elevated in patients with advanced cirrhosis, low transferrin, acute liver failure, or acute liver injury 1
• Serum ferritin is a non-specific marker that can be elevated in inflammatory conditions 2
• Alcohol consumption can be a confounding factor and exacerbate iron overload 2
• Diagnosis may be delayed due to non-specific early symptoms 2
• Not all individuals with genetic mutations will develop clinical disease due to variable penetrance 1

Early diagnosis and treatment with phlebotomy are essential to prevent irreversible organ damage and improve long-term outcomes in patients with hemochromatosis.