Flashcards in Genes, Cancer and Liver Deck (26)
What is the normal regulation of iron in the body?
hepcidin synthesized in liver inhibits ferroportin (iron export protein on BL membrane) - decreases entry of iron into body
What are the factors that regulate hepcidin synthesis?
What happens to iron once it has been absorbed by the body?
binds to circulating plasma transferrin - delivers to cells for heme or enzyme formation
excess stored as ferritin
regulatory proteins like hepcidin balance uptake with storage to maintain normal levels
What are the causes of genetic iron overload?
classic hereditary hemochromatosis = type 1 - mutation in HLA like molecule HFE1 --> increased iron absorption despite overload - increased ferritin in liver
final common pathway is failure of ferroportin regulation by hepcidin
What is the cause of parenteral iron overload?
no normal pathway for excretion of excess - transfusions --> secondary overload
underlying anemia can increase absorption from diet despite extra-intestinal stores
What are the effects of iron mediated cell and tissue injury in iron overload states?
accumulates in liver, heart, pancreas --> cirrhosis, cardiomyopathy, diabetes
if excess from diet, liver disproportionately affected due to first pass
ferritin stores saturated, then iron-mediated fibrosis
What is the clinical presentation of iron overload?
usually asymptomatic, nonspecific fatigue or arthralgias, elevated iron found on standard tests
What is the role of liver biopsy in investigation of iron overload?
only if liver function or enzymes abnormal because of risk of HCC
if biopsy contra-indicated --> phlebotomy
What is the role of genetic diagnosis in hemochromatosis?
look for Cys282Tyr mutation
beneficial effects in heterozygotes --> high prevalence in Celtic
genetic test for HFE available
What is the ddx of iron overload?
genetic - hemochromatosis - HFE related normally interacts with transferring receptor 1, other rare mutations in ferroportin and hepcidin
secondary = hemosiderosis - transfusion, hyperabsorption in response to anemia or hypoxia, meds or diet, advanced liver dz
What is the management of iron overload?
remove excess iron - phlebotomy
outcome is normal life expectancy in non-cirrhotic
complications of heart failure, diabetes, or HCC reduces survival in cirrhotic
arthritis and hypogonadotropic hypogonadism not reversed
What is the normal absorption of copper?
rapidly transported into epithelial cells of upper small intestine
bound to metallothioneins or transported across BL
25-60% dietary reaches circulation and bound to albumin - from albumin to hepatocytes
typically little escapes hepatic uptake and is excreted in urine
What happens to copper once it reaches the hepatocyte?
apo-ceruloplasmin synthesized in liver - iron then incorporated - most serum copper
increased ceruloplasmin during inflammation - decrease during protein-losing states and in advanced liver dz
How is copper excreted?
biliary excretion is major control mechanism
How does copper overload happen?
impaired biliary excretion
What is responsible for the copper overload in Wilson's disease?
intra-cellular copper transporter defective - not incorporated into ceruloplasmin or excreted in bile
How does Wilson disease present?
hepatic or neuropsychiatric illness (movement disorders) - hepatic 5-10 yrs earlier
hemolytic anemia - Cu injures RBCs
What investigations are seen in Wilson's dz?
elevated urine copper in symptomatic
high hepatic copper
(could get false positives of urine and hepatic in cholestasis)
common markers flank gene on long arm of ch 13
When can ceruloplasmin be low other than in wilsons?
low protein disorders, heterozygosity for Wilsons
What is the management of wilsons?
copper chelation with D-penicillamine
What are risk factors for dev of HCC?
Hep B (w/o cirrhosis) or C
cirrhotic liver dz - hemochromatosis, alcoholic, etc
carcinogen exposure - aflatoxin, hormones, smoke
What factors are determine if management for HCC can be operative?
sufficient liver function must remain for normal life
surgical resection not possible if patient has advanced liver dz - only transplant
What are non-operative managements of HCC?
radio frequency ablation
tyrosine kinase inhibitor sorafenib
What are palliative managements for HCC?
narcotic analgesic regimens
What, other than HCC, can cause elevated alpha fetoprotein?