Acute Liver Failure

Acute Liver Failure (ALF) - Revision Notes

Acute Liver Failure (ALF) is equivalent to the now archaic term “fulminant hepatic failure.”
Dual characteristics of coagulopathy and encephalopathy develop within days or weeks of liver injury.
Absence of previous liver disease is typically required, except for cases like severe reactivations of hepatitis B or acute presentations of Wilson disease (despite established cirrhosis).

Key Differences

ALF should not be confused with Acute-on-Chronic Liver Failure (ACLF), which occurs in patients with cirrhosis and is often precipitated by factors like infection or gastrointestinal hemorrhage.
Cerebral edema is almost exclusively seen in ALF, differentiating it from ACLF.

Etiological Factors and Survival

ALF is an umbrella term for a heterogeneous condition with varying clinical syndromes.
Survival rates without liver transplantation range from 10% to 90%:
- Best outcomes: Pregnancy-related syndromes, severe acetaminophen hepatotoxicity, hepatitis A.
- Worse outcomes: Older patients and young children.

Subclassification of ALF

The rate of progression of the disease helps subclassify patients:
1. Hyperacute ALF: Encephalopathy within 7 days of the onset of jaundice.
2. Acute ALF: Encephalopathy within 8-28 days of the onset of jaundice.
3. Subacute ALF: Encephalopathy after 28 days of the onset of jaundice.

Etiology of Acute Liver Failure (ALF) - Revision Notes

Epidemiology

ALF is a rare condition in the West, with fewer than 5 cases per million population per year.
Viruses and drugs account for the majority of cases.
There is a significant variation in global patterns of ALF.

Common Causes

Acetaminophen (Paracetamol) Overdose:
- Most common cause of ALF in the UK and US.
- In the UK, associated with suicidal/parasuicidal intent.
- In the US, up to 50% of cases follow therapeutic use due to unintentional overdosing or accelerated metabolism (e.g., liver enzyme induction from antiepileptic therapy or regular alcohol use).
- Legislation limiting purchase quantities of acetaminophen in the UK has reduced ALF hospitalizations by 50%.
King's College Criteria for Liver Transplantation (LTP) in Acute Liver Failure (ALF) - Revision Notes

Paracetamol-Induced ALF:
- Criteria:
  - pH < 7.30 (irrespective of grade of encephalopathy)
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                    **OR**
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  - Prothrombin Time (PT) > 100 seconds
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                      **+**
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  - Serum Creatinine > 300 μmol/L
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                      **+**
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  - Encephalopathy of Grade 3 or 4
Non-Paracetamol Induced ALF (Irrespective of encephalopathy):
- Criteria:
  - PT > 100 seconds
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           **OR**
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  - Any three of the following:
    - Age <10 years or >40 years
    - Etiology: Non-A, Non-B hepatitis, Halothane toxicity, or Drug reaction
    - Jaundice lasting > 7 days before encephalopathy
    - PT > 50 seconds
    - Bilirubin > 300 μmol/L
  - Drug-Induced ALF:
    - Most are rare idiosyncratic reactions.
    - Risk of ALF due to idiosyncratic reactions varies:
  - 0.001% for NSAIDs.
  - 1% for isoniazid/rifampicin combination.
    - Nontherapeutic drugs like Ecstasy (MDMA) are also known to cause ALF, presenting as hyper-ALF or subacute liver failure.

Viral Causes

Hepatitis A: ALF occurs in 0.1% to 0.3% of hospitalized cases and 0.4% of all cases in the US.
Hepatitis B: ALF occurs in 1% to 4% of hospitalized patients. Hepatitis D coinfection increases risk.
- Now often seen due to reactivation of subclinical, non-cirrhotic hepatitis B following immunosuppression (e.g., after chemotherapy).
Hepatitis E: Common in Asia and Africa, with a risk of ALF ranging from 0.6% to 2.8%, increasing to over 20% in pregnant women (especially in the third trimester).
- Also found in Europe and US, possibly explaining some indeterminate hepatitis cases.

Indeterminate Hepatitis

Indeterminate hepatitis is a common cause of ALF, especially in the Western world.
- Often sporadic; may be due to unidentified toxins or autoimmune processes.
- Frequently affects middle-aged females with ALF rates of 2.3% to 4.7% of hospitalized cases.

