Epidemiology
- Definition: reversible brain dysfunction which occurs in association with significant liver dysfunction
- Cirrhosis (see End-Stage Liver Disease, [[End-Stage Liver Disease]])
- Congestive Hepatopathy (Passive Hepatic Congestion) (see Congestive Hepatopathy, [[Congestive Hepatopathy]]): rare etiology of hepatic encephalopathy
Etiologic Precipitants
Dehydration/Hypovolemia (see Hypovolemic Shock, [[Hypovolemic Shock]])
- Diarrhea (see Diarrhea, [[Diarrhea]])
- Diuretics
- Bumetanide (Bumex) (see Bumetanide , [[Bumetanide ]])
- Furosemide (Lasix) (see Furosemide, [[Furosemide]])
- Spironolactone (Aldactone) (see Spironolactone, [[Spironolactone]])
- Hemorrhage
- Gastrointestinal Hemorrhage (see Gastrointestinal Hemorrhage, [[Gastrointestinal Hemorrhage]])
- Hemoperitoneum (see Hemoperitoneum, [[Hemoperitoneum]])
- Large-Volume Paracentesis (see Paracentesis, [[Paracentesis]])
- Vomiting (see Nausea and Vomiting, [[Nausea and Vomiting]])
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
- Transjugular Intrahepatic Portosystemic Shunt (TIPS) (see Transjugular Intrahepatic Portosystemic Shunt, [[Transjugular Intrahepatic Portosystemic Shunt]])
- Spontaneous Portosystemic Shunt
Vascular Occlusion
- Portal Vein Thrombosis (see Portal Vein Thrombosis, [[Portal Vein Thrombosis]])
- Hepatic Vein Thrombosis (see Hepatic Vein Thrombosis, [[Hepatic Vein Thrombosis]])
Drugs/Toxins
- Benzodiazepines (see Benzodiazepines, [[Benzodiazepines]])
- Ethanol (see Ethanol, [[Ethanol]])
- Opiates (see Opiates, [[Opiates]])
Other
- Acute Kidney Injury (AKI) (see Acute Kidney Injury, [[Acute Kidney Injury]])
- Hepatocellular Carcinoma (see Hepatocellular Carcinoma, [[Hepatocellular Carcinoma]])
- Hypoglycemia (see Hypoglycemia, [[Hypoglycemia]])
- Hyponatremia (see Hyponatremia, [[Hyponatremia]])
- Hypoxia (see Hypoxemia, [[Hypoxemia]])
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
- 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
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
- Rifaximin (see Rifaximin, [[Rifaximin]]): effective (usually added to lactulose, although whether an additional benefit is achieved is unknown)
- 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
- Lactulose (see Lactulose, [[Lactulose]])
- Probiotics: formulations of microorganisms that may have beneficial properties for the host
- Lactobacillus
- Bifidobacteria
- Prebiotics: substances that promote the growth of organisms
- Acarbose
- Flumazenil (Romazicon) (see Flumazenil, [[Flumazenil]])
- Zinc (see Zinc, [[Zinc]])
- Melatonin (see Melatonin, [[Melatonin]])
- L-Carnitine
- Glutamatergic Antagonists
- Serotonin Antagonists
- Opioid Antagonists
Prognosis
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]