classification of chronic hepatitis non-biliary 1- viral: hbv,hcv,hbv+hdv 2- non-viral: aih,,nash,...
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Classification of Chronic Hepatitis
• Non-Biliary 1- Viral: HBV,HCV,HBV+HDV 2- Non-Viral: AIH,,NASH, Wilson,s Hemochromatosis……
• Biliary 1-PBC 2-PSC 3-AIC (Overlap Syndrome)
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Etiology of CH in 413 Patients Shariati Hospital Tehran 1371-1374
Viral----------------------------------- -61%
1- HBV----------------- 54% 2- HCV------------------7% Non-Viral---------------------------- ---30%
1- AIH--------------- ----16% 2- PSC,PBC--------------6.5% 3- Alcohol,Drugs--------4.5% 4-NASH-------------------2.5% 5-Wilson’s----------------2.5% Cryptogenic--------------------------- 9%
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Non-Viral Hepatitis162 Patients in Shariati Hospital
AIH--------------- ----40%Drugs---------------------8 %NASH-------------------- 7 %PSC------------------------7 %Wilson’s---------------- --6 %Alcohol,-------------------% 4 PBC------------------------4 %Others---------------------24%
Non-Viral Hepatitis162 Patients in Shariati Hospital
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Inherited Causes of Cirrhosis In USA
1 – antitrypsindeficiency
1 – antitrypsindeficiency
OtherOther
CFCF
Wilson'sWilson's
Familial intrahepatic cholestasis
Familial intrahepatic cholestasis
Hemochromatosis
Newborn and infantsNewborn and infants AdultsAdults
Genetic Diseases - LiverGenetic Diseases - Liver
Inherited Causes of Cirrhosis
Bacon BR and Britton RS, 2002Bacon BR and Britton RS, 2002
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Inherited Causes of Cirrhosis in Iran
Wilson's Disease
Hemochromatosis
a1 – antitrypsindeficiency
Familial intrahepatic cholestasis
Other
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Wilson’s Disease In Iran
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Kayser-Fleischer ringsNeuropsychiatric disorders
Kayser-Fleischer ringsNeuropsychiatric disorders
CardiomyopathyCardiomyopathy
Hepatitis CirrhosisHepatitis Cirrhosis
HemolysisHemolysis
Osteoporosis and arthropathyOsteoporosis and arthropathy
Fanconi syndromeFanconi syndrome
Genetic Diseases – Wilson’s DiseaseGenetic Diseases – Wilson’s Disease
Wilson’s Disease
Cox and Roberts, 2002Cox and Roberts, 2002
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• 0.6 to 3 mg/day Cu intake (2/3 absorbed in the upper SB) Alb. Binding take up by dif tissues
• Cu + apoCLP (in the liver) CLP (90% of the circulating Cu)
• Excretion via bile: 85-95% of the total daily intake, the rest by the liver
Normal Copper Balance
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Normal Copper Balance
Copper (Cu)1.5 – 4.0 mg/dayCopper (Cu)
1.5 – 4.0 mg/day
CeruloplasminCeruloplasmin
Cu excreted in bile
Cu excreted in bile
Urine output (<70 g/day)Urine output (<70 g/day)
Cu excreted in stool
Cu excreted in stool
Free Cu absorbed
ApoceruloplasminApoceruloplasmin
Normal Copper Balance
Cox and Roberts, 2002Cox and Roberts, 2002
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Ch 13Ch 13
Copper Overload DisordersCopper Overload Disorders
PrimaryPrimary SecondarySecondary
Chronic cholestasis
• Primary biliary cirrhosis
• Byler’s syndrome
Chronic cholestasis
• Primary biliary cirrhosis
• Byler’s syndrome
Genetic Diseases – Wilson’s DiseaseGenetic Diseases – Wilson’s Disease
Copper Overload Disorders
Autosomal recessive inheritance
Autosomal recessive inheritance
Cox and Roberts, 2002Cox and Roberts, 2002
Wilson’s Disease
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• Pregnancy or estrogen therapy.
