GI & Hepatology JC065: A Jaundiced And Incoherent Patient: Liver Failure

Question 1

Liver failure

Answer 1

Classification:
1. Acute liver failure
2. Acute-on-chronic liver failure
3. Decompensated cirrhosis (underlying cirrhosis gradually deteriorating)

Question 2

1. Acute liver failure (ALF)

Answer 2

Definition:
- Development of severe acute liver injury
- with Encephalopathy + **Impaired synthetic function (INR >1.5)
- in a patient **without pre-existing cirrhosis / chronic liver disease

Causes:
1. **Drug-related
- paracetamol overdose
- idiosyncratic drug reactions
- herbal-related
2. **Acute viral hepatitis (HAV, HEV, Acute HBV)
3. Pregnancy-related causes (acute fatty liver of pregnancy / HELLP syndrome) (rare)
4. Other causes (rare e.g. mushroom poisoning)

Question 3

***Clinical features of Acute liver failure (ALF)

Answer 3

Generally very vague, require investigation of biochemical profile, LFT

Markers of liver failure:
- **Severe hepatitis (↑ liver enzymes)
- **Deterioration of synthetic function
—> ↑ INR
—> ↓ Albumin
—> ↑ Bilirubin (↓ hepatocyte uptake, ↓ conjugation, ↓ hepatocyte secretion of bilirubin)

1. Whole body
   - systemic inflammatory response
2. Liver
   - loss of metabolic function
   - **hypoglycaemia (↓ gluconeogenesis)
   - **lactic acidosis (↓ lactate clearance)
   - **hyperammonaemia (↓ NH3 clearance)
   - **coagulopathy (↓ synthetic capacity)
3. Brain
   - ***hepatic encephalopathy
4. Heart
   - high output state
5. Kidney
   - dysfunction / failure
6. Lungs
   - acute lung injury
7. BM
   - suppression
8. Leukocytes
   - ***impaired function —> high risk of sepsis
9. Pancreas
   - pancreatitis
10. Adrenal glands
    - inadequate glucocorticoid production —> hypotension
11. Portal hypertension

Question 4

2. Acute-on-chronic liver failure (ACLF)

Answer 4

Definition:
- Acute liver insult
- manifesting **Jaundice + **INR >1.5
- complicating within 4 weeks by **Ascites / **Encephalopathy
- in patients ***with underlying chronic liver disease (which may be undiagnosed previously) (i.e. need to exclude underlying liver disease if suspect ALF)

Examples:
1. HBV-related
- severe **exacerbation of HBV
- immunosuppressive agents (steroids, rituximab etc.) lead to **flare up of Hep B

2. Infections
   - ***superimposed HAV / HEV
   - other systemic infections
3. External agents
   - ***alcoholic hepatitis
   - hepatotoxic drugs / herbs

Question 5

Specific “Hepatotoxic” drugs

Answer 5

• Generally safe in vast majority of people
• Usually idiosyncratic (unpredictable, independent of dose, usually in patients newly start on a drug —> drug history is very important!!!)

1. ***Paracetamol (overdose)
2. NSAIDs
3. Statins (very rare)
4. ***Anti-TB (Isoniazid, Rifampicin, Pyrazinamide)
5. Other anti-microbials
6. Anticonvulsants
7. ***Rheumatological (Methotrexate, Azathioprine)
8. Amiodarone

Question 6

Herbs

Answer 6

• > 102 types of hepatotoxic herbs reported
• but difficult to interpret ∵ idiosyncratic + can be from different origin (grow in different places) + lack of standardisation —> a lot of uncertainties
• beware of TCM in tablet / capsule form (中成藥)
• some may not have packaging at all

Question 7

***Systemic effects of Hepatocellular failure

Answer 7

1. General non-specific Malaise
2. ***Encephalopathy (confused / comatose)
3. Ascites (usually late stage)
4. Jaundice (usually late stage)
5. Fetor hepaticus (usually late stage)
6. Circulatory changes (very vague in clinical setting)
   - ↑ CO
   - ↓ Peripheral resistance
   - ↓ Renal bloodflow
7. Nitrogenous (N2) metabolism (very vague in clinical setting)
   - **↑ NH3
   - **↓ Urea (∵ ↓ urea production from NH3)
   - Amino acid abnormalities
   - ***↓ Albumin
8. ***Hepatitis
   - ↑ Parenchymal enzymes
   - depends on acute / chronic:
   —> if liver failure caused by chronic cirrhosis resulting in decompensated cirrhosis —> liver enzymes may not ↑ (∵ no acute insult, simply failure of liver)

