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BRS > Liver Failure > Flashcards

Liver Failure Flashcards

1
Q

What is jaundice characterised by?

A

Elevated unconjugated serum BR levels →Yellowish pigmentation

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2
Q

What is the normal plasma [BR]?

A

17 micromol/L

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3
Q

If [BR] is elevated > 30 micromol/L what happens?

A

Yellow sclera and mucous membranes

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4
Q

If [BR] is elevated > 34 micromol/L what happens?

A

Skin turns yellow

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5
Q

Define cholestasis.

A

Slow/cessation of bile flow due to impaired secretion by hepatocytes or a result of obstructive flow through common hepatic/bile ducts or MPDs.

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6
Q

What does cholestasis normally result in and how?

A

Jaundice

^ bile and BR retention within hepatocytes (Conjugated BR and bile are unable to enter the duodenum)

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7
Q

If a patient has jaundice does it mean they will have cholestasis?

A

No

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8
Q

List the pre-hepatic causes of jaundice.

A

Haemolysis - haemolytic anaemia + toxins
Ineffective erythropoiesis
Massive transfusion (transfused erythrocytes short lived) - Large haematoma resorption

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9
Q

What diseases can lead to haemolysis (haemolytic anaemia)?

A

SCA and healthy spherocytes undergo haemolysis within the spleen, whereby the haem oxidative cleavage proceeds producing unconjugated BR → Serum concentration increases.

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10
Q

What is a haematoma and how can it cause jaundice?

A

Collection of erythrocytes deep to skin. Degradation and haemolysis of erythrocytes within a large haematoma will resultantly produce aberrant levels of unconjugated BR levels for resorption.

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11
Q

List the intrahepatic causes of jaundice.

A 
Gilbert Syndrome = decreased uptake of BR 
Crigler-Najjar Syndrome = decreased conjugation of BR 
Dubin-Johnson and Rotor Syndrome = reduced BR secretion into biliary canaliculi → Black liver 
Intrahepatic cholestasis (decreased outflow) = Sepsis, TPN and drugs
LF (acute/chronic)
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12
Q

What does Dubin-Johnson and Rotor Syndrome do to conjugated BR levels in plasma?

A

Increase

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13
Q

What is Gilbert syndrome?

A

Autosomal recessive due to a mutation in UGT1A1 gene → decreased activity of bilirubin diphosphate glucuronosyltransferase enzyme. Reduced uptake of BR into hepatocytes subsequently increase serum unconjugated BR levels within sinusoidal space and systemic circulation.

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14
Q

Explain the pathogenesis of LF.

A

Rate of hepatocyte death > regeneration.
Combination of apoptosis and/or necrosis - necroptosis.

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.

N.B. Clinically, LF is concerned with coma/death due to multi-organ failure.

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15
Q

What are the 2 types of acute LF?

A

Fulminant or sub-fulminant

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16
Q

Define fulminant hepatic failure (type of ALF).

A

Rapid development (<8 weeks) of severe acute liver injury. Impaired synthetic function (INR/PT, albumin) resulting in hypoalbuminemia.

Encephalopathy

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17
Q

What is encephalopathy?

A

Pathological impairment of the brain. Well-compensated liver disease.

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18
Q

Define sub-fulminant hepatic failure (type of ALF).

A

<6 months

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19
Q

Define chronic LF.

A

Failure persisting for a period greater than 6 months, concerned with liver cirrhosis.

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20
Q

What are the common causes of ALF in the west?

A

Paracetamol (deliberate overdose)
Amanita phalloides
Bacillus cereus

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21
Q

What are the common causes of ALF in the east?

A 
Exacerbations of chronic Hep B (Hong Kong) 
Hep E (India)
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22
Q

How does paracetamol overdose lead to ALF?

A

N-acetyl-p-benzoquinone imine (NAPQI) metabolites is conjugated with glutathione, inhibiting cellular enzymes (Glutamine dehydrogenase) and impairing mitochondrial respiration (Inhibits cytochromes and uncouples OP). Superoxide anion formation directly kills hepatocytes via oxidative stress.

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23
Q

How does amanita phalloides lead to ALF?

A

Toxin inhibit RNA polymerase → Reduction of PS → Cell necrosis

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24
Q

How does bacillus sereus lead to ALF?

A

Inhibition of hepatocyte mitochondrial Beta-oxidation

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25
Q

List diseases of pregnancy that can cause ALF.

A

Acute fatty liver of pregnancy (AFLP)

HELLP (Haemolysis Elevated Liver enzyme Low Platelet count)

HEV

Budd-Chiari

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26
Q

Explain how AFLP + HELLP leads to ALF.

