Development of Chronic Liver Disease

Development of chronic liver disease 1. Chronic liver disease 2. Compensated cirrhosis a. Development of complications: variceal haemorrhage, ascites, encephalopathy, jaundice 3. Decompensated cirrhosis 4. Death Complications of cirrhosis • Portal hypertension o Variceal haemorrhage o Ascites ▪ Spontaneous bacterial peritonitis ▪ Hepatorenal syndrome o Encephalopathy • Liver insufficiency o Encephalopathy o Jaundice o Pitting oedema Portal hypertension • Pressure (P) = resistance (R) x flow (F) • Portal hypertension can result from: o Increase in resistance to portal flow o Increase in portal venous inflow • Causes (portal hypertension is classified according of the site of increased resistance) o Pre-hepatic e.g. portal or splenic vein thrombosis o Pre-sinusoidal e.g. schistosomiasis → caused by parasitic flatworms o Sinusoidal e.g. cirrhosis (most common cause) o Post-sinusoidal e.g. veno-occlusive disease o Post-hepatic e.g. Budd-Chiari syndrome Hepatic lobule structure Portal hypertension in cirrhosis 1. Increased intrahepatic resistance o Structural: sinusoidal fibrosis and regenerative nodules o Functional: active vasoconstriction ▪ Normally NO regulate intrahepatic resistance ▪ Cirrhosis: NO activity in the intrahepatic vasculature is reduced (deficiency) → vasoconstriction ▪ Vasodilators decrease intra-hepatic resistance e.g. nitroprusside, prostaglandin E1 ▪ Because of this portal hypertension persists despite the formation of collaterals 2. Increased portal venous flow o Splanchnic vasodilation due to increased NO (overproduction) in the extrahepatic vasculature sustains portal hypertension 3. Increased collateral resistance Complications • Circulation o Hyperdynamic circulatory state is present in both experimental and human portal hypertension o Splanchnic and systemic vasodilation (↑NO) + sodium retention + blood volume expansion → hyperdynamic circulatory state in cirrhosis o Can cause/worsen cirrhosis complications • Varices: abnormally dilated vessel with tortuous (twisted) course o Splanchnic vasodilation → ↑ portal venous inflow → variceal growth o 50% of cirrhotic patients will have oesophageal varices o 50% with oesophageal varices will eventually bleed from their varices o Mortality rate for oesophageal varices at their first bleed = 40-70% o Primary prevention of variceal bleeding: EVL is used to treat acute bleeding • Collaterals: o Portal hypertension → transmission of backpressure leads to increased flow in patent normal portosystemic anastomoses o Almost any vein in the abdomen may serve as a potential collateral channel o Caput medusae: appearance of distended and engorged superficial epigastric veins radiating from the umbilicus across the abdomen • High output heart failure o Caused by decreased peripheral utilisation of O2 • Ascites o Caused by an obstruction of blood flow in portal circulation ▪ Portal vein obstruction almost never leads to ascites ▪ Hepatic vein obstruction leads to ascites formation Cirrhosis → hepatic venous outflow block → ↑ sinusoidal pressure → ascites Cirrhosis → ↓ arteriolar resistance (vasodilation) → ↓ effective arterial blood volume → ↑ activation of neurohumoral systems (renin, angiotensin, aldosterone) → sodium and water retention → ascites o Neuorhumoral systems are activated in cirrhotic patients with ascites (↑ renin and aldosterone) o Urinary sodium excretion is decreased in cirrhotic patients with ascites Hepatorenal syndrome o Peripheral vasodilation → peripheral sodium and water retention → ascites → renal vasoconstriction → hepatorenal syndrome o Worsening of cirrhosis leads to worsening of ascites and hepatorenal syndrome o o • • Hepatic encephalopathy: neuropsychiatric abnormalities e.g. personality changes, intellectual impairment, depressed consciousness o Simple bedside tests: draw a star, simple handwriting o Caused by loss of liver’s ability to remove toxic substances from blood → metabolises urea o ↑ ammonia → upregulation of astrocytic peripheral benzodiazepine receptors (PBR) → neurosteroid production → modulation of GABAA receptor → hepatic encephalopathy