Acute Liver Failure + Cirrhosis Flashcards
Definition of acute liver failure
Potentially reversible condition
- Severe acute liver injury (no underlying disease)
- Liver injury (AST/ALT >2-3x ULN)
- Impaired liver function (jaundice and coagulopathy)
+ hepatic encephalopathy within 12 weeks of onset of jaundice
Recent onset (<26 weeks) encephalopathy, coagulopathy, liver derangement in the absence of pre-existing liver disease
- Elevated aminotransferases
- Hepatic encephalopathy
- Prolonged prothrombin time
Subtypes of acute liver failure
- Hyperacute: encephalopathy within 7 days of the onset of jaundice, eg: paracetamol toxicity
- Acute: jaundice to encephalopathy from 8 to 28 days
- Subacute: Jaundice to encephalopathy from 5 to 12 weeks
Causes of ALF
- Drugs: paracetamol, statins, phenytoin
- Vascular: budd chiari syndrome (occlusion of hepatic veins), hypoxic hepatitis
- Hep A, B, E
- CMV, HSV, VZV
- Toxins: amanita phalloides (mushroom)
- Wilson disease
- Lymphoma, autoimmune
- Pregnancy: HELLP
Features that indicate a high positive predictive value for liver transplantation for paracetamol overdose
- Arterial pH < 7.25 after adequate fluid resus, NAC for >24 hours
OR all 3 of:
- Prothrombin >100s (INR >6.5)
- Creatinine >300 or anuric
- Grade 3/4 encephalopathy
Features that indicate a high positive predictive value for liver transplantation for non- paracetamol overdose
PT > 100 (INR >6.5)
or 3/5
- Prothrombin time >50s (INR > 3.5)
- Bili >300
- Jaundice to encephalopathy > 7 days
- Age < 10, >40
- Unfavourable aetiology (seronegative, drug)
Causes of decompensated cirrhosis and their treatment
- Hep B: antiviral
- Hep C: antiviral
- MAFLD: weight loss, exercise, metformin
- Alcohol: abstinence
- Primary biliary cholangitis: ursodeoxycholic acid, obeticholic acid
- Haemochromatosis: phlebotomy
- Autoimmune hepatitis: steroids/azathioprine
- Wilson disease: chelation therapy
Child Pugh Score
Child Pugh Score: assess the prognosis of chronic liver disease and severity
- Ascites
- Albumin
- Bilirubin
- INR
- Encephalopathy
Compensated A: 5-6
Decompensated B: 7-9
C: 10-15
Meld score
Measure of how severe liver disease and 3 month pretransplant mortality
- Bili
- Creatinine
- INR
- Sodium
Difference between acute decompensation vs acute on chronic liver failure
Acute Deompensation
- Variceal bleeding
- Ascites
- Hepatic encephalopathy
Acute on Chronic Liver Failure
- AD plus ORGAN FAILURES
What are the features of hepatic encephalopathy
Cirrhosis –> portal hypertension –> increased SPLANCHNIC blood flow –> peripheral arterial vasodilatation
- Bleeding varices
- Hepatic encephalopathy
- Ascites
- Hepatorenal syndrome
- Hyponatremia
- Hepatopulmonary syndrome
- High output cardiac failure
Causes and investigation for ascites
SAAG - serum - (minus) ascites albumin gradient
SAAG >11g/L = ascites due to portal hypertension
SAAG < 11g/L = ascites not due to portal HTN
Portal HTN
- Hepatic cirrhosis
- Alcoholic hepatitis
- Heart failure
- Fulminant hepatic failure
- Portal vein thrombosis
Causes of ascites not due to portal HTN
- Peritoneal carcinomatosis
- Inflammation of the pancreas or biliary system
- Nephrotic syndrome
- Peritonitis
- Ischaemic or obstructed bowel
What are the SAAG and Hepatic vein pressure of:
- Cirrhosis
- Cardiac ascites
- Peritoneal malignancy /Peritoneal TB
- Cirrhosis
SAAG >11 (high)
WHVP, HVPG: high, FHVP: normal - Cardiac ascites
SAAG > 11 (high)
WHVP, FHVP: high, HVPG normal - Peritoneal malignancy /Peritoneal TB
SAAG< 10, hepatic pressures normal
WHVP: wedged hepatic venous pressure
FHVP: free hepatic venous pressure
HVPG: Hepatic venous pressure gradient
Wedged hepatic venous pressure (WHVP) is an estimate of pressure within the portal venous system, whereas free hepatic venous pressure reflects systemic venous pressure. A HVPG ≤ 5 mm Hg is normal, whereas a gradient >5 mm Hg is diagnostic for portal hypertension.
