Metabolic Diseases of the Liver PDF

Developmental Abnormalities, Metabolic and Vascular Diseases of the Liver Prof. Dr. Çiğdem Ataizi ÇELİKEL Nonneoplastic Liver Diseases Hepatitis Biliary Diseases Alcoholic Liver Diseases Metabolic Liver Diseases Drug/toxin-induced Liver Diseases Vascular Diseases I...

Developmental Abnormalities, Metabolic and Vascular Diseases of the Liver Prof. Dr. Çiğdem Ataizi ÇELİKEL Nonneoplastic Liver Diseases Hepatitis Biliary Diseases Alcoholic Liver Diseases Metabolic Liver Diseases Drug/toxin-induced Liver Diseases Vascular Diseases Infectious Diseases Developmental Diseases Metabolic and other Liver Diseases Wilson’s Disease Hemochromatosis 1-Antitrypsin Deficiency Cystic Fibrosis Glycogen Storage Disease Thyrosinemia Mucopolysaccaridosis Gaucher Disease Nieman-Pick Disease Others…  copper is uptaken to the cytoplasm of WILSON’S DISEASE the hepatocyte and this free copper after it is absorbed from the albumin normal copper metabolism it comes to the hepatocyte, cytoplasm of the hepatocyte and it is binded to alpha-2 globulin. ingested copper  40-60% absorbed (duodenum + proximal small intestine)  alb + copper  liver  within hepatocytes free copper + 2glb (ceruloplasmin)  blood and excess copper transported to bile total body copper = 50-150 mg ceruloplasmin accounts for 90-95 % of plasma copper  WILSON’S DISEASE OR ATP7B mutation T ATPase on hepatocyte canalicular membrane impaired copper exretion into the bile failure to incorporate copper into ceruloplasmin inhibits ceruloplasmin secretion into the blood Nonceruloplasmin bound copper  circulation  hemolysis/injury  brain, cornea, kidneys, bone, joints, parathyroid injury through copper catalyzed formation of reactive oxygen species  WILSON’S DISEASE Serum copper levels are the main daignotic method in wilsons disease. False 6-40 years of age accumulation of copper  liver, brain, eye  hepatolenticular degeneration  serum ceruloplasmin  hepatic copper content  urinary excretion serum copper levels  , N,  hepatic copper content  > 250 microgram WILSON’S DISEASE Pathology fatty change acute / chronic hepatitis massive hepatocyte necrosis Mallory bodies toxic injury to neurons cornea  Kayser-Fleisher rings WILSON’S DISEASE Pathology fatty change acute / chronic hepatitis massive hepatocyte necrosis Mallory bodies toxic injury to neurons cornea  Kayser-Fleisher rings HEMOCHROMATOSIS total body iron pool = 2-6 gr (0.5 gr-liver) Hereditary Hemochromatosis homozygous-recessive HFE gene (chromosome 6, short arm) encodes HLA class I-like mol. → regulates intestinal absorption of dietary iron excess iron absorption Secondary Hemochromatosis (hemosiderosis) parenteral iron overload ineffective erythropoesis increased oral intake of iron congenital atransferrinemia chronic liver disease Hereditary Hemochromatosis 5th-6th decade of life (>20gm) M>F (5 to 7:1) Micronodular cirrhosis Diabetes mellitus ( 75-80 %) Skin pigmentation ( 75-80 %) lipid peroxidation via iron catalyzed free radical reactions stimulation of collagen formation interactions of reactive oxygen species and of iron itself with DNA leading yo lethal injury or predisposition to HCC morphology deposition of hemosiderin liver pancreas myocardium pituitary gland adrenal gland thyroid and parathyroid glands joints, skin cirrhosis pancreatic fibrosis  1-Antitrypsin Deficiency 1-Antitrypsin – plasma glycoprotein synthesized within hepatocytes (mostly) Function : inhibition of proteases (elastase, cathepsin G, proteinase 3) OR (1-Antitrypsin gene locus  chromosome 14) substitution in the polypeptide gene 1/2000 live births; 10-15 %  liver injury (most common genetic cause of liver disease) Pathogenesis : (Pi: protease inhibitör, genotype of two alleles) Most common genotype (wild-type genotype)  Pi (PiMM - 90%) PiS  reduced serum