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
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
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
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
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
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]