• The stress of acute inflammation, such as hepatitis.
• Thus, 5% of patients with Wilson's disease have a ceruloplasmin level in the normal range.
Increased serum ceruloplasmin is seen in:
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• Heterozygous carriers
• Acute viral hepatitis
• Chronic hepatitis
• Drug-induced liver disease
• Alcohol-induced liver disease
• Malabsorption
A low serum CLP: not specific for WD, also in
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Wilson’s Disease Gene
• Located in Chromosome 13
• ATP7B
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Space of DisseSpace of Disse
Normal Copper Balance Abnormal Copper Balance
CopperCopper
CeruloplasminCeruloplasmin
Bile ductalsBile ductals
LysosomesLysosomes
Golgi complexGolgi complex
Copper build-up leads to cell stress and deathCopper build-up leads to cell stress and death
Genetic Diseases – Wilson’s DiseaseGenetic Diseases – Wilson’s Disease
Wilson’s Disease
Schaefer M, et al. Gastroenterology 1999; 117:1380Schaefer M, et al. Gastroenterology 1999; 117:1380 154154
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• Increase in hepatic Cu • Excess copper: initially bound to metallothionein
and distributed evenly in the cytoplasm• Progressive Cu accumulation exceeding the
capacity of metallothionein Cu deposition in lysosomes hepatic
dysfunction (? free radicals)• Severe mitochondrial dysfunction in these patients
is a sign of oxidative damage
Progressive Cu accumulation
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• Rare before age 6 and almost always before the age of 30 (later ages also reported)
• Adolescents: liver disease
• Young adults: neuropsychiatric disease
• All patients with neuropsychiatric disease have compensated cirrhosis (often not detected until Wilson's disease is diagnosed)
Clinical manifestations
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Genetic Diseases – Wilson’s DiseaseGenetic Diseases – Wilson’s Disease
CM - Kayser-Fleischer Ring
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Genetic Diseases – Wilson’s DiseaseGenetic Diseases – Wilson’s Disease
CM - Wilson’s Disease
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Genetic Diseases – Wilson’s DiseaseGenetic Diseases – Wilson’s Disease
Copper depositsCopper deposits
CM - MRI of the Brain
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• Serum ceruloplasmin levels are usually, but not invariably, low, below 20 mg/dl, in homozygotes
Diagnosis
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Usual Features in Homozygotes
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
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
Genetic Diseases – Wilson’s DiseaseGenetic Diseases – Wilson’s Disease
Features in Homozygotes and Heterozygotes
Usual Features in Heterozygotes
Cox DW, Roberts EA. In Sleisenger & Fordtran’s Gastrointestinal and Liver Disease; Pathophysiology, Diagnosis and Management. Edited by M. Fledman, et al. Saunders, Philadelphia 2002; 67: 1269-1277
Cox DW, Roberts EA. In Sleisenger & Fordtran’s Gastrointestinal and Liver Disease; Pathophysiology, Diagnosis and Management. Edited by M. Fledman, et al. Saunders, Philadelphia 2002; 67: 1269-1277
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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
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
Genetic Diseases – Wilson’s DiseaseGenetic Diseases – Wilson’s Disease
Indications for Testing
Cox DW, Roberts EA. In Sleisenger & Fordtran’s Gastrointestinal and Liver Disease; Pathophysiology, Diagnosis and Management. Edited by M. Fledman, et al. Saunders, Philadelphia 2002; 67: 1269-1277Cox DW, Roberts EA. In Sleisenger & Fordtran’s Gastrointestinal and Liver Disease; Pathophysiology, Diagnosis and Management. Edited by M. Fledman, et al. Saunders, Philadelphia 2002; 67: 1269-1277
