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KHI > Liver/ paracetamol toxicity > Flashcards

Liver/ paracetamol toxicity Flashcards

1
Q

what is bilirubin derived from?

A

Breakdown of RBC’s in the spleen and liver. Macrophages (e.g. kuppfer cells in liver) break down the RBC’s.
- Globin -> reused for amino acids/protein production
- heme -> biliverdin by heme oxygenase -> bilirubin by biliverdin reductase.

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2
Q

Normal bilirubin levels?

A

0.1-1.2mg/dL

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3
Q

What happens to bilirubin after it is formed by biliverdin reductase?

A

Unconjugated bilirubin is hydrophobic and so is bound to albumin in the blood.
- taken to the liver where it diffuses into hepatocytes for conjugation
- conjugated to glucoronic acid by UDP-glucoronosyl transferase -> now water soluble and can be excreted.
- conjugated bilirubin transported into Gall bladder via biliary tract.
- transported to 2nd part of duodenum within bile:

-> intestinal bacteria deconjugate it and convert it into urobilinogen (via beta glucoronidase)
-> 80% of urobilinogen is converted to stercobilin in colon and excreted in faeces.
-> 20% reabsorbed into blood (90% undergoes enterohepatic recycling, 10% excreted in urine as urobilin)

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4
Q

What does steatosis mean?

A

Abnormal accumulation of fats within the hepatic parenchymal cells.
The liver is susceptible for fatty changes due to its role in fat metabolism
Can also happen in heart, muscle, kidneys.

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5
Q

4 causes of steatosis

A

Alcohol abuse (most common)
Diabetes mellitus
Obesity
Protein malnutrition.

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6
Q

How does excess alcohol result in fatty liver.

A
  1. Decreased NAD+ / NADH ratio
    - NAD+ needed for mitochondrial and enzyme function in order to effectively process fats via fatty acid oxidation.
  2. Excess acetylaldehyde is hepatotoxic
    - can further diminish liver ability to process fats.
  3. Excess NADH can also stimulate hepatic lipogenesis.

This can all lead to reduced carrier protein/apoproteins synthesis needed to remove fats as lipoproteins + inability to process fats in the first instance.

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7
Q

what is the most telling precursor to liver cirrhosis

A

Collagen deposition in the space of Disse.

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8
Q

outline the pathogenesis of liver cirrhosis

A
  1. Stellate Cells activated in response to injury/ inflammatory cytokines -> transform to myofibroblasts + deposit collagen in space of disse -> obliteration of vessels -> further fibrotic response.
  2. Kuppfer Cells, activated by various factors, play a crucial role in liver inflammation and fibrosis by promoting stellate cell activation, ECM synthesis, and inflammation.
  3. Hepatocytes, targeted by many toxins, viruses, and alcohol, contribute to fibrosis by releasing reactive oxygen species, fibrogenic mediators, and undergoing apoptosis.
  4. Cytokines like PDGF, TGF-β, TNF-α, and interleukins regulate HSC activation and fibrogenesis, with TGF-β being a key inducer of fibrosis.

Continual injury will result in irreversible fibrosis i.e. cirrhosis.

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9
Q

3 types of cirrhosis and causes

A

Micronodular: alcohol abuse
Macronodular: viral hepatitis
Mixed

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10
Q

How does paracetamol toxicity occur?

A

-Excess paracetamol results in saturation of the sulphation pathway of metabolism

  • CYP2E1 and CYP1A2 isozymes take over the extra -> this pathway produces NAPQI.
  • As more and more NAPQI is produced, glutathione tries to bind NAPQI however glutathione eventually becomes depleted.
  • This results in lots of free NAPQI which covalently binds to essential mitochondrial proteins.

-Early lactic acidosis happens due to mitochondrial impairment causing a shift from aerobic -> anaerobic metabolism -> lowering of pH and loss of consciousness

-Late hepatic damage results from prolonged lactic acidosis if acetylcysteine is not given-> liver cannot convert ammonia to urea for excretion -> hepatic encephalopathy

-Impaired gluconeogenesis can precipitate hypoglycemia.

