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24 Cards in this Set
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Hemochromatosis and Iron overload disease: whole body metabolism of iron
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Ingest ~10-20 mg/day in our diet
Intestine absorbs ~1-2 mg/day Iron is transported by Transferrin in blood; iron is stored in cells bound to Ferritin Body content of iron ~ 4 g; ~ 1 g is stored in hepatocytes ~ 20 mg/day is delivered to the bone marrow for incorporation into hemoglobin of erythroid precursors & mature red cells ~ 20 mg/day is derived from macrophage destruction of senescent red cells ~1-2 mg/day are lost from the iron pool ~ 30 mg/month is lost in Menses |
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Iron homeostasis -cellular metabolism
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DMT1 – Absorbs iron is absorbed from gut
Iron is stored bound to ferritin Iron is pumped into blood via Ferroportin Ceruloplasmin converts Fe2+ ->Fe3+ In blood, iron is transported bound to transferrin Transferrin receptor 1 (liver & other tissues) clears the iron-Transferrin complex. 7. Iron is stored in hepatocytes bound to ferritin 8. Iron from phagocytosed red cells is stored in macrophages Amount of iron in circulation is controlled by the expression of Ferroportin |
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Hepatocytes and regulation of blood levels of iron
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HFE, TfR2, and hemojuvelin (HJV) are iron
sensors in the hepatocyte 2. If there is excess iron, these iron sensors increase expression of the HAMP gene and secretion of its gene product (Hepcidin) 3. Hepcidin bind to and inhibits Ferroportin activity and expression 4. Intestinal iron absorption is blocked; iron stays stored bound to ferritin in macrophage; iron homeostasis is restored. |
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hereditary hemochromatosis
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Hereditary Hemochromatosis leads to excess amounts of iron entering the circulatory pool and progressive accumulation of iron in parenchymal cells (liver, heart, pancreas, endocrine glands)
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mechanism of hereditary hemochromatosis
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Mutations in the HFE gene are responsible for most cases of HH
2 major mutations: Cysteine 282->tyrosine (C282Y) Histidine 63->aspartic acid (H63D) C282Y homozygosity produces major clinical manifestations Highly prevalent in individuals of Northern European descent, rare in Arica and Asia; frequency of C282Y homozygotes is ~1/250 for Anglo-Celic-Nordic population. |
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Clinical manifestations of Hereditary Hemochromatosis
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Liver
Abnormal liver function tests Cirrhosis Hepatocellular carcinoma Cardiac Cardiomyopathy Arrhythmias Joint Arthropathy Endocrine Diabetes mellitus Testicular atrophy Pituitary (gonadotropin insufficiency) Other Skin bronzing Weakness or lethargy Impotence in men Other findings include: Hepatomegaly, splenomegaly, & other complications of chronic liver disease such as ascites, edema, and jaundice. Serum aminotransferase elevations are usually mild. |
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Proportion of patients with C282Y Homozygous HH who Develop Liver Disease
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HCC-1-2%
Cirrhosis 6% Liver fibrosis 25% |
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Dx of Hemochromatosis
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labs
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Tx of hereditary hemochromatosis
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Perform phlebotomy of 500 mL (1 unit) of whole blood weekly
until hematocrit value drops below 37%. ( 1 unit ~ 200-250 mg iron) The iron-chelating drug deferoxamine can be used in those patients who cannot tolerate phlebotomy. Monitoring Check transferrin saturation and ferritin levels at 2- to 3-month intervals to monitor response (optional). Maintenance Once iron stores are depleted (serum ferritin <50 ng/mL; transferrin saturation <50%), proceed to maintenance phlebotomy of 1 unit of whole blood every 2 to 3 months. Aim to keep transferrin saturation <50%; if successful, ferritin should remain <50 ng/mL. |
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Reversible manifestations of H. Hemochromatosis
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Cardiac dysfunction, glucose intolerance,
hepatomegaly, skin pigmentation |
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Irreversible manifestations of hemochromatosis
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Cirrhosis, arthropathy, hypogonadism, risk of
hepatocellular carcinoma |
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Wilsons Disease overview
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Rare inherited metabolic, copper accumulation in liver and brain
Prevalence ~ 1:30,000 (carrier state 1: 90) Autosomal recessive disease caused by mutation in ATP7B gene (> 300 mutations) Defective biliary excretion of copper; copper overload affects multiple organs Commonly presents with liver or neurological symptoms Variable age of onset for symptoms (usually 6 - 40 years of age) Undiagnosed and untreated is generally fatal by age 30 Early diagnosis and treatment can yield almost complete recovery with normal life Treated with chelating agents or zinc (rarely with liver transplantation) |
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Overview of Copper Metabolism
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Essential nutrient. Copper is an essential cofactor for many
enzymes, including Cytochrome-c oxidase, superoxide dismutase, Catechol oxidase, Protein-lysine 6-oxidase, Ceruloplasmin, Dopamine-α-monooxygenase Dietary Sources: oysters, liver, crab, shrimp, cod, yeast, olives, hazelnuts, whole wheat bread, peas RDA: 0.9 mg Daily Intake (Western diet): 4-6 mg Absorption: 40-60% efficiency Transport in Blood: ceruloplasmin (>95%), albumin (<5%) Storage: Liver (regulated) Excretion: Bile (major route), urine (minor route) |
