Liver Flashcards
What is hepatitis?
Inflammation of hepatocytes e.g. due to virus, alcohol, obesity
What are gallstones?
Stones that form in the gallbladder and stop the secretion of bile- blocking the bile duct.
What is cholangitis?
Inflammation of the bile duct that causes narrowing
What is haemochromatosis?
Inherited iron overload
What is Wilson’s disease?
Inherited copper overload
What is Gilbert’s disease?
Inability to metabolise bilirubin properly.
How do you classify acute vs chronic liver disease ?
Acute:
- Usually self-limiting- e.g. due to drugs or virus
- Causes hepatocyte inflammation/damage- but liver cells are good at repairing and regenerating
- occasionally can be severe and result in liver failure
Chronic:
- Inflammation persists for >6 months
- Results in permanent damage with structural changes
e.g. cirrhosis (fibrosis, scarring) = loss of hepatic function and death
- most common cause is alcohol abuse
Describe the progression of liver disease?
Normal liver
Then some kind of damage occurs e.g. alcohol, viral infection, Non-alcoholic fatty liver disease (NAFD), autoimmune disorder, cholestatic disorder
This leads to inflammation and potentially a fatty liver. This inflammatory damage leads to activation of pro-inflammatory cytokines, immune cells, matrix deposition, parenchymal cell death and angiogenesis.
This all leads to early fibrosis (note; at this stage id underlying cause can be removed or anti-fibrotic drugs can be used, the liver can be resolved to the normal liver phase above).
Early Fibrosis leads to late fibrosis and cirrhosis- this is irreversible.
Causes disrupted structure, loss of hepatocyte function.
Hepatocytes will be regenerated but to sub-standard function.
This can lead to liver failure and portal hypertension
at this stage, a liver transplant is required
This process usually takes from 5-50 years, dependent on co-factors such as obesity, alcohol, genetics and epigenetic markers.
What is a ‘Fatty liver’?
A reversible condition in which large vacuoles of triglyceride fats are deposited in the liver.
Has increased TGs, LFTs and liver fat
20-30% of adults have a fatty liver and 15-20% go on to have non-alcoholic fatty liver disease. This can lead to inflammation, fibrosis and steatosis (fat build up in liver cells). This may progress to cirrhotic liver and hepatocellular carcinoma.
What are the treatments for fatty liver?
There are no treatments available until the patient has cirrhosis and they become eligible for a liver transplant. This is not common though.
What are happening to different cell types during advanced fibrosis?
- Loss of hepatic stellate cells
- Immune cells e.g. lymphocytes are infiltrating
- Activated kupfer cells- try to phagocytose dead cells
- Hepatocytes are dying
- Sinusoid lumen has increased resistance to blood flow due to scarring and fibrosis
What are the potential causes of liver disease?
VIRUSES:
Can cause hepatitis of liver and inflammation
e.g.
Hepatitis A: faecal- oral transmission
causes acute inflammation that should usually resolve spontaneously
is a preventative vaccine available
Hep B: In Bodily fluids eg. blood (common in drug users)
can pass from mum to baby
acute but can progress to chronic inflammation
there is a vaccine and it is often given to healthcare workers
Hep C: bodily fluids
chronic inflammation
no vaccine
Hep D: body fluids
requires concomitant infection with hep B to survive
Hep E: Contaminated food and water
usually self-limited
Hep G: bodily fluids, chronic infection
DRUGS
- Some drugs require an over-dose in order to cause liver damage e.g. Paracetamol
- Some drugs can cause damage even when appropriately prescribed (Need LFTs) e.g.
Statins
Antibiotics e.g. amoxicillin, tetracycline
Methotrexate
- Some natural products can cause damage e.g. herbal remedies (kava kava), high dose vitamin A, wild mushrooms.
ALCOHOL
Most common cause
Is directly toxic to liver cells- inflammation progressing to fatty liver and fibrosis. fibrosis alters structure and blood flow = portal hypertension which causes back pressure back into the liver
- Damage tends to occur in >40g/day in men and >20g/day in women (1 unit = 9g)
What can cause cholestasis?
