University:
Michigan State University
Course:
MED 615 | Gastroenterology Clerkship
Academic year:

2021
Views:

446

Pages:

45
Author:

FrextWhestembki

Inherited Causes of Cirrhosis Genetic Diseases - Liver Inherited Causes of Cirrhosis Hemochromatosis Familial intrahepatic cholestasis Wilson's CF Other a1 – antitrypsin deficiency Newborn and infants Adults Clinical Manifestations Genetic Diseases - Hemochromatosis - Clinical Manifestations Pituitary Gonadotropin deficiency Skin bronzing Cardiomyopathy Conduction disorders Cirrhosis Hepatocellular carcinoma Diabetes mellitus Bacteremia Testicular atrophy Arthropathy Arthritis Pseudogout Iron Overload Disorders Genetic Diseases - Hemochromatosis Iron Overload Disorders • Transfusion • Ineffective erythropoiesis • African iron overload Hemochromatosis - Overview Genetic Diseases Cystic Fibrosis Hemochromatosis • Incidence is population-dependent • Inheritance is autosomal recessive • HFE gene mutations are present • Functional defect results in increased iron absorption Frequency and Genetics Genetic Diseases - Hemochromatosis Frequency Very common in Caucasians Heterozygote - 1 in 12 Homozygote - 1 in 400 HFE Protein Structure Genetic Diseases - HFE Protein Structure a Heavy chain H63D Mutation a1 a2 NH2 b 2 microglobulin COOH COOH NH2 a3 C282Y Mutation HFE Gene Mutations Genetic Diseases - Hemochromatosis HFE Gene Mutations Abnormal intestinal epithelial protein Increased intestinal iron absorption Iron-induced tissue injury and fibrogenesis Stages of Hemochromatosis Genetic Diseases Stages of Hemochromatosis • Iron overload without organ injury • Iron overload with organ injury without clinical manifestations • Iron overload with organ injury and clinical manifestations Normal Iron Balance Genetic Diseases – Hemochromatosis - Normal Iron Balance Ingested 10-20 mg/day Absorbed 1-2 mg/day Lost Gut, skin, urine - 1-2 mg/day Menses - 30 mg/month Iron Transport and Storage Genetic Diseases – Hemochromatosis Iron Transport and Storage Transport Transferrin - two iron atoms Intracellular storage Ferritin - thousands of iron atoms Total body iron - 4g RBCs Storage iron Other Phenotype Expression Genetic Diseases – Hemochromatosis Phenotype Expression • Men > women • Increases with age • Correlates with amount of iron in the diet • Chronic hemolysis, alcoholism, steatohepatitis, hepatitis C Causes of Iron Overload States Genetic Diseases – Hemochromatosis Hereditary Forms of Iron Overload Familial or hereditary forms of hemochromatosis • Hereditary hemochromatosis (HFE-related) • C282Y homozygosity • C282Y / H63D compound heterozygosity • Hereditary hemochromatosis, non-HFE related • Juvenile hemochromatosis • Neonatal iron overload • Autosomal dominant hemochromatosis (Solomon islands) Acquired Causes of Iron Overload Genetic Diseases – Hemochromatosis Acquired Causes of Iron Overload Acquired iron overload • Iron-loading anemias • Thalassemia major • Sideroblastic anemia • Chronic hemolytic anemia • Dietary iron overload • Chronic liver diseases • Hepatitis C • Alcoholic liver disease • NAFLD Iron Measurements Genetic Diseases – Hemochromatosis – Iron Measurements Normal Hereditary hemochromatosis 60-180 11-32 20-50 180-300 32-54 55-100 20-200 15-150 300-3000 250-3000 0,1+ 3+, 4+ 300-1500 5-27 3000-30,000 53-536 <1.1 >1.9 Serum Iron (mg/dL) (mmol/L) Transferrin saturation % Ferritin Males (ng/mL or mg/L) Females (ng/mL or mg/L) Liver