11.10 - Liver Failure Flashcards
What is normal plasma bilirubin?
17 umol/L
What happens if bilirubin increases above 30 umol/L?
Yellow sclera (eyes) and mucous membranes
What happens if bilirubin increases above 34 umol/L?
Skin turns yellow
What is cholestasis?
- slow/cessation of bile flow
- normally results in jaundice
- but jaundice does not necessarily mean there is cholestasis
What are the three types of jaundice?
- pre-hepatic
- hepatic
- post-hepatic
What causes pre-hepatic jaundice?
- problems with bilirubin before liver
- too much BR made in spleen than downstream structures can cope with, can be due to:
- haemolysis (haemolytic anaemia, toxins)
- massive transfusion (transfused erythrocytes short-lived)
- large haematoma resorption (cells quickly die and BR released)
- ineffective erythropoiesis
- blood tests mainly show unconjugated BR (as conjugation occurs in liver)
What causes intrahepatic jaundice?
- normal BR levels arrive at liver but hepatocytes killed/damaged –> defective uptake, conjugation and excretion of BR
- can be due to liver failure - acute due to paracetamol overdose, chronic due to viral hepatitis, alcohol injury, autoimmunity etc
- can be due to intrahepatic cholestasis (sepsis, TPN, drugs) –> reduced outflow
- blood test shows mainly unconjugated BR but liver enzymes are abnormal (damaged hepatocytes)
What specific defects cause intrahepatic jaundice?
- decreased BR uptake - Gilberts syndrome (autosomal recessive condition causes elevated unconjugated BR and episodes of mild jaundice when overexerting/fasting)
- decreased BR conjugation - Crigler-Najar syndrome (autosomal recessive, decreases conjugation - high levels unconjugated BR in blood –> brain damage especially in infants)
- decreased BR secretion into biliary canaliculi - Dubin-Johnson syndrome (autosomal recessive, increase in conjugated BR as it has been processed), Rotor syndrome (autosomal recessive, causes increase in conjugated BR)
What causes post-hepatic/obstructive jaundice?
- physical obstruction reducing bile and thus BR flow into duodenum and colon
- less BR can be excreted and it builds up
- can be due to gallstones/CBD stones, tumour (hepatic, pancreatic, biliary)
- blood tests show mainly conjugated BR
- less BR in colon –> less stercobilinogen + stercobilin –> white pale faeces
- some BR excreted from kidneys –> dark urine
- pruritus (itching) can occur
In basic terms, when does liver failure happen?
- when rate of hepatocyte death > regeneration
- normally due to combination of apoptosis (e.g. paracetamol) and/or necrosis (e.g. ischaemia)
- can rapidly lead to coma/death due to multi-organ failure
What is fulminant hepatic failure? (Acute liver failure)
- rapid development (<8 weeks) of severe acute liver injury
- impaired synthetic function –> e.g. increased PT time (as liver produces clotting factors)
- encephalopathy
- previously normal liver or well-compensated liver disease (liver is scarred but still able to function)
What is sub-fulminant hepatic failure? (Acute liver failure)
Acute liver disease that develops in <6 months
What are common causes of acute liver failure in the West?
Toxins:
- paracetamol
- Amanita phalloides (death cap mushroom)
- Bacillus cereus
What are common causes of acute liver failure in the East?
Inflammation:
- exacerbations of chronic Hep B (Hong Kong)
- hepatitis E (India)
What diseases of pregnancy can cause acute liver failure?
- AFLP - acute fatty liver of pregnancy
- HELLP syndrome - haemolysis, elevated liver enzymes, low platelets
- hepatic infarction
- hepatitis E
- Budd-Chiari syndrome
What idiosyncratic drug reactions can cause acute liver failure?
- single agent - isoniazid, NSAIDs, valproate
- drug combinations - amoxicillin/clavulanic acid, trimethoprim/sulphamethoxazole, rifampicin/isoniazid
What vascular diseases can cause acute liver failure?