Cholestasis is the lack of bile entering the GI tract.
Can be due to hepatocytes:
- failure of bile production and secretion. Causes: hepatitis due to virus, alcohol, drugs, pregnancy
Can be due to problems with bile ducts e.g. obstruction in bile ducts via gall stones, carcinoma, cholangitis (progressive scarring).
What are the symptoms of acute liver disease?
May be asymptomatic!
- general malaise
- anorexia, appetite loss
- fever
- jaundice
What are the symptoms of chronic liver disease?
- fatigue, weakness
- weight loss, cachexia, muscle wasting
- N+V
- loss of apetite
- abdominal swelling
- right upper quadrant abdominal pain and tenderness
- jaundice
- bruising and bleeding- loss of coagulation factors
What are the symptoms of cirrhosis?
As disease progresses to cirrhosis, so does the symptoms:
- Inability to metabolise waste = bilirubin build up = jaundice
- failure ti produce proteins- hepatocytes stop = can’t clot blood, no albumin = swelling
- bruising (lack of clotting factors)
- Gynecomastia - increase in male breast size
- impotence- erectile dysfunction
- confusion
- Ascites- abdo swelling
- Portal hypertension
- oesophageal varices- enlarged veins in the oesophagus, can cause bleeding
What is jaundice?
Yellowing of skin & mucuos membranes (sclera-white of eye) due to build up of bilirubin.
What are the possible causes/types of jaundice?
- Haemolysis (haemolytic jaundice)- RBCs are breaking down but the liver isn’t removing the heme so bilirubin is building up in the skin
- Hepatocellular damage (Hepatic jaundice)- damage to hepatocytes
- Cholestasis (obstructive jaundice)- bile is being made but can’t reach the GI tract due to obstruction in bile duct.
What is portal hypertension- inc complications?
This is a back pressure caused by resistance of blood flow into liver as a result of fibrosis, causing back pressure in the portal vein (carries blood from GI tract and spleen to liver). This leads to blood being used into surrounding blood vessels inc thin walled veins in the oesophagus which can rupture and bleed. Uncontrolled bleeding can lead to shock and death.
Portal hypertension can lead to complications including ascites, GI bleeding, hepatic encephalopathy, splenomegaly.
What is ascites-inc causes?
A swelling of the abdomen due to abnormal accumulation of fluid in the peritoneal cavity due to a pressure imbalance between inside the circulation (blood vessels) (higher) and outside in the peritoneal cavity (lower).
Fluid moves from high pressure to low causing a build up in the peritoneal cavity that needs to be drained.
Causes:
Activation of the renin-angiotensin system due to decreased renal blood flow due to disordered liver anatomy= secondary hyperaldosteronism- fluid retention. This is exaggerated by aldosteone not being metabolised by the liver like normal.
Portal HTN- oedema localises in abdomen
Low plasma albumin- as not made in the liver like normal = decreased. osmotic pressure in plasma = oedema
retention of salt and water in kidneys e.g. secondary to renal problems e.g. hyperaldosteronism
What is hepatic encephalopathy- inc symptoms and causes?
Is caused by a build up of ammonia in the bloodstream which is normally converted to urea in the liver and excreted by the kidney.
- Ammonia build up is an issue as it can cross the BBB and lead to neurological abnormalities in the brain.
Symptoms:
altered mental state
fetor hepaticus- chronic bad breath- musty smell
Asterixis- hand tremor
drowsiness
confusion
coma
Causes/worsened by:
dehydration
hypovalemia
gi bleed
CNS drugs
alcohol
increased protein intake
constipation
What is wernicke’s encephalopathy/korsakoff syndrome?
Is a neurological abnormality due to deficiency of thiamine (Vit B).
This deficiency is often seen in chronic alcohol abuse as this decreases thiamine absorption and malnutrition. presents similarly to hepatic encephalopathy.
What causes anaemia in liver disease?