Management of ascites
DDTTT
- Diet – salt restriction ≤2.5g/day
- Diuretics – Spironolactone 50-100mg mane (or amiloride 10-20mg mane);
o Bump up if severe ascites to spironolactone 100mg daily and increase by 100mg/day every 4-7 days as required to max 400mg daily.
o Can also add in frusemide, avoid thiazide
o NB: diuretics may precipitate hyponatraemia, changes in potassium concentrations and renal impairment, so monitor serum electrolyte concentrations and renal function regularly - Tap (large volume paracentesis)
o With infusion of albumin given at 6-8g/L of aspirated ascitic fluid
o Ensure adequate intake of protein 1-1.5 protein/kg/day - TIPS (transjugular intrahepatic porto-systemic shunt)
o Ensure not encephalopathic – as can precipitate hepatic encephalopathy by promoting ammonia shunting to systemic circulation (hence currently contraindicated in this case) - Transplantation
Complications of diuretics in cirrhosis
Hyponatremia Hypo/hyperkalaemia Hepatic encephalopathy Renal impairment Gynaecomastia Muscle cramps
SBP
- Most common organisms
- Diagnosis
- Treatment
- It is often culture negative but the more common pathogens include Escherichia coli, Klebsiella pneumoniae, enterococcal species, and Streptococcus pneumoniae.
- Culture: PMN >250
Tx:
- IV ceftriaxone 2g daily
- IV albumin 20% 100mL BD for 3 days if Cr >1 or Bili >4 due to risk of hepatorenal syndrome
- Secondary prophylaxis: bactrim or norfloxacin
Side effects of telipressin
Telipressin: treatment of hepatorenal syndrome
SE:
Abdominal pain (ischaemia)
Diarrhoea
Cardiovascular/circulatory overload/arrhythmia
Indications and contraindications of TIPSS
TIPSS - transjugular intrahepatic portosystemic shunt
Indications
- Refractory ascites
- Portal hypertensive bleeding
- Hepatic hydrothorax
- Budd chiari syndrome (hepatic vein occlusion)
Absolute Contraindications
- RHF
- Severe pulmonary hypertension
- Active infection
- Biliary obstruction
Relative Contraindications
- Hepatic encephalopathy
- Portal vein occlusion
- HCC
What is hepatic encephalopathy
- Brain dysfunction caused by liver insufficiency and/or portosystemic shunting
- Occurs in response to ammonia and other precipitating factors
Inflammatory cytokines
Benzodiazepine receptor like agonists
Cannabanoid receptor agonists
Hyponatremia - Occurs in 30-40% of patients with cirrhosis
PPI and SBP + hepatic encephalopathy
Studies have shown that PPI are a risk factor for hepatic encephalopathy and SBP in patients with cirrhosis with ascites
Treatment of hepatic encephalopathy
- Lactulose aiming for 2-3 semisoft stools/day
- Rifaximin
Bleeding and thrombosis in cirrhosis
- INR elevation does not correlate with peri-procedural bleeding events in cirrhosis
Consequence of Hypercoagulation in Cirrhosis
- Portal vein thrombosis
- DVT/PE
- Progression of compensated to decompensated cirrhosis
- May have a role in pulmonary microthrombi
Bone disease in cirrhosis
Other complications
- Complication of end stage liver disease
- Primary mechanism is reduced bone formation and low bone turnover
- DEXA scan
Malnutrition, frailty, sarcopenia
Risk factors for MAFLD (metabolic associated fatty liver disease)
- T2DM
- Obesity
- Dyslipidaemia
- Metabolic syndrome
Features of lean NAFLD
- NAFLD in the absence of obesity
- Associated with increased visceral obesity (as opposed to general obesity), high fructose, fat intake and genetic risk factors
- Patients are usually sedentary, insulin resistant and have higher plasma trigs when compared with matched controls
- Increased CV risk
What is the most important determinant of outcome in MAFLD?
Fibrosis
Steatosis NASH Cirrhosis Decompensation Death
Complications of MAFLD
- More likely to die from cardiovascular disease than liver disease
- Associated with breast cancer, hepatocellular and colorectal cancer
Treatment for MAFLD
- Lifestyle intervention
- Mediterranean diet, aim is to >7-10% weight reduction
- Bariatric Surgery - weight loss is key!
