What are the causes and management of increased iron saturation leading to hemochromatosis?

Causes and Management of Increased Iron Saturation Leading to Hemochromatosis

Hereditary hemochromatosis (HH) is primarily caused by genetic mutations leading to inappropriate iron absorption and requires early diagnosis and phlebotomy treatment to prevent life-threatening complications including cirrhosis, hepatocellular carcinoma, diabetes, and heart disease. 1

Causes of Increased Iron Saturation

Genetic Causes

• HFE-related hemochromatosis (most common form):
  • C282Y homozygosity (>90% of cases)
  • C282Y/H63D compound heterozygosity (3-5% of cases)
  • Other HFE mutations (less common)
• Non-HFE hemochromatosis:
  • Juvenile hemochromatosis
  • Autosomal dominant hemochromatosis
  • Other gene mutations affecting hepcidin production or ferroportin resistance 1, 2

Secondary Causes of Iron Overload

• Iron-loading anemias:
  • Thalassemia major
  • Sideroblastic anemia
  • Chronic hemolytic anemias
• Chronic liver diseases:
  • Hepatitis B and C
  • Alcoholic liver disease
  • Porphyria cutanea tarda
  • Fatty liver disease
• Other causes:
  • Excessive dietary iron intake
  • African iron overload
  • Aceruloplasminemia
  • Congenital atransferrinemia 1

Pathophysiology

Hemochromatosis develops through a series of stages:

1. Early stage (0-20 years): Clinically insignificant iron accumulation (0-5g parenchymal iron)
2. Middle stage (20-40 years): Iron overload without disease (10-20g parenchymal iron)
3. Late stage: Iron overload with organ damage (>20g parenchymal iron) 1

The primary mechanism involves:

• Mutations affecting hepcidin production or action
• Uncontrolled intestinal iron absorption
• Iron accumulation in parenchymal tissues
• Ferroptosis (iron-dependent cell death)
• Production of reactive oxygen species (ROS)
• Organ damage and dysfunction 3

Diagnostic Approach

Target Populations for Screening

• Symptomatic patients:
  • Unexplained liver disease
  • Type 2 diabetes with hepatomegaly or elevated liver enzymes
  • Early-onset arthropathy, cardiac disease, or sexual dysfunction
• Asymptomatic priority groups:
  • First-degree relatives of confirmed HH cases
  • Individuals with abnormal iron markers on routine testing
  • Patients with unexplained elevated liver enzymes 1

Diagnostic Tests

1. Initial screening:

   • Transferrin saturation (TS) - fasting value >50% for women, >60% for men has high sensitivity (92%) and specificity (93%)
   • Serum ferritin - elevated in iron overload

2. Confirmatory testing:

   • Genetic testing for HFE mutations (C282Y, H63D)
   • Liver biopsy for hepatic iron concentration and fibrosis staging when necessary 1

Management Protocol

Treatment Algorithm

1. Initial Iron Depletion:

   • Weekly or biweekly phlebotomy (removal of 500mL blood)
   • Check hematocrit/hemoglobin before each procedure
   • Allow hematocrit to fall by no more than 20% of prior level
   • Monitor serum ferritin every 10-12 phlebotomies
   • Continue until serum ferritin reaches 50-100 μg/L 1

2. Maintenance Therapy:

   • Individualized phlebotomy schedule based on iron reaccumulation rate
   • Some patients require monthly phlebotomy
   • Others may need only 1-2 units removed per year
   • Maintain serum ferritin between 50-100 μg/L 1

3. Monitoring:

   • Regular assessment of iron parameters
   • Surveillance for HCC in patients with cirrhosis
   • Evaluation of end-organ complications 1

Important Precautions

• Avoid vitamin C supplements during phlebotomy (accelerates iron mobilization)
• Prevent iron deficiency by monitoring hemoglobin and ferritin levels
• Avoid raw shellfish (risk of Vibrio vulnificus infection)
• Consider liver transplantation for decompensated cirrhosis 1, 4

Clinical Outcomes and Prognosis

The major causes of death in untreated HH are:

• Decompensated cirrhosis
• Hepatocellular carcinoma (30% of deaths)
• Diabetes mellitus
• Cardiomyopathy 1

Early diagnosis and treatment are critical: Survival is normal in patients treated before the development of cirrhosis or diabetes. Treatment can improve certain symptoms (fatigue, skin pigmentation, insulin requirements, abdominal pain) but has limited effect on established arthropathy, hypogonadism, and cirrhosis 1.

Common Pitfalls to Avoid

• Delayed diagnosis due to nonspecific early symptoms
• Excessive phlebotomy leading to iron deficiency
• Inadequate monitoring of iron parameters during maintenance therapy
• Failure to screen first-degree relatives
• Overlooking secondary causes of iron overload
• Neglecting surveillance for HCC in cirrhotic patients 1, 4