The effects on iron homeostasis due to splenomegaly caused by postural hypertension.
- alcohol is toxic to bone marrow
- can be due to decrease in clotting factor synthesis
- bruising and bleeding occurs
What circulatory and skin changes may occur as a result of liver disease/damage?
Circulatory:
- Palmer erythema: rash like dermatitis- red but NOT dry
- Spider naevi- clusters of blood vessels on skin surface- vascular lesion
- finger clubbing- due to changes inn interstitial fluid
skin
- pruritus- due to toxic substances being laid down in skin rather than being metabolised by the liver.
What tests are used in diagnosing liver disease?
- Medical history- signs and symptoms
- LFTs
- Electrolytes
- FBC- in end stake LF = bone marrow suppression causing decreased RBC, WBC, Platelets
- Viral screens
- Prothrombin time- blood clotting capability of liver
Imaging- assess function and structure of liver, gall bladder, bile ducts and look for cancer
- Ultrasound
- CT
- MRI
- liver biopsy
What LFTs are looked at in liver disease?
SERUM ENZYMES:
- Aspartate transaminase (AST)
- Alanine transaminase (ALT)
- Gamma glutamyl transferase (GGT)
- Alkaline phosphatase (ALP)
Others:
- Bilirubin
- plasma proteins and albumin
- prothrombin time
- urea and ammonia
Discuss use of AST in liver diagnosis?
Aspartate transaminase (AST) has a role in gluconeogenesis catalysing the reversible conversion of aspartate and alpha veto glutamate to oxaloacetate and glutamate.
Reference range 5-40 IU/L
- is found in liver, but also heart, brain, skeletal muscles = not used in isolation?
What is the normal AST levels?
Reference range 5-40 IU/L
Discuss use of ALT in liver diagnosis?
Alanine transaminase (ALT) also plays a role in gluconeogenesis to catalyse the reversible transfer of an amino group from L-alanine to alpha kept-glutarate = pyruvate and L-Glutamate
Reference range = 5-30 IU/L
Is more specific to liver than AST.
What is the normal ALT levels?
Reference range 5-30 IU/L
How are AST & ALT used in diagnosing liver disease?
- Very high levels of AST & ALT occur in acute viral/toxic hepatitis
- High (but not as as above) in cholestatic jaundice, cirrhosis
USE THE RATION OF AST/ALT IN DIAGANOSING DIFFERENT TYPE OF LIVER DISEASE:
AST/ALT: >2 could indicate possible alcohol injury
Most other liver injuries, AST:ALT is <1
Discuss use of GGT and ALP in liver diagnosis?
Gamma glutamyl transferase (GGT):
Catalyses the transfer of a gamma glutamyl moiety of glutathione to an AA, peptide or water.
Reference range: 5-45 IU/L
- is very high in biliary obstruction
- is elevated (but lower) inc chronic alcohol or drug toxicity, hepatitis, cirrhosis, cholestasis.
- can indicate alcohol consumption/abuse- levels will decrease in 3-6 weeks after abstinence.
Alkaline phosphate (ALP):
- Removes phosphate groups from nucleotides, proteins, alkaloids
Reference: 100-200 IU/L
- very high in billiard onstruction
What is the normal GGT levels?
5-45 IU/L
What is the normal ALP levels?
100-200 IU/L
What is the reference value (normal) for bilirubin?
0-17 micromol/L
What bilirubin level does jaundice occur at?
Bilirubin that is >35 micromol/L
What are the types of bilirubin that can be measures?
Conjugated and unconjugated- can differentiate type of disease.
Conjugated: issue with liver itself
Unconjugated: Excessive RBC breakdown
Discuss use of albumin
in liver diagnosis?
Albumin is solely synthesised in the liver- t1/2 = 20-26 days so any decrease in albumin indicates long-term liver damage because of this extended half-life.
Reference range (normal): 35-50g/dL
<20g/dL albumin - changes in plasma protein pressure and can lead to oedema and fluid overload.
What is the reference value (normal) for albumin?
