Managing encephalopathy in the outpatient setting

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Abbreviations

BCAA

branched‐chain amino acid

CHE

covert hepatic encephalopathy

HE

hepatic encephalopathy

LOLA

l‐ornithine‐l‐aspartate

MHE

minimal hepatic encephalopathy

MMSE

mini‐mental state examination

OHE

overt hepatic encephalopathy

PHES

psychometric hepatic encephalopathy score

PSS

portosystemic shunt

QOL

quality of life

SIP

sickness impact profile

Hepatic encephalopathy (HE) refers to brain dysfunction caused by liver insufficiency and/or portosystemic shunting, manifesting as a wide spectrum of neuropsychiatric abnormalities ranging from subclinical alterations to coma. It has traditionally been classified according to severity into minimal hepatic encephalopathy (MHE) and HE grades I to IV. MHE includes patients with mild neurocognitive decline apparent only on specialized testing. Grade I HE includes subtle behavioral changes such as inattention, mood changes, and sleep disturbances, which are often difficult to detect on routine clinical evaluation. Therefore, the new classification includes both grade I HE and MHE into covert hepatic encephalopathy (CHE).1 CHE is seen in 40% to 84% of patients with cirrhosis and is associated with poor quality of life (QOL), impaired driving skills, poor work performance, and reduced overall survival (Fig. 1).2

Diagnosis of MHE

The diagnosis of MHE requires specialized neurocognitive testing; however, these tests may be impaired in other causes of cognitive dysfunction as well. Only those with mini‐mental state examination (MMSE) score greater than 24 may be considered for MHE testing. At least two different tests should be used depending on the local population norms, with one being a widely validated test. This would serve as a comparator for multicentre trials, as well as minimize missed cases (Table 1).3 New biomarkers (S100β, an astrocytes protein, 3‐nitrotyrosine, a reactive nitrogen intermediate) and imaging techniques (diffusion tensor imaging, voxel‐based morphometry) have recently been described to characterize MHE and even predict survival. However, these need further evaluation and validation before they may be considered as diagnostic parameters.4, 5, 6

Table 1.

Tests for Diagnosis of MHE

Test	Description	Reliability	Advantages	Disadvantages
Paper‐Pencil
PHES	5 paper and pencil tests: number connection tests A and B, digit symbol, line tracing and serial dotting tests Adjusted for age, education	Sensitivity: 96% Specificity: 100%	• Extensively validated	• Time‐consuming • Requires psychologist • Learning effect • Requires good neuromuscular control
Repeatable Battery for the Assessment of Neuropsychological Status	Paper or pencil battery testing two domains, cortical and subcortical	—	• Has US reference data	• Copyrighted • Requires psychologist • Language and memory not much impaired in CHE
Computerized
Inhibitory control test	Presentation of letters at 500‐ms intervals Patients instructed to respond only when X and Y are alternating	Sensitivity: 87% Specificity: 77%	• Validated • Does not require a psychologist	• Requires highly functioning patients • Requires a practice session
Cognitive Drug Research	Psychometric battery presented on computer with patients responding via a two‐button YES/NO response box	High degree of correlation with PHES	• No need for prior computer knowledge	• Requires highly functioning patients
Stroop EncephalApp	Identification of the color of symbols or text presented, while the word names a different color	Sensitivity: >70% Specificity: 90%	• Easy to administer • Quick • Reliable • Freely available	• Cannot be performed in color‐blind
Scan test	Computerized digit recognizing task measuring the reaction times and errors	Mortality hazard ratio: 2.4 (95% confidence interval: 1.1‐5.3)	• Reliable, predicts mortality	• Need practice sessions, knowledge of computer
Neurophysiological
Electroencephalogram ± evoked potentials	Can detect changes in cerebral activity across the spectrum of HE	Sensitivity: 43‐100%	• Independent of patient cooperation • No learning effect	• Requires interpretation by a neurologist • Expensive and labor‐intensive
Critical flicker frequency	Highest frequency at which the flicker of a light source can be detected, above which light is perceived to be continuous	Sensitivity: 40‐100% Specificity: 91%	• Simple • Reliable • Not influenced by age, education	• Requires highly functioning patients, binocular vision, absence of red‐green color blindness
Continuous reaction time	Repeated registration of the motor reaction time to an auditory stimulus	—	• Quick	• Requires good hearing
Rapid Screening Test
SIP‐CHE score	Rapid screening method composed of four questions	Sensitivity: 81‐88% Specificity: 24‐37%	• Quick • No special training required	• Poor specificity • Needs validation

Abbreviations: PHES, psychometric hepatic encephalopathy score; SIP, sickness impact profile.

Table 2.