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11
Q

MOA of acetylcysteine

A

Given intravenously
- donates a cysteine for production of glutathione.
- acetylcysteine can also bind NAPQI itself.

Does not work if severe liver injury as liver will lack the functional capacity to make glutathione even if cysteine is donated.

Cysteine, Glutamate, Glycine needed to make glutathione.

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12
Q

What is considered a toxic paracetamol dose?

A

> 60mg/kg/day
12g taken STAT can be fatal

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13
Q

List the 3 poor prognostic indicators following a paracetamol overdose

A
  1. Arterial pH < 7.3 on or after day 2 of overdose
  2. Combination of:
    -Prothrombin time >100secs
    -Plasma creatinine >300 micro mol /litre
    -Grade 3 of 4 hepatic encephalopathy
  3. Increase in Prothrombin time between days 3 and 4 after overdose
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14
Q

List 3 scenarios when acetylcysteine should be given immediately

A
  1. Plasma-paracetamol concentration falls on orabove the paracetamol treatment graph line.
  2. If patient presents 8-24 hours after taking a paracetamol overdose ( >150mg/kg)
  3. If clinical picture suggests overdose.
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15
Q

Signs of paracetamol toxicity

A

<24 hours: malaise, nausea, vomiting, pallor

<48 hours: Tachycardia, hypotension

<4 days: Jaundice, hepatic encephalopathy

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16
Q

What scoring system is used to assess for severity of liver cirrhosis? what variables does it include?

A

Child-Pugh Score

categories measured:
-Bilirubin
-Albumin
-PTT
-encephalopathy
-Ascites

Each category given a score 1-3

<7 = A
>9 = C and is indicative of <12 months survival

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17
Q

Outline the process of liver regeneration following injury/surgery

A

-Regeneration occurs because hepatocytes are stable cells (Quiescent but can either regenerate or undergo apoptosis)
-Regeneration occurs after almost all liver injuries except for fulminant or chronic liver conditions
-Hepatocyte proliferation is via compensatory hyperplasia

  1. Priming phase
    -Kuppfer cells release cytokines (IL-6, TNF-a) which makes hepatocytes receptive to growth factors.
    -Growth factors (TGF-a) stimulates entry into G1 phase and progression to S phase.
    -There is a wave of hepatocyte regeneration and then a wave of non-parenchymal regeneration.
    -Once complete, cells return to G0.
  2. Liver regeneration from progenitor cells
    - occurs when regenerative capacity of hepatocytes is limited e.g. chronic liver injury of inflammation.
    -Progenitor cells in the canals of Hering act as stem cells for hepatocytes and choangiocytes.
    -Proliferation begins in zone 1 -> zone 3
18
Q

List 3 types of jaundice

A

Pre-hepatic
Intra-hepatic
Post-hepatic

19
Q

Normal stool/urine colour, yellowing skin; what type of jaundice? list 3 causes

A

Pre-hepatic jaundice - unconjugated hyperbilirubinemia.

*Urine and stool are normal colour because urobilin and stercobilin are still being produced (bilirubin is still being conjugated, its just that the enzyme UDP-glucoronosyl transferase is at capacity).
*There is skin discolouration because there is an excess of unconjugated bilirubin produced secondary to excess RBC lysis. This is circulating in the blood.

3 causes of pre-hepatic jaundice:
(i) Hemolytic anemia
(ii) massive blood transfusion resulting in excess RBC lysis
(iii) Immature or defective UDP-glucoronosyl transferase enzyme
(iv) medications such as rifampin, atanazavir (can impair bilirubin uptake by hepatocytes)

20
Q

very dark urine, pale stool: What form of bilirubin is high? What might be causing this?