35-50 g/dL
What is the reference value (normal) for total protein?
60-80g/dL
Discuss use prothrombin time (PT)
in liver diagnosis?
This is the time it takes for blood to clot. Reference: 10-15 seconds
As lack of clotting factors increases, the PT will increase.
Is dependent on factors II, VII and X
These factors require vitamin K to be produced- this vitamin requires bile salts for absorption and so vitamin K can be used for differential diagnosing.
How can vitamin K be used to differentially diagnose liver problems?
Vitamin K is required for production of clotting factors exp 2, 7 and 10. In order for vitamin K to be absorbed, bile salts are needed.
- If administer vitamin K and the patient has underlying hepatocellular damage, the patient will be unresponsive as no matter how much vitamin k is given, the liver still can’t produce the clotting factors.
- If cholestasis- increased Prothrombin time as the deficiency in bile salts is responsible for Vit K absorption. Give vitamin K injection 10mg IV for 3 days to replace the Vet K that hasn’t been absorbed due to bile salt deficiency = improvement in PT time.
If decreased prothrombin time is a result of cholestasis and lack of bile salts, what can be used to treat it?
- If cholestasis- increased Prothrombin time as the deficiency in bile salts is responsible for Vit K absorption. Give vitamin K injection 10mg IV for 3 days to replace the Vet K that hasn’t been absorbed due to bile salt deficiency = improvement in PT time.
What is the reference (normal) urea levels?
2.5-7.8 mmol/L
What is the reference (normal) Ammonia levels?
Males: 16-60
Females: 11-51
unit - micromol/L
What happens to levels of urea and ammonia in liver disease?
Urea is decreased due to reduction in synthesis by the liver.
Ammonia is increased due to failure of liver in converting ammonia to use. This accumulate can lead to hepatic encephalopathy if ammonia crosses the BBB
What factors are responsible for the change in drug clearance and pharmacokinetics in liver disease?
changes in intestinal absorption
decreases plasma proteins binding
hepatic extraction ratio
liver blood flow changes
portal-systemic shunting - consequence of collateral circulation due to portal HTN
biliary excretion
enterohepatic circulation
renal clearance - decreased renal and liver blood flow
What is the purpose and process of drug metabolism?
Purpose: Structural modification to make the drug more polar and less lipid soluble = aid excretion from body
2 stages:
Phase 1
- Oxidation (e.g. in azathioprine), reduction (e.g. in halothane) or hydrolysis (e.g. in atropine, pethidine)
Phase 2:
- Conjugation with large polar groups to aid excretion:
glucoronidation e.g. paracetamol, morphine
- Sulphonation e.g. steroids
- acetylation e.g hydralazine, phenelzine
- methylation e.g. nicotine
What does it mean for a drug to have a high or a low extraction ration?
High:
Clearance depends on hepatic blood flow.
Undergoes extensive 1st pass metabolism in liver
High value or ratio- close to 1
likely require a greater reduction in dose in liver disease
e.g. morphine, propranolol, verapamil, metoprolol, pethidine, lignocaine
Low:
Clearance depends on metabolising capacity of liver
Ratio tends to be closer to 0
e.g. phenytoin, diazepam, warfarin, atenolol, furosemide, prednisolone, lorazepam
What 2 factors does rate of drug removal by liver depend on?
Capacity to metabolise drug
Blood flow through the liver
What are some examples of CYP-450 inhibitors?
Cimetidine
ciprofloxacin
erythromycin
COCs
ketoconazole
cirrhois
congestive cardiac failure
viral infection
What are some examples of CYP-450 inducers?
phenytoin
phenobarbitol
carbamazepine
primidone
rifampicin
smoking
Alcohol
What will you see in the LFTs of a patient on CYP P450 inducers?