Other Etiologies of Acute Liver Failure (ALF) - Revision Notes

Pregnancy-Related ALF
- Occurs in approximately 1:100,000 pregnancies, typically during the third trimester.
- Three entities with considerable overlap:
  1. Acute fatty liver of pregnancy:
    - Common in primigravidae carrying a male fetus.
    - Characterized by severe microvesicular steatosis.
  2. HELLP syndrome:
    - Defined by hemolysis, elevated liver enzymes, and low platelet count.
  3. ALF complicating preeclampsia/eclampsia:
    - Exhibits very high serum aminotransferase levels.
    - Abnormal tissue perfusion patterns on CT due to microvascular infarction.
Wilson Disease
- May present as ALF, typically during the second decade of life.
- Characterized by:
  - Coombs-negative hemolytic anemia.
  - Presence of Kayser-Fleischer rings (majority of cases).
  - Low serum ceruloplasmin levels (though not always).
  - Increased serum and urinary copper levels.
Mushroom Poisoning (Amanita phalloides)
- Common in Central Europe, South Africa, and the US west coast.
- Symptoms:
  - Severe diarrhea and vomiting begin 5+ hours after ingestion.
  - Liver failure develops 4-5 days after ingestion.
Autoimmune Hepatitis
- Can present as ALF, but typically unresponsive to corticosteroids or immunosuppressive therapy.
Budd-Chiari Syndrome
- Presents with ALF and suggested by hepatomegaly.
- Confirmed by demonstrating hepatic vein thrombosis.
Ischemic Hepatitis
- Caused by hypoperfusion due to systemic shock or cardiac failure.
- Increasingly recognized, particularly in older patients.
Malignancy Infiltration
- Often masquerades as ALF, typically seen with lymphoma.
- Associated with hepatomegaly, primarily affecting older patients.

Diagnosis of Acute Liver Failure (ALF) - Revision Notes

Cardinal Features

Encephalopathy and coagulopathy are the key features of ALF.
- Encephalopathy can range from drowsiness to coma.
- In subacute liver failure, encephalopathy may be subtle and require psychometric testing for detection.
- Diagnosis is supported by elevated arterial ammonia levels.
- Exclude hypoglycemia as an alternative cause for mental impairment.

Steps for Diagnosis

Establish Clinical Diagnosis:
- Determine if acetaminophen or mushroom ingestion is responsible (from patient history).
- Use a systematic approach if the etiology is unclear.
Investigations:
- Routine tests (refer to Table 77.2 for all patients).
- Specific tests based on circumstance (refer to Table 77.3).
- Liver imaging:
  - Assess liver size (usually small in ALF).
  - Screen for portal hypertension (ascites or splenomegaly may indicate subacute liver failure or Wilson disease).

Histological Assessment

Confluent necrosis is the most common histologic finding.
- Can be zonal or panlobular.
- Zonal necrosis is more likely from toxic insult or ischemia.
- Subacute liver failure often shows a "map-like" pattern of regeneration with small areas or larger nodules.

Specific Diagnoses from Histology

Sodium valproate toxicity: Characterized by microvesicular steatosis.
Wilson disease:
- Associated with established cirrhosis, interface hepatitis, hepatocyte ballooning, and steatosis.
Pregnancy-related liver diseases: Histology helps in precise diagnosis.
Budd-Chiari syndrome: Shows extreme sinusoidal dilation, congestion, and coagulative necrosis.
Malignant infiltration: Strong indication for liver biopsy, especially if the liver is enlarged.

Liver Biopsy

Helps differentiate ALF from:
- Established cirrhosis.
- Acute alcoholic hepatitis (whether associated with cirrhosis or not).
Acute alcoholic hepatitis can mimic subacute liver failure but is suggested by a history of high alcohol consumption and investigational findings (Box 77.2).

Not a Feature of Acute Alcoholic Hepatitis - MCQ

Question: Which of the following is not a feature of acute alcoholic hepatitis?

a) Elevated TLC not responding to antibiotics

b) Elevated IgA

c) Hepatomegaly

d) Shrunken nodular liver in USG

Answer: D

Shrunken, nodular liver on USG is more indicative of chronic liver disease or cirrhosis, not acute alcoholic hepatitis.

Key Features of Acute Alcoholic Hepatitis

Elevated TLC (Total Leukocyte Count) often does not respond to antibiotics.
Elevated IgA levels are commonly associated with alcoholic liver disease.
Hepatomegaly (enlarged liver) is a typical finding in acute alcoholic hepatitis.