Chronic Hepatocellular failure:
1. Skin changes (∵ vasodilatation)
- **Spider angioma
- **Palmer erythema

2. Endocrine changes
   - **Hypogonadism
   - **Hyperaldosteronism (∵ ↓ BP)
3. ***Bleeding tendency
   - Defective coagulation, ↓ Platelet, ↑ Fibrinolysis

Question 8

3. Decompensated cirrhosis

Answer 8

Unlike ALF, in Cirrhosis:
- liver injury takes many years to present its results

Regardless of etiology:
Start with Minor Fibrosis (Portal fibrosis)
—> ↑ Fibrosis
—> Advanced Fibrosis (Septal fibrosis)
—> **Compensated cirrhosis
—> **Decompensated cirrhosis

Detect fibrosis:
Vibration controlled transient elastography
- ***USG-based technique
- non-invasive
- determines level of fibrosis

Question 9

Prognostic factors for ***Cirrhosis

Answer 9

1. Child-Pugh score
2. MELD score (Model for End-stage Liver Disease)

Question 10

1. Child-Pugh score

Answer 10

Offers good but not accurate differentiation of level of cirrhosis

5 Prognostic factors (**記: ABCDE), **3 points for each:
1. Bilirubin (2 points: 2-3 / 38-57)
2. Albumin (2 points: 2.8-3.5)
3. Coagulopathy (PT / INR prolongation) (2 points: 4-6)
4. Distension (Ascites) (2 points: mild)
5. Encephalopathy (2 points: grade 1-2)

Compensated cirrhosis:
Child A: 5-6 points
- Bilirubin, Albumin, PT are normal / near-normal + No Ascites / Encephalopathy

Decompensated cirrhosis:
Child B: 7-9 points
Child C: 10-15 points
- If see **Ascites / **Deranged PT, INR —> at least Child B

Question 11

Disadvantages of Child-Pugh score

Answer 11

1. ***Limited discrimination
   - only 8 levels between Child A, B, C
   - same score for different values of bilirubin, albumin, PT etc.
2. ***Subjective assessment of ascites / encephalopathy
3. Variability of PT + Albumin in different laboratories
4. PT + Albumin measurements can be “manipulated”
   - e.g. FFP infusion, albumin infusion

Question 12

2. MELD score (Model for End-stage Liver Disease)

Answer 12

• Very good in prediction of ***3-month mortality
• Useful to prioritise patients for ***liver transplant (determine who will benefit most from liver transplant)

Version 1:
3.8 x loge (Bilirubin) + 11.2 x loge (INR) + 9.6 (***Creatinine) + 6.4

**3 variables (記: BCCS):
1. Bilirubin
2. INR
3. **Creatinine (concurrent renal dysfunction)
(NO albumin ∵ can be artificially manipulated)

Version 2 addition (MELD-Na score):
4. Na (HypoNa reflect patient in very dilutional stage related to ***fluid retention from cirrhosis)

Question 13

Prognostic factors for ***Acute liver failure

Answer 13

1. King’s college criteria
   - Irrespective of grade of encephalopathy
   - PT >100s (INR >6.5)
   or 3 of following:
   - Age <10 / >40
   - Duration of jaundice before encephalopathy >7 days (indicate low reversibility)
   - PT > 50s (INR >3.5)
   - Bilirubin > 300 umol/L
   - Non-A, Non-B, Halothane or Idiosyncratic drug reaction, Wilson’s disease

For paracetamol poisoning:
- pH <7.3
or
- PT >100 + Creatinine >300 + Grade 3/4 encephalopathy

Question 14

Prognostic factors for ***Acute-on-chronic liver failure (ACLF)