Increased GGT levels
Patients with severe liver disease, have an increased sensitivity to many drugs. Give some examples
- Those that affect clotting/bleeding- due to decreased production of clotting factors in LD
- Drugs that affect the CNS- increased risk of hepatic encephalopathy- risk in hypovalemia and hypokalaemia - both can occur as a consequence o diuretic use
- Diuretics
- Constipation- if drugs cause constipation, there is an increased risk of hepatic encephalopethk as slowing of gut motility means nitrogenous waste products remain in gut for longer = increased absorption = increased HE risk
Why should you be cautious with drugs that cause constipation in LD?
if drugs cause constipation, there is an increased risk of hepatic encephalopethy as slowing of gut motility means nitrogenous waste products remain in gut for longer = increased absorption = increased HE risk
What lifestyle advice should you offer to LD patients?
Lose weight
Stop alcohol use
Quit smoking
Exercise
How do you manage/treat cirrhosis and end-stage liver disease?
- Low protein diet
- low sodium diet- may require diuretics to decrease water retention
- Draining of ascites fluid by paracentesis
- Surgery to trat portal HT and decrease bleeding risk
- Transplant
- Medication- dependent on disease and complications
What are the symptoms of acute alcohol withdrawal?
CNS hyperactivity: Insomnia, tremor, anxiety, GI upset, headache, diaphoresis (sweating), palpitations. These tend to resolve within 24-48 hours
- Seizures- conclusions within 12-48 hours of last drink. If untreated can result in delirium tremens
- Alcoholic hallucinations- resolve with 24-48hrs
- Delerium tremens- 48-96 hrs after last drink- hallucinations, disoriented, tachycardia, hypertension, hyperthermia, diaphoresis- this can be fatal
- fluids and electrolyte imbalances
What is the treatment for acute alcohol withdrawal?
Benzodiazepines- control psychomotor agitation and prevent worsening
e.g. Chlordiazepoxide
or Oxazepam
These have a shorter half life
Use as a reducing dose regimen over around 9 days.
Aim is the lowest possible dose that surpasses symptoms without excess sedation- risk of encephalopathy.
- Ideally, DON’T send patient home with benzos due to risk of dependence and overdose that can lead to repsiratory depression ( complete in hospital)
Also:
- IV fluids
- Nutrient supplementation
- Frequent assessment of vital signs
What is cholestatic pruritis and how is it treated?
Severe itching associated with LD.
Treatments are symptom control( but we also want to try and treat underlying cause):
- Anti-histamines- non-sedating to avoid hepatic encephalopathy e.g. Cetirizine, Loratadine
- Calamine lotion, menthol in aqueous cream- cooling effect
What tends to be the earliest and most common LD complication?
Ascites- 50% have within 10 years of diagnosis
What is the treatment for ascites?
- Diuretics:
1st line: Spironolactone- as it is an aldosterone antagonist - Can add a loop diuretic e.g. Furosemide, if aldosterone is insufficient or also has other oedemas
- Bedrest
- Sodium and fluid restriction
- If diuretics and fluid restriction is insufficient = Paracentesis (a needle is inserted into the peritoneal cavity to drain ascitic fluid)
AIM: weight loss:
0.5-0.75kg per day
Up to 1-1.5kg per day if pt also had peripheral oedema
Therapeutic monitoring- weight loss, symptom reduction
Toxic: hypovalemia, hyponatraemia, hypokalaemia ( can occur if weight loss too rapid). Due to risk of hepatic encephalopathy.
What is the first line diuretic choice for ascites?
1st line: Spironolactone- as it is an aldosterone antagonist
- Can add a loop diuretic e.g. Furosemide, if aldosterone is insufficient or also has other oedemas
What are the weight loss targets for ascites treatment?
AIM: weight loss:
0.5-0.75kg per day
Up to 1-1.5kg per day if pt also had peripheral oedema
What are the therapeutic and toxic monitoring parameters for a diuretic used for ascites?
Therapeutic monitoring- weight loss, symptom reduction
Toxic: hypovalemia, hyponatraemia, hypokalaemia ( can occur if weight loss too rapid). Due to risk of hepatic encephalopathy.
