Liver Failure

Question 1

What causes jaundice?

Answer 1

High bilirubin concentration
Normal plasma {BR} is 17 micromol/L
If {BR} is > 30 micromol/L then you get yellow sclera and mucous membranes
If [BR] > 34 micro mol/L then skin turns yellow

Question 2

What is the term given to slow/ cessation of bile flow?

Answer 2

Cholestasis

It normally results in jaundice but doesn’t mean a patient with jaundice has cholestasis

Question 3

What are pre- hepatic causes of jaundice?

Answer 3

Haemolysis (haemolytic anaemia, toxins)

Massive transfusion (transfused erythrocytes are short-lived)

Large haematoma resorption

Ineffective erythropoiesis

Question 4

What are intrahepatic causes of jaundice?

Answer 4

Specific defects:

• Reduced BR uptake- Gilberts syndrome
• Reduced conjugated BR- Crigler Najar syndrome
• Reduced excretion of BR into biliary canaliculi- Dubin-Johnson syndrome and Rotor syndrome

Intrahepatic cholestasis- reduced bile flow (sepsis, TPN and drugs)

Liver failure (Acute and chronic)

Question 5

What’s the pathophysiology of liver failure?

Answer 5

Occurs when hepatocyte destruction > regeneration
Can be a cause of apoptosis (e.g. due to paracetamol) and/or necrosis (e.g. ischaemia)

The clinic result is catastrophic illness and can rapidly lead to coma/ death due to multi-organ failure

Question 6

What is acute liver failure?

Answer 6

Fulminant hepatic faliure:

• Has rapid development (<8 weeks) of severe liver injury
• Impaired synthetic function (INR/PT, albumin)
• Encephalopathy
• Previous normal liver or well compensated liver disease

Sub-fulminant = <6 months

Question 7

What is chronic liver failure?

Answer 7

Occurs over years

Cirrhosis

Question 8

What are common causes of acute liver failure?

Answer 8

Toxins (west)

• Paracetamol
• Amanita phalloides
• Bacillus cereus

Inflammation (East)

• Exacerbations of chronic Hep B (Hong Kong)
• Hepatitis E (india)

Question 9

What are other causes of acute liver failure?

Answer 9

Disease of pregnancy: AFLP, HELLP, hepatic infarction, HEV, Budd-Chiari

Idiosyncratic drug reactions:

• single agent- Isoniazid, NSAIDs, valproate
• drug combinations- Amoxicillin/ clavulanic acid, trimethoprim/ sulphamethoxazole, rifampicin/isoniazid

Vascular diseases: ischaemic hepatitis, post-OLTx hepatic artery thrombosis, post-arrest, VOD

Metabolic causes: Wilson’s disease, Reye’s disease

Question 10

What are causes of chronic liver failure and cirrhosis?

Answer 10

Inflammation - e.g. by chronic persistent viral hepatitis
Alcohol abuse
Side effects of drugs- e.g. folic acid antagonist phenylbutazone
Cardiovascular causes e.g. reduced venous return- right heart faliure
Inherited diseases
Glycogen storage diseases, Wilson’s disease, Galactosaemia, Haemochromatosis, alpha1-antitrypsin deficiency
Non-alcoholic steatohepatitis
Autoimmune Hepatitis, PCB, PSC

Question 11

What is the pathophysiology of cirrhosis?

Answer 11

Activation of kupffer cells and activation of granulocytes and lymphocytes leads to release of growth factors and cytokines
These lead to an increase in ECM and then fibrosis

Question 12

What are consequences of liver failure vs normal liver function?

Answer 12

Coagulopathy and bleeding vs production of clotting factors
Ascitis vs protein synthesis
Encephalopathy and cerebral oedema vs detoxification
Hypoglycaemia vs glycogen storage
Increased susceptibility to infection vs immunological function and globulin production
Circulatory collapse, renal failure vs maintenance of homeostasis

Question 13

What causes ascites and what are consequences of ascites?

Answer 13

Decreases albumin synthesis leads to ascities
This leads to decreased plasma volume which leads to:
- 2nd degree hyperaldosteronism
- hypokalaemia
-alkalosis

Question 14

What clotting factors are affected in liver failure?

Answer 14

Hepatocytes synthesis all clotting factors apart from VWF and factor VIII

Question 15

What does cholestasis lead to?

