Haemochromatosis

Question 1

what are the four types of hereditary hemochromatosis?

Answer 1

• type 1: HFE (e.g. human homeostatic iron regulator)
• type 2A-B: HJV (e.g. hemojuvelin BMP co-receptor), HAMP (e.g. hepcidin antimicrobial peptide)
• type 3: TFR2 (e.g. transferrin receptor 2)
• type 4A-B: SLC40A1 (e.g. solute carrier family 40 member 1)

Question 2

what is the normal total body iron content in adult females and males, and why might hemochromatosis go unrecognised until later in life?

Answer 2

normal total body iron: ~2.5 g in adult females, ~3.5 g in adult males

symptoms may be delayed until iron accumulation exceeds 10–20 g

Question 2

why are clinical manifestations of hemochromatosis uncommon in females before menopause?

Answer 2

iron loss due to menses (and sometimes pregnancy and childbirth) tends to offset iron accumulation

Question 3

what is the underlying mechanism of iron overload in both HFE and non-HFE hemochromatosis?

Answer 3

increased iron absorption from the gastrointestinal tract, leading to chronic deposition of iron in the tissues

Question 4

what role does hepcidin play in iron absorption?

Answer 4

• hepcidin, a liver-derived peptide, is the critical control mechanism for iron absorption
• hepcidin is normally up-regulated when iron stores are elevated and, through its inhibitory effect on ferroportin (which participates in iron absorption), it prevents excessive iron absorption and storage in normal people

Question 5

how does iron deposition cause tissue injury in hemochromatosis?

Answer 5

from reactive free hydroxyl radicals generated when iron deposition in tissues catalyzes their formation

Question 6

how does iron overload contribute to liver damage in hemochromatosis?

Answer 6

• iron-associated lipid peroxidation induces hepatocyte apoptosis, which stimulates Kupffer cell activation and release of pro-inflammatory cytokines
• these cytokines activate hepatic stellate cells to produce collagen, resulting in pathologic accumulation of liver fibrosis and risk of HCC

Question 7

what are the common manifestations of hereditary hemochromatosis?

Answer 7

• systemic (e.g. weakness, lethargy)
• skin hyperpigmentation
• diabetes
• arthropathy
• erectile dysfunction
• cardiomyopathy

Question 8

what is the most common complication of hereditary hemochromatosis?

Answer 8

hepatic cirrhosis

Question 9

what is the second most common complication of hereditary hemochromatosis?

Answer 9

cardiomyopathy (e.g. HF)

Question 10

what skin condition is commonly seen in hereditary hemochromatosis?

Answer 10

hyperpigmentation (e.g. ‘bronze diabetes’)

Question 11

what are the investigations for hereditary haemochromatosis?

Answer 11

• ↑ serum ferritin
• fasting serum iron
• ↑ transferrin saturation
• gene assay
• ? biopsy of the liver

Question 12

what is the treatment for hereditary haemochromatosis?

Answer 12

• phlebotomy
• 500 mL of blood (approximately 250 mg of iron) is removed weekly or every other week until serum ferritin levels reach 50 to 100 ng/mL

Question 13

how should patients with advanced fibrosis or cirrhosis due to iron overload be screened for hepatocellular carcinoma (HCC)?

Answer 13

should be screened for hepatocellular carcinoma every 6 months with a liver ultrasound and serum biomarkers (e.g. alpha fetoprotein)