- ischaemic hepatitis
- post-liver transplant hepatic artery thrombosis
- post-arrest
- VOD
What metabolic causes can cause acute liver failure?
- Wilson’s disease
- Reye’s syndrome
Over what period of time does chronic liver failure develop and what usually causes it?
- over many years
- cirrhosis is a major cause
What are the causes of cirrhosis?
- inflammation - chronic/persistent viral hepatitis
- alcohol abuse
- side effects of drugs - folic acid antagonists and phenylbutazone
- cardiovascular causes - reduced venous return –> right heart failure –> back pressure on liver = cirrhosis
- inherited diseases - e.g. glycogen storage diseases, Wilson’s disease, galactosaemia, haemochromatosis, a1-antitrypsin deficiency
- non-alcoholic steatohepatitis (NASH)
- autoimmune hepatitis - e.g. primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC)
Describe the process of developing cirrhosis.
- noxious factors (alcohol, virus) cause necrosis of hepatocytes
- causes lysosomal enzyme leak
- causes cytokine release
- activates Kupffer cells in sinusoids + granulocytes and lymphocytes
- releases more growth factors and cytokines
- Ito cells (hepatic stellate cells in space of Disse) are activated into myofibroblasts; cytokines also convert monocytes to macrophages = fibroblast proliferation along with cytokines
- causes ECM collagen, proteoglycans etc to increase –> fibrosis –> cirrhosis
- positive feedback loop - more fibrosis –> more inflammation –> more fibrosis
What are the consequences of liver failure for production of clotting factors?
- less clotting factors since hepatocytes produce all coagulation proteins except VWF and factor VIIIC
- leads to coagulopathy and bleeding
What are the consequences of liver failure for protein synthesis?
- decreased albumin = cannot retain fluid in vasculature –> ascites
- decrease in plasma volume –> secondary hyperaldosteronism, hypokalaemia (lower K+) and alkalosis
What are the consequences of liver failure for detoxification?
Encephalopathy and cerebral oedema
What are the consequences of liver failure for glycogen storage?
Hypoglycaemia
What are the consequences of liver failure for immunological function and globulin production?
Increased susceptibility to infection
What are the consequences of liver failure for maintenance of homeostasis?
Circulatory collapse, renal failure
What does cholestasis do?
- leads to liver damage
- decrease in bile salts
- this means less micelle formation and absorption of vitamin K
- this means less gamma-carboxylation of vitamin-K dependent clotting factors (II, VII, IX, X)
- aggravates any bleeding tendency, particularly GI bleeding
What are the mechanisms of cholestasis?
- canalicular dilation + bile cannot get out
- decreased cell membrane fluidity
- deformed brush borders
- biliary transporters problem e.g. carriers inserted on wrong side
- increased tight junction permeability - due to increased bile in duct
- decreased mitochondrial ATP synthesis
What are the consequences of cholestasis?
- increased BR –> jaundice
- pruritus (itching)
- cholesterol deposition (particularly around eyes)
- malabsorption
- cholangitis
What does portal hypertension cause?
- decreased lymphatic flow –> worsens ascites
- thrombocytopenia from splenomegaly - blood trying to leave spleen via splenic vein into portal vein but cannot so platelets sequester and are used up (reduced active clotting factors)
- oesophageal varices occur
- these cause severe bleeding
- exudative enteropathy
What is exudative enteropathy?
- blood trying to leave large bowel but cannot so you get increased ascites –> loss of albumin from plasma
- this favours bacteria in large bowel being fed with proteins
- causes liberation of ammonium (toxic to brain) –> encephalopathy
What are the three types of causes of portal hypertension?
- overall caused by increased vascular resistance
- pre-hepatic
- post-hepatic
- intra-hepatic
What are pre-hepatic causes of portal hypertension?
- thrombus (blockage) outside liver
- portal vein thrombosis
What are post-hepatic causes of portal hypertension?
- right heart failure
- constrictive pericarditis - blood cannot leave so back pressure through liver occurs
What are intrahepatic causes of portal hypertension?