levels/without clinical manifestation PiZ  (homozygote) reduced serum levels (%10)/clinical  defect in the migration of this glycoprotein (Glu342 to Lys342) from endoplasmic reticulum to Golgi apparatus → secretion of mutant protein from hepatocytes autophagocytic response / mitochondrial dysfunction/ activation of proinflammatory NF-kappaB 1-Antitrypsin Deficiency Pulmonary emphysema, bronchiectasis Liver Chronic hepatitis/cirrhosis Neonatal hepatitis +/- cholestasis Childhood cirrhosis Cutaneous panniculitis Arterial aneurysm Wegener granulomatosis Cystic Fibrosis Autosomal recessive trait (long arm of chromosome 7)  CF transmembrane conductance regulator (CFTR) – chloride channels Chronic pulmonary diseases + deficient exocrine pancreatic function + other complications of inspissated mucus in a number of organs, including the small intestine, the liver and reproductive tract 10 %  secondary biliary cirrhosis not hepatitis type of problem as Wilson's disease or other one, antitrypsin deficiency, it leads to chronic secondary biliary problem due to the obstruction of the bowel flow because this mucus accumulates within the biliary tract. Nonneoplastic Liver Diseases Hepatitis Biliary Diseases Alcoholic Liver Diseases Metabolic Liver Diseases Drug/toxin-induced Liver Diseases Vascular Diseases Infectious Diseases Developmental Diseases Developmental Abnormalities and Liver Diseases in Childhood Anatomical anomalies of Neonatal choleastasis the liver Extrahepatic biliary atresia Hepatic vascular Neonatal hepatitis anomalies Paucity of the Bile duct anomalies intrahepatic bile ducts Congenital dilatations of Inborn errors of the bile ducts metabolism Polycystic kidney disease Reye’s syndrome Solitary cyst Kawasaki’s disease Infectious diseases The histiocytoses of childhood Hepatic Vascular Anomalies ❑ Hepatic artery / Portal vein / Hepatic veins ❑ Hereditary hemorrhagic telengiectasia (Osler- Rendu-Weber) Autosomal dominant, 1-2/100000 Telangiectases (skin, mucous membranes) + arteriovenous fistulas of the liver (30 %), lungs, central nervous system + aneurysms ❑ von Hippel Lindau Disease ❑ Focal Nodular Hyperplasia  Congenital Bile Duct Anomalies (dilatation) ❑Choledocal Cyst (dilatation of common bile duct) ❑Caroli’s Disease (segmental dilatation of the large intrahepatic bile ducts +/- inspissated bile) ❑Polycystic Liver-Kidney Disease ❑Autosomal Recessive ❑Autosomal Dominant ❑von Mayenburg Complex ❑Choledocal Cyst (dilatation of common bile duct) congenital / < 60 %  < 20 years of age 80 % female associated with biliary duct anomalies Clinical findings : Children  jaundice Adults  ascending cholangitis or pancreatitis Complications : perforation, liver abscesses, stone formation, secondary biliary cirrhosis, pancreatitis, amyloidosis and carcinoma of the biliary tree (adenocarcinoma) Treatment : drainage by choledocho-cysto-jejenostomy ❑Caroli’s Disease (segmental dilatation of the large intrahepatic bile ducts +/- inspissated bile) Autosomal recessive Pathogenesis: total or partial arrest of remodeling of the ductal plate of the larger intrahepatic bile ducts Clinical findings : fever, pain, jaundice (stone) Complications :recurrent cholangitis, liver abscesses, stone formation,, pancreatitis, amyloidosis, septicemia and pyemia, carcinoma of the biliary tree (adenocarcinoma) Treatment : internal / external drainage Polycystic Liver-Kidney Disease ❑Autosomal recessive Perinatal, neonatal, infantile presentation juvenile and adult presentation ( congenital hepatic fibrosis) Pathogenesis: abnormal differentiation of the primitive duct structures Gross: normal/enlarged,firm Histology: communicate with the rest of the biliary system Polycystic Liver-Kidney Disease ❑Autosomal dominant Short arm of chromosome 16 Average age = 53, male=female Gross:diffusely cystic (