What is the treatment for wernicke’s encephalopathy/korsakoff syndrome
In hospital:
- IV Pabrinex (iv vit B/C preparation)
Infusion over 30 minutes
Comes as 2 pairs of ampoules that are mixed and given TDS for 3-5 days
Is potential for anaphylaxis so be prepared.
Long-term:
Oral Thiamine e.g. 100mg TDS
Start at the same time as pabrinex while in hospital, but then continue for 3-6 months after abstinence or indefinitely
What is the treatment for hepatic encephalopathy?
- Lactulose: high-dose (30-50mLs) TDS
Adjust to aim for 2-3 soft stools per day (stool chart is part of therapeutic monitoring)
Want to avoid diarrhoea as it can cause dehydration and hypovalemia (toxic m.p)
If can’t take/tolerate oral lactulose, can give phosphate enemas - Rifaximin- can be added where optimised lactulose is insufficient.
is a semi-synthetic derivative of rifamycin antibiotic that decreases production/absorption of gut ammonia
Avoid precipitating factors for development of HE:
- Dehydration
- hypokalemia
- gi haemorrhage risk
- caution with CNS-acting drugs
- Avoid high protein intake- nitrogenous waste
- things that cause constipation- increases time for ammonia to be absorbed
What factors that can precipitate hepatic encephalopathy should be avoided?
- Dehydration
- hypokalemia
- gi haemorrhage risk
- caution with CNS-acting drugs
- Avoid high protein intake- nitrogenous waste
- things that cause constipation- increases time for ammonia to be absorbed
What is the MOA of lactulose in treating hepatic encephalopathy?
has 3 MOAs:
Is a disaccharide that breaks down to lactic, acetic and formic acid= decreases pH of intestine from 7 to 5 which causes:
- Ionisation of nitrogenous compounds to decrease their absorption in gut
- alters intestinal flora to decrease amount of ammonia-producing bacteria
- increases speed of gut transit time = less absorption into system ( ammonia and N waste).
What is the treatment for portal hypertension?
Aim of treatment is to decrease portal BP and resting heart rate by 25%
- Propranolol (beta-blocker)- low dose as undergoes extensive 1st pass metabolism which is decreased in LD. So start low and go slow
- Other vasodilator can be added if this is insufficient e.g. nitrates
What is the treatment aim for portal HTN?
Aim of treatment is to decrease portal BP and resting heart rate by 25%
What is the treatment for bleeding oesophageal varices?
This is a complication of portal HTN as the compensatory collateral system has thin walls that are liable to rupture.
Requires resuscitation and hypovalemia correction:
Blood transfusions
IV fluids
Try to stem bleeding:
IV injection of vasoactive therapy e.g. Vasopressin, Terripressin or octreotide
= causes vasoconstriction of collateral blood vessels and decrease portal BP- start ASAP
Ongoing management after initial resuscitation:
- Endoscopy to identify site of bleed
Then try to control:
- Sclerotherapy- inject bleeding varies with Ethanolamine- stops bleeds
- Ligation/banding
- balloon tamponade
- TIPS- transjegular intrahepaic portal system stent shunt
What is the treatment for clotting abnormalities in LD?
Prothrombin time of >18 seconds
Treatment:
IV Phytomenadione (IV Vitamin K). May not work in severe liver disease, as the liver is still unable to produce the clotting factors.
- If increased prothrombin time is due to cholestasis/decreased absorption of bile salts, this will work as replaces the vit K not absorbed due to lack of bile salts.
What should be avoided in patients with clotting abnormalities?
Any drugs that increase bleeding risk e.g. Aspirin, NSAIDs, Warfarin, where possible.
What prothrombin times indicative of clotting abnormalities?
> 18 seconds
What are the risk factors for drug-induced liver disease?
Age- increasing age
Under 3s on sodium valproate for epilepsy or under 16s on aspirin (risk of Reye’s which is a type of HE)
Female- 2x more likely
Alcohol
Pre-existing liver disease
Genetic factors
Co-morbidities e.g. HIV
drug formulation
What are the two types of adversed drug reactions (ADRs) associated with drug-induced liver disease?
