hemachromatosis

Question 1

excessive absorption of iron regulated by intestine
deposited in heart liver pancreas
hereditary or acquired
total body iron is 2-6 g
severe: may exceed 50 g

Answer 1

micronodular cirrhosis
DM
abnormally pigmented skin
HFE gene located on chromosome 6 next to HLA gene cluster. the most commonly mutated gene
HFE gene encodes a class 1 HLA jo k regulate krta ha the formation of hepcidin in hepatocytes
HFE gene mutated cysteine to tyrosine C282Y at amino acid 282.
70 pc

Question 2

other mutations in HFE as well as mutations in transferrin receptor 2 and in hepcidin
the onset of disease after 20 gm of stored iron Excessive iron directly toxic
Lipid peroxidation via iron-catalyzed free radical reactions
• Stimulation of collagen formation by activation of hepatic stellate cells
• DNA damage by reactive oxygen species, leading to lethal cell injury or predisposition to HCC

Answer 2

tissue deposit of hemosiderin(golden yellow prussian blue staining granules)
enlarged choc brown liver
fibrous septa then develop
and cause
cirrhosis
pancreatic fibrosis
becomes pigmented,acquires diffuse interstitial fibrosis,may show parenchymal atrophy. hemosiderin in acinar and pancreatic islet cells
hemosiderin granulations causing brown myocardium and enlarged heart
skin pigmentation from melanin and deposition of hemosiderin deposition in dermal macrophages and fibroblasts.

Question 3

Pseudogout

Answer 3

renders the skin slate-gray. With hemosiderin deposition in the joint synovial linings, an acute synovitis may develop. There is also excessive deposition of calcium pyrophosphate, which damages the articular cartilage and sometimes produces disabling polyarthritis, referred to as pseudogout

Question 4

SYMPTOMS

Answer 4

earlier in men than in women since menstrual bleeding limits the accumulation of iron until menopause. This results in a male-to-female ratio of clinically significant iron overload of approximately 5 : 1 to 7 : 1.
homozygosity for the most common HFE mutation (C282Y) shows variable penetrance; thus disease development is not inevitable
LIVER
hepatomegaly, abdominal pain, skin pigmentation (particularly in sunexposed areas)
Pancreas:
deranged glucose homeostasis or frank diabetes mellitus due to destruction of pancreatic islets
HEART and muscle
cardiac dysfunction (arrhythmias, cardiomyopathy), and atypical arthritis. In some patients, the presenting complaint is hypogonadism (e.g., amenorrhea in the female, impotence and loss of libido in the male

Question 5

Wilson’s

Answer 5

Wilson disease is an autosomal recessive disorder caused by mutation of the ATP7B gene, which results in impaired copper excretion into bile and a failure to incorporate copper into ceruloplasmin.

Question 6

toxic levels of copper in many tissues and organs, principally the liver, brain, and eye

Answer 6

60% of ingested copper (2–5 mg/day) is absorbed in the duodenum and proximal small intestine.

from where it is transported complexed with albumin and histidine to the liver.

free copper dissociates and is taken up by hepatocytes, where copper is incorporated into enzymes and α2-globulin (apoceruloplasmin) to form ceruloplasmin, which is secreted into the blood.

Ceruloplasmin carries 90% to 95% of plasma copper. Circulating ceruloplasmin is eventually desialylated, endocytosed by the liver, and degraded within lysosomes, after which the released copper is excreted into bile.

This degradation/excretion pathway is the primary route for copper elimination

Question 7

ATP7B gene, located on chromosome 13, encodes a transmembrane copper-transporting ATPase that is expressed on the hepatocyte canalicular membrane

Answer 7

heterozygotes with different loss-of-function mutations affecting each ATP7B allele. The overall frequency of mutated alleles is 1 : 100, and the prevalence of the disease is approximately 1 : 30,000 to 50,000
Loss of ATP7B protein function impairs the transport of copper into the bile and the incorporation of copper into ceruloplasmin

Question 8

Accumulating copper causes liver injury through the production of reactive oxygen species by the Fenton reaction

Answer 8

non-ceruloplasmin–bound copper is released from injured hepatocytes into the circulation, causing red cell hemolysis and allowing copper to deposit in other tissues, such as the brain, corneas, kidneys, bones, joints, and parathyroid glands. urinary excretion also inc.

Question 9

fatty change (steatosis) associated with focal hepatocyte necrosis
Chronic hepatitis in Wilson disease: moderate to severe inflammation and hepatocyte necrosis, areas of fatty change, and features of steatohepatitis (hepatocyte ballooning with prominent Mallory-Denk bodies). In advanced cases, cirrhosis.
rhodamine stain for copper, orcein stain for copper-associated protein).

Answer 9

 all patients with neurologic involvement develop eye lesions called Kayser-Fleischer rings, green to brown deposits of copper in Desçemet membrane in the limbus of the cornea.

Question 10

acute or chronic liver injury

neuropsychiatric manifestations

Question 11

low levels of serum ceruloplasmin, an increase in hepatic copper content (the most sensitive test), and increased urinary excretion of copper (the most specific test). Hepatic copper content in excess of 250 µg per gram dry weight of liver is taken to be diagnostic, but is only about 80% sensitive

Answer 11

liver copper levels, the diagnosis depends on other abnormalities, such as elevated urinary copper, low serum ceruloplasmin, and the presence of Kayser-Fleischer rin