Renal Failure in Acute Liver Failure (ALF) - Overview

Renal dysfunction and acute kidney injury (AKI) are common in ALF, affecting 40% to 80% of patients.
Risk factors for AKI in ALF include:
- Increasing age.
- Acetaminophen (Paracetamol) toxicity: AKI in these cases is often a result of direct drug toxicity.
- Infection: A significant precipitant of AKI, with a frequency of 40-80% in patients with ALF.

Etiology and Mechanisms of AKI in ALF

Multifactorial etiology: AKI in ALF is caused by a combination of factors such as drug toxicity, sepsis, or pre-renal insults (e.g., hypovolemia).
Early renal dysfunction is common in:
- Wilson disease.
- Pregnancy-related syndromes.

Urea vs. Creatinine

Urea synthesis is impaired in ALF, making serum creatinine a more reliable marker for monitoring renal function than blood urea levels.

AKI in Chronic Liver Disease (CLD)

Occurs in up to 50% of hospitalized CLD patients.
Strongly predicts poor survival in both short and long-term scenarios.
Subtypes of AKI in CLD:
1. Hepatorenal syndrome (HRS-AKI):
  - Results from portal hypertension, splanchnic vasodilation, and renal vasoconstriction.
2. Non-HRS-AKI:
  - Caused by factors such as hypovolemia, sepsis, or drug-induced tubular injury.

Management of Renal Dysfunction in ALF

Intravascular optimization is crucial in patients with deteriorating renal function.
Terlipressin combined with albumin infusions is commonly used in Europe to manage AKI in CLD, improving both renal function and survival.
Renal replacement therapy (RRT):
- Early intervention is recommended in ALF, especially with continuous hemofiltration, which is associated with:
  - Less hemodynamic instability.
  - Lower risk of exacerbating cerebral edema compared to intermittent hemodialysis.

MCQ Discussion - Renal Dysfunction in ALF

Question: Which of the following is not true about renal dysfunction in ALF?

a) Early in pregnancy-related and Wilson disease

b) Common in paracetamol toxicity due to direct drug action

c) Blood urea is more reliable than creatinine as most are AKI

d) Infection precipitates AKI (40-80%)

Answer: C

Blood urea is not more reliable than creatinine in ALF because urea synthesis is impaired, making serum creatinine the preferred marker for monitoring renal function.

Key Points:

Early renal dysfunction is seen in Wilson disease and pregnancy-related syndromes (Answer A is true).
Acetaminophen toxicity directly causes AKI due to drug action (Answer B is true).
Infection precipitates AKI in 40-80% of ALF cases (Answer D is true).

Management of Acute Liver Failure (ALF) - Revision Notes

Key Management Areas:

Fluid and Electrolyte Balance:
- Essential to prevent dehydration and maintain hemodynamic stability.
Acid and Base Balance:
- Correcting metabolic acidosis or alkalosis as needed.
Blood Glucose Monitoring:
- Prevent hypoglycemia which is common in ALF.
Nutrition:
- Provide adequate caloric intake and avoid catabolism.
Renal Function:
- Use of hemofiltration to manage acute kidney injury (AKI).
Respiratory Support:
- Ventilation may be required to manage respiratory failure and prevent hypoxia.
Cerebral Edema:
- Monitoring and treatment of cerebral edema is critical in ALF management.
Infection Control:
- Treatment of bacterial and fungal infections is essential due to increased susceptibility.

Outcomes:

Mortality in ALF is 50%, despite all treatments.

Liver Transplantation:

Orthotopic liver transplantation (OLT) or Auxiliary Partial Orthotopic Liver Transplantation (APOLT) are options, but they have poor short-term outcomes in ALF.

Hepatocyte Transplantation - Revision Notes

Hepatocyte transplantation shows promise for treating inherited liver disorders and liver insufficiencies that can eventually lead to liver failure.

Indications for Hepatocyte Transplantation:

Inherited Liver Disorders:
- Tyrosinemia.
- Hyperbilirubinemia (Crigler-Najjar syndrome Type I).
Acute Liver Failure (ALF):
- Used as a bridge to liver transplantation.
Ornithine transcarbamylase deficiency:
- Partial correction of metabolic disorders through hepatocyte transplantation.

Experimental and Clinical Success:

Animal studies:
- Successful hepatocyte transplantation in animals with enzyme deficiencies.
- Gunn rats: Corrected bilirubin conjugation deficiency using hepatocyte transplantation.
Human applications:
- Intravenous infusion of hepatocytes in the portal vein.
- Experimental models suggest transplanted hepatocytes can assume the full range of liver functions.
- Partially corrected disorders like Crigler-Najjar syndrome Type 1 and ornithine transcarbamylase deficiency.