Agents Used in Outpatient Treatment of HE

Therapeutic Modality	Mechanism	Role			Comments
		CHE	Secondary Prophylaxis of OHE	Primary Prophylaxis of OHE
Lactulose	Osmotic laxative Acidification of the colon ↓ Urease‐producing bacteria ↓ Ammonia production ↓ Ammonia absorption	Improved cognitive function, driving performance Cost effective in preventing accidents	Most extensively studied. ↓ Progression to OHE	↓ Likelihood of OHE	Mainstay of HE treatment and prophylaxis Cost effective
Rifaximin	↓ Urease‐producing bacteria ↓ Ammonia production	Improves cognitive function, QOL	↓ Breakthrough HE, hospitalization	Not studied	Modulates flora Does not cause resistance
Probiotics	Improve dysbiosis	Improvement in cognitive tests Improved QOL ↓ Endotoxins	↓ Risk for hospitalization	Not studied	Well tolerated Available without prescription
BCAA	Promote the synthesis of glutamine from ammonia in skeletal muscle	Unclear	Improves recurrent HE	Not studied	No effect on overall mortality
LOLA	Ammonia scavenging ↑ Production of urea in hepatocytes, activating glutamine synthase in hepatocytes and skeletal muscle	No improvement in CHE ↓ Progression to OHE	↓ Progression to OHE	Not studied	Evidence conflicting except in OHE, more studies needed
Glycerol phenylbutyrate	↑ Excretion of glutamine	Not studied	↑ Time to recurrence	Not studied	No benefit in patients on rifaximin
Zinc	If deficient, reduced urea cycle utilization of ammonia	Improvement in cognitive tests	None	Not studied	No evidence on other outcomes

Treatment of HE in the Outpatient Setting

According to the new nomenclature, CHE includes both MHE and grade I HE considering the difficulty in distinguishing between the two without specialized testing. However, a recent study demonstrated that patients with grade I HE had higher mortality and complication rates as compared with those with MHE.7 In a barter between semantic accuracy and practical considerations of a busy outpatient setting, the treatment has been described in terms of CHE and is to include both MHE and grade I HE (Fig. 2).

Treatment of HE depends on severity. Overt hepatic encephalopathy (OHE) is usually treated in‐hospital, and on resolution, prophylaxis to prevent future episodes is recommended. There are no clear recommendations for treating CHE yet. However, CHE profoundly affects QOL, work productivity, and predicts a higher risk for development of OHE. Adding to this the increase in caregiver burden and the risk to society considering the possibility of accidents while driving and operating heavy machinery, treatment of CHE may well be justified.

Nonabsorbable Disaccharides

Lactulose forms the mainstay of treatment of HE. Dhiman and colleagues8 have shown an improvement in CHE in 64% of patients with lactulose. It has also shown good results when used as primary as well as secondary prophylaxis for HE in cirrhosis. Use as primary prophylaxis is currently limited to only patients who have a high risk for development of OHE; however, the exact threshold is not yet defined. In our opinion, patients with decompensated cirrhosis may be considered for primary prophylaxis. Diarrhea, bloating, and nausea are common side effects.

Antibiotics

Rifaximin is the antibiotic of choice in the management of HE. It modulates the gut flora, improves gut dysbiosis, and has not been shown to induce resistance. Addition of rifaximin to lactulose therapy halves the chances of breakthrough HE in patients with one or more episodes of OHE. Monotherapy with rifaximin has also been shown to be effective in HE prophylaxis.9

Probiotics

Interest in the pathophysiology of the gut–brain axis is rapidly emerging. Pathogenic gut bacteria play an important role in ammoniagenesis, and the improvement of gut dysbiosis by probiotics leads to improvement in HE. A recent meta‐analysis suggested that probiotics led to improvement in CHE, reduced recurrence of OHE, and were well tolerated. Different strains have been used by studies, notably VSL#3, probiotic yogurt, and Bifidobacterium longum. VSL#3 has been found to be as effective as lactulose for secondary prophylaxis.10

Ammonia Scavengers

l‐Ornithine‐l‐aspartate (LOLA) has shown good results in treatment of OHE but showed no immediate improvement in patients with CHE. However, 6 months after administration, patients given LOLA were less likely to experience development of OHE, which may be caused by the modulation of lipid and peptide metabolism. Overall evidence on its use in CHE is still conflicting.

Nutrition

Detoxification of ammonia is impaired in liver disease, and ammonia metabolism shifts to the muscles and brain. Malnutrition and sarcopenia further divert ammonia to brain, worsening HE. A diet rich in protein (1.2‐1.5 g/kg) and energy (35‐40 kcal/kg) is thus recommended. Vegetable and dairy protein should be preferred. Meals should be small, frequent, and evenly distributed. A late‐night snack rich in complex carbohydrates mitigates a prolonged fasting state overnight. Branched‐chain amino acids (BCAAs) may be given in patients who are unable to tolerate protein intake.

Shunt Occlusion

Patients who have recurrent or persistent OHE refractory to medical management should be screened for the presence of a spontaneous portosystemic shunt (PSS). Occlusion of shunts with balloon‐occluded retrograde transvenous obliteration has shown rapid improvement in symptoms and better survival than those on medical management in patients with recurrent HE. Patients with transjugular intrahepatic PSSs may need a revision to reduce the shunting.

Conclusion

HE affects a majority of cirrhotic patients at some point in time. Although the overt form is self‐evident, CHE is often neglected. Considering the accumulating evidence of its consequences, it would be prudent to test and treat for CHE. Disaccharides, antibiotics, and probiotics are effective options. Evidence with newer drugs is evolving and appears to be promising.

Figure 1.

Consequences of CHE.

Figure 2.

Algorithm for outpatient management of HE.