JC65 (Medicine) - Liver Failure, Hepatic encephalopathy Flashcards
Define liver failure into 3 entities
Define acute liver failure
Define acute-on-chronic liver failure
Acute:
Development of severe, acute liver injury with encephalopathy and impaired synthetic function (INR >1.5)
In a patient without pre-existing cirrhosis/ Chronic liver disease
Acute-on-chronic:
Acute liver insult manifesting Jaundice. INR> 1.5
Complicating within 4 weeks by ascites and/ or encephalopathy
In patient with underlying chronic liver disease
Common Causes of acute liver failure
Drug-related (50%)
- Paracetamol overdose
- Idiosyncratic drug reactions: e.g. halothane, isoniazid
- Herbal-related
Acute viral hepatitis (HAV, HBV, HEV)
Pregnancy-related: Acute fatty liver of pregnancy, HELLP
Metabolic: Wilson’s disease
Acute liver failure
Effect on liver metabolism and clinical manifestations
Liver: Loss of metabolic functions:
- Decrease gluconeogenesis >> Hypoglycaemia
- Decrease lactate clearance >> Lactic acidosis
- Decrease ammonia clearance >> Hyperammonaemia
- Decrease synthetic function >> Coagulopathy
Acute liver failure
Effect on lungs, Adrenal glands, Brain, Heart, Kidney
Lungs:
- Acute lung injury
- ARDS
Adrenals:
- Low glucocorticoid production >> hypotension
Brain:
- Hepatic encephalopathy
- Cerebral edema
- Intracranial hypertension
Heart:
- High output and myocardial injury
Kidneys:
- Dysfunction or failure
Causes of acute-on-chronic liver failure
- HBV-related: severe exacerbation or immunosuppression without prophylaxis
- Infections: Superimposed HAV/HEV or systemic infections
- External agents: Alcoholic hepatitis, Hepatotoxic drugs/ herbs
Systemic effects of liver failure (most common/ pertinent S/S)
General, non-specific malaise
Encephalopathy
Ascites - hypoalbuminaemia
Renal impairment (low blood flow)
Hyperammoniaemia
Coagulopathy
Jaundice
Fetor hepaticus
Describe liver fibrosis - histological features
- Diffuse process affecting entire liver
- Regenerative nodules of hepatocytes
- Nodules surrounded by fibrous connective tissue
Prognostic scoring systems for liver cirrhosis
Child-Pugh score
MELD score - Model for End-stage Liver Disease
Child-Pugh Score
Outline metrics and classes
Child-Pugh score
Limitations/ Disadvantages
Limited discrimination between classes of severity
Subjective assessment of ascites and encephalopathy
Variable PT and Albumin levels in different laboratories
Albumin and PT measurements have many confounding factors e.g. FFP infusion, haemodilution…etc
MELD score
Formula/ metrics measured
Function
Bilirubin, INR, Creatinine measured
Function: Prediction of 3-month mortality >> prioritize patients for liver transplant
Name one criteria for poor prognosis prediction for acute liver failure
- King’s criteria: (know name only)
- PT >100s or 3 of the following
- Age under 10 or over 40
- Duration of jaundice before encephalopathy > 7 days
- PT > 50s
- Bilirubin >300
- non Hep-A or Hep-B, or idiosyncratic drug reaction
Metrics for poor prognosis prediction of paracetamol-induced liver failure
pH < 7.3 or
PT > 100s, Creatinine > 300, Grade III or IV hepatic encephalopathy
Complications of liver failure
- Infections
- Variceal bleeding
- Ascites and spontaneous bacterial peritonitis
- Hepatorenal syndrome
- Hepatic encephalopathy
- Coagulopathy
Increased infection tendency due to liver failure
Pathogenesis
Prevalence
Causative agents
Tx
Reticuloendothelial dysfunction + reduce complement production and opsonization of bacteria
Bacteremia common, 25% fulminant liver failure
Causative: Staphylococcus, Streptococcus and Gram negative rods
Common respiratory and urinary infection
Tx: Broad spectrum antibiotics with fungal coverage
Causes of Fulminant liver failure leading to encephalopathy
Fulminant liver failure >> Decompensated cirrhosis >> Spontaneous portosystemic shunts + Progressive hepatic failure in detoxification >> nitrogenous products shunted to systemic circulation to brain >> encephalopathy
Fulminant liver failure:
→ Viral hepatitis
→ Drug-induced, eg. paracetamol, halothane, isoniazid
→ Herbs and health food products
→ Metabolic, eg. pregnancy, Reye syndrome, Wilson’s disease
→ Cardiovascular, eg. shock, heatstroke
Precipitants of hepatic encephalopathy in cirrhotic patients
□ ↑nitrogen-containing products in diet, sepsis, GI bleeding, renal failure, transfusion, constipation
□ ↓vascular volume leading to ↓O2 to liver: GI bleeding, overdiuresis, excessive paracentesis with inadequate Alb replacement, diarrhoea and vomiting
□ Sedatives
□ Electrolyte imbalance, esp hypoK and Acid-base imbalance
□ Artificial portosystemic shunts, eg. TIPS, surgery
Pathogenesis of Hepatic encephalopathy
- Increase arterial ammonia:
→ liver cannot detoxify NH3 to urea
→ Increase cerebral metabolic rate and BBB permeability to NH3
→ Increase cerebral NH3: astrocyte damage by oxidative stress: swelling and mitochondrial dysfunction - Systemic and neuroinflammation:
Increase BBB permeability due to systemic inflammation, ↑permeability to neurotoxins
Neuroinflammation may induce ↑cerebral cytokines (eg. TNF, IL-1B) leading to HE - Changes in cerebral energy metabolism: Ammonia may inhibit glycolytic enzymes → ↑cerebral lactate concentration
- Manganese accumulation in basal ganglia: extrapyramidal symptoms with dopamine depletion
- Impaired neurotransmission: GABA-BDZ neurotransmitter system mediate neurotoxicity
Clinical features of hepatic encephalopathy
- Cognitive deficits: Poor attention, increase reaction time, Poor working memory
- Depressed consciousness: sleep disturbance, proceed to lethargy, disorientation, coma
- Psychiatric abnormalities: Mood fluctuation, irritability, disinhibition, delirium
-
Neuromuscular: tremor, apraxia, asterixis, impaired handwriting, slurred speech, ataxia, hyper-reflexia, bilateral
Babinski sign or even dilated pupils - Fetor hepaticus
- Cerebral edema: uncommon in chronic encephalopathy but frequent in acute fulminant failure (80%)
Outline the metrics of grading system for hepatic encephalopathy
List the most pertinent features of each grade
Consciousness and intellect
Clinical features
EEG
0 – Psychomotor test
1 – Sleep pattern inverted, apraxia/ tremor
2 – Asterixis, Areflexia
3 – Babinski, Hyperreflexia, Flapping tremor
4 – Coma, Decerebrate position
Confusion in cirrhosis is ONLY due to hepatic encephalopathy
True or false
Why?