A

Haemolysis, elevated liver enzymes and a low platelet count (HELLP) syndrome → DIC. Hepatic infarction of hepatic portal veins and arteries.

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27
Q

Explain how Budd Chiari syndrome leads to ALF.

A

Vascular occlusion of central veins and hepatic veins (left, right and middle hepatic veins are thrombosed).

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28
Q

List the idiosyncratic drug reactions that cause ALF.

A

Single agent: Isoniazid, NSAIDs, valproate.

Drug combinations: Amoxicillin/clavulanic acid, trimethoprim/sulphamethoxazol, rifampin/isoniazid.

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29
Q

What vascular diseases can cause ALF?

A

Ischaemia hepatitis
Post-OLTx hepatic artery thrombosis
Post-arrest
Veno-occlusive disease (VOD).

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30
Q

What metabolic diseases can cause ALF?

A

Wilson’s disease → Elevated Cu2+ deposition.

Reye’s syndrome → Hepatic swelling post viral infection (aspiring prescription), prevalent in infants.

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31
Q

List all the causes of CLF via cirrhosis.

A 
Inflammation - chronic persistent viral hepatitis (A or B) 
Alcohol abuse 
Side effects of drugs 
CV causes 
Inherited diseases 
Inherited causes 
Non alcoholic steatohepatitis (NASH) 
Autoimmune hepatitis - PBC (primary biliary cirrhosis), PSC (primary sclerosing cholangitis)
32
Q

How does alcohol abuse lead to CLF?

A

Enhances gut permeability increasing the absorption of endotoxins into portal hepatic veins (reduces detoxication hepatic capacity) → Kupffer cells within sinusoidal space release free radicals, including oxidative damage.

33
Q

Side effects of which drugs can cause CLF?

A

Folic acid antagonists phenylbutazone.

34
Q

How can CVD cause CLF?

A

Decreased venous return → Right HF (or constrictive pericarditis)

Increased backflow pressure and reduced oxygenated perfusion of hepatocytes.

35
Q

List the inherited diseases that can cause CLF.

A

Glycogen storage diseases Wilson’s disease
Galactosaemia
Haemochromatosis
A1AT deficiency.

36
Q

Explain the pathogenesis of cirrhosis.

A
  1. Necrosis concerned with ischaemia results in hepatocyte degradation, releasing intracellular enzymes, in addition to cytokine release. Intracellular contents stimulate chemotaxis of inflammatory cells. (neutrophils and monocyte differentiation into macrophages).
  2. Cytokines activate Kupffer cells → Growth factor and cytokine release → Activation of hepatic stellate cells.
  3. Hepatic stellate cells and macrophages undergo fibroblast proliferation, depositing extracellular collagen matrix.
  4. Increased collagen, proteoglycans and matrix GP deposition → Fibrosis of hepatic tissue.
37
Q

List the functions of hepatocytes.

A
  1. Metabolic and catabolic functions: Synthesis and utilisation of carbohydrate, lipids and proteins.
  2. Secretory and excretory functions: Synthesis and secretion of proteins, bile and waste products.
  3. Detoxification and immunological functions: Breakdown of ingested pathogens and processing of drugs.
38
Q

List some consequences of LF that can lead to death.

A 
Coagulopathy and bleeding 
Ascites 
Encephalopathy and cerebral oedema 
Hypoglycaemia 
Increased susceptibility to infection 
Circulatory collapse, renal failure
39
Q

List more consequences of LF

A

Dysfunctional production of clotting factors - Vitamin K is an essential co-factor for the carboxylation for glutamic acid residues for the synthesis of factors II, VII, IX X → Coagulopathy (clotting impairment) and bleeding.

Protein synthesis problems - Ascites

Decreased BP - leads to secondary hyperadlosteronism → Hypokalaemia and alkalosis (H+ secretion)

Inability to detoxify - Toxin serum concentrations will increase within systemic circulation passing through the BBB → Encephalopathy and cerebral oedema.

Glycogen storage dysfunction - Hypoglycaemia

Deficit in immunological function and globulin production - Increased susceptibility to infection due to reduced globulin synthesis (Ig)

Maintenance of homeostasis - Circulatory collapse and renal failure

40
Q

What is ascites?

A

Accumulation of fluid in the peritoneal cavity, causing abdominal swelling. Reduction in serum albumin will subsequently reduce oncotic pressure within capillaries, therefore this will reduce water retention ability for interstitial fluid to be drawn onto the capillaries.

