Hepatic Encephalopathy (Portosystemic Encephalopathy)

Epidemiology

  • Definition: reversible brain dysfunction which occurs in association with significant liver dysfunction

Etiologic Precipitants

Dehydration/Hypovolemia (see Hypovolemic Shock, [[Hypovolemic Shock]])

Increased Ammonia Synthesis

  • Constipation (see Constipation, [[Constipation]])
  • Excessive Dietary Protein
  • Gastrointestinal Hemorrhage (see Gastrointestinal Hemorrhage, [[Gastrointestinal Hemorrhage]]): may result in decreased oxygen delivery to the brain
  • Hypokalemia (see Hypokalemia, [[Hypokalemia]]): results in potassium movement out of cells to replenish extracellular stores with associated movement of hydrogen ions into cells -> intracellular acidosis within renal tubular cells increases ammonia synthesis
  • Infection: may result in decreased oxygen delivery to the brain
    • Sepsis (see Sepsis, [[Sepsis]]): in addition to impaired oxygen delivery to the brain, hypotension may have an exaggerated effect due to the impairment in cerebral autoregulation of blood flow in liver disease
    • Spontaneous Bacterial Peritonitis (SBP) (see Spontaneous Bacterial Peritonitis, [[Spontaneous Bacterial Peritonitis]])
    • Urinary Tract Infection (UTI) (see Urinary Tract Infection, [[Urinary Tract Infection]])
  • Metabolic Alkalosis (see Metabolic Alkalosis, [[Metabolic Alkalosis]]): enhances the conversion of ammonium, NH4+ (a charged particle which cannot cross the blood-brain barrier), into ammonia, NH3, which can cross the blood-brain barrier

Portosystemic Shunt

  • Radiographically/Surgically-Placed Portosystemic Shunt
  • Spontaneous Portosystemic Shunt

Vascular Occlusion

Drugs/Toxins

Other

Physiology

Role of the Neurotoxin Ammonia

  • Ammonia is the Best Characterized Neurotoxin in Hepatic Encephalopathy: it accumulates systemically, traverses the the blood-brain barrier, and results in brain dysfunction
  • Ammonia Synthesis and Clearance
    • Ammonia is synthesized from glutamine by enterocytes, by bacterial catabolism of nitrogenous compounds (ingested protein, secreted urea), and possibly from urea digested by Helicobacter pylori in the stomach
    • The normally functioning liver clears all of the portal vein ammonia and converts it to glutamine
      • Glutamine is metabolized in mitochondria to glutamate and ammonia: glutamine-derived ammonia may interfere with mitochondrial function leading to astrocyte dysfunction
    • Muscle wasting also contributes to lack of ammonia clearance, since the muscles are an important site of extrahepatic ammonia removal
  • Ammonia Effects on the Brain: ammonia accumulates in the systemic circulation and subseqently croses the blood brain barrier -> brain dysfunction
    • Other toxins, such as mercaptans or short-chain fatty acids (C4 to C8), potentiate cerebral ammonia toxicity
    • Hyperammonemia may increases cerebral uptake of neutral amino acids (tyrosine, phenylalanine, tryptophan) by enhancing the activity of the blood-brain barrier L-amino acid transporter: these neutral amino acids affect the synthesis of the neurotransmitters dopamine, norepinephrine, and serotonin
    • Ammonia inhibits the generation of excitatory and inhibitory postsynaptic nerve potentials
    • Cerebral Edema: has been observed in hyperammonemia and hepatic encephalopathy, with various mechanisms being implicated
      • Increased astrocyte metabolism of ammonia to glutamine (an osmolyte) -> increased intracellular osmolarity
      • Ammonia-induced oxidative stress and changes in mitochondrial permeability
      • Glutamine serves as a carrier of ammonia into the mitochondria -> astrocyte swelling
      • Ammonia-induced cerebral water accumulation (likely due to astrocyte swelling) -> cerebral hyperemia

Role of the Neurotoxin Oxindole

  • Oxindole is a Tryptophan Metabolite
    • Oxindole is formed by intestinal bacteria (via indol) and is normally cleared by the liver (similar to ammonia)
    • Oxindole can cause sedation, musclea weakness, hypotension, and coma

