15.4.4 Acute Liver Dysfunction Flashcards
Define Hepatitis
Inflammation of the liver
Define Acute hepatitis
Inflammation of the liver of less than 6 months duration
Define acute liver failure NB
coagulopathy within 8 weeks of onset of liver disease that is, not correctable with vitamin K, no evidence of chronic liver disease, may or may not have encephalopathy if liver injury is severe – coagulopathy
Mechanisms of acute liver dysfunction
- Infections
- viral
- bac
- parasitic - Drugs or toxins 3. Cardiovascular
- Metabolic 5. Immune
-viral -bacterial -parasitic
- predictable dose-dependent
- idiosyncratic (allergic or non-allergic)
- inherited metabolic disorders - acquired metabolic disorders
- autoimmune hepatitis
slide 4
Infections Pathogenesis
Hepatotropic viruses
hepatitis A, B, C, D, E
• Other viruses
herpes simplex virus 1&2, EBV, CMV, adenovirus, parvovirus, Covid-19, enteroviruses, HHV- 6/7/8, varicella zoster virus
• Bacterial infections Congenital syphilis
Salmonella, Shigella, Campylobacter, Streptococcus
• Parasitic infections malaria
Hep A virus
- Most common cause of acute hepatitis in South African children
- Most cases asymptomatic (95%)
- Faecal-oral transmission
- Acute liver failure in <1% associated with high mortality
-No chronic infection, no chronic liver disease after recovery - Lifelong immunity after infection
NB Pathogenesis related to a combination of direct cytopathic effect of virus and immune-mediated damage to infected hepatocytes
Hep B
Transmission in Children:
- Vertical & horizontal
- Sharing toothbrushes or masticated foods
- Acute Liver Failure: 2%
- Chronic infection:
Neonatal infection >90%
< 5 years 20%
Adult 5%
Hep B virus (HBV)
- HBV is not cytopathic
- Immune response directed against virus contributes to hepatocyte
injury
- Cytokines eg interferon involved
- T cells infiltrate the liver and destroy hepatocytes
Drug induced liver injury: pathogenesis
Two types
Dose-dependent predictable hepatotoxicity
Example: paracetamol hepatotoxicity: single high dose (>125mg/kg) or cumulative high dose over several days
- Paracetamol is metabolised in the liver by conjugation with glucuronides or sulphates, but also via cytochrome P450 enzymes to toxic metabolite N- acetyl-para-benzoquinone-imide (NAPQI)
- NAPQI is conjugated and inactivated through glutathione
- With high doses of paracetamol, glutathione stores in liver depleted, NAPQI metabolites accumulate→hepatocellular necrosis
- N-acetylcysteine=antidote – restores depleted glutathione
Idiosyncratic hepatotoxicity
Example: halothane hepatitis (also: antibiotics, NSAIDs)
- Halothane hepatitis – immune-mediated adverse drug reaction
➡️typically only after second exposure
➡️sensitization to auto-antigens and halothane-altered liver cell determinants lead to liver injury
➡️specific antibodies involved in hepatic injury
Cardiovascular pathogenesis
- Hepatic ischaemia due to significant hypotension may lead to hepatic injury – inadequate perfusion of any cause
- Congestive cardiac failure may lead to hepatic congestion that may lead to hepatic injury and dysfunction due to back pressure and congestion of the liver
- Budd- Chiari syndrome = occlusion of the hepatic veins – obstruction of venous drainage of liver may lead to liver failure
Causes either:
- acute cariogenic liver injury
- congestive hepatopathy
NB Budd-Chiari syndrome
- Occlusion of at least two hepatic veins may be due to any condition that increases thrombosis eg thrombophilic conditions, compression of veins by mass (eg neoplasm)
Pathogenesis of metabolic diseases
- Liver has central role in metabolism
- Most inherited metabolic disorders (IMDs) are single gene conditions and the faulty protein is an enzyme
- May present as liver disease or involve multiple organ systems
- Presentation may be varied: acute liver failure ↔ encephalopathy ↔ hepatomegaly ↔ cholestasis
Inherited Metabolic Disorders
Don’t need to know everything, just the concept
- Carbohydrate metabolism: galactosaemia, hereditary fructose intolerance, glycogen storage disorders, disorders of gluconeogenesis (many present with hypoglycaemia as part of presentation)
- Protein metabolism: tyrosinaemia, urea cycle disorders, organic acidaemias
- Lipid metabolism: fatty acid oxidation defects
- Storage disorders: lysosomal storage disorders, peroxisomal
disorders, - Mitochondrial disorders
Metabolic disease pathogenesis: galactosaemia
- Example: galactosaemia
- Autosomal recessive genetic disorder
- Deficiency in enzyme galactose-1-phosphate uridyl transferase
- Accumulation of galactose
- Human breast milk contains lactose (glucose + galactose)
- Become ill rapidly due to toxic effects of accumulation of excess galactose – acute liver failure, cataracts, hypoglycaemia, raised intracranial pressure, failure to thrive, renal tubulopathy
- Treatment: lifelong avoidance of galactose (in all feeds and medications) – infants need sucrose-containing milks eg soya
Immune pathogenesis: Autoimmune hepatitis
- Aetiology unknown – suspected both genetic predisposition and environmental factors
- Initial trigger – ?viral infection
- Autoantigenic peptide on hepatocytes presented to helper T cells – activated→autoantibody production by B cells and autoreactive cytotoxic T cells
- ?Impairment of immune regulatory pathways
Symptoms of acute hepatic dysfunction
- Children may be completely asymptomatic – incidentally picked up by liver tests (raised transaminases)
- Jaundice – only symptom
- Symptoms of acute hepatitis: jaundice with abdominal pain, nausea, vomiting, tender hepatomegaly, dark urine
