HEMOCHROMATOSIS

HEMOCHROMATOSIS

• Hemochromatosis is an iron storage disorder in which there is excessive accumulation of iron in parenchymal cells with eventual tissue damage and functional insufficiency of organs

• Two types

  • Primary (Hereditary) hemochromatosis – inherited disorder

  • Secondary hemochromatosis– consequence of parenteral administration of iron

• Pathogenesis

  • It is an autosomal recessive disorder of excessive accumulation of iron

  • In hereditary hemochromatosis regulation of intestinal absorption of dietary iron is abnormal leading to net iron accumulation of 0.5 to 1gm/yr

  • Disease manifests itself typically after 20gm of stored iron are accumulated.

  • Main regulator of iron absorption is Hepcidin

  • Hepcidin protein is encoded by HAMP gene and secreted by liver

  • Hepcidin name is because it is hepatocellular protein with bactericidal activities

  • Hepcidin binds to the cellular iron efflux channel ferroportin causing its internalization and proteolysis, there by inhibiting the release of iron from intestinal cells and macrophages

  • Thus hepcidin lowers plasma iron levels and conversely deficiency of hepcidin causes iron overload

  • Transcription of hepcidin is increased by cytokines and iron and decreased by iron deficiency, hypoxia and ineffective erythropoiesis

Other proteins which regulate iron metabolism by regulating hepcidin levels are

• Hemojuvelin (HJV) expressed in liver, heart and skeletal muscle

• Transferrin receptor-2 (TFR-2) which is highly expressed in hepatocytes

• HFE (High Iron Fe) product of hemochromatin gene

• Decreased hepcidin synthesis is caused by mutations in hepcidin, HJV, TFR2 and HFE has a central role in the pathogenesis of hemocromostasis

Mutations of HAMP and HJV cause severe juvenile hemochromatosis

Adult forms of hemochromatosis is almost always caused by mutations of HFE (mutations of TFR2 is as less common)

• Mechanism of liver injury

  • Lipid peroxidation via iron catalysed free radical reaction

  • Stimulation of collagen formation by activation of hepatic stellate cells

  • Interaction of reactive oxygen species and iron itself with DNA leading to lethal cell injury and predisposition to Hepatocellular carcinoma

• Morphology

  Severe hemochromatosis is characterised by

  • Deposition of hemosiderin in the following organs in decreasing order of severity i.e., liver, pancreas, myocardium, pituitary gland, adrenal gland, thyroid and parathyroid glands, joints and skin

Morphology in liver

• Grossly:

  • • Liver early stage-liver is typically larger than normal dense and chocolate brown

    • Fibrous septa develop slowly leading ultimately to small shrunken liver with a micronodular pattern of cirrhosis.

    • Later stages liver is dark brown to nearby black due to over whelming iron accumulation.

• Microscopy 

  • • Iron in hepatocytes appear as golden yellow hemosiderin granules in the cytoplasm.

    • Prussian blue is used to stain the iron.

    • With increased iron load there in progressive involvement of the rest of lobule along with bile duct epithelium and kupffer cell pigmentation.

• Pancreas – Intensely pigmented has diffuse interstitial fibrosis and may exhibit some parenchymal atrophy

• Heart – Enlarged and has hemosiderin granules within the myocardial fibres producing brown colouration to myocardium

• Skin – Skin pigmentation due to hemosiderin deposition in dermal macrophages and fibrosis.

• Joints- Hemosiderin deposition in the synovium acute synovitis

• Testes- Small and atrophic, secondary to derangement in hypothalamic pituitary axis resulting in reduced gonadotropin and testosterone levels.

Clinical features

• Patients with well developed disease presents with triad of

  • Micronodular cirrhosis

  • Diabetes Mellitus in 75% to 80% of patients

  • Abnormal skin pigmentation in 75% to 80% of patients.

• Due to last two features it is termed as “Bronze diabetes”

• Cardiac dysfunction (Arrhythmias, cardiomyopathy)

• Atypical arthritis

• Some patients present with hypogonadism

• Death may result from cirrhosis or cardiac disease

Diagnosis: Screening involves

• Demonstration of very high levels of serum iron and ferritin

• Exclusion of secondary causes of iron overload

• Liver biopsy

• Screening of family members of probands

Treatment – Regular phlebotomy steadily depletes iron stores.

Reference

• Neil D. Theise .Liver and Gallbladder. In:Robbins and Cotrans Pathologic Basis of Disease. 9th edition.