Author:
JeremyGraham
Matthew N.Graber
Description
Hepatic encephalopathy (HE) is characterized by changes in behavior and consciousness with motor disturbances, associated with hepatic insufficiency and the accumulation of substances normally metabolized by the liver. HE may result from a combination of:
- Accumulation of ammonia (NH3) from:
- Protein degradation by colonic enzymes and bacteria
- Deamination of glutamine in small bowel, kidney, and muscle
- Accumulated NH3 crosses the blood-brain barrier. Astrocytes uptake NH3 and metabolize it into glutamine which causes cellular swelling. Ultimately leads to cerebral edema and cerebral mitochondrial dysfunction
- Accumulation of other neurotoxins:
- Short-chain fatty acids
- Manganese toxicity
- Neurosteroids
- Phenols
- Mercaptans
- Amino acids such as tryptophan
- Increased levels of inhibitory neurotransmitters:
- Benzodiazepines
- γ-aminobutyric acid (GABA)
- Serotonin
- Decreased levels of excitatory neurotransmitters:
- Glutamate
- Dopamine
- Aspartate
- Catecholamines
- Other contributing factors to HE:
- Decreased cerebral blood flow and oxygen
- Increased glucose consumption and possible hypoglycemia
- Zinc deficiency
- Genetics:
- Inherited errors of the urea cycle
Etiology
- Classification based on the eleventh World Congress of Gastroenterology:
- Type A: HE associated with acute liver injury and fulminant hepatic failure (FHF)
- Type B: HE associated with portosystemic bypass and no intrinsic liver disease
- Type C: HE associated with cirrhosis and portal hypertension
- Precipitating events:
- GI bleeding (more common in elderly)
- Hypokalemia and hyponatremia (diuretics)
- Alkalosis decreases renal NH4 excretion
- Sepsis (likely via inflammatory cytokines)
- Spontaneous bacterial peritonitis (SBP) or other infections
- Constipation
- Noncompliance with treatment regimen in chronic liver failure
- Hypoglycemia
- Hypovolemia (e.g., post large-volume paracentesis)
- Azotemia (e.g., diuretic or diarrhea induced)
- Narcotics or sedatives, including alcohol
- Zinc deficiency as multiple urea cycle enzymes are zinc dependent
- Hepatocellular injury
- Viral- or drug-induced hepatitis
- Post portosystemic shunt placement
- Recurrent encephalopathy can occur without precipitating factors
Signs and Symptoms
- Type A: Rapidly progresses to seizures, decerebrate rigidity, coma, and frequently death from cerebral edema
- Type B and C are chronic conditions that may manifest as minimal or overt HE. Overt HE may be classified as episodic or persistent:
- Minimal HE: Characterized by impaired psychomotor speed, visual perception, and attention and concentration, slow mental processing, and memory loss. Only detected by psychometric testing
- Overt HE: Slow monotonous speech pattern, loss of fine motor skills, hyperreflexia, clonus, hyperventilation, extrapyramidal type movement disorder, seizures, confusion, coma, decerebrate/decorticate posturing
- Overt HE episodic: Characterized by short period of changes in consciousness over hours to days that usually return to a normal mental state with treatment. In persistent HE, patients do not return to a normal mental state
- Grading (West Haven Criteria):
- Stage 0:
- No apparent clinical changes
- Abnormal neurophysiologic and neuropsychological tests
- May present with falls and driving accidents
- No asterixis
- Stage I:
- Personality changes, irritability, depression, or euphoria
- Reversal of normal sleep pattern
- Impairment of writing, drawing, addition, subtraction
- Asterixis may be present
- Stage II:
- Significant behavioral changes, often inappropriate
- Lethargy
- Slow responses
- Asterixis
- Slurred speech
- Ataxia
- Stage III:
- Disorientation to time and place
- Amnesia
- Paranoia
- Nystagmus and midposition pupils
- Hypoactive reflexes
- Positive Babinski reflex
- Semistupor to stupor
- Stage IV:
- Dilated pupils
- Stupor or coma
Essential Workup
- Elicit history of liver disease and prior episodes of HE
- Search for precipitating cause (particularly GI bleeding and infection)
- Check for electrolyte abnormalities:
- Even minimal abnormalities may manifest as significant clinical changes
Diagnostic Tests & Interpretation
Lab
- Blood NH3 level:
- Level correlates poorly with the degree of HE or the presence of cerebral edema
- Helpful in detecting HE in cases of altered mental status (AMS) of unknown cause
- Although up to 10% of HE patients may have normal NH3 levels, this finding with suspected HE warrants a search for other causes of AMS
- Must be kept on ice and assayed within 30 min
- Consider hemoccult testing and nasogastric (NG) lavage to rule out GI bleeding
- CBC to search for anemia
- Electrolytes, BUN, creatinine, glucose
- PT/INR with elevations suggesting significant liver failure
- Liver profile/liver enzymes
- Urinalysis for possible infection
- Culture urine and ascitic fluid to search for infectious cause
- Toxicology screen for alternate cause of altered level of consciousness:
- Additional labs as clinical scenario dictates:
- Thyroid studies
- Blood gases for pH and CO2 narcosis
- Magnesium
- Viral serology
Imaging
- CXR for pneumonia and signs of CHF
