1 / 41

Hot Topics in Liver Disease Wilson Disease a -1-Antitrypsin Deficiency

Hot Topics in Liver Disease Wilson Disease a -1-Antitrypsin Deficiency. Norman L. Sussman, MD Baylor College of Medicine St. Luke’s Center for Liver Disease. Copper Absorption and Excretion. CMT1: Copper membrane transporter 1 ATOX1 Metallothionein.

devaki
Download Presentation

Hot Topics in Liver Disease Wilson Disease a -1-Antitrypsin Deficiency

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Hot Topics in Liver DiseaseWilson Diseasea-1-Antitrypsin Deficiency Norman L. Sussman, MD Baylor College of Medicine St. Luke’s Center for Liver Disease

  2. Copper Absorption and Excretion • CMT1: Copper membrane transporter 1 • ATOX1 • Metallothionein • Copper is a cofactor for a number of enzymes • Ceruloplasmin (CPN), cytochrome c oxidase, dopamine b-hydroxylase, superoxide dismutase, tyrosinase • ATP7B (P-type ATPase) • Catalyzes self-phosphorylation of aspartate in the Cu2+ pump • Excretes copper into the canaliculus • Attaches copper to ceruloplasmin

  3. Samuel Alexander KinnierWilson1878 – 1937 • Born in Cedarville, NJ, moved to Edinburgh at one year of age after the death of his father • Graduated with MB from University of Edinburgh in 1902 • Trained in Paris with Pierre Marie and Joseph Babinski • Returned to King’s College in London • MD in 1912: "Progressive lenticular degeneration” and introduced the word “extrapyramidal”

  4. Question 1Which of the following is true of Wilson disease (one answer): • Autosomal dominant disease. • Is caused by a mutation in the ceruloplasmin gene. • Is caused by a mutation in the ATP7B gene. • Is always associated with discoloration of the cornea (Kayser-Fleishcher rings). 1

  5. The Genetic Basis of Wilson DiseaseHepatoleticular DegenerationAutosomal Recessive • Copper storage disease – caused by defective copper export • Accumulates in the liver, brain, cornea • Not added to ceruloplasmin shortened half-life (low serum level) • Not added to AP  low level • Mutations in ATP7B - multiple mutations • The gene was identified in 1993 • Prevalence ~30/million population

  6. Kayser–Fleischer Rings 50% in patients with liver disease 98% in patients with neurologic disease Schrag A, Schott JM. N Engl J Med 2012;366:e18.

  7. Question 2Which of the following is not true (one answer): • Wilson disease may cause acute hepatitis in children. • Wilson disease may cause acute liver failure • Adults with Wilson disease may have no definite liver disease • Neurological disease is the most common presentation in newborns 1

  8. Wilson DiseaseClinical Manifestations • Hepatic, neurologic, psychiatric, hemolysis (ALF) – presentation may vary, even within a family • Liver: 18-84% • Neurologic: 18-73% • Psychiatric: 10-100% • Usually present at 5-35 years (up to 70s) • Children typically present with liver disease (9-13 years) • Older patients usually present with neurologic and/or psychiatric symptoms (15-21 years)

  9. Wilson DiseaseClinical Manfestations • Mild: abnormal liver tests, hepatomegaly, NAFLD • Advanced: cirrhosis (with all complications) • Acute liver failure (ALF) • Neurologic • Movement disorders (arms, gait, swallowing) • Psychiatric

  10. Sunflower Cataract

  11. Wilson Disease – Diagnosis • Classic presentation (about 50% of patients) • 5-40 years old, cirrhosis, neurological findings, K-F rings, low ceruloplasmin • Genetic diagnosis – better for confirmation • Expensive • Not universally available • Sometimes inconclusive • The rest – scoring system

  12. Wilson Disease – Diagnosis • Very low ceruloplasmin (CPN) is strongly predictive • Uric acid – usually low, but not validated • Non-CPN bound copper is usually >25 mg/dL (250 mg/L) in untreated patients (normal = 15 mg/dL) • Binding is ~3.15 mg of Cu2+ per mg CPN • Free Cu2+ = serum Cu2+ (mg/dL) – 3x CPN (mg/dL) • Google: ceruloplasmin-free copper calculator • Caveat: may be elevated in chronic cholestasis, copper intoxication, and ALF of any cause

