RCSI Liver Dysfunction and Cirrhosis Lecture PDF

RCSI Royal College of Surgeons in Ireland Coláiste Ríoga na Máinleá in Éirinn Turning Point ID: GIHEPPathL1 The Histopathology of Liver Dysfunction and Cirrhosis Course Pathology Lecturer Dr Clive Kilgallen Date October 11th 2024 LEARNING OUTCOMES D...

RCSI Royal College of Surgeons in Ireland Coláiste Ríoga na Máinleá in Éirinn Turning Point ID: GIHEPPathL1 The Histopathology of Liver Dysfunction and Cirrhosis Course Pathology Lecturer Dr Clive Kilgallen Date October 11th 2024 LEARNING OUTCOMES Describe the structure and function of the liver Describe the different patterns of damage to the liver Describe "grade and "stage" of liver damage Describe the concept of cirrhosis Describe how portal hypertension and ascites develop Distinguish between compensated and decompensated cirrhosis Describe how liver disease presents OVERVIEW OF LIVER DISEASE Increasing reason for morbidity/mortality, life years lost But less common than heart disease, cancer, stroke Managed by gastroenterologists, sometimes specialised as hepatologists Surgeons: gall stones, pancreatitis, sometimes extrahepatic biliary tract disease GPs: abnormal liver blood tests Different patterns depending on where in world Cirrhosis: alcohol versus chronic viral disease (HBV) Tumours: liver metastases and pancreatic cancer versus primary hepatocellular carcinoma CAUSES OF LIVER DAMAGE Alcohol Non-alcoholic fatty liver disease ▪ a/w metabolic syndrome (type 2 DM, obesity etc.) Viruses (acute +/- chronic in some – A, B, C, E) Drugs Autoimmune Inherited metabolic (HFE, Wilson’s, A1AT def) Vascular (congestion or ischaemia) Chronic biliary disease (injury to liver from retained bile salts) LIVER STRUCTURE 1.5kg Large functional reserve “Stable” cell population ▪ Capable of regeneration Limited repertoire of responses/patterns to acute and chronic injury Importance of history, examination and tests Different causes of injury may interact NORMAL LIVER Gross appearance for comparison LIVER STRUCTURE 2 Blood supply – dual ▪ Hepatic artery ▪ Portal vein Blood flows into sinusoids (blood spaces) separating plates of hepatocytes (liver cells) Sinusoids lined by fenestrated endothelium & macrophages (Kupffer cells) Space of Disse between sinusoids and hepatocytes contains hepatic stellate cells Venous drainage - hepatic vein to IVC to RV HEPATIC STELLATE CELLS LIVER STRUCTURE- PLATES LIVER STRUCTURE- SPACE DISSE LIVER PLATES ARE LIKE PLATES IN A DISHWASHER They are arranged to allow free flow of fluid NORMAL LIVER Blood flows from portal tract thru sinusoids to hepatic venule PORTAL TRACT MICRO Portal tract connective tissue stained blue by trichrome stain. Sharp interface between portal tract and surrounding hepatocytes NORMAL LIVER Note: sinusoids between plates of hepatocytes sinusoids drain into central hepatic vein branch LIVER STRUCTURE 3 Portal tracts Smallest branches of ▪ Portal vein ▪ Hepatic artery ▪ Bile duct Sharp interface between portal tract and surrounding parenchyma LIVER STRUCTURE 4 Bile drainage Bile formed by hepatocytes Secreted into canaliculi between hepatocytes Small ductules form from canaliculi, these then join to form small ducts in portal tracts Left + right hepatic duct = Common hepatic duct Common hepatic duct joined by cystic duct = Common bile duct 75%: CBD + pancreatic duct join at ampulla Gall bladder for bile storage only LIVER MICRO - ANATOMY Acinus – now favoured concept, centred on portal tracts (blood supply) The acinus refers to hepatocytes and sinusoids from two adjacent lobules supplied by one portal tract Explanation for patterns of damage ▪ Ischaemic/toxic injury most severe in zone 3 Allows description pattern damage/fibrosis Revise histology picture in which zones of acinus are marked NORMAL LIVER Portal tract left, central vein right Zones 1, 2 & 3 of acinus marked VASCULAR INJURY TO THE LIVER Chronic (passive) venous congestion of liver ▪ a/w right heart failure (e.g. cor pulmonale, mitral stenosis), most marked in rare tricuspid incompetence, constrictive pericarditis ▪ Mild elevation of liver blood tests (ALT, AST) Obstruction to venous outflow from liver (hepatic vein/IVC) ▪ Budd Chiari syndrome