What is the pathophysiology and management of hemochromatosis?

Hemochromatosis: Pathophysiology and Management

Hemochromatosis is a genetic disorder characterized by excessive iron absorption that leads to progressive iron accumulation in organs, causing significant morbidity and mortality if left untreated, but early diagnosis and treatment with phlebotomy can normalize life expectancy. 1

Pathophysiology

Genetic Basis

• Hereditary hemochromatosis (HH) is predominantly caused by mutations in the HFE gene located on chromosome 6p, with C282Y homozygosity (C282Y/C282Y) found in >90% of patients with phenotypic HH 1
• Compound heterozygosity (C282Y/H63D) accounts for 3-5% of cases 1
• The prevalence of C282Y homozygosity is approximately 1 in 250 individuals of European descent, particularly those of Nordic or Celtic ancestry 1
• Despite the high prevalence of genetic susceptibility, fewer than 10% of C282Y homozygotes develop full clinical manifestations of the disease 1

Iron Regulation and Hepcidin

• Hepcidin, a 25-amino acid peptide produced by hepatocytes, is the principal iron-regulatory hormone 1
• HFE protein forms a complex with transferrin receptor-1 (TfR1) and influences iron-dependent regulation of hepcidin 1
• In hemochromatosis, mutations in the HFE gene lead to decreased hepcidin expression or resistance to hepcidin binding 2
• Decreased hepcidin results in:
  • Increased intestinal iron absorption
  • Enhanced iron release from macrophages
  • Progressive iron accumulation in parenchymal cells of various organs 1

Tissue Damage Mechanisms

• Iron-induced oxidative damage occurs through:
  • Iron-dependent lipid peroxidation in hepatocytes causing cellular injury or death 1
  • Activation of Kupffer cells by products from injured iron-loaded hepatocytes 1
  • Production of profibrogenic cytokines that stimulate hepatic stellate cells to synthesize collagen, leading to fibrosis 1
• Ferroptosis, an iron-dependent form of regulated cell death, is involved in hemochromatosis through:
  • Release of intracellular free iron from ferritin via ferritinophagy
  • Mitochondrial injury with additional iron accumulation
  • Excessive production of reactive oxygen species (ROS) and lipid peroxidation 2

Disease Progression

• The clinical condition evolves in stages:
  • Stage 1: Genetic susceptibility without increased iron stores (0-20 years of age, 0-5g parenchymal iron storage) 1
  • Stage 2: Iron overload without organ damage (20-40 years of age, 10-20g parenchymal iron storage) 1
  • Stage 3: Iron overload with organ damage (>20g parenchymal iron storage) 1

Clinical Manifestations

Symptoms and Signs

• Classic triad of "bronze diabetes": cirrhosis, diabetes, and skin pigmentation 1, 3
• Common symptoms include:
  • Fatigue and weakness (19-83% of patients) 1
  • Arthralgias, particularly of the second and third metacarpophalangeal joints (13-57%) 1
  • Abdominal pain (0-58%) 1
  • Sexual dysfunction (decreased libido, impotence) (12-56%) 1
  • Cardiac failure symptoms (0-35%) 1
• Physical findings include:
  • Hepatomegaly (3-83%) 1
  • Skin pigmentation (5-82%) 1
  • Cirrhosis (3-94%) 1
  • Clinical diabetes (6-55%) 1
  • Testicular atrophy (14-50%) 1

Organ Involvement

• Liver: Fibrosis, cirrhosis, hepatocellular carcinoma 1
• Pancreas: Diabetes mellitus 1
• Heart: Cardiomyopathy, congestive heart failure 1
• Joints: Arthritis, chondrocalcinosis 1, 2
• Endocrine system: Hypogonadotropic hypogonadism, hypopituitarism 2

Diagnosis

Screening and Target Populations

• Screening should target:
  • First-degree relatives of confirmed HH cases 1
  • Patients with unexplained liver disease or abnormal iron studies 1
  • Individuals with type 2 diabetes, particularly with hepatomegaly or elevated liver enzymes 1
  • Patients with early-onset atypical arthropathy, cardiac disease, or male sexual dysfunction 1

Diagnostic Tests

• Initial testing:
  • Transferrin saturation (TS) - elevated in all C282Y homozygotes (100% positive predictive accuracy) 1
  • Serum ferritin - reflects hepatic iron content 1, 2
• Confirmatory testing:
  • Genetic testing for HFE mutations (C282Y, H63D) 1, 4
  • Liver biopsy with hepatic iron concentration measurement in selected cases 1

Diagnostic Challenges

• Many patients are now identified while asymptomatic through screening 1
• Clinical features may be nonspecific and overlap with other conditions 2
• Elevated ferritin can occur in inflammatory conditions, requiring exclusion of other causes 2

Management

Treatment Goals

• Early diagnosis to prevent organ damage 1
• Screening and early detection of asymptomatic cases to reduce mortality 1
• Adequate treatment to promote rapid, safe, and effective removal of iron 1
• Vigilant follow-up and maintenance treatment 1

Therapeutic Phlebotomy

• Primary therapy for iron depletion is phlebotomy 5, 4
• Treatment should be initiated before development of cirrhosis or diabetes to normalize survival 1
• Phlebotomy regimen:
  • Initial iron depletion phase: Regular phlebotomy to normalize iron stores 5
  • Maintenance phase: Lifelong phlebotomy to prevent reaccumulation of iron 5, 2

Additional Management Considerations

• Dietary modifications to reduce iron absorption 5
• Chelating agents as adjunctive therapy in selected cases 4
• Orthotopic liver transplantation for patients with advanced cirrhosis or acute liver failure 2, 4

Prognosis

• The degree of iron overload directly impacts life expectancy 1
• Major causes of death include decompensated cirrhosis, hepatocellular carcinoma, diabetes mellitus, and cardiomyopathy 1
• Survival is normal in patients treated before development of cirrhosis or diabetes 1
• Early diagnosis and treatment are essential to prevent complications and improve outcomes 6

Important Clinical Considerations

• Despite high genetic prevalence, phenotypic expression varies significantly - only about 70% of C282Y homozygotes have elevated ferritin and fewer than 10% develop full clinical manifestations 1
• Men are more likely to develop clinical symptoms earlier than women due to menstrual blood loss in women providing some protection against iron accumulation 4
• Alcohol consumption can exacerbate iron overload and should be minimized 2
• Regular monitoring of ferritin levels is essential during both initial treatment and maintenance phases 5