(Yellow + distended abdomen)

41
Q

What clotting factors don’t hepatocytes synthesise?

A

VWF and factor VIIIc

42
Q

List the causes of death due to LF

A 
Bacterial and fungal infections 
Circulatory instability 
Cerebral oedema 
Renal failure
Respiratory failure 
Acid-base and electrolyte disturbance 
Coagulopathy
43
Q

Explain cholestasis (more depth)?

A

Cessation of bile flow in CBDs and biliary tree due to obstruction in AoV will reduce bile secretion into duodenum → Decrease in bile salt secretion into duodenum → reduce micelle formation and absorption of Vitamin K → Reduced carboxylation of glutamic acid residues for clotting factors II, VII, IX and X → GI Bleeding

44
Q

Outline the pathogenesis of cholestasis due to LF.

A
  1. Biliary transporters are incorrectly positioned, insertion of carriers will reduce bile salt secretion into the biliary canaliculi.
  2. Bile salts ^ tight junction permeability → this ^ amount of bile salt passing through in the sinusoidal space, reducing bile flow in the canaliculi.
  3. Canalicular dilation → reduction in bile flow pressure and fluid mechanics.
  4. Decreased cell membrane fluidity.
  5. Decreased mitochondrial ATP synthesis → reduces ability for active transportation of bile salts and xenobiotics into hepatocyte.
  6. Deformed brush border
45
Q

List the consequences of cholestasis.

A 
^ BR > jaundice 
Pruritus (itching)
Cholesterol deposition (in eyes for example) 
Malabsorption 
Cholangitis
46
Q

Why does cholestasis lead to pruritus?

A

Bile salts in circulation are deposited as crystals deep to the skin, resulting in irritation.

47
Q

Explain how LF leads to portal hypertension.

A

Fibrotic portal veins coupled with obstruction to venous supply to the liver → hypertension. Increased intrahepatic pressure develops portal hypertension → Influences extra-hepatic vascular beds in splanchnic and systemic circulations causing collateral vessel formation and arterial vasodilation → helps ^ blood flow into the portal vein.

48
Q

How does portal hypertension lead to thrombocytopenia?

A

Reduction in VK absorption and clotting factor synthesis, reduces serum clotting factors → increased susceptibility to bleeding, varices and collaterals.

49
Q

How does portal hypertension lead to oesophageal varices?

A

Develop due to increased hydrostatic pressure exuding fluid into interstitial spaces.

50
Q

What does ‘varices’ mean?

A

Varices are veins that are enlarged or swollen.

When enlarged veins occur on the lining of the oesophagus, they are called oesophageal varices.

51
Q

What is exudative enteropathy (protein losing enteropathy)?

A

Refers to any condition of the GIT (e.g. damage to the gut wall) that results in a net loss of protein from the body.

52
Q

What does exudative enteropathy due to portal hypertension lead to?

A

Increased ascites → Loss of albumin from plasma and GIT → Favours bacteria in large bowel being “fed” with proteins→ NH4 compound liberation → Encephalopathy.

53
Q

Explain how portal hypertension leads to the formation of an extrahepatic circulation.

A

Portal hypertension develops portal-systemic collateral vessel formation → Blood diverted into collateral vessel. Collateral vessels form via opening of pre-existing vessels or angiogenesis. Changes in portal pressure detected → Angiogenic factors released to promote collateral formation to ^ blood supply to liver.

Collaterals can’t accommodate significant blood flow nor pressure, therefore result in spontaneous rupture → internal haemorrhaging due to thrombocytopenia.

Increased blood flow to spleen (portal vein backflow) → Splenomegaly

54
Q

What are the causes of portal hypertension?

A

Increased vascular resistance:
Pre-hepatic:
Portal vein thrombosis

Post-hepatic causes:
RHF - backward pressure in venous system due to insufficient contractility of the right atria.
Constrictive pericarditis - Inflammation + reduced elasticity of the pericardium.

Intra-hepatic causes:
Pre-sinusoidal - Chronic hepatitis, primary biliary cholangitis (PBC) granulomas (schistosomia, TB)
Sinusoidal - Acute hepatitis, alcohol, fatty liver, toxins, amyloidosis
Post-sinusoidal - Venous occlusive disease of venules and small veins → Budd-Chiari (Vascular occlusion of central hepatic veins).

55
Q

List the consequences of portal hypertension as a result of increased portal vein pressure.

A

Malabsorption

Splenomegaly (anaemia + thrombocytopenia)

Vasodilator secretion (NO, glucagon, VIP, substance P, prostacyclins)

Encephalopathy - toxins from intestine (NH3, biogenic amines, FFAs) normally extracted from portal blood and detoxified by hepatocytes → pass BBB into the CNS.

