Hepatic Encephalopathy

Hepatic encephalopathy is a reversible condition in which elevated ammonia levels cause impaired brain function in patients with advanced liver disease. Hepatic encephalopathy can be precipitated by conditions that affect the normal absorption, metabolism, or clearance of ammonia, including dehydration, renal failure, infections, and gastrointestinal bleeding. Patients present with a progression of symptoms, from minimal confusion and asterixis to stupor and coma. Diagnosis is clinical and requires the exclusion of alternative diagnoses. Management involves addressing the causative factor and decreasing the systemic absorption of ammonia with lactulose or rifaximin.

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Epidemiology and Etiology

Epidemiology

  • 30%–45% of patients with cirrhosis
  • 10%–50% of patients who undergo transjugular intrahepatic portosystemic shunts (TIPS)
  • 2nd-most common cause of hospitalization for cirrhotic patients (behind ascites)

Etiology

Hepatic encephalopathy is seen in patients with severe liver disease or liver failure, and can be exacerbated by:

  • Decreased metabolism or clearance of ammonia
    • Renal failure
    • Diuretics
    • Transjugular intrahepatic portosystemic shunt (TIPS)
  • Increased production or absorption of ammonia
    • Excess dietary protein intake
    • Gastrointestinal (GI) bleed
    • Constipation
    • Infection (spontaneous bacterial peritonitis)
  • Electrolyte disturbances
    • Hypokalemia
    • Metabolic alkalosis
  • Respiratory issues
    • Hypoxia
    • Hypercapnia
  • Vascular occlusion
    • Portal vein thrombosis
    • Hepatic vein thrombosis
  • Drugs
    • Opiates
    • Benzodiazepines
    • Alcohol
    • Hypnotics

Precipitating factors for hepatic encephalopathy can be remembered by the mnemonic “HEPATICS”:

HHemorrhage in the GI tract
EExcess dietary protein
PPotassium (hypokalemia)
AAlkalosis or azotemia
TTIPS procedure
IInfection
CConstipation
SSedatives
Major risk factors for hepatic encephalopathy

Major risk factors for hepatic encephalopathy in a patient with liver failure
AKI: acute kidney injury
SBP: spontaneous bacterial peritonitis

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Pathophysiology

Normal physiology:

  • The GI tract is the primary source of ammonia, where it is produced by:
    • Enterocytes from glutamine
    • Catabolism of nitrogen by colonic bacteria
  • Ammonia enters the circulation via the portal vein.
  • Liver clears this ammonia by converting it into glutamine → prevents entry into the systemic circulation

Liver disease allows disruption of normal ammonia regulation through:

  • Hepatocyte dysfunction: ↓ conversion of ammonia to glutamine → ↑ serum ammonia
  • Splanchnic and peripheral vasodilation: portosystemic shunting away from the liver → ↑ serum ammonia
  • ↑ blood-brain barrier permeability: allows ↑ delivery of ammonia to astrocytes

Impaired brain function results from a buildup of ammonia, where it:

  • Is utilized to produce glutamine → ↑ osmotic pressure and swelling of astrocytes → cerebral edema
  • Binds to γ-aminobutyric acid (GABA) receptors → ↑ GABA-energic inhibitory function
  • Inhibits a step in the Krebs cycle → ↓ metabolic fuel supply
Effects of hyperammonemia on the glutamate-glutamine cycle

Ammonia (NH3) crosses the blood–brain barrier and is absorbed and metabolized by astrocytes. These cells use ammonia when synthesizing glutamine from glutamate. The increased levels of glutamine lead to a rise in osmotic pressure in the astrocytes, which become swollen and result in brain edema. Ammonia also increases activity of the inhibitory GABA system and reduces energy production.

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Clinical Presentation

Symptoms

  • Cognitive impairment (including mental slowing, confusion, somnolence, and coma)
  • Sleep-pattern disturbances
    • Insomnia
    • Hypersomnia
    • Usually precedes other mental status changes
  • Mood changes
    • Euphoria
    • Depression

Physical exam findings

  • Asterixis (flapping of outstretched and dorsiflexed hands)
  • Ataxia
  • Hyperreflexia
  • Nystagmus
  • Evidence of chronic liver disease (e.g., jaundice, abdominal distension, ascites, edema)

Severity

The West Haven criteria are used to grade the clinical severity.

StageConsciousnessIntellect and behaviorNeurological findings
0NormalNormalNormal
1Mild lack of awarenessSlowed intellect, apathy, restlessness, disordered sleepMild asterixis, impaired computation
2LethargicModerate disorientation, drowsiness, inappropriate behaviorAsterixis, slurred speech
3Somnolent but arousableDisorientation, incoherent speechAsterixis, hyperreflexia, clonus, muscular rigidity
4ComaComaDecerebrate or decorticate posturing, asterixis is typically absent

Diagnosis

Hepatic encephalopathy is a clinical diagnosis, and other conditions must be excluded.

