LIVER PATHOLOGY 1
What causes vomiting and nausea in alcoholic liver disease?
Acetylaldehyde
What is the leading cause of liver cirrhosis globally?
Chronic hepatitis B
Death will be declared upon irreversible cessation of what 3 things?
1. circulation (syncope)
2. respiration (asphyxia)
3. innveration (coma)
What is the conjugate that prevents NAPQI from causing hepatocyte damage normally?
BONUS: What is the antidote to NAPQI overdose?
Glutathione conjugation
N-acetylcysteine
What are the 3 stages of liver biotransformation and drug elimination?
1. transport drugs from blood
2. biotransformation in liver (phase 1 and phase 2)
3. elimination (biliary excretion and efflux to blood for eventual renal excretion)
BONUS: When are they present?
Hyaline bodies --> aggregated intermediate cyto-keratin filaments in the cell cytoplasm
Seen in alcoholic hepaitits
What is the primary target for antifibrotic therapy?
Myofibroblasts
Why do people get an end of life fever?
Because the hypothalamus cannot regulate their temperature anymore
What does zero order kinetics mean?
BONUS: saturation of what leads to the zero order profile in alcohol metabolism?
Rate of drug elimination is constant, regardless of the plasma concentration.
Saturation of alcohol dehydrogenase
What determines the hepatic clearance of a drug that is highly extracted compared with one that is poorly extracted?
Highly extracted: blood flow and hepatocyte function
Poorly extracted: hepatocyte function alone
What are the three main microscopic changes that must be present for it to be called cirrhosis?
1. nodules - micronodules
2. bridging fibrosis
3. disorganised liver architecture
What are 3 causes of congenital cirrhosis and 3 causes of acquired cirrhosis?
Congenital: congenital syphilis, haemochromatosis, wilson disease, a1 antitrypsin deficiency, glycogen storage disease
Acquired: post-hepatic, alcohol, biliary cirrhosis, cryptogenic
What is apparent death?
BONUS: What is another name for apparent death?
A state in which vital functions are reduced to a minimum and the person appears dead (pulse not palpable, heart sounds not audible, respiratory movements are not visually perceptible, reflexes are either absent or difficult to elicit), the person is not actually dead and resuscitation is possible in many cases.
Suspended animation
Explain what happens in phase 1 and phase 2 of biotransformation in the liver.
Phase 1: oxidative reactions --> make drug more polar, oxidation via BYP450 enzymes, udually add -OH, -NH2, -SH groups
Phase 2: conjugation to polar ligands --> conjugate drug with carrier molecule, leading to decreased activity
What are the modes of aquisition of a liver abscess?
- faeco-oral (parasites)
- haematogenous seeding from GIT (multiple small abscesses)
- ascending cholangitis
- direct invasion from nearby single large abscess
What is the treatment for liver abscesses?
Bacterial: IV pip taxobactam + metronidazole for 2-3 weeks
Amebiasis: IV metronidazole for 7-10 days + dixanide furoate or paromomycin for 10 days after finishing metronidazole
Hyatid: albendazole for 3-6 months
What are the histological features of hepatocellular carcinoma (3)?
Hyperchromatism, prominent nucleoli, cytoplasm eosinophilic
What is the supravital period and what does this period depend on?
Brief period between somatic death and cellular death where cells are still functioning off the stores.
Depends on oxygen supply and metabolic activity
What are the 4 effects on the body after alcohol is converted to acetylaldehyde?
1. increased FFA synthesis and decreased FFA oxidation
2. inhibits gluconeogenesis, leading to hypoglycaemia
3. reacts directly with hepatocyte proteins leading to fibrosis
4. reacts with and depletes glutathione
What is the difference between an experimental and observational study and give an example of each?
Experimental: participants in the study are assigned to groups, such as new experimental drug vs. existing treatment (RCT)
Observational: the event occurs naturally, so you pick a way to study the event and observe what happened (case-control, cohort study)
Where are each of the liver enzymes located?
ALT --> cytosol
AST --> mitochondria + cytosol
ALP --> canalicular surface
GGT --> canalicular surface + microsomes
5'-NT --> canalicular surface
Explain what happens to hepatic stellate cells to cause fibrosis
In response to continuous liver injury HSCs reduce the expression of genes such as glial fibrillar acidic protein (GFAP) and peroxisome proliferator-activated receptor gamma (PPARy), lose lipid droplets and activate into myofibroblasts.
Myofibroblasts start expressing fibrogenic genes such alpha-smooth muscle actin (a-SMA) and collagen type
What is the difference between cerebral cortex damage and brainstem damage?
Cerebral cortex damage: loss of higher mental function, brainstem is still intact (breathing and circulation), 3 possible outcomes --> recovers vegetative state, brain death
Brainstem damage: no CNS control to breathing or circulation --> irreversible (brain death)
What are the 2 main families of drug transporters and what is the difference between them?
P-glycoprotein: efflux pump, found in gut, liver, kidney + blood-brain barrier --> transports drugs from enterocytes into intestinal hepatocytes into bile for elimination
Organic anion transporting polypeptides (OATPs): influx pump, found in gut, liver, kidney + blood-brain barrier --> transport drug into cells
What do you need to check for when verifying normal death?
Neurological and reflex checks: arousal test, pupil reflexes, corneal reflexes, motor or facial response to pain
Circulation checks: absence of central pulse, check apex of heart
Respiratory checks: look for chest wall movement and listen to trachea/lungs
Other signs of irreversible death: rigor mortis, hypostasis, decomposition