Answer 14

NO consensus yet
- MELD increasingly used

Question 15

***Associated complications of Liver failure

Answer 15

Same as complications of Cirrhosis
1. **Infections (∵ Reticuloendothelial dysfunction + Reduced opsonisation)
2. **Variceal bleeding
3. **Ascites / Spontaneous bacterial peritonitis
4. **Hepatorenal syndrome
5. **Hepatic encephalopathy
(6. **Coagulopathy —> Bleeding tendency (consider when drainage of ascites))

Question 16

***Hepatic encephalopathy (HE) in Decompensated cirrhosis

Answer 16

Causes:
Cirrhosis
- spontaneous ***portal-systemic shunts
—> N2 products in portal circulation after absorption from GI tract
—> shunted to systemic circulation
- progressive hepatic failure in detoxification

Additional **precipitating factors for cirrhotic patients
1. ↑ N2 products via
- **diet (high protein)
- **sepsis
- **GI bleed (urea-containing blood absorbed in GI tract —> end up in systemic circulation again)
- ***renal failure
- transfusion
- constipation

2. ↓ Vascular volume —> ↓ O2 to liver
   - **GI bleed
   - **overdiuresis
   - **excess paracentesis with inadequate albumin replacement
   - dehydration from diarrhoea + vomiting
   - **sedatives
   - **electrolyte imbalance esp. **↓ K
   - acid base imbalance
   - artificial P-S shunt (TIPS (transjugular intrahepatic portosystemic shunt), surgery)

Question 17

Hepatic encephalopathy (HE) in Acute / ACLF

Answer 17

Causes:
**Fulminant liver failure (Acute / ACLF)
- **Viral hepatitis
- ***Drugs (e.g. paracetamol, halothane, INAH)
- Metabolic (e.g. pregnancy, Reye syndrome, Wilson’s disease)
- CVS (e.g. shock, heat stroke)
- Herbal medicines, health food products

Question 18

***Underlying mechanism for HE

Answer 18

Liver failure
—> ↓ Ability of liver to detoxify NH3 to Urea
—> ↑ Cerebral metabolic rate + permeability to NH3
—> ↑ NH3 in brain
—> Astrocyte damage

1. **Hyperammonaemia (↑ arterial ammonia / N2 compounds)
   —> **↑ NH3 levels in brain
   —> Lactate accumulation in brain
2. **Systemic inflammation / ↑ Proinflammatory state (usually found in patients with end-stage cirrhosis)
   —> **↑ BBB permeability
   —> Allow NH3 go into brain

—> Microglial activation
—> ↑ Levels of Cerebral proinflammatory cytokines (e.g. TNF, IL1B) + Neuroinflammation
—> Encephalopathy

Others:
- **↑ Cerebral lactate
- **Manganese accumulation in basal ganglia
- GABA receptor upregulation

Question 19

***HE Grading + Clinical features

Answer 19

Grading (0-4) on 3 aspects (**記: CCE):
1. **Consciousness / Intellect
- forgetfulness, irritability (grade 1)
- lethargic (grade 2)
- somnolent, aggressive (grade 3)
- coma (grade 4)

2. ***Clinical features
   - apraxia (grade 1)
   - flapping tremor (grade 2)
   - babinski +ve (grade 3)
   - decerebrate (grade 4) (extensor predominant posture)
3. ***EEG
   - slow 5 cps triphasic waves (grade 1-3)
   - slow 2-3 cps delta waves (grade 4)

Subclinical (between 0 and 1): Normal Consciousness / Intellect + EEG except Psychomotor testing abnormality (i.e. Clinical features)

Other clinical features:
1. **Fetor hepaticus (hard to detect)
2. **Cerebral edema (frequent in ***acute fulminant failure but uncommon in chronic encephalopathy from decompensated cirrhosis)
—> hard to differentiate from HE clinically —> need CT to tell whether there is edema or not

Question 20

DDx of Confusion in Cirrhosis

Answer 20

Confusion in Cirrhosis =/ HE!!!

