61 Acute Liver Failure Overview

Acute Liver Failure

• Acute liver failure is a rare but life-threatening syndrome characterized by acute liver injury, encephalopathy (brain dysfunction), and deranged coagulation (INR > 1.5) in a patient with a previously normal liver.
• Caused by hepatitis due to various factors, such as viral infections, drug overdose, toxins, and other underlying conditions.
• Histologically, there is necrosis of the liver acini, involving a large portion of the liver tissue.
• Severe fatty change may occur in some cases, including pregnancy, Reye syndrome, or after intravenous tetracycline administration.

Causes of Acute Liver Failure

• Viral infections: Hepatitis A, hepatitis B, cytomegalovirus, hemorrhagic fever viruses
• Drugs: Paracetamol, antibiotics, antidepressants, salicylate (Reye syndrome), NSAIDs, herbal medicines
• Toxins: Organic solvents, mushroom toxins
• Pregnancy: Acute fatty liver of pregnancy, HELLP syndrome
• Vascular causes: Budd-Chiari syndrome, portal vein thrombosis
• Alpha-1 antitrypsin deficiency
• Wilson disease
• Malignancy and extensive metastases
• Heatstroke

Clinical Features of Acute Liver Failure

• Jaundice
• Hepatic encephalopathy
• Fever, vomiting, low blood pressure, and low blood glucose
• Cerebral edema occurs in 80% of patients.
• Impaired gluconeogenesis (glucose production by the liver)
• Kidney injury: Hepatorenal syndrome and acute tubular necrosis.

Hepatorenal Syndrome

• Renal impairment secondary to liver disease.
• Haemodynamic changes due to portal hypertension reduce renal perfusion, often associated with ascites.
• Diagnosis of exclusion: other kidney pathologies should be ruled out.
• Poor prognosis

Hepatic Encephalopathy

• A spectrum of neuro-psychiatric abnormalities seen in liver dysfunction and/or portosystemic shunting (abnormal blood flow bypassing the liver).
• Functional disturbance of the brain, potentially reversible.
• In severe cases, it can be associated with cerebral edema and cerebral hypoperfusion.

Classification of Hepatic Encephalopathy Types

• Type A: Acute liver failure.
• Type B: Porto-systemic shunting with a normal liver.
• Type C: Cirrhosis (decompensated cirrhosis).
• Episodic: May be recurrent, with or without persistent HE.

Stages of Hepatic Encephalopathy

• Stage 1: Confusion
• Stage 2: Drowsiness
• Stage 3: Somnolence
• Stage 4: Coma

Minimal HE

• May be detected through psychometric testing.
• Can affect social function, work life, behavior, and driving ability.
• Minimal HE and Stage 1 HE are considered covert HE, while Stages 2 to 4 are considered overt HE.

Pathogenesis of Hepatic Encephalopathy

• Reduced detoxification in the liver.
• Portosystemic shunting allows more ammonia to enter the systemic circulation, bypassing the liver.
• Detoxification of ammonia occurs primarily in skeletal muscle and kidney, converted to glutamate, rather than urea as in the liver.
• Astrocytes in the brain also detoxify ammonia through glutamine synthetase.
• Increased glutamine in the brain draws more water into astrocytes, leading to swelling and cerebral edema, causing increased intracranial pressure.

Management of Hepatic Encephalopathy

• Identify and correct precipitating factors:

  • Infections.
  • Bleeding and other causes of hypoperfusion.
  • Dehydration due to diuretics.
  • Drugs (sedatives such as opiates, alcohol).

• Reduce Ammonia Production and Absorption:

  • Lactulose (oral or enema): Gut acidification
  • Non-absorbable antibiotics (e.g. rifaximin): To reduce urease-producing bacteria
  • Fluids: Dehydration reduces toxin clearance.
  • Stop diuretic therapy.

Portal Hypertension

• Classified by the level or site of origin of the portal hypertension.
• Cirrhosis is the most common cause.
• Pathogenesis in cirrhosis:
  • Initiated by increased resistance to portal blood flow.
  • Augmented by increased portal blood flow.

Classification of Portal Hypertension Causes

• Pre-hepatic: Portal vein thrombosis
• Hepatic:
  • Cirrhosis: Most common cause.
  • Non-cirrhotic: Portal tract fibrosis due to schistosomiasis.
• Post-hepatic: Obstruction of venous outflow from the liver (rare).

Consequences of Portal Hypertension

• Porto-systemic collaterals:

  • Extrahepatic portal vein and systemic venous circulations anastomose (connect).
  • Varices: Esophageal and gastric varices (high risk of bleeding).
  • Rectal: Dilated veins in the rectum
  • Periumbilical: Dilated abdominal wall veins ("caput medusae")

• Shunting of portal venous blood: Reduced liver function.

