RCSI Pathology Lecture 2024 Bahrain PDF

RCSI Royal College of Surgeons in Ireland Coláiste Ríoga na Máinleá in Éirinn Alcoholic and non-alcoholic liver disease Class Year 2 Course Pathology Lecturer Prof Paul Murray Date October 2024 LEARNING OUTCOMES Describe the spectrum of fatty liver disease Describe what is me...

RCSI Royal College of Surgeons in Ireland Coláiste Ríoga na Máinleá in Éirinn Alcoholic and non-alcoholic liver disease Class Year 2 Course Pathology Lecturer Prof Paul Murray Date October 2024 LEARNING OUTCOMES Describe the spectrum of fatty liver disease Describe what is meant by fatty change, emphasising its significance & aetiology Discuss how alcohol affects the liver Describe the spectrum of pathological effects of alcohol Describe non-alcoholic fatty liver disease Describe the diagnosis and treatment of hereditary haemochromatosis (HFE) Compare and contrast the similarities & differences between autoimmune hepatitis & other causes of hepatitis Describe how autoimmune liver disease is diagnosed and define cirrhosis and list the causes and discuss its complications  FATTY CHANGE Macrovesicular versus microvesicular Depends: size and number of droplets within hepatocyte cytoplasm Macrovesicular common/typical type, single large droplet, unless specifically qualified, fatty change = macrovesicular Reversible cellular change, metabolic response, associated with: Alcohol Metabolic syndrome Other causes: starvation, bariatric surgery, TPN, amiodarone Microvesicular very rare, associated with acute liver failure Reflects profound metabolic upset in hepatocyte mitochondria Acute fatty liver of pregnancy, tetracycline toxicity TPN=Total Parenteral Nutrition  Metabolic syndrome, an individual must have at least three of five risk factors: – Abdominal obesity: generally, waist circumference >40 inches in men and 35 inches in women – Hypertension: BP>130/85 mm Hg, or need for antihypertensive medication. – Elevated fasting blood glucose: >100 mg/dL (5.6 mmol/L) or use of medication for hyperglycaemia. – High triglyceride >150 mg/dL (1.7 mmol/L) or higher, or treatment for elevated triglycerides. – Low HDL cholesterol: 11, 000) suggest that specific statins (mainly atorvastatin) ameliorate NAFLD/NASH and reduce CVD events twice as much as in those with normal liver function  HAEMOCHROMATOSIS Excessive deposition of iron in tissues causes damage Hereditary haemochromatosis Progressive excessive absorption relative to need Specific genetic defect in HFE gene in most patients Rarely non-HFE gene-associated hereditary haemochromatosis Secondary haemochromatosis -secondary iron overload Multiple transfusions, ineffective erythropoiesis associated with hereditary anaemias (e.g. thalassaemia) HFE is gene symbol, gene name is ‘Homeostatic Iron Regulator’ GENETICS OF HEREDITARY HAEMOCHROMATOSIS Autosomal recessive, HFE gene, chromosome 6p ▪ Two mutations C282Y and H63D ▪ Most cases of HFE are C282Y/C282Y homozygotes ▪ 60% of compound C282Y/H63D heterozygotes at risk Genetic change commoner than phenotypic evidence of iron overload (30-50% penetrance, 10-30% for clinical effects- biochemical overload commoner than clinical disease Screen first-degree relatives if mutation identified  HAEMOCHROMATOSIS Iron deposition toxic to: Liver (fibrosis and cirrhosis) Endocrine pancreas (secondary diabetes mellitus) Myocardium (dilated cardiomyopathy) Anterior pituitary (secondary hypogonadism and impotence) Arthropathy Fatigue Skin hyperpigmentation (‘bronze diabetes’) Symptoms rare F  IRON METABOLISM Duodenal enterocytes absorb dietary iron, release small amounts to compensate for non-specific losses. Iron transported in blood by transferrin (% saturation indicates iron storage status) Hepatocytes store excess iron, can be mobilized to plasma under iron deficiency. Iron efflux to plasma from macrophages, enterocytes or hepatocytes negatively regulated by hepcidin, a liver-derived hormone-binds to the iron exporter ferroportin and promotes its degradation. HFE positively regulates hepcidin synthesis NB. Prolonged inflammatory stimulation of hepcidin leads to anaemia of chronic disease  DIAGNOSIS OF HAEMOCHROMATOSIS Biochemistry: High % saturation of transferrin/total iron binding capacity (iron/transferrin levels expressed as %), >55% significant Ferritin level sensitive but less specific ▪ Acute phase reactant, associated with inflammation ▪ Good for follow-up Perl stain showing iron in hepatocytes ▪ Hereditary haemochromatosis excluded if transferrin saturation 90%, SMA negative Higher power of above showing damaged bile duct epithelium containing lymphocytes. No granulomas present in this case (1/3 overall)  PRIMARY BILIARY CHOLANGITIS (PBC) Old name Primary Biliary Cirrhosis- originally described in autopsy cases with cirrhosis, BUT cirrhosis only end-stage of disease Increasing recognition of asymptomatic patients with slow progression Treatment Ursodeoxycholic acid (UDCA)- responders may have no excess mortality Steroids not effective Treat symptoms OLT can be considered  PRIMARY SCLEROSING CHOLANGITIS (PSC) Chronic fibro-obliterative destruction of bile ducts Intrahepatic and/or extrahepatic ducts, commonly both If intra-hepatic mainly: progressive cholestasis with clinical features similar to PBC, going on to cirrhosis If extrahepatic mainly stricture with CBD obstruction, risk of ascending cholangitis Incidence four times higher in females, much less common than PBC p-ANCA +, AMA -) Strong association with IBD especially ulcerative colitis ▪ UC present in 70% of patients with PSC (but