  13. Wilson Disease – Diagnosis24-Hour Urine Copper • Diagnostic at 100 mg/24 hours (1.6 mmol/24 hours) in symptomatic patients • Many labs use 40 mg as the cutoff • May be <100 mg at presentation in 16%-23% • Penicillamine challenge (500 mg at 0 and 12 Hr)  1,600 mg (25 mol) copper/24 hours • Validated in children, but not adults

  14. Wilson Disease – DiagnosisLiver Biopsy • Early: mild steatosis(micro and macrovesicular) • May show classic histological features of AIH • Cirrhosis – macronodular and micronodular • May be absent, even with neurological disease • Copper stain is unreliable (metallothionein-bound) • Absence of stainable copper does not exclude WD • ALF – massive necrosis on a background of cirrhosis

  15. Copper StainsRhodanine

  16. Electron MicroscopyWilson disease with steatosis • Mitochondria vary in size and shape • Increased density of the matrix • Inclusions including lipid and fine granular material (copper) • Pathognomonic increased intracristal space & dilatation of the tips of the cristae Elongated mitochondria and dense deposits. X15,000 Iancu & Manov, Technion, Haifa

  17. Wilson Disease – DiagnosisHepatic Parenchymal Copper Concentration • Copper copper content >250 mg/g dry weight • 8% were <250, and all were >95 mg/g* • Heterozygotes rarely exceed 250 mg/g • Chronic cholestasis and copper intoxication • Heterogeneous distribution – biopsy size • Copper stain – unreliable (metallothionein-bound) • Radiocopper labeling – rarely performed *Merle U, Schaefer M, Ferenci P, StremmelW. Gut 2007;56:115-120

  18. MRI Brain – T2-weighted Images “Face of the giant panda” in the midbrain with high signal in tegmentum and normal red nuclei (arrow) Hyperintensesignal in the bilateral thalami and putamen “Face of miniature panda” in pons with hypointensity of central tegmental tracts (arrow) with hyperintensity of aqueductal(4th ventricle)

  19. Genetic Analysis • Screening after the proband is diagnosed • Over 300 mutations around ATP7B • Not all gene changes cause Wilson Disease • Single predominant mutation in some populations • Sardinia, Iceland, Korea, Japan, Taiwan, Spain, Brazil and Canary Islands • Eastern Europe –H1069Q mutation

  20. Wilson Disease – TherapyUniformly Fatal Without Therapy • British anti-Lewisite (BAL, dimercaprol) – introduced in1951 • Developed to treat arsenic-based chemical warfare agent • Still used for metal poisoning (arsenic, antimony, gold, etc.) • Free sulfhydryl groups binds copper

  21. Wilson Disease – TherapyD-penicillamine – John Walsh, 1956Chelates, induces metalothionein, prevents collagen cross-linking, immunosuppressant • Initial worsening of neurologic symptoms in 10-50% • Intolerance – 30% of patients • Early – fever, eruptions, lymphadenopathy, neutropenia, thrombocytopenia • Late – lupus-like (ANA+) – renal injury (hematuria, proteinuria), skin lesions • Monitor with 24-hr urine and serum free copper • 1,000 mg (16 mmol) (early) to 200-500 mg (3-8 mmol)/24h • Non-ceruloplasmin copper • Non-compliance vs inadequate chelation

  22. Wilson Disease – TherapyTrientine (triethylenetetraminedihydrochlorideor 2,2,2-tetramine, trien • Polyamine-like structure - copper forms a stable complex with 4 nitrogensin a planar ring • Neurological worsening less common then with penicillamine • Do not co-administer with iron: • Chelates iron  toxic complex • Check effectiveness as for penicillamine • Non-adherence: non-ceruloplasmin bound copper is over 150 mg/L

  23. Wilson Disease – TherapyZinc • Zinc induces enterocyte metallothionein which has a greater affinity for copper than for zinc  binds copper in the enterocyte  feces • Used for maintenance or early cases – less toxic and more specific than chelating agents • Dosed in mg elemental zinc – 50 mg TID for adults

  24. Wilson Disease – TherapyAmmonium Tetrathiomolybdate • Strong de-coppering agent – two mechanisms: • Interferes with intestinal uptake if taken with meals • Binds copper from plasma if taken between meals • TM remains an experimental therapy in the USA • Does not cause neurological deterioration

  25. And Now for Something Completely Different

  26. Question 3Which of the following is true of AAT • The null mutation causes severe liver disease • A mutation in one AAT gene may predispose a patient to alcoholic liver disease • Liver disease and lung disease are both caused by low circulating levels of the enzyme • Patients with the SS phenotype are particularly predisposed to liver disease 1