- perisinusoidal - chronic hepatitis, PBC, granulomas (schistosomiasis, TB etc)
- sinusoidal - acute hepatitis, alcohol, fatty liver, toxins, amyloidosis
- postsinusoidal - venous occlusive disease of venules and small veins, Budd-Chiari syndrome (obstruction of large hepatic veins - right, middle and left)
What are the consequences of portal hypertension?
- malabsorption
- splenomegaly - anaemia and thrombocytopenia
- vasodilators (glucagon, VIP, substance P, prostacyclin, NO etc release) - decrease BP = increased cardiac output to compensate –> hyperperfusion of abdominal organs –> varices
- encephalopathy - toxins from intestine (NH3, biogenic amines, FFAs etc) normally extracted from portal blood by hepatocytes –> cross BBB –> CNS problems
- varices
What are varices?
- since big arteries and veins blocked (e.g. SMV and portal vein), blood takes routes down other vessels that are not meant to take high volumes of blood
- this dilates them –> thin-walled collateral vessels prone to sudden rupture
- this combined with thrombocytopenia and decreased clotting factors –> bad bleeding
What does encephalopathy cause?
Apathy, memory gaps, tremor, liver coma
What physiological changes cause encephalopathy?
- hyperammonaemia - GI bleeding increases colonic proteins and liver cannot convert toxic NH3 and NH4+ into urea
- hypokalaemia - secondary hyperaldosteronism causes it –> intracellular acidosis –> activates NH4+ formation in proximal tubules –> systemic alkalosis
- toxins (amines, phenols and FFAs) bypass liver and not extracted - contribute to encephalopathy
- ‘false transmitters’ (e.g. serotonin) from aromatic amino acids in brain are increased in liver failure –> encephalopathy
Where are the locations of varices (portal-systemic anastomoses)?
- oesophageal varices - anastomoses open up between oesophageal tributaries of gastric vein and azygos veins
- between middle and inferior rectal veins and superior rectal veins - can get torrential bleeds from rectal mucosa
- between paraumbilical veins and superficial veins of anterior abdominal wall
How is severity of liver failure assessed?
- Child-Pugh score - also a prognosticator for peri-op death
- more points on worsening total BR, serum albumin, INR, ascites and hepatic encephalopathy
- score divided up into three classes:
- class A: 5-6 points - expectancy of 15-20 years, 10% peri-op mortality
- class B: 7-9 points - transplant candidates, may have 30% post-op mortality
- class C: 10-15 points - life expectancy 1-3 months, 82% post-op mortality
What is the supportive treatment for encephalopathy?
- reduce protein intake
- phosphate enema/lactulose - try to empty bowels
- no sedation
What is the supportive treatment for hypoglycaemia?
Infusion 10-50% dextrose
What is the supportive treatment for hypocalcaemia?
10ml 10% calcium gluconate
What is the supportive treatment for renal failure?
Haemofiltration
What is the supportive treatment for respiratory failure?
Ventilation
What is the supportive treatment for hypotension?
- albumin
- vasoconstrictors
What is the supportive treatment for infection?
- frequent cultures
- antibiotics
What is the supportive treatment for bleeding?
- vitamin K
- FFP
- platelets
What are the causes of death with liver failure?
- bacteria and fungal infections
- circulatory instability
- cerebral oedema
- renal failure
- respiratory failure
- acid-base and electrolyte disturbance
- coagulopathy
What are liver support devices?
- artificial (MARS, Bio-Logic DT) - albumin exchange system, based on selective removal of albumin-bound toxins from blood
- bioartificial hepatocytes in culture - to remove toxins, not very effective
- hepatocyte transplantation - none really effective
What are the indications for liver transplantation?
- effective for hepatocellular cancer since it comes from cirrhotic liver (and originates in liver and does not metastasise)
- cirrhosis
- cholestatic disease
- acute liver failure
- metabolic disease
- others - Budd-Chiari, benign liver tumours, polycystic liver disease