- HCC surveillance
- Transplant
Hyperferritinaemia in MAFLD
- Elevated ferritin levels are see in 60% of patients with NASH but increased hepatic iron content is uncommon
- Elevated ferritin levels in patients with MAFLD associated with fibrosis severity and increased all cause mortality
- Phlebotomy: not associated with significant improvement
- Phlebotomy not recommended in patients with NAFLD + hyperferritinemia
Spectrum of liver disease due to alcohol
- Simple steatosis (>60% of people who drink >60g/day)
- Alcoholic steatohepatitis
- Progressive fibrosis
- Cirrhosis
- Hepatocellular cancer
Alcohol management
- Abstinence
- Nutrition/vitamins
- Treat complications
- Liver transplantation
Criteria for liver transplantation in alcoholic liver disease
- > 6 months abstinence from alcohol
- Adequate social support
- Concern in patients with active smoking, personality disorder, psychosis, hx of alcohol dependence
- R/V by psych and D+A team
Medications for alcohol dependence
- Naltrexone (first-line agent): reduces cravings for alcohol
Long acting opioid receptor antagonist, reduce alcohol induced reward pathway. - Disulfiram: exacerbates intoxication symptoms and induces negative conditioning (only recommended in patients who show strong motivation and commitment for abstinence)
Leads to unpleasant N+V, flushing, headache and palpitations with alcohol use.
Irreversible aldehyde dehydrogenase antagonist causing build-up of acetaldehyde. - Acamprosate: blocks central glutamate receptors and reduces cravings for alcohol
- Topiramate or gabapentin: for patients who do not tolerate or respond to other medications
a1-antitrypsin deficiency in the liver
○ Alpha 1 antitrypsin deficiency causes pathological polymerization of the variant AAT, resulting in intrahepatocyte accumulation of AAT molecules (toxic gain of function)
- Only those genotypes associated with pathologic polymerization of AAT within the endoplasmic reticulum of hepatocytes (eg, PI*ZZ type AATD) produce disease
- Liver disease does not occur in null homozygotes who have severe deficiency of AAT, but no intra-hepatocytic accumulation
- Clinically results in liver cirrhosis
Codominant inheritance
a1 antitrypsin deficiency in lung and skin
LUNG
- Alpha 1 antitrypsin in the lung normally inhibits neutrophil elastase from break down elastin
- Alpha 1 antitrypsin deficiency causes increased neutrophil elastase and other proteases causing destruction of elastin
- Cigarette smoking and infection increase the elastase burden
- Clinically results in early onset emphysema
SKIN
- Can result in panniculitis (hot, painful, red nodules or plaques characteristically on the thigh or buttocks)
a1 antitrypsin deficiency in lung and skin
LUNG
- Alpha 1 antitrypsin in the lung normally inhibits neutrophil elastase from break down elastin
- Alpha 1 antitrypsin deficiency causes increased neutrophil elastase and other proteases causing destruction of elastin
- Cigarette smoking and infection increase the elastase burden
- Clinically results in early onset emphysema
SKIN
- Can result in panniculitis (hot, painful, red nodules or plaques characteristically on the thigh or buttocks)
Paracetamol overdose
- Acute overdose = potential for toxicity with a single paracetamol ingestion of >200mg/kg (or >10g) (whichever is less)
- Hepatotoxicity = serum AST >1000IU/L
- Serum paracetamol level 4 hours after ingestion
Antidote = N-acetylcysteine (NAC)
- Most effective within 8 hours of poisoning. NAC works by acting as a glutathione substitute and antioxidant, preventing hepatocyte death.
Titrate according to ALT
How does NAC work in paracetamol toxicity?
A. Increased production of non-toxic metabolites B. Reduced formation of NAPQI C. Increased formation of NAPQI D. Increased glutathione synthesis E. Inhibits CYP 1A2
D. Increased glutathione synthesis
Metabolism of Paracetamol by the Hepatocyte
- 90% of paracetamol is metabolised to inactive sulphate and glucuronide conjugates that are excrete in the urine
- Metabolism of the remainder is via cytochrome p450 (chiefly 2E1 and 3A4) and results in the highly reactive toxic metabolite, NAPQI.
NAPQI is conjugated byglutathioneto non-toxic cysteine and mercapturic acid moieties which is then eliminated in the urine
Paracetamol Toxicity
The Phase II conjugation enzymes are saturated, and a higher fraction is converted to NAPQI.
