liver failure

Question 1

• What bilirubin concentration [BR] will lead to yellow sclera and a persons skin turning yellow respectively?

Answer 1

Yellow sclera and mucous membrane: >30 micromol/L

Skin turns yellow: >34 micromol/L

Question 2

• Define cholestasis

Answer 2

Slow/cessation of bile flow, which normally results in jaundice

(Jaundice doesn't necessarily mean there is cholestasis)

Question 3

• List and explain the causes of pre-hepatic jaundice

Answer 3

Haemolysis- from haemolytic anaemia, toxins and massive blood transfusion-
Transfused short-lived erythrocytes

Haematoma - Collection of erythrocytes deep to skin → Degradation and haemolysis of erythrocytes increases levels of unconjugated bilirubin for resorption

ineffective erythropoiesis- more RBC to break down

Question 4

• List and explain the intrahepatic causes of jaundice

Answer 4

Reduced uptake of BR into hepatocytes → increased serum unconjugated BR levels within sinusoidal space and systemic circulation eg Gilbert Syndrome

Decreased conjugation of BR → Enters into systemic circulation and passes through BBB eg Crigler-Najjar Syndrome

Reduced BR secretion into biliary canaliculi → Black liver eg Dubin-Johnson and Rotor Syndrome

Intrahepatic cholestasis- Sepsis TPN (total parenteral nutrition) feeding, drugs

Question 5

• What are the post-hepatic causes of jaundice?

Answer 5

Gallstones and tumours

Question 6

• Define acute LF

Answer 6

Fulminant epatic failure leading to rapid development (<8 weeks) of severe acute liver injury:

- Impaired synthetic function (clotting factors, albumin)
- Encephalopathy
- Previously normal liver or well-compensated liver disease

Sub-fulminant: <6 months

Question 7

• Define chronic LF

Answer 7

Failure persisting over years , concerned with liver cirrhosis

Question 8

• Outline the pathophysiology of liver failure (LF)

Answer 8

Rate of hepatocyte death > regeneration

Hepatocyte death is attributed with a combination of apoptosis (acetaminophen=paracetamol) and necrosis (ischaemia)

Within a hepatic acinus, Zone 3 (central vein region) is sensitive to necrosis and ischaemia due to its relative distance to oxygenated blood supply

Clinically, LF is concerned with coma/death due to multi-organ failure. (catastrophic)

Question 9

• What are the commonest causes of acute LF?

Answer 9

Toxins (West) - paracetamol, amanita phalloides, bacillus cereus

Inflammation (East) - exacerbations of chronic Hep-B (Hong Kong) and Hep-E (India)

Question 10

• What are the other causes of acute LF and give examples of each?

Answer 10

Diseases of pregnancy
- Acute fatty liver of pregnancy (AFLP), HELLP syndrome, hepatic infarction, Hepatitis-E Virus (HEV), Budd-Chiari

Idiosyncratic drug reactions

- Single agent - isoniazid, NSAIDs, valproate
- Combinations of drugs 

Vascular diseases
- Ischaemic hepatitis, post Orthotopic Liver Transplantation hepatic artery thrombosis, post-arrest, veno-occlusive disease (VOD)

Metabolic diseases - Wilson’s disease , Reye’s disease

Question 11

• What are the causes of chronic LF?

Answer 11

Inflammation - chronic persistent viral hepatitis.
Alcohol abuse
Side effects of drug (folic acid antagonists e.g. phenylbutazone)
CV causes - decreased venous return (right HF)
Inherited diseases - glycogen storage disease, Wilson’s disease, galactosaemia, haemochromatosis, A1AT deficiency
Non-alcoholic steatohepatitis (NASH)
Autoimmune hepatitis, primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC)

Question 12

• Outline the pathophysiology of cirrhosis

Answer 12

1) Necrosis concerned with ischaemia results in hepatocyte degradation
2) Releasing intracellular enzymes, in addition to cytokine release.
3) Intracellular contents stimulate chemotaxis of inflammatory cells. (neutrophils and monocyte differentiation into macrophages)
4) Cytokines activate Kupffer cells → Growth factor and cytokine release → Activation of hepatic stellate cells
5) Hepatic stellate cells and macrophages undergo fibroblast proliferation, depositing ECM
6) Increased collagen, proteoglycans and matrix glycoprotein deposition → Fibrosis of hepatic tissue

Question 13

• What are the main hepatocyte functions?

Answer 13

Metabolic and catabolic - synthesis/ use of carbohydrates, lipids and proteins

Secretory and excretory - excretion of bile and waste products 

Detoxification and immunological- process drugs, breakdown of pathogens

Question 14

• List the causes of death as a consequence of LF

Answer 14

Bacterial and fungal infections - due to loss of immunological ability

Circulatory instability - lack of homeostasis

Cerebral oedema - encephalopathy

Renal failure 

Respiratory failure 

Acid-base and electrolyte disturbance 

Coagulopathy- as loss of clotting factors

Question 15

• Which vitamin is lacking due liver failure and what does this lead to?
• Why is it lacking?

Answer 15

Vitamin K essential cofactor for the carboxylation for glutamic acid residues for the synthesis of factors II, VII, IX, X → coagulopathy & bleeding

lack of bile salts, decreased micelles and absorption of vitamin K

Question 16

• Why does ascites occur in liver failure?