VASCULAR INJURY TO THE LIVER (CONTINUED) Infarction of liver extremely unusual Ischaemic injury to liver (‘ischaemic hepatitis’, ‘shock liver’) ▪ a/w hypoperfusion, hypotension/shock/circulatory failure ▪ Marked elevation of liver blood tests (ALT, AST) ▪ Outcome depends on cause ▪ Susceptibility increased by passive venous congestion or cirrhosis NORMAL LIVER Gross appearance, cut surface, for comparison CHRONIC PASSIVE VENOUS CONGESTION OF LIVER Gross appearance, cut surface = “Nutmeg liver” Congestion most obvious around central hepatic vein branches LIVER FUNCTION Synthesis of most plasma proteins Clotting Bile formation Bilirubin: excretion Bile salts: digestion - fat/fat-soluble vitamins ADEK Detoxification endogenous/exogenous compounds Intermediary metabolism – alteration and/or store Immune All three above: buffer between gut/rest of body Storage normal/abnormal Haematopoiesis (foetal/infant)  DAMAGE TO THE LIVER Acute Liver has reserve and regenerative capacity Possible outcomes? Depends on: ▪ Degree of damage? ▪ If very extensive, risk of acute liver failure ▪ If transient and no acute liver failure, recovery ▪ If on-going/repeated insult – chronic damage Chronic If on-going insult, chronic disease (defined as >6/12) ▪ Fibrosis, increasing degrees with progression to: ▪ Cirrhosis Different causes may co-exist, be superimposed, potentiate  DAMAGE TO THE LIVER (CONTINUED) Patterns of cell damage/death Different types of cell injury (reversible or irreversible) Different triggers for injury ▪ Direct cytopathic/cytotoxic/ischaemic effects ▪ Damage to hepatocytes rendered antigenic (e.g. HBV) ▪ Damage to cells perceived as antigenic (e.g. autoimmune hepatitis) Different degrees of injury ▪ Single cells die (apoptosis) ▪ Small groups of cells die (spotty necrosis) ▪ Large confluent groups of cells die (bridging necrosis) ▪ Massive hepatic necrosis ASSESSMENT OF LIVER DAMAGE Inflammation +/- necrosis: extent = “grade” Is inflammation portal/periportal or lobular (parenchymal)? ▪ How much portal/periportal and/or lobular inflammation is there? ▪ Interface inflammation = “piecemeal necrosis” ▪ Specific pattern of portal/periportal damage Is necrosis present, single cells, spotty or bridging? Predominant inflammatory cell type: ▪ Depends on aetiology, not whether disease is of acute and/or chronic duration ASSESSMENT OF LIVER DAMAGE (CONTINUED) Fibrosis: degree/extent = “stage” Portal fibrosis Periportal fibrosis (sometimes perivenular/perisinusoidal pattern in alcohol/NAFLD) Bridging fibrosis: portal to portal tract or portal to central vein Cirrhosis Liver biopsy: complex scoring systems Assess grade and stage independently STAGES OF LIVER FIBROSIS, TRICHROME STAIN Fibrous tissue (stained blue by trichrome stain) DEFINITION OF CIRRHOSIS Diffuse distortion of liver architecture Fibrous bands/septa, surrounding Regenerative nodules Distorted vascular relationships Cirrhosis causes portal hypertension Functional capacity of liver reduced Risk of hepatocellular carcinoma CIRRHOSIS Structural state = end-stage of chronic liver disease due to ongoing chronic damage Diminished reserve Vascular changes in liver due to cirrhosis: ▪ Obliteration/thrombosis of veins within liver ▪ Collateral channels/shunts form within liver ▪ Sinusoids become “capillarised” (lose fenestrations) ▪ Hepatic venous pressure gradient (HVPG) rises CIRRHOSIS Gross (macroscopic) appearance NORMAL LIVER Histology for comparison, H&E CIRRHOSIS Histology, H&E: Diffuse architectural distortion: nodules of regenerative parenchyma separated by fibrous bands CIRRHOSIS, TRICHROME STAIN Fibrous tissue (stained blue by trichrome stain) separates regenerative nodules PORTAL HYPERTENSION IN CIRRHOSIS Initiated by increased hepatic resistance to portal blood flow, HVPG rises (structural > functional) Augmented by splanchnic vasodilatation (via. NO), increasing portal blood flow Splanchnic vasodilatation lowers TPR and BP Compensatory increase in cardiac output = hyperdynamic circulation of cirrhosis Splanchnic vasodilatation triggers compensatory mechanisms  PORTAL HYPERTENSION IN CIRRHOSIS SIMPLIFIED 1. There is an increase in blood supply to the intestines due to splanchnic vasodilation. This means if there is more blood getting to the intestines, then more blood must leave the intestines. Therefore there is more blood in the portal system flowing faster. This increases the pressure. 