• Haemodynamic alterations:

  • Ascites and hepatorenal syndrome.

• Splenomegaly (congestive): Secondary hypersplenism (overactive spleen destroying blood cells).

Esophageal and Gastric Varices

• About 30% of patients with esophageal varices will experience bleeding.
• High mortality rate due to bleeding and high recurrence rate.
• Heavy alcohol users are at higher risk.

Management of Esophageal and Gastric Varices

• Primary prevention:
  • Screening to identify and treat moderate to severe varices before the first bleed.
  • Endoscopic band ligation and/or non-selective beta-blockers.
• Secondary prevention:
  • Treatment to prevent recurrent bleeding.
  • Endoscopic band ligation and/or non-selective beta-blockers.
• Variceal bleed:
  • Resuscitation, medications to reduce portal blood flow.
  • Prevention and treatment of complications (aspiration pneumonia, infections, HE).
  • Endoscopic treatment of varices by band ligation.
  • Endoscopic sclerotherapy is not favored due to complications.
  • If the above fail: Placement of TIPS (Transjugular intrahepatic portosystemic shunt) or surgery.

Ascites in Liver Disease

• Causes:

  • Sodium retention by the kidneys: Increases the volume of extracellular fluid.
  • Increased hydrostatic pressure due to portal hypertension.
  • Lower oncotic pressure (fluid retention) due to low albumin.

• Clinical Presentation:

  • Abdominal distension.
  • Shifting or flank dullness on percussion (sound of organs being tapped, dullness shifts when the patient changes positions).

Causes of Ascites

• Cirrhosis: Most common cause, more than 80%.
• Malignancy: Ovarian cancer is classic, but GI cancers can also cause it.
• Rare Causes:
  • Non-cirrhotic portal hypertension.
  • Heart failure, pancreatitis, tuberculosis.

Management of Ascites

• Paracentesis: Tap of ascites fluid:

  • Diagnostic tap: Cell count, microbiology (blood culture bottles), albumin, cytology.
  • Therapeutic tap: For diuretic-resistant ascites in cirrhosis.

• General Management:

  • Sodium restriction.
  • Diuretics (spironolactone).
  • Avoid NSAIDs (risk of acute renal failure and hyponatremia, reduces the effect of diuretics).
  • High index of suspicion for infection (low threshold for paracentesis).
  • Diuretic-resistant: Refractory ascites.

Spontaneous Bacterial Peritonitis (SBP)

• Infection of ascites fluid without a surgically treatable intra-abdominal cause.
• Associated with cirrhosis, commonly caused by E. coli and Klebsiella.
• Early diagnosis and prompt treatment improve outcomes.
• Subtle or silent presentation.
• Clinical Suspicion:
  • Fever, abdominal pain/tenderness, altered mental state.
• Treatment:
  • Treat if ascites fluid cell count >250 polys/mm3.
• Antibiotic prophylaxis: Recommended for high-risk patients (e.g., previous SBP or bleed).

Liver Blood Tests

• Related to liver cell (hepatocellular) damage:

  • Transaminases (ALT, AST).

• Related to obstruction to bile flow (cholestasis):

  • Alkaline phosphatase (ALP), Gamma-glutamyl transferase (GGT).
  • Bilirubin.

• Related to liver function:

  • Bilirubin: Abnormality is not liver or biliary tract specific.
  • Albumin: Long half-life, indicates chronic damage.
  • Coagulation function (PT/INR): Clotting factors have short half-lives, a better indicator of acute damage.

### Hepatocellular Damage: Liver Enzymes

• Alanine transaminase (ALT):
  • Sensitive and specific marker for hepatocellular damage.
• Aspartate transaminase (AST):
  • Less specific, found in muscle, myocardium, and kidney.
  • Both enzymes leak from damaged hepatocytes.
• AST/ALT Ratio:
  • Usually approximately 2:1 in healthy individuals.
  • Can be informative in diagnosing different causes of liver damage.

  • 5 indicates an extrahepatic source of AST.

Obstructive (Cholestatic) Liver Enzymes

• Alkaline phosphatase (ALP):
  • Located on the hepatocyte border of bile canaliculi.
  • Elevated levels indicate obstruction to bile flow.
  • Also found in bone and placenta.
• Gamma-glutamyl transferase (GGT):
  • Very sensitive but not specific.
  • Helps identify liver-specific elevation of ALP.
  • Induced by alcohol and drugs.