Answer 16

Reduction in serum albumin
reduces the oncotic pressure within the capillaries
therefore this will reduce the water retention ability for interstitial fluid to be drawn into the capillaries
so water deposited to abdominal spaces

Question 17

• What does the decreased plasma volume lead to as a result of liver failure?

Answer 17

Secondary hyperaldosteronism → Hypokalaemia and alkalosis

Question 18

name the consequence to liver failure that corresponds with the liver function

• production of clotting factors
• protein synthesis
• detoxification
• glycogen storage
• production of globulins/ immunological function
• maintenance of homeostasis

Answer 18

coagulopathy and bleeding
ascites
encephalopathy and cerebral odema
hypoglycaemia
increased susceptibility to infection
circulatory collapse and renal failure

Question 19

• Explain the some pathogenesis of cholestasis

Answer 19

Biliary transporters are incorrectly positioned, insertion of carriers will reduce bile salt secretion into the biliary canaliculi, transporters may be present on the basolateral membrane

Bile salts increase tight junction permeabilty → increasing amount of bile passing through sinusoidal space → reducing bile flow in canaliculi

Canalicular dilation - reduction in bile flow pressure and fluid mechanics

Decreased cell membrane fluidity

Decreased mitochondrial ATP synthesis - reduces ability for active transport of bile salts and xenobiotics into hepatocyte

Deformed brush border

Question 20

• Why might pruritis be a consequence of cholestasis?

- What is the general cause of portal hypertension?

Answer 20

Bile salts secreted into circulation are deposited as crystals deep to the skin resulting in irritation

Fibrotic portal veins coupled with obstruction to venous supply to the liver leads to hypertension

Question 21

• Explain how thrombocytopenia, oesophageal varices and exudative enteropathy are all consequences of portal hypertension?

Answer 21

Thrombocytopenia - when too many platelets are destroyed or accumulate within an enlarged spleen

Oesophageal varices-   Blood flow through the liver slows, the pressure in the portal vein goes up, pushes blood into vessels of oesophagus 

Exudative enteropathy - Increased ascites → Loss of albumin from plasma into intersititial fluid and GIT → Favours colonic bacteria → NH4+ compound liberation → Encephalopathy

Question 22

• Why might splenomegaly result from portal hypertension?

Answer 22

blood backs up into the spleen- cant get out, causes an enlarged spleen, leading to breakdown of red blood cells (anaemia) white blood cells (leukopenia) and platelets (thromocytopenia)

Question 23

• What is a pre-hepatic cause of portal hypertension?

- What are the post-hepatic causes of portal hypertension?

Answer 23

Portal vein thrombosis

Right heart failure - causes backwards pressure within venous system due to insufficient contractility of right atria

Constrictive pericarditis - inflammation and reduced elasticity of the pericardium

Question 24

• What are the intrahepatic causes of portal hypertension?

Answer 24

Presinusoidal - chronic hepatitis, primary biliary cholangitis, granulomas

Sinusoidal - acute hepatitis, alcohol, fatty liver, toxins, amyloidosis

Post-sinusoidal - venous occlusive disease of venules and small veins: Budd-chiari

Question 25

- How does hepatic encephalopathy present? | - How can hyperammonaemia lead to hepatic encephalopathy?

Answer 25

Apathy, memory gaps, tremor and liver coma exudative enteropathy when less albumin in plasma, colonic bacteria is fed proteins liberation of ammonia (hyperammonaemia) toxic to brain

Question 26

- What 3 ways can toxins lead to encephalopathy?

Answer 26

toxins bypass liver → not extracted or detoxified → passes blood brain barrier → encephalopathy False transmitters from aromatic amino acids in brain → encephalopathy exudative enteropathy

Question 27

- What is hepato-renal syndrome?

Answer 27

portal hypertension leads to arterial vasodilation through decreased vascular resistance → activating vasoconstrictor factors (RAAS, SNS, vasopressin ) → renal vasoconstriction decreased glomerular filtration rate

Question 28

- What does the Child-Pugh score assess? | - what are the five areas assessed?

Answer 28

Disease severity for end-stage liver disease, and a prognosticator for peri-op death bilirubin, serum albumin, INR/PT, ascites, hepatic encephalopathy

Question 29

- How do you treat encephalopathy?

Answer 29

Reduce protein intake Phosphate enemas/lactose No sedation

Question 30

- How do you treat hypoglycaemia, hypocalcaemia and renal failure?

Answer 30

Hypoglycaemia - Infusion 10-50% dextrose Hypocalcaemia - 10ml 10% calcium gluconate Renal failure - Hemofiltration

Question 31

- How do you treat respiratory failure, hypotension and infection?

Answer 31

Respiratory failure - Ventilation Hypotension - Albumin and Vasoconstrictors Infection - Frequent cultures and antibiotics

Question 32

- How do you treat bleeding?

Answer 32

Vitamin K Fresh Frozen Plasma Platelets

Question 33

how does portal hypertension cause malnutrition how does portal hypertension cause vasodilators to be released

Answer 33

nutrient filled blood cant get into liver, nutrients cant be processed vasodilators (eg glucagon, VIP , substance P, prostacyclin and NO) released to decrease blood pressure, increased cardiac output, causes hyperperfusion of abdominal organs and varices