Confusion in Cirrhosis: Multiple causes / DDx —> totally different management from HE:
1. Drug / alcohol-related
2. **Withdrawal state from chronic drinker
- **Delirium tremens —> IV Thiamine immediately
- **Wernicke’s encephalopathy (not withdrawal related, self notes)
3. Head injuries
4. **CNS infections
5. **Systemic infections
6. **Metabolic disturbances (e.g. alcohol-induced **hypoglycaemia)
7. Psychiatric
- etc.
—> **Need to exclude above causes to conclude patient has HE

Question 21

Diagnosis of HE

Answer 21

1. ***Exclude other DDx
2. **Arterial ammonia
   - sometimes not ↑ (∴ need to exclude DDx first) (depend on type of N2 compound in systemic circulation)
   - **may not correlate with severity of HE
   - normally 40% by bacterial action, 60% directly from protein breakdown
3. ***EEG abnormalities
4. Other features
   - **Fetor hepaticus
   - **Flapping tremor
   - ***Psychometric tests e.g. Constructional apraxia (drawing five-pointed star), Number connection test (Reitan’s test)
   - Inhibitory control test (for Subclinical HE)
   - Critical flicker frequency (for Subclinical HE)

Question 22

Management of HE

Answer 22

1. Identifying + Correct precipitating factors
   - e.g. sepsis, GI bleeding
   - esp. look for SBP, ↓ K, withdraw sedatives
2. Medical treatment
   - **Lactulose
   - **Rifaximin
   - Fecal microbial transplantation (still experimental)
3. Diet
   - **avoid excessive protein intake but avoid dietary protein restriction!!! (except in active GI bleeding)
   - recommended protein intake: **40-60g / day
   - dietitian input important
4. Dietary supplements to ↑ NH3 removal
   - **BCAA (branch-chained amino acid)
   —> detoxifies NH3 via **glutamine production
   —> nutritional supplements
   —> mainly in protein-intolerant patients

• **LOLA (L-ornithine-L-aspartate)
  —> converts L-ornithine to glutamate in muscle
  —> conversion uses NH3 to produce **glutamine

Question 23

Lactulose

Answer 23

• Non-absorbable disaccharide
• Degraded in colon by urease-negative lactobacilli

MOA:
1. Osmotic laxative
2. ↓ Colonic pH
- inhibit ***urease-producing bacteria esp. E. coli —> stop NH3 production
- trap luminal NH3 —> NH4
- draws NH3 from mucosal blood to gut

Aim:
- ***2-3 times soft stool / day (can give enema form)

Question 24

Rifaximin

Answer 24

• ***Non-absorbable antibiotic —> stays in colon
• Alteration of colonic flora (esp. urease-producing)
• Effective when combined used lactulose
• Effective in ↓ recurrence of HE
• Replaced ***Neomycin (∵ potential nephrotoxicity / ototoxicity, no longer recommended)

Question 25

Coagulopathy in Liver failure

Answer 25

1. Platelet dysfunction (quantitative + qualitative)
   - ***Platelet transfusion required if
   —> bleeding / invasive procedure + <50
   —> prophylactically if <20
2. Prolongation of PT / INR
   - PT / INR important **prognostic indicators
   - **FFP only if active bleeding / invasive procedures

Question 26

Infections in Liver failure

Answer 26

**Reticuloendothelial dysfunction + **Reduced opsonisation
- very common (esp. respiratory / urinary)
- bacteriaemia up to 25% in fulminant liver failure
- Staph, Strept, Gram -ve rods most common
- ***Broad spectrum antibiotic prophylaxis recommended
- Risk of fungal infection esp. Candida

Question 27

Management of Acute liver failure (ALF)

Answer 27

1. Supportive (standard ***ICU care)
2. Identifying + Remove / Treat insult
   - Treat HBV
   - N-acetylcysteine for paracetamol poisoning
   - Activated charcoal for mushroom poisoning
3. Manage complications
   - **Infections
   - HE
   - ↑ ICP (Cerebral edema)
   - **Metabolic complications
   - ***Coagulopathy
4. ***Avoid long-acting sedatives / opioids (∵ precipitate HE)

Other treatments:
5. N-acetylcysteine (off-label)
- now also used in ALF with unknown etiology apart from paracetamol poisoning

6. Plasmapheresis
7. ***Organ-system support
8. ***Liver transplantation