Answer 15

Leads to liver damage which aggravates any bleeding tendency
It leads to:
reduced bile salts
reduced micelles and absorption of vitamin K
reduced gamma- carboxylation of vitamin K dependent clotting factors (prothrombin, 2, 7, 9, 10)

Question 16

Through what mechanisms does cholestasis occur?

Answer 16

Canalicular dilation
Decreased cell membrane fluidity
Deformed brush border biliary transporters
Increased tight junction permeability
Decreased mitochondrial ATP synthesis

Question 17

What are consequences of cholestasis?

Answer 17

Increased BR
Pruritus (itching)
Cholesterol deposition
Malabsorption
Cholangitis

Question 18

What does portal hypertension lead to?

Answer 18

Decreased lymphatic flow makes ascites worst
Thrombocytopenia resulting from splenomegaly
Oesophageal varices
Decrease in active clotting factors, thrombocytopenia and varices- leads to severe bleeding
Exudative enteropathy (loss of proteins):
- increased ascites- loss of albumin from plasma
- favours bacteria in large bowel veins ‘fed’ with proteins
- increased liberation of ammonium (toxic to brain)

Question 19

What are causes of portal hypertension?

Answer 19

Increased vascular resistance
Prehepatic- portal vein thrombosis
Posthepatic- right heart failure, constrictive pericarditis
Intrahepatic:
- Presinusoidal- chronic hepatitis, PBC, granulomas (schistosomiasis, TB, etc)
- Sinusoidal- acute hepatitis, alcohol, fatty liver, toxins, amyloidosis
-Postsinusoidal- venous occlusive disease (VOD) of venules and small veins, Budd-Chiari syndrome (obstruction of large hepatic veins)

Question 20

What are consequences of portal hypertension?

Answer 20

Malabsorption
Splenomegaly (anaemia and thrombocytopenia)
Vasodilators (glucagon, VIP, substance P, prostacyclin, NO)
Increased BP leads to increased CO which leads to hyperperfusion of abdominal organs and varices
Encephalopathy: toxins from intestines are normally extracted from portal blood by hepatocytes . Instead they enter the CNS
Varices- thin walled collateral vessels along with thrombocytopenia and reduced clotting factors leads to increased bleeding

Question 21

What are consequences of encephalopathy?

Answer 21

Apathy, memory gaps, tremor and liver coma

Question 22

What are causes of encephalopathy?

Answer 22

Hyperammonaemia increases:
- GI bleeding increases colonic proteins. Liver can’t convert ammonia to urea

Hypokalaemia:
- leads to intracellular acidosis which activates ammonium formation in proximal tubules and leads to systemic alkalosis

Toxins: they bypass liver and are not extracted

“False transmitters” (e.g. serotonin) from aromatic amino acids in the brain are all increased in liver failure

Question 23

How is the severity of liver failure measured?

Answer 23

Child- Pugh score
Class A: 5-6 points- Life expectancy of 15-20 years, 10% peri-operative mortality
Class B: 7-9 points- Transplant candidates. May have 30% P-O M
Class C: 10-15 points- Life expectancy 1-3 months, 82% P-O M

Question 24

What is treatment for liver failure?

Answer 24

Supportative

Encephalopathy- reduce protein intake (decrease ammonia produced), phosphate enemas/lactulose, no sedation
Hypoglycaemia- infusion 10-50% dextrose
Hypocalcaemia- 10ml 10% calcium gluconate
Renal failure- haemofiltration
Respiratory failure- ventilation
Hypotension- albumin, vasoconstrictor
Infection- frequent cultures, antibiotics
Bleeding- vit K, FFP, platelets

Question 25

What are causes of death in liver failure?

Answer 25

Bacterial and fungal infection most common
Circulatory instability
Cerebral oedema
Renal failure
Respiratory failure
Acid-base and electrolyte disturbances
Coagulopathy

Question 26

What are liver support devices trailed for treatment?

Answer 26

Artificial (MARS, Bio-Logic DT)- albumin exchange system. Based on removal of albumin-bound toxins from blood
Bioartifical (Hepatocytes in culture)
Hepatocyte transplantation

Question 27

What is the most common liver failure cause for transplantation?

Answer 27

Cirrhosis