Metabolic Liver Disease

Transcription

1 Metabolic Liver Disease Peter Eichenseer, MD No relationships to disclose. Outline Overview Alpha-1 antitrypsin deficiency Wilson s disease Hereditary hemochromatosis Pathophysiology Clinical features Diagnosis Treatment Family Screening Overview Inherited disorders of, prominent hepatic manifestations Multi system disorders; can lead to cirrhosis/liver failure 3 major adult disorders Alpha-1 antitrypsin deficiency Wilson s disease Hereditary hemochromatosis Many other inborn errors of in children. Not discussed here, but major indication for pediatric liver transplantation. 1

2 All Metabolic liver diseases Inborn errors of carbohydrate Inborn errors of protein Inborn errors of lipid Inborn errors of bile acid Glycogen storage disease Tyrosinemia Urea cycle defects Gaucher s disease Niemann-Pick disease I b f bil id Byler s disease Benign recurrent cholestasis Inborn errors of copper Inborn errors of iron Wilson s disease Hereditary hemochromatosis Unclassified Alpha 1 antitrypsin deficiency Cystic fibrosis Cliff notes Alpha-1 antitrypsin deficiency. Overview: Hepatic and pulmonary involvement. Autosomal co-dominant. Pathophysiology: Storage disease - Misfolded protein unable to be exported. Clinical features: Premature emphysema and liver disease. Diagnosis: Phenotyping and liver biopsy. Level not helpful. Treatment: Liver transplantation. Wilson s disease. Overview: Excess copper deposition; autosomal recessive. Multisystem. Pathophysiology: Decreased biliary excretion of copper Clinical features: Wide range - hepatic, neurologic, psychiatric, hematologic, ophthalmologic. Diagnosis: Ceruloplasmin, urinary excretion, slit-lamp examination. Liver biopsy. Treatment: Chelating agents, absorption inhibitors, liver transplantation. Hereditary hemochromatosis. Overview: Autosomal recessive. Multisystem. Most common genetic disorder in Caucasians. Pathophysiology: Unopposed iron absorption -> excessive iron deposition. Clinical features: Hepatic, cardiac, arthropathy. Diagnosis: Transferrin saturation, ferritin, HFE gene testing, liver biopsy. Treatment: Phlebotomy. Alpha-1 antitrypsin (AAT) deficiency Lung, liver, rarely skin Classic presentation is premature emphysema, especially in nonsmoker s, and liver disease Different mechanism of injury by site Lung increased enzyme destruction Liver = storage disease - misfolded protein unable to be exported 2

3 Alpha-1 antitrypsin deficiency Deficiency characterized by phenotype rather than genotype Normal = wild type = Pi*MM (Pi, protease inhibitor). 95% of population. Abnormal = Pi*MZ, Pi*SS (rare), Pi*ZZ (1:2000). MZ intermediate deficiency. Usually no cirrhosis unless 2 nd hit (EtOH, NAFLD) ZZ severe deficiency >50 y/o = 19% get cirrhosis Alpha-1 antitrypsin deficiency Consider in any patient with abnormal LFTs, especially where other common causes have been excluded Increased HCC risk, up to 30% Diagnosis based on phenotype. AAT levels not useful in liver disease Liver biopsy - not necessary, but confirmatory and assesses degree of fibrosis Alpha-1 antitrypsin deficiency No effective medical therapy Mainstay - avoidance of hepatotoxins and alcohol Once cirrhosis develops, liver transplantation only definitive therapy Recipient assumes donor phenotype Excellent long-term outcomes 3

4 Alpha-1 antitrypsin deficiency Inherited disorder of copper copper deposition in liver, brain, cornea, other organs Acute liver failure, chronic liver disease, neuropsychiatric symptoms (or combination) Autosomal recessive. 1/30000 homozygous. Mutation in gene ATP7B, genetic testing less useful. Hepatic Abnormal LFTs (often low alk phos), chronic hepatitis, cirrhosis, acute liver failure Neuropsychiatric Rigidity, tremor, ataxia, dysarthria, drooling, g,psychosis, depression Hematologic Coombs negative hemolytic anemia Ocular Kayser Fleischer rings 4

5 Strong clinical suspicion to make diagnosis Young patient with liver disease and neuropsychiatric symptoms Young patient t with acute liver failure and hemolytic anemia Initial evaluation ceruloplasmin, 24-hour urine copper, slit lamp exam Liver biopsy necessary to confirm diagnosis Treatment is lifelong Treatment remove copper or block copper absorption Liver transplant for acute liver failure or cirrhosis Chelating agents 1 st line = trienterine Alternative = penicillamine, numerous side effects Inhibition of copper absorption Zinc acetate for presymptomatic and pregnant patients. 5

6 Siblings have a 25% risk. Screening Scee with ceuopas ceruloplasmin,,slit lamp, 24- hour urine copper. Not for children under 5 Treatment in the presymptomatic phase cam prevent disease progression Inherited disorder of iron iron deposition in organs Chronic liver disease, cardiomyopathy, or arthropathy. Autosomal recessive Mutation in HFE gene C282Y and H63D Normally, HFE bound to transferrin signals body to stop absorbing iron. HH = most common genetic disorder in US Caucasians Mutated HFE = unopposed iron absorption leads to iron excess 1/10 = heterozygous (carrier) 1/250 = homozygous (disease) 6

7 Manifestations appear in 50s Hepatomegaly, LFTs, skin bronzing, diabetes, cardiomyopathy, conduction abnormalities, cirrhosis, HCC, hypogonadism, arthropathy Nearly all manifestation are preventable if detected and treated early Now, usual diagnosis is via labs pre-manifestations Increased risk HCC (200 fold) Diagnosis = clinical, lab, histopathology Screening = transferrin saturation >45% Morning lab while fasting Ferritin not for screening Abnormal screening, then HFE gene testing C282Y/C282Y most iron overload C282Y/H63D (compound heterozygote) less iron overload H63D/H63D Heterozygote (single copy) no iron overload Liver biopsy not required, but helpful to assess fibrosis and if unclear diagnosis 7

8 Asymptomatic homozygous, without end organ damage and ferritin less than 500 no treatment. Instead annual labs. End organ damage requires phlebotomy Phlebotomy Start q1 2 weeks (500mL, goal ferritin 50, goal hgb >12 Maintenance phlebotomy q 2 4 months, goal ferritin Limit alcohol, iron supplements, high dose vitamin c First degree family members should be screened 25% risk for siblings Spousal screening - more accurate assess risk for children If no HFE mutation, children not affected If cirrhosis, q6 mo afp and imaging recommended. Fewer than 1% of all liver transplants and US 8