Acute Liver Failure

• Acute liver failure is a rare but life-threatening syndrome characterized by acute liver injury, encephalopathy, and deranged coagulation (INR > 1.5) in a patient with a previously normal liver.
• Most common causes of acute liver failure: viral hepatitis and paracetamol overdose.
• The causes vary across the world, for example, paracetamol overdose is common in the UK.
• Histologically, acute liver failure is characterized by necrosis of acini involving a substantial part of the liver.
• Severe fatty change can be observed in some cases, such as in pregnancy, Reye syndrome, or after intravenous tetracycline.

Causes of Acute Hepatic Failure

• Viral causes: hepatitis A, hepatitis B, cytomegalovirus, hemorrhagic fever virus
• Drugs: paracetamol, antibiotics, antidepressants, salicylate (Reye syndrome), NSAIDs, herbal medicines
• Toxins: organic solvents, mushroom toxin
• Hepatic failure in pregnancy: acute fatty liver of pregnancy, HELLP syndrome
• Vascular causes: Budd-Chiari syndrome, portal vein thrombosis
• Alpha-1 antitrypsin deficiency
• Wilson disease
• Malignancy: extensive metastases
• Heatstroke

Clinical Features of Acute Liver Failure

• Jaundice
• Hepatic encephalopathy
• Fever, vomiting, low blood pressure, low blood glucose
• Cerebral edema in 80% of patients
• Impaired gluconeogenesis
• Kidney injury: hepatorenal syndrome
• Acute tubular necrosis

Hepatorenal Syndrome

• Renal impairment secondary to liver disease
• This happens due to haemodynamic effects of portal hypertension, which reduce renal perfusion.
• It is typically associated with ascites and is a diagnosis of exclusion, meaning other kidney pathologies need to be ruled out.
• Poor prognosis.

Hepatic Encephalopathy

• Spectrum of neuro-psychiatric abnormalities seen in liver dysfunction and/or porto-systemic shunting
• Represents a functional disturbance of the brain, potentially reversible
• Severe cases can be associated with cerebral edema and cerebral hypoperfusion
• Classification:
  • Type A: acute liver failure
  • Type B: porto-systemic shunting with normal liver
  • Type C: cirrhosis (= decompensation)
  • Episodic (may be recurrent) HE +/- persistent HE

Stages of Hepatic Encephalopathy

• Stage 1: confusion
• Stage 2: drowsiness
• Stage 3: somnolence
• Stage 4: coma

Psychometric Testing for Covert HE

• Minimal HE can be detected using psychometric testing.
• Minimal HE can affect social function, work life, behaviour, and fitness to drive.
• Minimal HE + Stage 1 HE = covert HE.
• Stages 2 to 4 HE = overt HE.

Hepatic Encephalopathy: Pathogenesis

• Reduced detoxification in the liver
• Portosystemic shunting allows more ammonia to enter the systemic circulation, bypassing the liver
• Detoxification of ammonia occurs in skeletal muscle and kidney, converted to glutamate (NOT urea as in the liver).
• Astrocytes in the brain also detoxify ammonia via glutamine synthetase.
• This increases glutamine in the brain, which draws more water into the astrocytes. This leads to swelling of astrocytes, cerebral edema, and intracranial hypertension.

Hepatic Encephalopathy: Treatment

• Identify and correct precipitating factors:
  • Infection
  • Bleeding, other causes of hypoperfusion
  • Dehydration (diuretics)
  • Drugs (sedatives, e.g. opiates, alcohol).
• Reduce ammonia production and absorption:
  • Lactulose (oral or enema): gut acidification
  • Non-absorbable antibiotic (e.g. rifaximin): reduce urease-producing bacteria
  • Fluids (dehydration decreases toxin clearance)
  • Stop diuretic therapy

Portal Hypertension

• Classified by level/site of origin of portal hypertension.
• The most common cause is cirrhosis.
• Pathogenesis in cirrhosis:
  • Initiated: increased resistance to portal blood flow.
  • Augmented: increased portal blood flow.
• Classification of causes of portal hypertension:
  • Pre-hepatic: portal vein thrombosis
  • Hepatic:
    • Cirrhosis
    • Non-cirrhotic (e.g., portal tract fibrosis due to schistosomiasis)
  • Post-hepatic: obstruction of venous outflow from the liver (rare)

Consequences of Portal Hypertension

• Porto-systemic collaterals:
  • Extrahepatic anastomoses:
    • Varices (esophageal and gastric, risk of bleed)
    • Rectal, periumbilical (caput medusae)
• Shunting of portal venous blood (reduced liver function).
• Haemodynamic alterations:
  • Ascites and hepatorenal syndrome.
• Splenomegaly (congestive)
  • Secondary hypersplenism.

Oesophageal and Gastric Varices

• 30% of patients with oesophageal varices will experience a bleed.
• High mortality rates due to bleeding.
• High rate of recurrence.
• Heavy alcohol users are at higher risk.
• Important to remember: not all upper GI bleeds are varices.

