Hemochromatosis

Epidemiology and Etiology:

· Rarely evident before 40y

· Either excessive iron absorption or parenteral administration of iron

· There is no major iron excretion pathway in the body

· Primary

· Hereditary hemochromatosis – autosomal recessive

· HFE

· 6p21.3 (close to HLA gene locus)

· Encodes an HLA class I-like molecule that regulates intestinal iron absorption

· Interacts with transferrin receptor in basolateral enterocyte surface

· Causes cell to be unable to sense systemic iron levels

· G845A mutation is seen in 80-100% of patients

· HFE is in linkage disequilibrium with HLA-A3

· M:F = 5-7:1

· Physiologic iron loss in women delays iron accumulation

· Heterozygotes 6-10% of Caucasians

· Homozygotes 0.45% (1 in 220)

· But penetrance is only ~20%

· Secondary

· Transfusions

· Long-term hemodialysis

· Aplastic anemia

· Sickle cell disease

· Myelodysplastic syndromes

· Leukemias

· Infeffective erythropoiesis with increased erythroid activity

· Beta-thalassemia

· Sideroblastic anemia

· Pyruvate kinase deficiency

· Iron-dextran injections

· Increased oral intake of iron (ex. Bantu siderosis)

· Congenital atransferrinemia

· Chronic liver disease

· Porphyria cutanea tarda

· Iron is directly toxic to cells

· Lipid peroxidation via iron-catalyzed free radical reactions

· Stimulation of collagen formation

· Interactions of reactive oxygen species and of iron itself to DNA

Common sites:

· Liver

· Pancreas

· Myocardium

· Pituitary

· Adrenal

· Thyroid

· Parathyroids

· Joints

· Skin

·

Gross features:

· Liver

· Mild hepatomegaly

· Chocolate brown

· Micronodular cirrhosis (advanced)

· Skin pigmentation (75-80%)

· Characteristic slate-gray

· pancreas

· pigmented

·

· Pancreatic fibrosis

· Heart

· Enlarged

· Striking brown myocardium

· Testes

· Atrophic (pituitary dysfunction)

Histologic features:

· Periportal hepatocytes are the first to show increased iron

· Then rest of lobule, bile duct epithelium, Kupffer cells

· Inflammation absent characteristically

· Pancreas:

· Interstitial fibrosis

· Hemosiderin in acinar and islet cells

· Heart:

· Hemosiderin granules within myocardial fibres

· Interstitial fibrosis maybe

Immunophenotype:

Marker:

Sensitivity:

Specificity:

Molecular features:

· Primary

· Hereditary hemochromatosis – autosomal recessive

· HFE

· 6p21.3 (close to HLA gene locus)

· Encodes hereditary hemochromatosis protein, an HLA class I-like molecule that regulates intestinal iron absorption

· Interacts with transferrin receptor in basolateral enterocyte surface

· Causes cell to be unable to sense systemic iron levels

· G845A mutation is seen in 80-100% of patients

· C282Y / C282Y (60-90%)

· H63D mutation

· C282Y / H63D

· HFE is in linkage disequilibrium with HLA-A3

· Testing:

· Targeted mutation analysis

· sequencing

Other features:

· Diabetes mellitus (75-80%)

· Pseudogout

· hypogonadism

· Biochemical determination of iron content of unfixed liver tissue is the gold standard

· Serum iron and ferritin very high (nonspecific)

· HCC risk 200x greater than general pop.

· Regular phlebotomy can prevent cirrhosis and other complications

·

References:

· Kumar V, Fausto N, Abbas A. Robbins & Cotran Pathologic Basis of Disease, Seventh Edition. 7th ed. Saunders; 2004.