- Head CT scan: For new-onset AMS, focal neurologic deficit, suspected cerebral edema, or trauma
- MRI of the brain may have common findings but is not sensitive or specific enough for diagnostic use; this may diagnose manganese toxicity
Diagnostic Procedures/Surgery
- ECG for dysrhythmia and electrolyte imbalance
- CSF exam:
- For new-onset or unexplained worsening of HE
- CSF glutamine level correlates with severity of HE
- Paracentesis for SBP workup and culture of ascitic fluid
- EEG is usually abnormal, most commonly with generalized slowing and other nonspecific changes
Differential Diagnosis
- Alcohol withdrawal syndromes including delirium tremens and Wernicke-Korsakoff syndrome
- Cerebrovascular accident
- Global confusional state
- Congestive heart failure
- CO2 narcosis
- Head trauma with concussion or intracranial hemorrhage
- Hypocalcemia and hypercalcemia
- Hypoglycemia
- Hypokalemia
- Meningitis or encephalitis
- Metabolic encephalopathy
- Neuropsychiatric disorders
- Toxic confusional states secondary to:
- Sedative overdose
- Alcohol intoxication
- Illicit drugs
- Medications
- Uremia
Pediatric Considerations |
- Consider Reye syndrome early (most common cause of fulminate hepatic failure in children) even if PT is only mildly prolonged
- Consider fatty acid β-oxidation disorder:
- Freeze serum and urine sample for subsequent testing
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Initial Stabilization/Therapy
- Oxygen
- Airway protection:
- Patients with grade 3 or 4 HE may require intubation for airway protection. Propofol is the preferred agent for sedation
- Cardiac monitor
- Fluid resuscitation
- Initial AMS treatment:
ED Treatment/Procedures
Identification and removal of precipitating factors is key and may improve clinical picture alone
ALERT |
- Liver failure predisposes patients to both hypoglycemia and HE, and these can be additive to the clinical picture; therefore, frequent glucose checks are of absolute importance
- Identification of early cerebral edema is important as brain perfusion must be preserved and herniation prevented (associated but not limited to grade 3/4 HE)
- Treatment of complicating conditions:
- Acute GI bleeding
- Sepsis
- Electrolyte and pH abnormalities
- Coagulopathy
- Renal and electrolyte disturbances
- Avoid sedative/narcotics if possible:
- If necessary, use agents not metabolized by the liver
- Increase NH3 elimination:
- Bowel cleansing with nonabsorbable sugars (i.e., lactulose is mainstay of treatment). Retention enema preferred in grade 3/4 HE
- Decrease NH3-producing intestinal flora (in combination with lactulose):
- Rifaximin: Recommended for lactulose-resistant HE
- Neomycin (nephrotoxic and ototoxic)
- Metronidazole (PO)
- Correct zinc deficiency
- Precautions to prevent bodily harm to the confused patient with HE
- Liver transplantation provides cure for severe, spontaneous, or recurrent HE
- Protein restricted diet no longer recommended
- Possibly of benefit:
- L-ornithine-L-aspartate (LOLA)—may be helpful in lactulose-resistant HE
- Branched-chain amino acids
- Probiotics
- L-carnitine
- Albumin dialysis
- Broad-spectrum antibiotic coverage
- N-acetylcysteine
- Metabolic ammonia scavenger
- Hypertonic saline for HE-induced cerebral edema
- Chelation of manganese with edetate calcium disodium
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Medication
- Dextrose: 1-2 amps (25 g) of 50% dextrose (child: 2 mL/kg D25W) IV
- Lactulose: 30 mL (peds: 0.3 mL/kg) PO/NG tube q6h titrated to produce 2 or 3 soft stools per day and stool pH <5 or retention enema at 300 mL + 700 mL saline/tap water q4-6h
- Metronidazole: 250 mg PO/NG (peds: 10-30 mg/kg/d) q8h for 2 wk
- Narcan: 2 mg (peds: 0.1 mg/kg) IV/IM initial dose
- Neomycin: 1-3 g (peds: 50-100 mg/kg/d) PO q6h
- Rifaximin: 550 mg PO/NG q12h (safety not established for children <12 yr)
- Mannitol: 0.5-1 g/kg IV
- Thiamine (vitamin B1): 100 mg (peds: 50 mg) IV/IM
- Zinc acetate or sulfate: 220 mg PO/NG q8h
Disposition
Admission Criteria
- HE grade 2, 3, or 4 or inadequate social support
- Type A HE (any grade) and type B or C (grade 2 or above) should be admitted to the ICU with urgent GI consult
- Associated complicating condition (GI bleeding and sepsis)
- Uncertainty about cause of AMS
Discharge Criteria
- Known chronic or intermittent HE
- Grade 0 or 1 with remediable cause
- Adequate supervision with close follow-up
- Those appropriate for discharge should go home with:
Issues for Referral
- Refer to primary physician or GI for consideration of medication if recurrent early-stage HE episodes
- For any grade of type A HE, consider transfer to a liver transplant facility
Follow-up Recommendations
- Dietary consultation if possible cause of exacerbation
- Alcohol counseling if it is a concern
- FerenciP. Hepatic encephalopathy . Gastroenterol Rep (Oxf). 2017;5(2):138-147.
- ShawcrossDL, DunkAA, JalanR, et al. How to diagnose and manage hepatic encephalopathy: A consensus statement on roles and responsibilities beyond the liver specialist . Eur J Gastroenterol Hepatol. 2016;28(2):146-152.
- WijdicksEFM. Hepatic encephalopathy . NEJM. 2016;375(17):1660-1670.
See Also (Topic, Algorithm, Electronic Media Element)
Hypoglycemia