Oesophageal and Gastric Varices: Prevention and Management

• Primary prevention: screen to identify and treat moderate to severe varices before the first bleed.
  • Endoscopic band ligation and/or non-selective beta blockers.
• Secondary prevention: treat to prevent recurrent bleeding.
  • Endoscopic band ligation and/or non-selective beta blockers.
• Variceal bleed:
  • Resuscitate, drugs to reduce portal blood flow.
  • Prevent/treat complications: aspiration, infection, HE.
  • Endoscopic treatment of varices by band ligation.
  • Endoscopic sclerotherapy is not favoured due to complications.
  • If the above measures fail: placement of TIPS or surgery.

Ascites in Liver Disease

• Sodium retention by the kidneys increases the volume of extracellular fluid, leading to ascites and edema.
• Increased hydrostatic pressure due to portal hypertension.
• Lower oncotic pressure due to low albumin.
• Clinical features:
  • Abdominal distension.
  • Shifting dullness on percussion.

Ascites

• Cirrhosis: most common cause (>80%)
• Other causes:
  • Malignancy (ovarian cancer classic, but also GI cancers)
  • Rare: non-cirrhotic portal hypertension
  • Rare: heart failure, pancreatitis, TB

Ascites: Management

• Paracentesis: tap ascites fluid.
  • Diagnostic tap: do cell count, microbiology, albumin, cytology.
  • Therapeutic tap: diuretic-resistant ascites in cirrhosis.
• Sodium restriction and diuretics (spironolactone).
• Avoid NSAIDs: risk of acute renal failure and hyponatremia, lowers the effect of diuretics.
• High index of suspicion for infection: low threshold for paracentesis.
• Diuretic-resistant = refractory ascites.

Spontaneous Bacterial Peritonitis

• Infection of ascites fluid without evidence of a surgically treatable intra-abdominal cause.
• Infection associated with cirrhosis (E.coli, Klebsiella).
• Early diagnosis and prompt treatment improve outcomes.
• Subtle/silent presentation.
• Low threshold for paracentesis of ascites fluid.
• Suspect: fever, abdominal pain/tenderness, altered mental state.
• Treat if ascites fluid cell count >250 polys/mm3.
• Antibiotic prophylaxis for high-risk patients (e.g., previous SBP or bleed).

Liver Blood Tests

• Related to liver cell (hepatocellular) damage:
  • Transaminases (ALT, AST)
• Related to obstruction to bile flow (cholestasis):
  • Alkaline phosphatase (ALP), Gamma-glutamyl transferase (GGT)
  • Bilirubin
• Related to liver function:
  • Bilirubin (abnormality is not liver or biliary tract specific).
  • Albumin (long half-life, indicator of chronic damage).
  • Coagulation function (PT/INR) (clotting factors have short half-life - better indicator of acute damage).

Hepatocellular Damage: Liver Enzymes

• Alanine transaminase (ALT): sensitive and specific marker for hepatocellular damage.
• Aspartate transaminase (AST): less specific, also found in muscle, myocardium, kidney.
• Both ALT and AST leak from damaged hepatocytes.
• The level of rise in these enzymes is poorly correlated with severity or prognosis.
• Very high levels in acute hepatocellular damage.
• May be only mildly elevated or normal despite chronic liver disease.

AST/ALT Ratio

• The ratio of AST to ALT produced by hepatocytes is approximately 2.5:1. AST is removed from serum by the liver sinusoidal cells twice as quickly, so resulting serum levels are basically equal in healthy individuals.
• However, in conditions with chronic, constant hepatocyte damage (e.g., alcoholic hepatitis, hepatocellular carcinoma), the ratio is closer to 1.
• During early-stage acute liver damage (e.g. viral hepatitis), the serum levels of AST and ALT reflect levels closer to background in hepatocytes.
• An AST/ALT ratio >5 indicates an extrahepatic source of AST.

Obstructive (Cholestatic) Liver Enzymes

• Alkaline phosphatase (ALP):
  • Situated on the hepatocyte border of bile canaliculi.
  • Hepatocytes react to obstruction of bile flow by leaking ALP.
  • Other sources: bone, placenta.
• Gamma-glutamyl transferase (GGT):
  • Very sensitive but not specific.
  • Good for correlating with elevated alkaline phosphatase to demonstrate that ALP is of liver origin.
  • Also induced by alcohol and drugs.

Explore the critical aspects of acute liver failure, a life-threatening condition characterized by severe liver injury and brain dysfunction. This quiz covers its causes, including viral infections, drug overdose, and toxins, as well as major histological changes. Test your knowledge on this important medical syndrome and its implications.