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)

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%

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

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

Inherited Causes of Cirrhosis in Iran

Wilson's Disease

Hemochromatosis

a1 – antitrypsindeficiency

Familial intrahepatic cholestasis

Other

Wilson’s Disease In Iran

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

• 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

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

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

• 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:

• 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

Wilson’s Disease Gene

• Located in Chromosome 13

• ATP7B

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

• 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

• 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

Genetic Diseases – Wilson’s DiseaseGenetic Diseases – Wilson’s Disease

CM - Kayser-Fleischer Ring

Genetic Diseases – Wilson’s DiseaseGenetic Diseases – Wilson’s Disease

CM - Wilson’s Disease

Genetic Diseases – Wilson’s DiseaseGenetic Diseases – Wilson’s Disease

Copper depositsCopper deposits

CM - MRI of the Brain

• Serum ceruloplasmin levels are usually, but not invariably, low, below 20 mg/dl, in homozygotes

Diagnosis

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

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

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

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

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

• D-Penecillamine 500 mg QID

• Trientine

• Tetrathiomolybdate (neurologic cases)

• Zinc acetate or Zinc Sulphate

Copper Chelation

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