GI & Hepatology JC065: A Jaundiced And Incoherent Patient: Liver Failure Flashcards
Liver failure
Classification:
1. Acute liver failure
2. Acute-on-chronic liver failure
3. Decompensated cirrhosis (underlying cirrhosis gradually deteriorating)
- Acute liver failure (ALF)
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)
***Clinical features of Acute liver failure (ALF)
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)
- Whole body
- systemic inflammatory response - Liver
- loss of metabolic function
- **hypoglycaemia (↓ gluconeogenesis)
- **lactic acidosis (↓ lactate clearance)
- **hyperammonaemia (↓ NH3 clearance)
- **coagulopathy (↓ synthetic capacity) - Brain
- ***hepatic encephalopathy - Heart
- high output state - Kidney
- dysfunction / failure - Lungs
- acute lung injury - BM
- suppression - Leukocytes
- ***impaired function —> high risk of sepsis - Pancreas
- pancreatitis - Adrenal glands
- inadequate glucocorticoid production —> hypotension - Portal hypertension
- Acute-on-chronic liver failure (ACLF)
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
- Infections
- ***superimposed HAV / HEV
- other systemic infections - External agents
- ***alcoholic hepatitis
- hepatotoxic drugs / herbs
Specific “Hepatotoxic” drugs
- 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!!!)
- ***Paracetamol (overdose)
- NSAIDs
- Statins (very rare)
- ***Anti-TB (Isoniazid, Rifampicin, Pyrazinamide)
- Other anti-microbials
- Anticonvulsants
- ***Rheumatological (Methotrexate, Azathioprine)
- Amiodarone
Herbs
- > 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
***Systemic effects of Hepatocellular failure
- General non-specific Malaise
- ***Encephalopathy (confused / comatose)
- Ascites (usually late stage)
- Jaundice (usually late stage)
- Fetor hepaticus (usually late stage)
- Circulatory changes (very vague in clinical setting)
- ↑ CO
- ↓ Peripheral resistance
- ↓ Renal bloodflow - Nitrogenous (N2) metabolism (very vague in clinical setting)
- **↑ NH3
- **↓ Urea (∵ ↓ urea production from NH3)
- Amino acid abnormalities
- ***↓ Albumin - ***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
- Endocrine changes
- **Hypogonadism
- **Hyperaldosteronism (∵ ↓ BP) - ***Bleeding tendency
- Defective coagulation, ↓ Platelet, ↑ Fibrinolysis
- Decompensated cirrhosis
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
Prognostic factors for ***Cirrhosis
- Child-Pugh score
- MELD score (Model for End-stage Liver Disease)
- Child-Pugh score
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
Disadvantages of Child-Pugh score
- ***Limited discrimination
- only 8 levels between Child A, B, C
- same score for different values of bilirubin, albumin, PT etc. - ***Subjective assessment of ascites / encephalopathy
- Variability of PT + Albumin in different laboratories
- PT + Albumin measurements can be “manipulated”
- e.g. FFP infusion, albumin infusion
- MELD score (Model for End-stage Liver Disease)
- 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)
Prognostic factors for ***Acute liver failure
- 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
Prognostic factors for ***Acute-on-chronic liver failure (ACLF)
NO consensus yet
- MELD increasingly used
***Associated complications of Liver failure
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))
***Hepatic encephalopathy (HE) in Decompensated cirrhosis
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
- ↓ 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)
Hepatic encephalopathy (HE) in Acute / ACLF
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
***Underlying mechanism for HE
Liver failure
—> ↓ Ability of liver to detoxify NH3 to Urea
—> ↑ Cerebral metabolic rate + permeability to NH3
—> ↑ NH3 in brain
—> Astrocyte damage
-
**Hyperammonaemia (↑ arterial ammonia / N2 compounds)
—> **↑ NH3 levels in brain
—> Lactate accumulation in brain -
**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
***HE Grading + Clinical features
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)
- ***Clinical features
- apraxia (grade 1)
- flapping tremor (grade 2)
- babinski +ve (grade 3)
- decerebrate (grade 4) (extensor predominant posture) - ***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
DDx of Confusion in Cirrhosis
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
Diagnosis of HE
- ***Exclude other DDx
-
**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 - ***EEG abnormalities
- 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)
Management of HE
- Identifying + Correct precipitating factors
- e.g. sepsis, GI bleeding
- esp. look for SBP, ↓ K, withdraw sedatives - Medical treatment
- **Lactulose
- **Rifaximin
- Fecal microbial transplantation (still experimental) - Diet
- **avoid excessive protein intake but avoid dietary protein restriction!!! (except in active GI bleeding)
- recommended protein intake: **40-60g / day
- dietitian input important - 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
Lactulose
- 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)
Rifaximin
- ***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)
Coagulopathy in Liver failure
- Platelet dysfunction (quantitative + qualitative)
- ***Platelet transfusion required if
—> bleeding / invasive procedure + <50
—> prophylactically if <20 - Prolongation of PT / INR
- PT / INR important **prognostic indicators
- **FFP only if active bleeding / invasive procedures
Infections in Liver failure
**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
Management of Acute liver failure (ALF)
- Supportive (standard ***ICU care)
- Identifying + Remove / Treat insult
- Treat HBV
- N-acetylcysteine for paracetamol poisoning
- Activated charcoal for mushroom poisoning - Manage complications
- **Infections
- HE
- ↑ ICP (Cerebral edema)
- **Metabolic complications
- ***Coagulopathy - ***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
- Plasmapheresis
- ***Organ-system support
- ***Liver transplantation