Iron stains Iron concentration (mg/g dry weight) (mmol/g dry weight) Iron index (mmol/g dry weight ─ age in years) Diagnosis Genetic Diseases – Hemochromatosis Diagnosis • Homozygous C282Y HFE mutations • Heterozygous for both C282Y and H63D mutations Iron Balance Values Genetic Diseases – Hemochromatosis - Iron Balance Values Serum iron Transferrin Quantitative saturation Ferritin hepatic iron TIBC (mg/dL) (mg/dL) (%) (mg/dL) (mg/g dry wt) 60-180 230-370 20-50 20-200 300-1500 >50 >300 >3000 Normal Hemochromatosis >180 <300 Hemochromatosis Genetic Diseases – Hemochromatosis Cirrhosis, organ failure 40 Tissue injury 30 Total body iron (g) 20 10 Hepatic iron Serum iron Normal 0 10 20 30 Age (years) 40 50 Diagnostic Testing Genetic Diseases – Hemochromatosis – Diagnostic Testing Family history or suspicion of hemochromatosis Fe / TIBC -% saturation Ferritin % sat. >50% Ferritin >250 mg/L >300 mg/L HFE gene testing C282Y homozygous C282Y / H630 heterozygous No mutations Liver biopsy with iron stain and quantitative iron stainable Fe Iron index >2 Phlebotomy, response confirms diagnosis Indications for HFE Genetic Testing in Appropriate Clinical Setting Genetic Diseases – Hemochromatosis Indications for HFE Genetic Testing in Appropriate Clinical Setting • Family history of hemochromatosis • Chronic liver disease • Abnormal liver tests • Abnormal serum iron studies • Diabetes mellitus • Arthropathy • Heart disease Interpretation of Ferritin Levels Genetic Diseases – Hemochromatosis Interpretation of Ferritin Levels Hemochromatosis High Ferritin and High iron Acute liver injury  iron Acute phase reactant Normal ferritin and  iron Chronic disease  Ferritin and  iron Iron deficiency Hepatic Iron Index Genetic Diseases – Hemochromatosis Hepatic Iron Index Liver iron Age (mmol/g) (yr) 15 10 5 Cirrhotic 4 Index 3 2 Precirrhotic 1 0 Normals Alcoholic Hemochromatosis Heterozygotes Homozygotes Phlebotomy – Therapy for Iron Overload Genetic Diseases - Hemochromatosis Phlebotomy Acute 1 unit (250 mg Fe) weekly or biweekly until mildly anemic Maintenance Once iron stores are depleted (ferritin <50ng/ml, transferrin sat <50%) continue with phlebotomy every 2-3 months. Monitor hemoglobin, ferritin and transferrin saturation Phlebotomy Improves Survival Genetic Diseases – Hemochromatosis Phlebotomy Improves Survival Preventable: all clinical manifestations Reversible: cardiac dysfunction, glucose intolerance, hepatomegaly, skin pigmentation Irreversible: cirrhosis risk of hepatocellular carcinoma arthropathy, hypogonadism Iron Depletion Improves Survival Genetic Diseases – Hemochromatosis Iron Depletion Improves Survival 100 80 Cumulative survival (%) Iron depleted after 18 months 60 Untreated after 18 months 40 20 0 0 5 10 15 Time (years) 20 25 Response to Phlebotomy Genetic Diseases – Hemochromatosis Response to Phlebotomy 100 2000 Transferrin saturation 80 1500 Serum ferritin Transferrin 60 % Hgb drops 40 1000 500 20 Phlebotomy 0 0 4 8 12 16 Time (months) 20 24 28 32 Ferritin ng/ml Trichrome Stain - Liver Trichrome Stain - Liver Liver Biopsy - Prussian Blue Stain for Iron Liver Biopsy - Prussian Blue Stain for Iron Wilson’s Disease Genetic Diseases – Wilson’s Disease Kayser-Fleischer rings Neuropsychiatric disorders Cardiomyopathy Hepatitis Cirrhosis Fanconi syndrome Hemolysis Osteoporosis and arthropathy Copper Overload Disorders Genetic Diseases – Wilson’s Disease Copper Overload Disorders Primary