Makindo Medical Notes

Related Subjects: | Chronic liver disease | Cirrhosis | Alkaline phosphatase (ALP) | Liver Function Tests | Ascites Assessment and Management | Budd-Chiari syndrome | Autoimmune Hepatitis | Primary Biliary Cirrhosis | Primary Sclerosing Cholangitis | Wilson disease | Hereditary Haemochromatosis | Alpha-1 Antitrypsin (AAT) deficiency | Nonalcoholic steatohepatitis (NASH) | Spontaneous Bacterial Peritonitis | Alcoholism and Alcoholic Liver Disease |Hepatitis C

About

• Hereditary haemochromatosis (HH) is an autosomal recessive disorder characterized by excess iron absorption from the small intestine, leading to iron overload in various tissues.
• The body has no regulated mechanism for iron excretion, resulting in progressive iron deposition in organs such as the liver, pancreas, heart, and joints.
• HH is the most common cause of iron overload and the leading cause of primary liver disease in the Western world.
• Early diagnosis and treatment can prevent complications such as cirrhosis, diabetes, and heart failure.

Genetics

• HH is caused by mutations in the HFE gene located on chromosome 6.
• The most common mutation is C282Y, with homozygosity (C282Y/C282Y) being the most significant risk factor for iron overload. A less common mutation is H63D.
• Homozygous C282Y mutations occur in 1 in 200 individuals, with a carrier frequency of 1 in 8 in people of Northern European descent.
• Heterozygous individuals (C282Y/H63D) may have mild iron accumulation but are generally asymptomatic.
• The disease shows incomplete penetrance, meaning not all homozygous individuals develop clinical manifestations.

Aetiology

• HFE gene mutations impair the regulation of iron absorption by interacting with the transferrin receptor and beta-2 microglobulin.
• As a result, iron is excessively absorbed, leading to deposition in tissues, especially the liver, pancreas, heart, joints, and skin.
• Chronic iron overload leads to cell injury, necrosis, fibrosis, and eventually cirrhosis in severe cases.
• Women are partially protected due to iron loss through menstruation and pregnancy; thus, they present later than men.

Pathology

• Iron is predominantly deposited in the liver, pancreas, and heart, leading to fibrosis and organ dysfunction.
• Liver iron levels can increase up to 50g, compared to a normal 0.5g to 6g in the liver, leading to cirrhosis.
• Prussian Blue stain is used to detect iron within hepatocytes, showing periportal iron deposition with sparing of Kupffer cells.

Prussian Blue stain shows iron within hepatocytes, with heavy periportal parenchymal iron deposition and sparing of Kupffer cells.

Clinical Features

• Fatigue, malaise, and general apathy are often the first symptoms to appear.
• Hepatomegaly and abdominal pain are common, with liver damage leading to cirrhosis in advanced cases.
• Secondary diabetes mellitus due to iron deposition in the pancreas.
• Hypogonadism and sexual dysfunction due to iron deposition in the pituitary gland.
• Cardiomyopathy (dilated or restrictive), heart failure, and arrhythmias due to iron deposition in the myocardium.
• Skin hyperpigmentation, leading to a "bronze diabetes" appearance due to iron and melanin deposition.
• Arthropathy (joint pain), particularly in the hands, with chondrocalcinosis (calcium deposition in cartilage).

Investigations

• Serum ferritin levels are elevated (>500 µg/L in many cases), but normal ferritin does not exclude HH.
• Transferrin saturation is typically >50% and often exceeds 90% in symptomatic patients.
• Genetic testing for HFE mutations (C282Y and H63D) is diagnostic for HH.
• Liver function tests may show elevated ALT and AST in cases with liver involvement.
• MRI T2-weighted imaging may demonstrate iron overload in the liver, pancreas, and myocardium.
• Transient elastography can assess liver stiffness and fibrosis in cases with suspected cirrhosis.
• Liver biopsy is rarely required but may be necessary in cases with severe iron overload to assess the extent of liver damage.

Complications

• Cirrhosis and hepatocellular carcinoma (HCC) in severe, untreated cases.
• Cardiac complications such as heart failure and arrhythmias.
• Diabetes mellitus due to iron deposition in the pancreas.
• Hypogonadism due to pituitary iron deposition, leading to sexual dysfunction and infertility.

Screening

• All adult patients of Northern European ancestry with unexplained elevated serum ferritin and transferrin saturation should undergo HFE genetic testing.
• First-degree relatives of individuals diagnosed with HH should also be screened for HFE mutations, especially C282Y homozygotes.
• Routine screening is recommended for siblings and children (over the age of consent) of affected individuals.

Management

• Regular venesection (phlebotomy) is the mainstay of treatment, aimed at reducing serum ferritin levels to 20-50 µg/L and maintaining transferrin saturation below 50%.
• In early stages, weekly venesection can deplete 500ml of blood, which removes approximately 200-250mg of iron.
• Once target iron levels are achieved, maintenance venesection is done monthly or quarterly for life.
• Iron chelation therapy (e.g., deferoxamine) is used in patients who cannot tolerate venesection or have severe anaemia.
• Liver cirrhosis warrants regular surveillance for hepatocellular carcinoma using alpha-fetoprotein (AFP) and ultrasound every 6 months.