Liver/ paracetamol toxicity Flashcards
what is bilirubin derived from?
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.
Normal bilirubin levels?
0.1-1.2mg/dL
What happens to bilirubin after it is formed by biliverdin reductase?
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)
What does steatosis mean?
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.
4 causes of steatosis
Alcohol abuse (most common)
Diabetes mellitus
Obesity
Protein malnutrition.
How does excess alcohol result in fatty liver.
- Decreased NAD+ / NADH ratio
- NAD+ needed for mitochondrial and enzyme function in order to effectively process fats via fatty acid oxidation. - Excess acetylaldehyde is hepatotoxic
- can further diminish liver ability to process fats. - 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.
what is the most telling precursor to liver cirrhosis
Collagen deposition in the space of Disse.
outline the pathogenesis of liver cirrhosis
- Stellate Cells activated in response to injury/ inflammatory cytokines -> transform to myofibroblasts + deposit collagen in space of disse -> obliteration of vessels -> further fibrotic response.
- Kuppfer Cells, activated by various factors, play a crucial role in liver inflammation and fibrosis by promoting stellate cell activation, ECM synthesis, and inflammation.
- Hepatocytes, targeted by many toxins, viruses, and alcohol, contribute to fibrosis by releasing reactive oxygen species, fibrogenic mediators, and undergoing apoptosis.
- 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.
3 types of cirrhosis and causes
Micronodular: alcohol abuse
Macronodular: viral hepatitis
Mixed
How does paracetamol toxicity occur?
-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.
MOA of acetylcysteine
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.
What is considered a toxic paracetamol dose?
> 60mg/kg/day
12g taken STAT can be fatal
List the 3 poor prognostic indicators following a paracetamol overdose
- Arterial pH < 7.3 on or after day 2 of overdose
- Combination of:
-Prothrombin time >100secs
-Plasma creatinine >300 micro mol /litre
-Grade 3 of 4 hepatic encephalopathy - Increase in Prothrombin time between days 3 and 4 after overdose
List 3 scenarios when acetylcysteine should be given immediately
- Plasma-paracetamol concentration falls on orabove the paracetamol treatment graph line.
- If patient presents 8-24 hours after taking a paracetamol overdose ( >150mg/kg)
- If clinical picture suggests overdose.
Signs of paracetamol toxicity
<24 hours: malaise, nausea, vomiting, pallor
<48 hours: Tachycardia, hypotension
<4 days: Jaundice, hepatic encephalopathy
What scoring system is used to assess for severity of liver cirrhosis? what variables does it include?
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
Outline the process of liver regeneration following injury/surgery
-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
- Priming phase
-Kuppfer cells release cytokines (IL-6, TNF-a) which makes hepatocytes receptive to growth factors.
-Growth factors (HGF and EGF) 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. - 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
List 3 types of jaundice
Pre-hepatic
Intra-hepatic
Post-hepatic
Normal stool/urine colour, yellowing skin; what type of jaundice? list 3 causes
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)
very dark urine, pale stool: What form of bilirubin is high? What might be causing this?
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
What blood tests might you do if you suspect pre-hepatic jaundice?
- Heptoglobin: protein that is usually bound to hemoglobin; usually very low or absent in hemolytic anemias.
- LDH: produced following cell breakdown; therefore will be high in hemolytic anemias.
- Total bilirubin: will be high
- Conjugated bilirubin: will be normal or low
- Unconjugated bilirubin: will be high.
- AST/ALT : should be normal if a pre-hepatic jaundice.
AST and ALT are found where? what is the relevance of AST:ALT ratio?
Hepatocytes
AST: ALT of >1 (i.e. 2:1) suggests alcoholic liver disease, cirrhosis or cancer
if <1 then suggests infectious or inflammatory cause.
GGT is found where?
Hepatocytes and biliary epithelial cells
ALP is found where?
Biliary cells and bones.