MCQ Discussion - Hepatocyte Transplantation

Question: Which of the following is not an indication for hepatocyte transplantation in humans?

a) Bridge to LTP in ALF

b) Crigler-Najjar syndrome Type I

c) Ornithine transcarbamylase deficiency

d) Gaucher’s disease

Answer: D

Gaucher's disease is not an indication for hepatocyte transplantation.
- Gaucher disease is typically treated with enzyme replacement therapy, not hepatocyte transplantation.

Key Points:

Hepatocyte transplantation is used as a bridge to liver transplantation in ALF (Answer A is true).
Crigler-Najjar syndrome Type I and ornithine transcarbamylase deficiency are corrected by hepatocyte transplantation (Answers B and C are true).

Features of Chronic Liver Disease (CLD) - Revision Notes

Clinical Features:

Lethargy: Generalized fatigue and weakness.
Fever: May be present due to inflammation or infection.
Jaundice: Yellowing of the skin and eyes due to elevated bilirubin.
Protein Catabolism (Wasting): Muscle wasting due to increased protein breakdown.
Coagulopathy: Bruising and bleeding tendencies due to impaired clotting.

Cardiac and Neurological Effects:

Hyperdynamic circulation: Increased cardiac output commonly seen in CLD.
Hepatic Encephalopathy: Neurological deterioration due to toxin accumulation.

Portal Hypertension:

Ascites: Accumulation of fluid in the abdomen.
Esophageal Varices: Swollen veins in the esophagus that can rupture and bleed.
Splenomegaly: Enlargement of the spleen.

Cutaneous Features:

Spider Naevi: Small, spider-like blood vessels visible on the skin.
Palmar Erythema: Redness of the palms.

Surgical Mortality and Risk Scores:

Child-Turcotte-Pugh (CTP) Scores:
- CTP A: 10% increase in surgical mortality.
- CTP B: 30% increase in surgical mortality.
- CTP C: 75-80% increase in surgical mortality.
MELD Score (Model for End-Stage Liver Disease):
- 1% increase in mortality for each MELD point up to 20.
- 2% increase in mortality for each point above 20.

Supporting a Failing Liver - Revision Notes

Liver Support Approaches:

Standard Medical Therapy: Initial supportive care measures.
Artificial Liver Support Systems:
- Non-Biologic Systems:
  - Methods like MARS (Molecular Adsorbent Recirculating System) and Prometheus.
- Biologic Systems:
  - Involves artificial liver cell lines for liver support.
  - Porcine hepatocyte cell lines.
  - Human hepatoblastoma cell lines.

MCQ Discussion - Supporting a Failing Liver

Question 1: Supporting a failing liver, all are true except:

a) MARS MWCO- 60 Kda vs Prometheus MWCO 250 Kda

b) Better detoxification in Prometheus

c) DIC more in MARS

d) Extracorporeal liver assist system - only bioartificial, using hepatoblastoma cell lines

Answer: C

DIC (Disseminated Intravascular Coagulation) is not more common in MARS; hence, option C is the correct answer.
MARS and Prometheus differ in their MWCO (Molecular Weight Cut-Off): MARS = 60 KDa, Prometheus = 250 KDa.
Prometheus has better detoxification capacity compared to MARS.
Extracorporeal liver assist systems use bioartificial systems, such as hepatoblastoma cell lines.

Question 2: All the following are non-biologic liver support systems except:

a) Plasma exchange/hemodiafiltration

b) Molecular adsorbent recirculating system (MARS)

c) Fractionated plasma separation and absorption (Prometheus)

d) Hepat Assist device

Answer: D

Hepat Assist device is a biologic system, hence it is not a non-biologic liver support system.
Non-biologic systems include:
- Plasma exchange/hemodiafiltration.
- MARS.
- Prometheus.

MCQ Discussion - Hepatocellular Zone 3 Necrosis

Question: All the following cause hepatocellular zone 3 necrosis except:

a) Amanita mushroom

b) Carbon tetrachloride

c) Acetaminophen

d) Yellow phosphorus

Answer: D

Yellow phosphorus causes zone 1 (Periportal) necrosis, not zone 3 (Perivenular).

Key Points:

Zone 3 necrosis is associated with low oxygen supply and involves toxic damage near the central veins.
Causes of Zone 3 necrosis include:
- Amanita mushroom poisoning (Answer A is true).
- Carbon tetrachloride (Answer B is true).
- Acetaminophen (Paracetamol) overdose (Answer C is true).

Acute Liver Failure