Secondary Ch 13 Chronic cholestasis • Primary biliary cirrhosis • Byler’s syndrome Wilson’s Disease Autosomal recessive inheritance Normal Copper Balance Normal Copper Balance Ceruloplasmin Apoceruloplasmin Copper (Cu) 1.5 – 4.0 mg/day Cu excreted in bile Free Cu absorbed Urine output (<70 mg/day) Cu excreted in stool Ceruloplasmin Genetic Diseases – Wilson’s Disease Ceruloplasmin A blue a2 globulin Binds copper irreversibly Normal serum level = 20-40 mg/dL Decreased serum ceruloplasmin is seen in: • Wilson’s disease 95% of homozygotes 20% of heterozygotes • Protein loss • Hepatic failure • Menkes syndrome Wilson’s Disease Molecular Defect Genetic Diseases – Wilson’s Disease – p-type ATPase 2 Metal binding 1 NH2 Misense mutations 3 ATP binding domain 4 Transcription 5 Phosphorylated D residue 6 Conserved cysteine-prolinecysteine motif COOH Channel 153 Wilson’s Disease Genetic Diseases – Wilson’s Disease Normal Copper Balance Abnormal Copper Balance Space of Disse Lysosomes Ceruloplasmin Copper Bile ductals Golgi complex Copper build-up leads to cell stress and death 154 Features in Homozygotes and Heterozygotes Genetic Diseases – Wilson’s Disease Usual Features in Homozygotes Usual Features in Heterozygotes Ceruloplasmin <20 mg/dl Rarely Urine copper >100 mg/day Rarely Kayser-Fleischer rings Never Hepatic histology abnormal Never Hepatic copper >250 mg/g Rarely Indications for Testing Genetic Diseases – Wilson’s Disease Indications for Testing • Liver disease in children, adolescents, young adults • Hemolysis with liver disease • Neurologic disease in the young • Parkinsonian tremor • Gait disturbance • Psychosis or other mental disorders • Fanconi syndrome • Hypouricemia • Kayser-Fleischer rings • Sunflower cataracts • Siblings of affected patients Wilson’s Disease Genetic Diseases – Wilson’s Disease 2000 800 Mean hepatic copper (mg/g dry weight) 600 400 200 0 Normal Cirrhosis PSC PBC Wilson’s Indian disease childhood cirrhosis Presentations Genetic Diseases – Wilson’s Disease Presentations Liver Abnormal liver tests Acute hepatitis Acute hepatic failure Liver disease with hemolysis Chronic hepatitis Cryptogenic cirrhosis CNS Parkinson-like disorders Psychiatric disorders Eye Kayser-Fleischer rings Sunflower cataracts Kidney Fanconi syndrome with hypouricemia Diagnostic Testing Genetic Diseases – Wilson’s Disease Diagnostic Testing Ceruloplasmin Slit lamp examination Urine copper Ceruloplasmin <20 mg/dL (5% of Wilson’s patients have normal ceruloplasmin levels) Kayser-Fleischer rings Urine copper >100 mg/24 hr Liver biopsy with quantitative copper determination confirms diagnosis Management Genetic Diseases – Wilson’s Disease Management Therapy Chelation + pyridoxine Zinc Avoid high copper foods Transplantation in selected cases Family screening Monitoring Urine copper Non-ceruloplasmin copper Do NOT monitor Kayser-Fleischer rings Results Treatment prevents disease Improves liver and CNS disease Prolongs life CM - Kayser-Fleischer Ring Genetic Diseases – Wilson’s Disease CM - Wilson’s Disease Genetic Diseases – Wilson’s Disease CM - MRI of the Brain Genetic Diseases – Wilson’s Disease Copper deposits CM - Hand Radiograph Genetic Diseases – Wilson’s Disease 170 Wilson’s Disease - Histology Genetic Diseases – Wilson’s Disease 171 Wilson’s Disease - Histology Genetic Diseases – Wilson’s Disease

Inherited Causes of Cirrhosis

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