Hepatic encephalopathy: current challenges and future prospects

Figures & data

Table 1 Precipitating factors to HE

Increased ammonia production	Portosystemic shunts	Others
Gastrointestinal hemorrhage	Spontaneous	Drugs, eg, opioids, benzodiazepines
Excess dietary protein	Iatrogenic, eg, TIPS	Infections, eg, spontaneous bacterial peritonitis
Blood transfusion		Malignancy, eg, hepatoma
Electrolyte imbalances, eg, hypokalemia Constipation

Figure 1 Contributing factors toward pathophysiology of HE.

Notes: Ammonia is produced from nitrogenous products by bacterial metabolism of urea and proteins in the gut and from deamination of glutamine in the small intestine. Normally, ammonia is cleared by liver and kidneys and metabolized in skeletal muscle. However, as a result of liver dysfunction and portosystemic shunting, ammonia cannot be cleared adequately. **Increased ammonia levels in the plasma increases metabolism to glutamine (via glutamine synthetase) in astrocytes, which subsequently causes intracellular swelling and edema.¹⁰⁹
Abbreviation: HE, hepatic encephalopathy.

Table 2 West Haven Criteria for hepatic encephalopathy and symptoms

WHC	Symptoms	Clinical findings
Minimal Covert	Psychometric or neuropsychological alterations of tests exploring psychomotor speed/executive functions or neurophysiological alterations without clinical evidence of mental change	Nil
Grade I	Trivial lack of awareness Euphoria or anxiety Shortened attention span Impairment of addition or subtraction Altered sleep rhythm	Mild asterixis or tremor
Grade II Overt	Lethargy or apathy Disorientation for time Obvious personality change Inappropriate behavior	Obvious asterixis, dyspraxia, slurred speech
Grade III	Somnolence to semistupor Responsive to stimuli Confused Gross disorientation Bizarre behavior	Muscular rigidity, clonus, hyperreflexia
Grade IV	Coma	Decerebrate posturing

Note: Data from a previous study.¹¹⁰

Abbreviation: WHC, West Haven Criteria.

Table 3 Differential diagnosis of HE

Metabolic encephalopathies	Toxic encephalopathies	Intracranial events
□	□	□
□ Hypoglycemia	□ Alcohol	□ VInfection
□ Hypoxia	□ Drugs, eg, opioids, barbiturates	□ Encephalitis
□ Electrolyte abnormalities	□ Heavy metals	□ Tumors
□ Uremia		□ Vascular events

Table 4 Psychometric tests used in the evaluation of MHE

Test name	Description	Equipment required
PHES^Citation42	Six tests evaluating cognitive and psychomotor processing speed and visuo-motor coordination	Pencil and paper
Stroop test^Citation57	Tests mental speed and reaction time – written color name differs from the color ink it is printed in, and the participant must say the written word not the color	Computer, pencil and paper, or mobile phone app
CFF test^Citation100	Assessment of ability to detect a light source flickering	Specialized equipment
CRT test^Citation101	Motor reaction time to auditory stimuli	Computer equipment and additional hardware
Scan test^Citation102	Computerized digit recognition task	Computer equipment
ICT^Citation103	Test of attention and response inhibition to presented letters	Computer equipment

Note: Data from a previous study.⁹⁴

Abbreviations: CFF, critical flicker frequency; CRT, continuous reaction time; ICT, inhibitory control test; MHE, minimal hepatic encephalopathy; PHES, psychometric hepatic encephalopathy score.

Figure 2 Mechanism of action of nonabsorbable disaccharides.

Notes: Lactulose and lacitiol are not absorbed in the small intestine and enter the colon unchanged, where they are metabolized to hydrogen and VFA. Bacteria use these as preferred substrate, thereby reducing the production of ammonia and promoting its incorporation into stool for excretion.
Abbreviation: VFA, volatile fatty acids.

Table 5 Summary of other potential therapies for HE

LOLA*	Mechanism of action:
	Stimulates enzyme activity leading to increased urea excretion
	LOLA is shown in several studies to be as effective as nonabsorbable disaccharides or placebo in improving HE and reducing ammonia levels with a few adverse effects^Citation86,Citation104
HAS	Mechanism of action:
	Possible modulation of factors that induce circulatory dysfunction causing oxidative stress
	Two small randomized trials suggest that intravenous HAS does not improve resolution of hepatic encephalopathy, but may improve survival^Citation88,Citation89
Ammonia scavengers (e.g., GPB, OP)	Mechanism of action:
	Lowers ammonia by providing an alternative pathway to urea for waste nitrogen excretion in the form of phenylacetyl glutamine, which is excreted in urine ^Citation90
	GPB decreases the likelihood of being hospitalized for HE or experiencing an episode of HE.^Citation90 Serious adverse effects of GPB have been described, which include impaired rate of liver regeneration^Citation105 and marked reduction in BCAAs.^Citation106 BCAA supplementation is recommended alongside GPB.^Citation107 OP reduces plasma ammonia levels.^Citation108 Current Phase IIb trial (STOP-HE [NCT01966419]) to investigate the use of OP in acute HE has completed recruitment

Note:

* Not available in the USA.