Varices - Stimulated angiogenesis and collateral vessel (thin wall) formation + thrombocytopenia (decreased clotting factors) → +++ internal haemorrhaging.

56
Q

Explain how portal hypertension leads to malabsorption.

A

Constricted hepatic portal veins reduces subsequent blood flow into sinusoidal space, therefore bile salt transport into hepatocytes is reduced.
Decreased bile secretion into bile canaliculi → reduced absorption of lipids and fat-soluble vitamins (ADEK)
Decreased portal hepatic vein flow → reduced nutrient delivery to liver from GI tract (SI).

57
Q

Explain why portal hypertension leads to vasodilator secretion.

A

Arterial vasodilation arises to compensate for ^ BP within the hepatic portal system. Reducing BP through arteries → increased blood flow into portal system → Increase CO → increased perfusion of abdomen, organs and varices.

58
Q

Explain how portal hypertension leads to splenomegaly.

A

Decreased blood flow through hepatic portal and splenic veins, therefore cause an accumulation of erythrocytes and blood within spleen → Congestion and enlargement arises due to insufficient removal mechanism.

59
Q

What does encephalopathy due to LF lead to?

A

Apathy, memory gaps, tremor and liver coma.

60
Q

List the consequences of hepatic encephalopathy due to LF and explain each one.

A

Hyperammonaemia - GI haemorrhaging supplement colonic bacteria with proteins → NH4+ and NH3 compound generation (Liver inability to detoxify ammonium compounds → Urea).

Hypokalaemia - Hyper-aldosteronism → increased K+ secretion into DCTs → Intracellular acidosis → Activates NH4 formation in proximal tubules → Systemic alkalosis.

Toxins (e.g.amines, phenols, FFAs) bypass liver → Not extracted or detoxified → passes BBB → Encephalopathy.
‘False transmitters’ (e.g. serotonin) from aromatic AAs in brain → increased in hepatic failure → Encephalopathy.

61
Q

Explain how LF leads to varices.

A

Portal venous system is normally independent from the systemic system. Portal hepatic vein transport GI blood to the liver. Tributaries form anastomoses with portal veins, veins from left gastric vein communicate with the azygous vein.

  • Anastomosed vessels are enlarged causing oesophageal varices
  • Superior rectal veins connect with middle rectal veins → Portal hypertension → Haemorrhoids
  • Umbilical vein opens up → Connects with the systemic system within the anterior abdomen walls (carpo-medusa).
62
Q

What is the most common type of varices?

A

Oesophageal varices

63
Q

Explain hepato-renal syndrome.

A

Arterial vasodilation through decreased vascular resistance → Stretches afferent arteriole → Activating vasoconstrictor factors (RAAS, SNS, AVP) → Renal vasoconstriction decreased GFR.

64
Q

What is the purpose of the Child-Pugh score?

A

Assess disease severity for end-stage liver disease and a prognosticator for peri-op death.

65
Q

Explain how to use a patients Child-Pugh Score.

A

Class A - 5-6 points - Expectancy of 15-20 years, 10% peri-operative mortality.

Class B - 7-9 points - Transplant candidates, may have 30% P-OM.

Class C - 10-15 points - LE 1-3 months, 82% P-OM.

66
Q

Supportive treatment for encephalopathy?

A

Reduce protein intake
Phosphate anaemias/lactulose
No sedation

67
Q

Supportive treatment for hypocalcaemia?

A

10ml 10% calcium gluconate.

68
Q

Supportive treatment for RF?

A

Hemofiltration

Ventilation

69
Q

Supportive treatment for hypotension?

A

Albumin

Vasoconstrictors

70
Q

Supportive treatment for infection?

A

Frequent cultures

ABs

71
Q

Supportive treatment for bleeding?

A

Vitamin K
FFP
Platelets

72
Q

What % of all transplants in the UK are liver transplants?

A

5%

73
Q

Survival rate for people with liver transplant?

A

5 year survival rate with OLTx between 60-80%

74
Q

List some liver support devices.

A

Artificial (MARS, Bio-Logic DT) 0 Albumin exchange system based on selective removal of albumin-bound toxins from blood.

Bio-artificial (hepatocytes in culture)

Hepatocyte transplantation

75
Q

What is the most effective method for treating someone with a hepatocellular cancer?

A

Livere transplant

76
Q

What is the biggest indication for liver transplantation?

A

Cirrhosis (58%)

Cancer - 14%

BRS (19 decks)

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