Impairment of Neurotransmission

  • Gamma-Aminobutyric Acid (GABA)/Benzodiazepine Neurotransmission: increased tone of the inhibitory GABA-benzodiazepine neurotransmitter system has been implicated in the development of hepatic encephalopathy
  • Neurosteroids: metabolites of progesterone which function as endogenously neuroactive compounds
    • Allopregnanolone and tetrahydrodeoxycorticosterone are potent selective positive allosteric modulators of the GABA-A receptor complex
  • Glutamatergic Neurotransmission: alterations in glutamatergic neurotransmitter function have been implicated in the central nervous system dysfunction in acute liver failure
  • Catecholamines: altered catecholamine concentrations in hepatic encephalopathy have been linked to altered amino acid metabolism
  • Serotonin: increase cerebral concentrations of the serotonin metabolite, 5-hydroxyindoleacetic acid (5-HIAA), is a consistent neurochemical finding in hepatic encephalopathy
  • Histamine: this neurotransmitter system is also altered in hepatic encephalopathy
  • Melatonin: the 24-hr cycle of melatonin (considered to be the output signal of the biological “clock”) is significantly altered in cirrhosis

Other Potential Mechanisms

  • Alteration in the Blood-Brain Barrier: specific changes in blood-brain barrier transport mechanisms have been observed in hepatic encephalopathy
  • Depression in Cerebral Glucose Metabolism: due in part to hyperammonemia (which likely results in increased glutamine synthesis)
  • Impaired Cerebral Perfusion: with impaired cerebral autoregulation of brain blood flow

Diagnosis

  • Serum Ammonia: increased in 90% of patients with hepatic encephalopathy
  • Head CT: required to rule out other structural pathologies, etc
  • Brain MRI: may be required
  • Electroencephalogram (EEG): diffuse slowing (consistent with toxic-metabolic encephaloapthy)
    • Grade I Hepatic Encephalopathy: usually normal
    • Grade II-IV Hepatic Encephalopathy: usually abnormal

Clinical Manifestations

Clinical Staging

  • Grade I: asterixis is variably present
    • Behavioral Changes: euphoria, depression
    • Mild Confusion
    • Dysarthria
    • Disordered Sleep
  • Grade II: asterixis is usually present
    • Lethargy
    • Moderate Confusion
  • Grade III: asterixis is usually present
    • Incoherent Speech
    • Marked Confusion/Stupor
    • Sleeping, But Arousable
  • Grade IV: asterixis is absent
    • Coma
    • Unresponsive to Pain

Neurologic Manifestations

  • Behavioral Changes
    • Depression (see Depression, [[Depression]])
    • Euphoria
  • Delirium (see Delirium, [[Delirium]])
  • Dysarthria (see Dysarthria, [[Dysarthria]])
  • Obtundation/Coma (see Obtundation-Coma, [[Obtundation-Coma]])
  • Seizures (see Seizures, [[Seizures]])
    • Epidemiology:

Other Manifestations

  • xxx

Treatment

Supportive Measures

  • Safety Measures: as required
    • Fall Prevention
    • Soft Restraints
  • Airway Protection: indicated for grade III-IV hepatic encephalopathy
  • Avoidance of Sedatives: particular benzodiazepines
  • Correction of Precipitating Etiologies: if present

Dietary Management

  • General Nutritional Targets: 35 to 40 kcal/kg/day with protein intake of 1.2-1.5 g/kg/day
  • Meal Pattern: eat small meals throughout the day with a late night complex carbohydrate snack (since fasting increases production of glucose from amino acids, with consequent ammonia production)
  • Restriction in Dietary Protein: not recommended for most patients (as protein restriction is associated with increased mortality)
    • Management of Subset of Patients Who Worsen with Protein Intake: generally occurs only in those patients with severe enough liver disease to merit a TIPS
      • Substitution of vegetable proteins for milk/fish/meat protein sources
      • Branched-chain amino acids + low protein diet

Haloperidol (Haldol) (see Haloperidol, [[Haloperidol]])