False
Differentials of cirrhosis and confusion:
- Drug/ alcohol related
- Drug withdrawal state: delirium tremens (e.g. alcoholic with cirrhosis)
- CNS/ systemic infections: poor immunity due to cirrhosis
- Metabolic disturbances: e.g. uremia
- Psychiatric cause and head injuries (not directly related to cirrhosis)
How to diagnose hepatic encephalopathy
NO single diagnostic tool/ criteria!!
Clinical P/E tests:
- Clinical exam by GCS, Neurological P/E: consciousness, intellect, tremor, reflexes, lapping tremor (≥grade 2) + Fetor hepaticus
- Psychometric test: MOST sensitive for minor deficits of mental function
Objective investigations:
- Arterial ammonia
- EEG: bilaterally synchronous ↓wave frequency with ↑wave amplitude
- Non-contrast CT brain: exclude alternative causes of confusion and detect cerebral oedema in acute HE
Outline psychomotor test for hepatic encephalopathy
→ Number connection (Reitan test): most commonly used
→ Five-pointed star drawing for constructional apraxia
→ Psychometric HE score (PHES): battery of 5 paper-and-pencil tests
→ Others, eg. inhibitory control test (ICT), critical flicker frequency
Ddx hepatic encephalopathy
Important d/dx:
□ Delirium tremens and Wernicke’s encephalopathy in alcoholic cirrhosis
□ Subdural haematoma from head injuries
□ Functional psychosis
□ Other metabolic encephalopathies, eg. hypo/hyperGly, uraemia, ↑CO2, ↓O2, hypoNa
First-line investigations for triggers of hepatic encephalopathy
- Clinical: drug/toxin exposure, Toxicology report
- GI bleed and hypovolaemia
- Infection screen: blood/urine culture, paracentesis for SBP
- Serum biochemistry: metabolic and electrolyte abnormalities
- AFP for HCC-induced hepatic decompensation
Management plan for hepatic encephalopathy
Identification and correction of precipitating factors
Dietary management
Specific therapy to lower blood ammonia level in overt hepatic encephalopathy:
→ Non-absorbable disaccharides, eg. lactulose, lactitol (1st line)
→ Oral non-absorbable antibiotics, eg. rifaximin, (neomycin)
→ AA supplementation: BCAA, L-ornithine-L-aspartate
Non-absorbable disaccharides for hepatic encephalopathy
Examples
PK
MoA
RoA
S/E
eg. lactulose, lactitol
Pharmacokinetics: non-absorbable synthetic syrup
MoA:
- As osmotic laxative to decrease nitrogenous compounds in gut
- Lower colonic pH to inhibit urease-producing bacteria (E.coli), Trap luminal NH3 by converting into NH4+, Draws NH3 from mucosal blood into gut
RoA: orally or in enema
S/E:
→ Adversion to sweet taste
→ Nausea and vomiting
→ Flatulence
→ Osmotic diarrhoea → dehydration, hyperNa, hypoK
→ Pneumatosis coli due to ↑gas production
Rifaximin for Hepatic Encephalopathy
MoA
Effectiveness
Rifaximin: most commonly used non-absorbable oral Abx
□ MoA: alteration of colonic flora, esp urease-producing → lower colonic NH3 production
Effects:
→ Effective when combined with lactulose (superior to lactulose alone)
→ Effective in ↓recurrence of HE
Dietary modifications for Hepatic encephalopathy
Diet targets:
Nutritional support: ensure 35-40kcal/kg/d (to ↓protein breakdown)
Moderate protein diet: keep ~40-60g/d
- Dietary protein restriction should NOT be done except active GI bleed
Increase ammonia removal: Amino acid supplementation
- Branch-chained amino acid (BCAA)
- L-ornithine-L-aspartate (LOLA)
BCAA and LOLA for hepatic encephalopathy
MoA
L-ornithine-L-aspartate (LOLA): as alternative to rifaximin and lactulose
MoA: ↑metabolism of NH3 into glutamine → ↓plasma NH3 concentrations
Branched-chain amino acids (BCAA): as additional therapy
MoA: BCAA detoxifies ammonia via production of glutamate
Acute liver failure:
Indications for treatment of coagulopathy
Correct platelet dysfunction with transfusion if:
- Active Bleeding
- Planning invasive procedure in pt under 50y
- Prophylactically in pt under 20y
Correct with Fresh Frozen Plasma for active bleeding/ invasive procedure
Monitor coagulopathy with PT/INR