  27. a-1 Antitrypsin (AAT) DeficiencyA Tale of Two Diseases • Common in Caucasians – 1-3% of pts with COPD • ~ 25 million people carry at least 1 deficient gene. • The mutant protein is not secreted • Liver: gets stuck in the hepatocyte  injury • Lung: Inadequate protection from leukocyte proteases e.g. trypsin, elastase, proteinase 3 • May affect neonates (hepatitis) or adults (CLD, COPD)

  28. a-1 AntitrypsinSerpins – enzyme inhibitors • Acute phase protein • 52-kDa protein - 394 amino acids • Produced in the liver – secreted into blood • Complex folding – globular tertiary structure • Neutrophil elastase binding site

  29. a-1 Antitrypsin (AAT) Deficiency

  30. a-1 Antitrypsin (AAT) Deficiency • Pair of genes at the protease inhibitor (Pi) locus. • The SERPINA1 (formerly Pi) gene on chr.14 • More than 100 allelic variants – classified based on serum levels of AAT protein. • M alleles (Pi MM) are the most common • Normal serum level • Most patients with clinical disease are homozygous ZZ or SS or heterozygous MS, MZ, or SZ

  31. a-1 Antitrypsin (AAT) DeficiencyPAS-positive, diastase-resistant granules

  32. a-1 Antitrypsin (AAT) Deficiency • Normal is Pi MM – mutant alleles are S, Z, null • Patients with liver disease typically have Pi ZZ • Liver disease has no relationship to serum AAT activity • May progress to cirrhosis and/or HCC • No specific therapy • Cirrhosis and HCC are indications for liver transplantation

  33. a-1 Antitrypsin (AAT) DeficiencyFrequency Kok et al. Netherlands Journal of Med, 2007

  34. a-1 Antitrypsin (AAT) DeficiencyFrequency GraziadeiIW et al. Hepatology 1998 (4):1058-63.

  35. a-1 Antitrypsin (AAT) DeficiencyMayo: 641 OLT patients (Mar 1985 - Dec 1996) • Phenotyping in 599 patients listed for liver transplant – examined for the Z allele • 51 patients identified, 49 with MZ allele (8.2%) • 2x frequency reported in the US population (2-4%) • Pi MZ found in 27% with cryptogenic cirrhosis GraziadeiIW et al. Hepatology 1998 (4):1058-63.

  36. a-1 Antitrypsin (AAT) DeficiencyHeterozygotes Liver DiseaseSwedish Study (1972-1974) – 200,000 Neonates Screened • 120 Pi ZZ (0.06%), 2 Pi Z-, 54 Pi SZ and 1 Pi S- • Only 14 Pi ZZ had prolonged jaundice – nine with severe disease • All appeared healthy at six months of age • Infants with a Pi SZ phenotype had no signs of liver disease. • At 16 years, elevated liver enzymes were found in 17% of Pi ZZ adolescents and in 8% of Pi SZ • Adults with liver disease in infancy were clinically healthy Kok et al. Netherlands Journal of Med, 2007

  37. a-1 Antitrypsin (AAT) DeficiencyHeterozygotes Liver DiseaseNorthern Itlay – Phenotyping in umbilical cord blood • Early childhood: • Pi SZ: 5% had elevated enzymes • Pi MZ: 7% had elevated liver enzymes • At the age of 5 and 10 years, none had liver disease. Kok et al. Netherlands Journal of Med, 2007

  38. a-1 Antitrypsin (AAT) DeficiencyLiver Transplantation– Mayo Clinic 1987-2012: 5,246 patients • 73 patients – 50 with ZZ and 23 with SZ phenotype • Mean age 52.8 years, 76% men • Pre-OLT AAT levels were lower in ZZ than SZ patients • 28.3 vs 58.0 mg/dl, p=0.0001 • Coexistent liver disease • 8% in ZZ • 43% in SZ • 90% in MZ Carey et al. Liver Transplantation, 2013 - epub

  39. Summary • Wilson disease – copper storage • Caused by defect in ATP7B – low CPN • Workup includes CPL, copper levels, biopsy • Treatment with chelating agents and/or zinc • AAT deficiency • Pi ZZ may cause liver disease and HCC • Pi MZ and Pi SZ may predispose to liver injury • No treatment is available for liver disease besides liver transplantation

More Related