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Molecular defect in hepatic copper transport into blood and bile
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copper comes into diet and carried by albumin mostly to liver. once in liver it can be excreted into bile or incorpd into cerruloplasmin. Defect is inability to secret coper into bile and inability to incorp copper into ceruloplasmin. Transport protein ATP7b problem
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Molecular defect in copper transport
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defect makes transportaion of copper to golgi not possible to so no incorp of copper into ceruloplasmin, copper is poorly secreted . Other defect is inability to move bile to copper canaliculus. Results in excess copper in liver and select tissues
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Presentation and clinical manifestations
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Liver
Abnormal liver function tests Acute hepatitis Acute hepatic failure Liver disease with hemolysis Chronic hepatitis Cryptogenic cirrhosis CNS Parkinson-like disorders dystonia, tremors Psychiatric disorders Eye Kayser-Fleischer rings Sunflower cataracts Kidney Fanconi syndrome with hypouricemia Bone/ Osteopenia Joint Arthropathy |
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Initial presentation of Wilsons disease
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40% liver disease
35% neurological 15% psychiatric 10% endocrine, renal cardiac, hematological |
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Wilsons disease Dx
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Unexplained Liver Disease or Neuropsychiatric Disorder + Liver Disease
- Measure serum ceruloplasmin (< 20 mg/dL) - Measure serum free copper (> 25 mcg/dL)* - Measure 24 h urinary Copper excretion (> 40 mcg) - Slit lamp exam (Kayser-Fleischer rings) - (Liver biopsy for histology or quantitative copper measurements) *Serum free copper = total copper – [serum ceruloplasmin (in mg/dL) x 3] Conventional WD testing utilizing serum ceruloplasmin and/or serum copper levels are less sensitive in identifying WD patients with acute liver failure |
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Tx of Wilsons disease
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Therapy: Chelation (Penicillamine or trientine) plus pyridoxine
Zinc Avoid high copper foods Liver transplantation* (*with acute liver failure or end-stage liver disease) Monitoring: Kayser-Fleischer rings Urinary copper excretion Serum free copper levels (non-ceruloplasmin-bound) Results: Prevents disease when begun early Improves liver and CNS disease Prolongs life |
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Drugs used to treat WD
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Penicillamine, Trietine, Zinc
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a-1 antitrypsin disease Summary
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Common inherited metabolic disease causing lung + liver disease
Most common genetic cause of liver disease in children Prevalence of deficiency allele combinations ~ 1:490 (North America); severe deficiency ~1:3500 live births (more common in Caucasians; rarely found in African Americans or Asians) Autosomal recessive disease Caused by mutations in α1-antitrypsin gene (SERPINA1) α1-AT binds and inactivates neutrophil elastase and other serine proteases; Α1-AT is the major serine protease inhibitor in blood α1-AT alleles are also called Protease inhibitor (Pi) alleles. Most common Pi alleles associated with disease: PiS, PiZ Protease inhibitor (Pi) alleles distinguished by isoelectric focusing or molecular genotyping Risk of pulmonary emphysema rises when serum α1-AT drops below ~ 11 µM Serum α1-AT levels do not strictly correlate with risk of liver disease Disease phenotype is defined by the serum levels and alleles Liver disease is associated with PiZ allele (lysine to glutamic acid at AA342) Absence of α1-AT is the primary mechanism for premature development of pulmonary emphysema or COPD in the affected patients Liver disease is caused by accumulation of misfolded α1-AT protein |
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Mechanism of a1AT disease
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Mechanisms of lung and liver injury are distinct
Lung injury is caused by an α1-AT deficiency (“loss of function”) Liver injury is caused by retention of misfolded α1-AT protein (“gain of function”) Mutations cause the α1-AT protein to polymerize in the ER of hepatocytes |
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Clinical presentation of a1At disease
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Most common genetic cause of liver disease in neonates and children
Clinical presentation is variable - Children often 1st present with jaundice - Adults usually present with cryptogenic cirrhosis with portal hypertension Distinct biomodal distribution for clinical presentation - Neonatal hepatitis/ cholestatic jaundice in infants Chronic liver disease in adults (mean age of diagnosis 5th decade) ~10% of PiZZ children develop neonatal hepatitis; ~2% progress to advanced fibrosis or cirrhosis requiring transplantation ~10-20% of adult PiZZ patients develop cirrhosis ~30% of adult PiZZ patients with cirrhosis develop hepatocellular carcinoma or hepatocholangiocarcinoma |
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Dx and Tx of a-1 AT disese
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No specific therapy is currently available (avoid alcohol, smoking, weight gain and obesity)
Treatment of complications of liver and lung disease Hepatocellular carcinoma surveillance Transplantation (cures the liver and lung disease) α1-AT infusions (treats the lung disease - emphysema) Family screening |