Abbreviations: BCAA, branched-chain amino acid; GPB, glycerol phenylbutyrate; HAS, human albumin solution; HE, hepatic encephalopathy; LOLA, l-ornithine-l-aspartate; OP, ornithine phenylacetate.

PatidarKRBajajJSCovert and Overt Hepatic Encephalopathy: Diagnosis and ManagementClin Gastroenterol Hepatol201513122048206126164219

 PubMed Web of Science ®Google Scholar

FerenciPHepatic encephalopathyGastroenterology Report20175213814728533911

 PubMed Web of Science ®Google Scholar

WeissenbornKEnnenJCSchomerusHRuckertNHeckerHNeuropsychological characterization of hepatic encephalopathyJ Hepatol200134576877311434627

 PubMed Web of Science ®Google Scholar

BajajJSThackerLRHeumanDMThe Stroop smartphone application is a short and valid method to screen for minimal hepatic encephalopathyHepatology20135831122113223389962

 PubMed Web of Science ®Google Scholar

Romero-GomezMCordobaJJoverRValue of the critical flicker frequency in patients with minimal hepatic encephalopathyHepatology200745487988517393525

 PubMed Web of Science ®Google Scholar

LauridsenMMThieleMKimerNVilstrupHThe continuous reaction times method for diagnosing, grading, and monitoring minimal/covert hepatic encephalopathyMetab Brain Dis201328223123423299303

 PubMed Web of Science ®Google Scholar

AmodioPDel PiccoloFMarchettiPClinical features and survivial of cirrhotic patients with subclinical cognitive alterations detected by the number connection test and computerized psychometric testsHepatology19992961662166710347105

 PubMed Web of Science ®Google Scholar

BajajJSHafeezullahMFrancoJInhibitory control test for the diagnosis of minimal hepatic encephalopathyGastroenterology2008135515911600.e159118723018

 PubMed Web of Science ®Google Scholar

EllulMAGholkarSACrossTJHepatic encephalopathy due to liver cirrhosisBMJ2015351h418726265724

 PubMed Web of Science ®Google Scholar

BaiMYangZQiXFanDHanGl-ornithine-l-aspartate for hepatic encephalopathy in patients with cirrhosis: a meta-analysis of randomized controlled trialsJ Gastroenterol Hepatol201328578379223425108

 PubMed Web of Science ®Google Scholar

ZhuGQShiKQHuangSSystematic review with network meta-analysis: the comparative effectiveness and safety of interventions in patients with overt hepatic encephalopathyAliment Pharmacol Ther201541762463525684317

 PubMed Web of Science ®Google Scholar

Simon-TaleroMGarcia-MartinezRTorrensMEffects of intravenous albumin in patients with cirrhosis and episodic hepatic encephalopathy: a randomized double-blind studyJ Hepatol20135961184119223872605

 PubMed Web of Science ®Google Scholar

RiggioONardelliSPasqualeCNo effect of albumin infusion on the prevention of hepatic encephalopathy after transjugular intrahepatic portosystemic shuntMetab Brain Dis20163161275128126290375

 PubMed Web of Science ®Google Scholar

RockeyDCVierlingJMMantryPRandomized, double-blind, controlled study of glycerol phenylbutyrate in hepatic encephalopathyHepatology20145931073108323847109

 PubMed Web of Science ®Google Scholar

KeQYangRNYeFImpairment of liver regeneration by the histone deacetylase inhibitor valproic acid in miceJ Zhejiang Univ Sci B201213969570622949360

 PubMed Web of Science ®Google Scholar

Brunetti-PierriNLanpherBErezAPhenylbutyrate therapy for maple syrup urine diseaseHum Mol Genet201120463164021098507

 PubMed Web of Science ®Google Scholar

HolecekMVodenicarovovaMPhenylbutyrate exerts adverse effects on liver regeneration and amino acid concentrations in partially hepatectomized ratsInt J Exp Pathol201697327828427381898

 PubMed Web of Science ®Google Scholar

Ventura-CotsMArranzJASimon-TaleroMSafety of ornithine phenylacetate in cirrhotic decompensated patients: an open-label, dose-escalating, single-cohort studyJ Clin Gastroenterol2013471088188723751856

 PubMed Web of Science ®Google Scholar