  • Supporting evidence: ↑ serum ammonia (aids in the evaluation, but is not diagnostic)
  • Evaluate for precipitants and alternative diagnoses:
    • Laboratory
      • Glucose → hypoglycemia
      • Basic metabolic panel → hypokalemia, alkalosis, renal failure
      • Complete blood count → infection, GI bleed
      • Thyroid-stimulating hormone → myxedema coma
      • Arterial blood gas → alkalosis, hypercapnia
      • Drug screen 
      • Alcohol level
      • Blood cultures → infection
      • Urinalysis → infection
    • Imaging
      • Brain computed tomography (CT) → rule out intracranial pathology
      • Ultrasound
        • Can assist with diagnosis of portal vein thrombosis
        • Evaluate for ascites → diagnostic paracentesis → rule out spontaneous bacterial peritonitis (SBP)

Tip: Spontaneous bacterial peritonitis should be ruled out in all patients presenting with hepatic encephalopathy and ascites.

Management

Management focuses on identifying and treating precipitating factors, and lowering the serum ammonia concentration.

  • General supportive care:
    • Establish a safe environment for the patient.
      • Hospitalization for severe symptoms or impairment that prevents adherence to the prescribed treatment
      • Mild symptoms can be managed on an outpatient basis.
    • Proper hydration
    • Avoid sedatives.
    • Treat precipitating causes.
    • Provide nutritional support.
  • Ammonia-lowering treatment:
    • Lactulose
      • Converted to lactic acid by intestinal flora → acidification leads to conversion of ammonia (NH₃) to ammonium (NH₄+) → ammonium is excreted in the feces → ↓ absorption 
      • Dose is titrated to produce at least 3 bowel movements per day. 
    • Rifaximin
      • Non-absorbable antibiotic to decrease the intestinal bacterial load
      • Used in patients who do not initially respond to, or cannot tolerate, lactulose 
    • Monitoring for improvement is based on the clinical exam, not ammonia levels.

Differential Diagnosis

  • Wilson’s disease: caused by a defect in copper transport within hepatocytes. Commonly presents in young adults with liver disease, neurologic manifestations, and psychiatric symptoms, which may be confused with hepatic encephalopathy; however, Wilson’s disease is associated with Kayser-Fleischer rings, low plasma ceruloplasmin, and high urinary copper excretion. Chelating agents are required for treatment.
  • Toxic-metabolic encephalopathy: a disruption of normal physiologic functions in the brain caused by other conditions, such as infection, renal dysfunction, electrolyte abnormalities, and medications. Patients present with somnolence, disorientation, motor abnormalities, or seizure. Asterixis is typically not present. Laboratory tests can help distinguish the cause and differentiate the condition from hepatic encephalopathy. Treatment focuses on the underlying cause. 
  • Ischemic stroke: a disease in which poor blood flow to the brain results in cell death. Symptoms include focal weakness, numbness, loss of vision, dysarthria, and altered mental status. Asterixis is not seen. Computed tomography and magnetic resonance imaging (MRI) of the brain are used for diagnosis, and will differentiate this condition from hepatic encephalopathy. Management includes aspirin, statins, and treatment of risk factors.
  • Encephalitis: a disruption of normal brain function due to inflammation, most commonly from a virus. Patients can have altered mental status, headache, fever, seizures, and movement disorders. Brain imaging may be helpful, but lumbar puncture with cerebrospinal fluid analysis is required for diagnosis and to differentiate encephalitis from hepatic encephalopathy. Treatment depends on the causative agent and includes antivirals, antibiotics, and supportive care.
  • Wernicke’s encephalopathy: a neurologic complication of thiamine deficiency, usually seen with chronic alcohol dependence. Patients may present with disorientation, agitated delirium, oculomotor dysfunction, gait ataxia, or coma. This is a clinical diagnosis, so history and exam should help differentiate Wernicke’s encephalopathy from hepatic encephalopathy. Treated with intravenous thiamine.

References

  1. Ferenci, P. (2020). Hepatic encephalopathy in adults: Clinical manifestations and diagnosis. In Robson, K.M. (Ed.), Uptodate. Retrieved November 2, 2020, from https://www.uptodate.com/contents/hepatic-encephalopathy-in-adults-clinical-manifestations-and-diagnosis
  2. Ferenci, P. (2020). Hepatic encephalopathy: Pathogenesis. In Robson, K.M. (Ed.), Uptodate. Retrieved November 2, 2020, from https://www.uptodate.com/contents/hepatic-encephalopathy-pathogenesis
  3. Ferenci, P. (2020). Hepatic encephalopathy in adults: Treatment. In Robson, K.M. (Ed.), Uptodate. Retrieved November 2, 2020, from https://www.uptodate.com/contents/hepatic-encephalopathy-in-adults-treatment
  4. Wolf, D.C. (2020). Hepatic encephalopathy. In Anand, B.S. (Ed.), Medscape. Retrieved November 2, 2020, from https://emedicine.medscape.com/article/186101-overview

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