ADR type A:
- intrinsic or predictable
- Reproducible injury in animals
- due to drug or metabolite
- 80% of ADRs
- Eg. paracetamol, carbon tetrachloride
ADR type B:
- Idiosyncratic or unpredictable
- Hypersensitivity or immunoallergenic e.g. phenytoin with fever, rash, eosinophilia
- e.g. chlor[romazine, halothane
or metabolic idiosyncratic- indirect, caused by metabolite rather than original drug.
What are the signs of drug-induced liver disease on LFTs?
Many drugs can cause increase in LFTs with no consequences, but if:
- Increased ALT to >2x normal upper limit
- Increased conjugation bilirubin to >2x normal upper limit
- combines increase in ALP and bilirubin with one >2x upper limit
- other symptoms of LD
What is the management for drug-induced liver disease?
- Drug withdrawal
- Give antidote if appropriate
- Can consider corticosteroids- controversial- if consequences remain till 6 months after discontinuation or if still deteriorating liver function 3 weeks after withdrawal
- supportive therapy
- yellow card report
How can drug-induced liver disease be prevented?
- Regular LFT monitoring
- Patient education:
Signs of LD e.g. malaise, fever, abdominal discomfort
Aware of risk of OTC meds e.g. no more than 4g paracetamol/per day
caution of herbal remedies
What is the most common drug causing drug-induced liver disease?
Paracetamol- causes >50% of acute liver failure
What are the 4 phases of paracetamol hepatotoxicity:
PHASE 1:
0.5-24 hours after ingestion
May be asymptomatic= delay in seeking help and increased risk of LD. 12 hours after ingestion shows decreased efficacy of antidotes
Can have N+V, malaise, anorexia
PHASE 2:
18-72 hours after
Right upper quadrant pain, tenderness, anorexia, N+V, oliguria (lack of urine production).
PHASE 3:
Hepatic phase- 72-96 hours after
Hepatic necrosis- jaundice, coagulopathy (clotting abnormalities), hypoglycaemia, hepatic encephalopathy, acute renal failure, death from multi organ failure
If untreated, all of these symptoms will occur.
If treated, Phase 4 occurs
PHASE 4: recovery- 4 days-3 weeks after
Complete resolution if survive phase 3 and complete resolution of organ failure.
At what time after paracetamol overdose, does the efficacy of antidotes begin to diminish?
12 hours after ingestion shows decreased efficacy of antidotes
Discuss the process of paracetamol metabolism?
- 95% of dose is conjugated with glucuronide and then excreted in the urine
- 5% undergoes metabolism to ‘NAPQI’ (N-acetyl-P-benzoquinone imine) via CYP P450. This is toxic.
But at normal doses, it is all detoxifies by conjugation with glutathione and excreted in urine. However, when paracetamol is taken in overdose, glutathione stores become depleted too quickly and so NAPQI can accumulate and bind directly to hepatocytes causing cell damage.
What are the treatments for a paracetamol overdose?
If detected within 1 hour of ingestion, the process is the same as all overdoses and poisonings:
- Activated charcoal or gastric lavage (stomach pumping)- removes unabsorbed paracetamol. However, within 1st hour is rare.
If not within the hour:
- Give Acetylcysteine IV- replenishes glutathione stores
- can use methionine (rare)- only oral not IV
Ideally acetylcystine should be given during first 8 hours of overdose. After 12 hours the efficacy decreases but is still given.
Dosing of acetylcystine is calculated according to plasma paracetamol concentrations and time after ingestion:
- blood test
- plot plasma conc in blood vs time since ingestion on a graph:
if above ‘normal treatment line’- treat with acetylcysteine
- note, there is also an ‘enhanced risk’ line for malnourished patients, those on enzyme inducers, HIV patients, alcoholics (toxicity at lower doses)
Which patient groups fall into needing the ‘enhanced risk’ line when assessing plasma paracetamol concs following an overdose?
malnourished patients
those on enzyme inducers
those with HIV
alcoholics
= toxicity occurs at lower doses
