JC65 (Medicine) - Liver Failure, Hepatic encephalopathy

Question 1

Define liver failure into 3 entities

Answer 1

Question 2

Define acute liver failure

Define acute-on-chronic liver failure

Answer 2

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

Question 3

Common Causes of acute liver failure

Answer 3

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

Question 4

Acute liver failure

Effect on liver metabolism and clinical manifestations

Answer 4

Liver: Loss of metabolic functions:

• Decrease gluconeogenesis >> Hypoglycaemia
• Decrease lactate clearance >> Lactic acidosis
• Decrease ammonia clearance >> Hyperammonaemia
• Decrease synthetic function >> Coagulopathy

Question 5

Acute liver failure

Effect on lungs, Adrenal glands, Brain, Heart, Kidney

Answer 5

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

Question 6

Causes of acute-on-chronic liver failure

Answer 6

1. HBV-related: severe exacerbation or immunosuppression without prophylaxis
2. Infections: Superimposed HAV/HEV or systemic infections
3. External agents: Alcoholic hepatitis, Hepatotoxic drugs/ herbs

Question 7

Systemic effects of liver failure (most common/ pertinent S/S)

Answer 7

General, non-specific malaise

Encephalopathy

Ascites - hypoalbuminaemia

Renal impairment (low blood flow)

Hyperammoniaemia

Coagulopathy

Jaundice

Fetor hepaticus

Question 8

Describe liver fibrosis - histological features

Answer 8

• Diffuse process affecting entire liver
• Regenerative nodules of hepatocytes
• Nodules surrounded by fibrous connective tissue

Question 9

Prognostic scoring systems for liver cirrhosis

Answer 9

Child-Pugh score

MELD score - Model for End-stage Liver Disease

Question 10

Child-Pugh Score

Outline metrics and classes

Answer 10

Question 11

Child-Pugh score

Limitations/ Disadvantages

Answer 11

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

Question 12

MELD score

Formula/ metrics measured

Function

Answer 12

Bilirubin, INR, Creatinine measured

Function: Prediction of 3-month mortality >> prioritize patients for liver transplant

Question 13

Name one criteria for poor prognosis prediction for acute liver failure

Answer 13

1. 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

Question 14

Metrics for poor prognosis prediction of paracetamol-induced liver failure

Answer 14

pH < 7.3 or

PT > 100s, Creatinine > 300, Grade III or IV hepatic encephalopathy

Question 15

Complications of liver failure

Answer 15

1. Infections
2. Variceal bleeding
3. Ascites and spontaneous bacterial peritonitis
4. Hepatorenal syndrome
5. Hepatic encephalopathy
6. Coagulopathy

Question 16

Increased infection tendency due to liver failure

Pathogenesis

Prevalence

Causative agents

Tx

Answer 16

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

Question 17

Causes of Fulminant liver failure leading to encephalopathy

Answer 17

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

Question 18

Precipitants of hepatic encephalopathy in cirrhotic patients

Answer 18

□ ↑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

Question 19

Pathogenesis of Hepatic encephalopathy

Answer 19

1. 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
2. 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
3. Changes in cerebral energy metabolism: Ammonia may inhibit glycolytic enzymes → ↑cerebral lactate concentration
4. Manganese accumulation in basal ganglia: extrapyramidal symptoms with dopamine depletion
5. Impaired neurotransmission: GABA-BDZ neurotransmitter system mediate neurotoxicity

Question 20

Clinical features of hepatic encephalopathy

Answer 20

1. Cognitive deficits: Poor attention, increase reaction time, Poor working memory
2. Depressed consciousness: sleep disturbance, proceed to lethargy, disorientation, coma
3. Psychiatric abnormalities: Mood fluctuation, irritability, disinhibition, delirium
4. Neuromuscular: tremor, apraxia, asterixis, impaired handwriting, slurred speech, ataxia, hyper-reflexia, bilateral
   Babinski sign or even dilated pupils
5. Fetor hepaticus
6. Cerebral edema: uncommon in chronic encephalopathy but frequent in acute fulminant failure (80%)

Question 21

Outline the metrics of grading system for hepatic encephalopathy

List the most pertinent features of each grade

Answer 21

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

Question 22

Confusion in cirrhosis is ONLY due to hepatic encephalopathy

True or false

Why?

Answer 22

False

Differentials of cirrhosis and confusion:

1. Drug/ alcohol related
2. Drug withdrawal state: delirium tremens (e.g. alcoholic with cirrhosis)
3. CNS/ systemic infections: poor immunity due to cirrhosis
4. Metabolic disturbances: e.g. uremia
5. Psychiatric cause and head injuries (not directly related to cirrhosis)

Question 23

How to diagnose hepatic encephalopathy

Answer 23

NO single diagnostic tool/ criteria!!

Clinical P/E tests:

1. Clinical exam by GCS, Neurological P/E: consciousness, intellect, tremor, reflexes, lapping tremor (≥grade 2) + Fetor hepaticus
2. Psychometric test: MOST sensitive for minor deficits of mental function

Objective investigations:

1. Arterial ammonia
2. EEG: bilaterally synchronous ↓wave frequency with ↑wave amplitude
3. Non-contrast CT brain: exclude alternative causes of confusion and detect cerebral oedema in acute HE

Question 24

Outline psychomotor test for hepatic encephalopathy

Answer 24

→ 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

Question 25

Ddx hepatic encephalopathy

Answer 25

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

Question 26

First-line investigations for triggers of hepatic encephalopathy

Answer 26

1. Clinical: drug/toxin exposure, Toxicology report
2. GI bleed and hypovolaemia
3. Infection screen: blood/urine culture, paracentesis for SBP
4. Serum biochemistry: metabolic and electrolyte abnormalities
5. AFP for HCC-induced hepatic decompensation

Question 27

Management plan for hepatic encephalopathy

Answer 27

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

Question 28

Non-absorbable disaccharides for hepatic encephalopathy

Examples

PK

MoA

RoA

S/E

Answer 28

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

Question 29

Rifaximin for Hepatic Encephalopathy

MoA

Effectiveness

Answer 29

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

Question 30

Dietary modifications for Hepatic encephalopathy

Answer 30

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)

Question 31

BCAA and LOLA for hepatic encephalopathy

MoA

Answer 31

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

Question 32

Acute liver failure:

Indications for treatment of coagulopathy

Answer 32

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