The conjugation of NAPQI to these metabolites occurs until glutathione is depleted from hepatic reserves, after which the toxic NAPQI accumulates and causes damage to the hepatocytes.
Acetylcysteine N-acetylcysteineor NAC is a glutathione precursor and functions by repleting glutathione stores.
What is the best marker for recent change in nutrition status? Albumin Prealbumin Ferritin B12 Folate
Prealbumin
Prealbumin
- Transthyretin (prealbumin) is a precursor to albumin
- Its half life is 2-4 days
- Better marker for acute changes of the nutritional state
- Prealbumin not influenced by intestinal protein losses in patients with protein-losing enteropathy. However can be decreased in infection, liver dysfunction etc
Albumin
- Albumin has a half life of 20-22 days and is a marker of nutritional status in the long term
- Albumin can decrease in acute illness, inflammation, hepatic insufficiency, renal losses in nephrotic syndrome and to losses via the GI tract in protein-losing enteropathies
What variant is associated with nonalcoholic fatty liver disease
PNPLA3
Also associated with alcoholic related cirrhosis + HCC
Causes of drug induced cholestasis
Chlopromazine Oestrogen induced cholestasis Ketoconazole Fluclox Checkpoint inhibitors
Wilson Disease
- Autosomal recessive
- Copper overload
- Low ceruloplasmin (screening test)
- Increased urine copper, decreased serum copper
- Low ALP, moderately elevated aminotransferases
- Molecular genetics; ATP7B
- If high index of suspicion = liver biopsy
- Neuropsych, dystonia, chorea, parkinsonian
- Liver disease early, neuro later
Tx: zinc, penacillamine, trientine
Zinc is also beneficial because it decreases
intestinal absorption of copper, but it should not be used alone
until copper has been depleted with a chelating agent
In patients with NASH, what is the most robust and independent predictor of liver related mortality?
A. Advanced hepatic fibrosis
B. T2DM
C. Presence of NASH with ballooning injury on biopsy
D. Morbid obesity
E. NASH not associated with increased mortality
A. Advanced hepatic fibrosis
Alcohol accounts for what % for all liver related deaths A. 15% B. 30% C. 45% D. 60%
45%
A patient with decompensated cirrhosis presents with acute renal insufficiency. Possible provocative factors include all but which of the following A. NSAIDs B. Culture negative neutrocytic ascites C. LVP without albumin replacement D. Recent TIPs E. Acute hepatic encephalopathy
E. Acute hepatic encephalopathy
Which of the following is a contraindication to the use of Direct Acting Antiviral (DAA therapy) A. Active ongoing IVDU B. Decompensated cirrhosis C. Chronic schizophrenia D. End stage renal impairment E. Concomitant carbamazepine administration
E. Concomitant carbamazepine administration
Co-administration of direct-acting antivirals (DAAs) with these AEDs (carbamazepine, phenytoin, phenobarbital) is contraindicated as plasma concentrations are markedly reduced2 potentially leading to loss of efficacy and virological failure
Treatment of alcoholic hepatitis
Maddreys DF >32 = HIGH risk
Maddreys DF < 32 = LOW risk
Can treat with steroids
The optimal management for a patient with alcoholic hepatitis. Maddrey’s DF= 35? A. Corticosteroids B. Pentoxifylline C. Corticosteroids+ Acetylcysteine (NAC) D. Corticosteroids+ Pentoxifylline
A. Corticosteroids
A 38 year old woman treated for advanced
melanoma with pembrolizumab (anti PD1 antibody)
presents after 8 weeks with new onset fatigue
ALT180, AST156, Bili25
Viral serology negative
- Observe
- Reduce Pembro dose
- Start prednisolone
- Liver biopsy
- Start prednisolone
- AIH like drug induced liver injury occurs in approx 1-5% of patients on checkpoint inhibitors
- Mainly within the first 6-12 weeks from starting tx
What is HVPG?
HVPG = WHVP - FHVP
HVPG: hepatic venous pressure gradient
WHVP: wedged hepatic venous pressure
FHVP: free hepatic venous pressure
HVPG = portal vein (WHVP) - hepatic vein (FHVP)
In compensated cirrhosis:
- HVPG: 10, development of gastroesophageal varices + development of HCC
- HVPG 12: variceal bleeding
- HVPG 16: decompensation
HPVG > 10 = clinically significant portal hypertension