A

This would be caused by a conjugated hyperbilirubinemia.
Excess Conjugated bilirubin in urine gives it a dark colour.
Seeing as though the stool is pale, would mean that the bilirubin is not making it to the bowel to be converted to stercobilin.
The dark urine would indicate a lot of conjugated bilirubin in the blood traveling to the kidneys.

This could be causing a post-hepatic jaundice due to an obstruction in bile flow.

Causes:
Bile duct stricture
Cholangitis
bile duct stone

21
Q

What blood tests might you do if you suspect pre-hepatic jaundice?

A
  1. Heptoglobin: protein that is usually bound to hemoglobin; usually very low or absent in hemolytic anemias.
  2. LDH: produced following cell breakdown; therefore will be high in hemolytic anemias.
  3. Total bilirubin: will be high
  4. Conjugated bilirubin: will be normal or low
  5. Unconjugated bilirubin: will be high.
  6. AST/ALT : should be normal if a pre-hepatic jaundice.
22
Q

AST and ALT are found where? what is the relevance of AST:ALT ratio?

A

Hepatocytes

AST: ALT of >1 (i.e. 2:1) suggests alcoholic liver disease, cirrhosis or cancer

if <1 then suggests infectious or inflammatory cause.

23
Q

GGT is found where?

A

Hepatocytes and biliary epithelial cells

24
Q

ALP is found where?

A

Biliary cells and bones.

25
Q

How might excess alcohol affect metabolism of other drugs?

A

When there is an excess of alcohol intake which saturates alcohol dehydrogenase (ADH), CYP450 enzymes take over.

CYP2E1 and CYP1A2 are mostly involved.

This can affect drug metabolism in the following ways:

(i) In times where there is excess alcohol in the system, the alcohol will compete with other drugs that are usually metabolised by these isozymes. Therefore there will be a reduction in metabolism of the drug which can reduce its affects/ cause more ADR’s.

(ii) When there is less alcohol in the system, these enzymes will still be very much induced and result in faster than usual metabolism- reducing the drugs’ affects

(iii) In terms of the CYP1A2/2E1 in particular, induction of these enzymes can result in increased metabolism of paracetamol via these enzymes which results in increased NAPQI production.

26
Q

5 pathologic features of alcoholic hepatitis

A
  1. Neutrophil infiltrate
  2. Hepatocyte degeneration/necrosis/ballooned cells
  3. Collagen deposition; space of disse.
  4. Fatty change
  5. Malory bodies: eosinophilic inclusions of intermediate filaments; associated with chronic alcoholism
27
Q

define hepatic encephalopathy and list 5 features.

A

Hepatic encephalopathy: fluctuation in mental status and cognitive function in the presence of severe liver disease.

  1. Asterixis
  2. Altered consciousness
  3. Fatigue/lethargy
  4. Slurred speech
  5. Coma.
  6. Clonus
28
Q

Outline the pathophysiology of hepatic encephalopathy

A

x4 underlying causes/triggers

  1. Cirrhotic liver: hepatocytes unable to metabolise nitrogenous compounds such as ammonia, mercaptans, phenols.
  2. Portal hypertension resulting in shunting of unfiltered blood directly into systemic circulation.
  3. Hypokalemia results in efflux of K+ from ICF -> ECF. H+ ions enter cells to maintain electrical charge. The resulting intracellular acidosis can results in increase ammonia production.
  4. Metabolic alkalosis
    -> Decreased H+ availability = decreased conversion of ammonia to ammonium resulting in increase ammonia levels.

-> Ammonia crosses BBB
-> Gets taken up into astrocytes for conversion of glutamate -> glutamine.
-> This results in increased oncotic pressure within astrocyte causing influx of water -> cerebral oedema and oxidative damage.
-> Increased GABA-A production
-> reduced neuonal excitability.

29
Q

Distinguish between the 3 types of hepatic encephalopathy

A

Type A: HE associated with acute liver injury; usually with cerebral oedema.