2. All of the extra blood is going into the liver. Under normal circumstances the liver has a low resistance and blood can pass through the liver to the right side of the heart. In cirrhosis the liver is blocked. Thus there is block to the flow of blood, this increases the pressure in the portal venous system further. PORTAL HYPERTENSION, ASCITES & HRS Compensation for widespread vasodilatation Activation renin-angiotensin-aldosterone system Stimulation of ADH secretion Sodium and water retention Reflex renal vasoconstriction (reducing perfusion and GFR – risk for hepatorenal syndrome [HRS]) PORTAL HYPERTENSION, ASCITES & HRS (CONTINUED) Ascites Sodium and water retention in a/w portal hypertension Preferential accumulation of fluid in peritoneal cavity Leakage from peritoneal vessels Higher mean hydrostatic pressure due to portal hypertension Lower oncotic pressure to keep fluid in, due to low albumin PORTAL HYPERTENSION & SHUNTS Attempt to decompress portal hypertension leads to development of collaterals: ▪ Intrahepatic porto-systemic shunts/collaterals ▪ Extrahepatic porto-systemic anastomoses dilate ▪ Therapeutic insertion of shunt (TIPS = transjugular intrahepatic porto-systemic shunt) “Shunted” blood by-passes liver ▪ Further reduces liver function (increases risk HE) ▪ Exacerbated by ‘capillarisation’ of sinusoids ▪ Reduces perfusion of liver (worsening damage) COMPENSATED VERSUS DECOMPENSATED CIRRHOSIS Compensated (“silent”) May or may not have biochemical/radiological abnormality May or may not have signs of chronic liver disease/portal hypertension May or may not have varices on OGD (gastroscopy) Potentially unstable state Further injury may trigger decompensation: Infection, bleeding, hypotension, alcohol, medications, dehydration, trauma, surgery COMPENSATED VERSUS DECOMPENSATED CIRRHOSIS (CONTINUED) Decompensated (i.e. key complications) Ascites (may become refractory to treatment) Hepatic encephalopathy Variceal haemorrhage Hepatorenal syndrome (HRS) Jaundice Infection (esp. spontaneous bacterial peritonitis) Hepatocellular carcinoma COMPENSATED VERSUS DECOMPENSATED CIRRHOSIS (CONTINUED) Key effect on prognosis (rate of progression) 1 year mortality compensated 1% 1 year mortality compensated with varices 4% 1 year mortality decompensated, ascites 20% 1 year mortality decompensated, other features >50%  NATURAL HISTORY OF CHRONIC LIVER DISEASE – SUMMARY DECOMPENSATION AFFECTS PROGNOSIS Development of cirrhosis Chronic liver Compensated Decompensated cirrhosis Death disease cirrhosis Median Median survival survival ~ 9 years Development ~ 1.6 of years complications Orthotopic liver Variceal hemorrhage transplant Ascites (OLT) Encephalopathy Jaundice  SURVIVAL TIMES IN CIRRHOSIS DECOMPENSATION AFFECTS PROGNOSIS 100 80 Median survival ~ 9 years 60 All patients with Probability cirrhosis of survival 40 20 Decompensated Median cirrhosis survival ~ 1.6 years 0 0 20 40 60 80 100 120 140 160 180 Months Gines et. al., Hepatology 1987;7:122 CHANGING CONCEPTS OF CIRRHOSIS - NEW Originally thought progression inevitable but now progression may be modified Treatment can induce regression of structural changes ▪ Fibrosis is a dynamic (not an entirely fixed) process ▪ Key importance of aetiology ▪ Active management ▪ Early diagnosis, limit progression, avoid complications ▪ “Advanced stage of chronic liver disease” ▪ To include advanced fibrosis and replace “cirrhosis”? ▪ Only becomes inevitable “end stage” when HVPG reaches critical threshold (= decompensation) PRESENTATION OF LIVER DISEASE Silent or mild non-specific symptoms or at-risk history ▪ Identified by liver blood tests ▪ Identified by imaging Symptoms/signs possible liver disease (e.g. jaundice) ▪ Acute liver disease (short of acute liver failure) ▪ Acute flare or exacerbation of a chronic disease ▪ End stage of chronic disease (cirrhosis) Acute liver failure Decompensation of cirrhosis ▪ i.e. major complications of cirrhosis QUESTION: WHAT DOES THIS LIVER SHOW?  END OF LECTURE ANY QUESTIONS?