  • May be useful in some cases with associated agitated delirium

Pharmacologic Therapy to Lower Blood Ammonia Level

  • Disaccharides
    • Lactitol: available in some countries outside of the US
    • Lactose: in patients with hepatic encephalopathy and lactase deficiency, lactose has many of the same effects as lactulose and is far less expensive
    • Lactulose (see Lactulose, [[Lactulose]])
      • Mechanism: lack of specific disaccharidase on luminal small intestinal surface allows entry of lactulose (beta-galactosidofructose) into the colon -> colonic acidification (and other mechanisms)
      • Response Rate: approximately 70-80% of patients with hepatic encephalopathy improve on lactulose therapy
      • Efficacy: lactulose is effective in hepatic encephalopathy, but does not improve mortality rate [MEDLINE]
      • PO Dose: 30 ml (20 g) q4-12hrs, titrated to 2-3 soft bowel movements per day
      • Enema Dose: 300 ml (200 g) retained for 30-60 min with rectal balloon catheter, q4-6hrs
  • Oral Antibiotics
    • Rifaximin (see Rifaximin, [[Rifaximin]]): effective (usually added to lactulose, although whether an additional benefit is achieved is unknown)
      • Dose: 500 mg PO BID
    • Neomycin (see Neomycin, [[Neomycin]]): second-line therapy in patients who cannot take rifaximin
      • Has not been shown to be efficacious in randomized trials
      • Dose: 500 mg PO TID
      • Adverse Effects: ototoxicity, nephrotoxicity
    • Metronidazole (Flagyl) (see Metronidazole, [[Metronidazole]]): may alternatively be used
      • Dose: PO
    • Vancomycin (see Vancomycin, [[Vancomycin]]): may alternatively be used
      • Dose: PO
    • Paromomycin
  • Ornithine-Aspartate: not available in the US
    • Mechanism: stimulates metabolism of ammonia
  • Polyethylene Glycol (see Polyethylene Glycol, [[Polyethylene Glycol]]): effective
    • Mechanism: cathartic
  • Branched Chain Amino Acids: may be used in patients who cannot tolerate other therapies
    • Dose: PO or IV
  • Sodium Benzoate: metabolic ammonia removal

Embolization of Large Spontaneous Portosystemic Shunts

  • Effective in select patients

Other Potential Therapies

  • Prebiotics/Probiotics: have been studied in small trials and may be efficacious
    • Prebiotics: substances that promote the growth of organisms
    • Probiotics: formulations of microorganisms that may have beneficial properties for the host
      • Lactobacillus
      • Bifidobacteria
  • Acarbose
  • Flumazenil (Romazicon) (see Flumazenil, [[Flumazenil]])
  • Zinc (see Zinc, [[Zinc]])
  • Melatonin (see Melatonin, [[Melatonin]])
  • L-Carnitine
  • Glutamatergic Antagonists
  • Serotonin Antagonists
  • Opioid Antagonists

Prognosis

  • Persistent Neurologic Deficits After Hepatic Encephalopathy: may occur [MEDLINE] [MEDLINE]

References

  • Management of agitation and convulsions in hepatic encephalopathy. Indian J Gastroenterol. 2003 Dec;22 Suppl 2:S54-8 [MEDLINE]
  • Nonabsorbable disaccharides for hepatic encephalopathy. Cochrane Database Syst Rev. 2004;(2):CD003044 [MEDLINE]
  • Persistence of cognitive impairment after resolution of overt hepatic encephalopathy. Gastroenterology. 2010 Jun;138(7):2332-40. doi: 10.1053/j.gastro.2010.02.015. Epub 2010 Feb 20 [MEDLINE]
  • Evidence of persistent cognitive impairment after resolution of overt hepatic encephalopathy. Clin Gastroenterol Hepatol. 2011 Feb;9(2):181-3. doi: 10.1016/j.cgh.2010.10.002. Epub 2010 Oct 15 [MEDLINE]
  • Persistent hepatic encephalopathy secondary to portosystemic shunt occluded with Amplatzer device.Ann Hepatol. 2014 Jul-Aug;13(4):456-60 [MEDLINE]
  • Right atrial pressure may impact early survival of patients undergoing transjugular intrahepatic portosystemic shunt creation. Ann Hepatol. 2014 Jul-Aug;13(4):411-9 [MEDLINE]
  • Hepatic encephalopathy in chronic liver disease: 2014 Practice Guideline by the American Association for the Study of Liver Diseases and the European Association for the Study of the Liver. Hepatology. 2014 Aug;60(2):715-35. doi: 10.1002/hep.27210. Epub 2014 Jul 8 [MEDLINE]