Type B: HE associated with portal-systemic shunting usually in the absence of hepatic pathology.

Type C: HE with liver cirrhosis

30
Q

List 3 management options for hepatic encephalopathy

A
  1. Lactulose - a disaccharide laxative that decreases absorption of ammonia in the bowel through its conversion to ammonium which is then excreted.
  2. Rifaximin - Oral antibiotic that will reduce the number of ammonia-producing gut bacteria.
  3. Liver transplant - the only definitive treatment option.
31
Q

list 4 contraindications to liver biopsy

A
  1. Prothrombin time >4secs more than control
  2. Use of anti-platelets within last 7 days
  3. severe thrombocytopenia
  4. un co-operative patient hindering precision
32
Q

Distinguish between a transudate and exudate

A

A transudate is a collection of clear interstitial fluid (plasma), with little cells or proteins, which has collected as a result of increased hydrostatic pressure in vasculature. Example: Ascites secondary to portal hypertension, congestive heart failure.

Exudate is extravascular fluid accumulation due to inflammation. The fluid is milky, high in protein, with white and red blood cells. There is increased vascular permeability and cellular damage. Example: infections, malignancies.

33
Q

Where is a liver biopsy performed?

A

Right side, area of max dullness is percussed in MAL - usually between 8th -> 10th ICS MAL

34
Q

Palpation of gall bladder where can elicit murphy’s sign for cholecystitis?

A

Inferior border of right lobe around 9th costal cartilage

35
Q

Pain afferents from biliary colic will travel back to what spinal levels?

A

T7-T9. Can refer to right scapula

36
Q

the common hepatic artery is a branch of what? What level?

A

Branch of coeliac trunk T12

37
Q

Outline the blood supply of the liver

A

Blood to the liver:
-70% is deoxygenated blood that requires filtering; brought to the liver via the hepatic portal vein; HPV is formed by the union of the splenic vein and sup mesenteric vein.
-30% is oxygenated blood from the hepatic artery; a branch of the coeliac trunk (T12).

Both of these vessels branch at the porta hepatis into left and right branches before subdivided to supply the lobes of the liver.

Blood leaving liver.
- The hepatic arterioles and portal venules drain in through sinusoids which are lined with Kupfer cells and hepatocytes.
- These sinusoids drain into a central vein.
- These central veins unit to form the left, right and middle hepatic veins which drain deoxygenated, filtered blood into the inferior vena cava.

The caudate lobe receives both rt and lt branches of the HPV and from hepatic artery, Blood from caudate drains directly into the IVC, bypassing main hepatic veins.

38
Q

List 5 functions of the liver

A
  1. Drug metabolism
  2. Bile, albumin and cholesterol production
  3. Glycogen synthesis
  4. Clotting factors
  5. Converts ammonia -> urea
39
Q

Describe the hepatic lobular/acinus model

A

Lobular model: central vein at the centre of the hexagonal lobule with terminal branches of the portal vein, hepatic artery and bile ducts at the periphery. The flow between periphery and central vein is via the sinusoids.

Acinar model: The acinus is a wedge within the lobule, and can be divided into 3 zones based on blood flood.

Zone 1 (most outer): zone closest the the hepatic artery and so is most oxygenated. Hepatocytes here take part in: B-oxidation of fatty acids, cholesterol synthesis, gluconeogenesis.

Zone 3 (most inner): zone furthest from hepatic artery and is less oxygented/more prone to ishcemic injury.

Zone 2 (in middle): glycolysis, lipogenesis, CYP450 based drug detoxification

40
Q

Kupffer and stellate cells: location and function

A

Kupffer cells
- macrophages lining the sinusoidal capillaries.
- phagocytosis of debris/pathogens
- RBC degradation -> unconjugated bilirubin

Stellate/Ito cells
- Found in the space of disse.
- store fat
- store vid D E K, B12
- Secrete reticular fibres
- Synthesis ECM and proteoglycans

KHI (16 decks)

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