Metabolic Disorders Hemochromatosis Excessive accumulation of body iron  deposit in parenchymal organs (e.g. liver and pancreas) May be secondary to a genetic defect (increased absorption) OR a consequence of parenteral administration of iron Over 1/3 of iron accumulated stored in the liver Increased risk of hepatocellular carcinoma

Metabolic Disorders Hemochromatosis Hereditary hemochromatosis Mutations involving hereditary hemochromatosis gene HFE Unrestricted re-absorption of iron in the small intestines Secondary or acquired  hemosiderosis Causes: multiple blood transfusions,hereditary anemias and alcohol abuse

Metabolic Disorders Hemochromatosis Features: Fully developed cases with micronodular cirrhosis (all patients), DM, and skin pigmentation Destruction of exocrine pancreas  malabsorption Males predominate due to delayed iron accumulation in women ( protected by menstrual loss)

Metabolic Disorders Hemochromatosis Morphology: Hemosiderin deposition in liver, pancreas, myocardium, pituitary gland, adrenal gland, thyroid & parathyroid glands, joints, and skin  stain with Prussian blue Liver cirrhosis Pancreatic fibrosis

Classic clinical triad: Metabolic Disorders Hemochromatosis Classic clinical triad: Pigment cirrhosis with hepatomegaly Skin pigmentation – increased melanin production Diabetes mellitus – destruction of β-islet cells Death due to cirrhosis or cardiac disease( cardiomyopathy and congestive heart failure) Risk for development of hepatocellular CA 200-fold greater Rx : venesection in non anemic patients and iron-chelators ( desferrioxamin) in anemic patients.

HAEMOCHROMATOSIS

Haemochromatosis is a condition in which the amount of total body iron is increased; the excess iron is deposited in and causes damage to several organs including the liver.

HEREDITARY (PRIMARY) HAEMOCHROMATOSIS In this disease iron is deposited throughout the body and total body iron may reach 20-60 g (normally 4 g). The important organs involved are the liver, pancreatic islets, endocrine glands and heart.

Aetiology Hereditary haemochromatosis (HHC) is caused by increased absorption of dietary iron and is inherited as an autosomal recessive gene located on chromosome 6. Iron loss in menstruation and pregnancy may protect females, as 90% of patients are male.

Clinical features Symptomatic disease usually presents in men aged 40 years or over with features of hepatic cirrhosis (especially hepatomegaly), diabetes mellitus or heart failure. Tiredness, fatigue and arthropathy are early symptoms. Leaden-grey skin pigmentation due to excess melanin occurs, especially in exposed parts, axillae, groins and genitalia; hence the term 'bronzed diabetes'. Impotence, testicular atrophy and arthritis are also common. Cardiac failure may complicate heart muscle disease.

Investigations The serum ferritin is greatly increased; the plasma iron is also increased, with a highly saturated plasma iron-binding capacity. CT may show features suggesting excess hepatic iron. The diagnosis is confirmed by liver biopsy, which shows heavy iron deposition and hepatic fibrosis which may have progressed to cirrhosis. The iron content of the liver can be measured directly.

Management Treatment consists of weekly venesection until the serum iron is normal; this may take 2 years or more. Thereafter, venesection is continued as required to keep the serum ferritin normal. First-degree family members should be investigated, preferably by genetic screening and also by checking the plasma ferritin.

Prognosis Pre-cirrhotic patients with HHC have a normal life expectancy; cirrhotic patients have a relatively good prognosis, compared with other forms of cirrhosis Screening for hepatocellular carcinoma is mandatory because this is the main cause of death, affecting about one-third of patients with cirrhosis irrespective of therapy.

ACQUIRED IRON OVERLOAD (SECONDARY HAEMOCHROMATOSIS) Many conditions, including chronic haemolytic disorders, sideroblastic anaemia, other conditions requiring multiple blood transfusion (generally over 50 litres), porphyria cutanea tarda, dietary iron overload and occasionally alcoholic cirrhosis, are associated with widespread secondary siderosis. The features are similar to primary haemochromatosis, but the history and clinical findings point to the true diagnosis.

Wilson’s Disease (Hepatolenticular degeneration) Metabolic Disorders Wilson’s Disease (Hepatolenticular degeneration) Copper accumulation particularly in liver, brain, and eye (demonstrated by rhodamine stain for copper) Due to mutation of Wilson’s disease gene (ATP7B) on chr. 13  decreased synthesis of ceruloplasmin  defective biliary excretion of copper

Metabolic Disorders Wilson’s Disease Morphology: Fatty change  acute hepatitis  chronic hepatitis  cirrhosis Massive liver necrosis a rare manifestation Brain – atrophy or cavitation of basal ganglia, particularly in putamen (movement disorder) Eye lesions – Kayser-Fleischer rings in Descemet’s membrane

Metabolic Disorders Wilson’s Disease Diagnosis: Decreased serum ceruloplasmin Increased hepatic copper content (>250 ug/gram dry weight) Increased urinary copper excretion Treatment: copper chelation therapy e.g. D-penicillamine and zinc.

Α1-Antitrypsin deficiency Metabolic Disorders Α1-Antitrypsin deficiency Autosomal dominant  normal genotype is PiMM  most common abnormal allele is Z PiZZ variant with decreased AAT in serum  cause liver damage Mutant protein cannot be secreted into blood

Α1-Antitrypsin deficiency Metabolic Disorders Α1-Antitrypsin deficiency Clinical Findings: Children Neonatal hepatitis with intrahepatic cholestasis Most common cause of cirrhosis in children Increased risk for hepatocellular carcinoma Young adults with panacinar emphysema