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PSCPSC PBCPBC Indian childhoodcirrhosis
Indian childhoodcirrhosis
Wilson’s disease
Wilson’s disease
20002000
NormalNormal CirrhosisCirrhosis00
400400
800800
200200
600600Mean hepatic copper (g/g dry weight)
Mean hepatic copper (g/g dry weight)
Genetic Diseases – Wilson’s DiseaseGenetic Diseases – Wilson’s Disease
Wilson’s Disease
Cox DW, Roberts EA. In Sleisenger & Fordtran’s Gastrointestinal and Liver Disease; Pathophysiology, Diagnosis and Management. Edited by M. Fledman, et al. Saunders, Philadelphia 2002; 67: 1269-1277Cox DW, Roberts EA. In Sleisenger & Fordtran’s Gastrointestinal and Liver Disease; Pathophysiology, Diagnosis and Management. Edited by M. Fledman, et al. Saunders, Philadelphia 2002; 67: 1269-1277
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PresentationsLiver Abnormal liver tests
Acute hepatitisAcute hepatic failureLiver disease with hemolysisChronic hepatitisCryptogenic cirrhosis
CNS Parkinson-like disordersPsychiatric disorders
Eye Kayser-Fleischer ringsSunflower cataracts
Kidney Fanconi syndrome with hypouricemia
Liver Abnormal liver testsAcute hepatitisAcute hepatic failureLiver disease with hemolysisChronic hepatitisCryptogenic cirrhosis
CNS Parkinson-like disordersPsychiatric disorders
Eye Kayser-Fleischer ringsSunflower cataracts
Kidney Fanconi syndrome with hypouricemia
Genetic Diseases – Wilson’s DiseaseGenetic Diseases – Wilson’s Disease
Presentations
Cox DW, Roberts EA. In Sleisenger & Fordtran’s Gastrointestinal and Liver Disease; Pathophysiology, Diagnosis and Management. Edited by M. Fledman, et al. Saunders, Philadelphia 2002; 67: 1269-1277Cox DW, Roberts EA. In Sleisenger & Fordtran’s Gastrointestinal and Liver Disease; Pathophysiology, Diagnosis and Management. Edited by M. Fledman, et al. Saunders, Philadelphia 2002; 67: 1269-1277
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Diagnostic Testing
CeruloplasminSlit lamp examinationUrine copper
CeruloplasminSlit lamp examinationUrine copper
Liver biopsy with quantitative copper
determination confirms diagnosis
Liver biopsy with quantitative copper
determination confirms diagnosis
Ceruloplasmin <20 mg/dL(5% of Wilson’s patients have normal
ceruloplasmin levels)
Kayser-Fleischer ringsUrine copper >100 g/24 hr
Ceruloplasmin <20 mg/dL(5% of Wilson’s patients have normal
ceruloplasmin levels)
Kayser-Fleischer ringsUrine copper >100 g/24 hr
Genetic Diseases – Wilson’s DiseaseGenetic Diseases – Wilson’s Disease
Diagnostic Testing
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• D-Penecillamine 500 mg QID
• Trientine
• Tetrathiomolybdate (neurologic cases)
• Zinc acetate or Zinc Sulphate
Copper Chelation
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Management
Genetic Diseases – Wilson’s DiseaseGenetic Diseases – Wilson’s Disease
Management
Therapy Chelation + pyridoxineZincAvoid high copper foodsTransplantation in selected casesFamily screening
Monitoring Urine copperNon-ceruloplasmin copperDo NOT monitor Kayser-Fleischer rings
Results Treatment prevents disease Improves liver and CNS disease
Prolongs life
Therapy Chelation + pyridoxineZincAvoid high copper foodsTransplantation in selected casesFamily screening
Monitoring Urine copperNon-ceruloplasmin copperDo NOT monitor Kayser-Fleischer rings
Results Treatment prevents disease Improves liver and CNS disease
Prolongs life
Cox DW, Roberts EA. In Sleisenger & Fordtran’s Gastrointestinal and Liver Disease; Pathophysiology, Diagnosis and Management. Edited by M. Fledman, et al. Saunders, Philadelphia 2002; 67: 1269-1277Cox DW, Roberts EA. In Sleisenger & Fordtran’s Gastrointestinal and Liver Disease; Pathophysiology, Diagnosis and Management. Edited by M. Fledman, et al. Saunders, Philadelphia 2002; 67: 1269-1277