**7. Treatment**

*Liver Disease and Surgery*

convenience and flexibility of using this test in the clinical situation [92]. It has been validated for the diagnosis and follow-up of MHE in the USA. It was found that the ICT is simple to administer and has higher sensitivity/specificity for screening MHE than the standard psychometric test (SPT). On the other side, Taneja et al. found that the ICT is not as useful as the PHES in diagnosing MHE in patients with

*Inhibitory control test. A continuous sequence of letters is displayed on the computer screen every 500 ms. The patient is educated to respond only if an X is preceded by a Y, or a Y is preceded by an X, but responses must be* 

In 2013, Bajaj et al. developed an application, the EncephalApp-Stroop App, for screening MHE that is operated by the iOS system on the iPhone and iPad. The core of this innovative application is the Stroop test, which assesses psychomotor speed and cognitive alertness by measuring the time required to correctly identify a series of symbols and printed words with different colors [86]. The Stroop test evaluates psychomotor speed and cognitive flexibility by the interference between recognition reaction time to a colored field and a written color name. [86]. In a multicenter study that compared the EncephalApp-Stroop App to the PHES and ICT, the EncephalApp-Stroop App had good sensitivity (70–80%) for MHE screening and

It is a computerized test that measures the patient's speed and accuracy to perform a digit recognition memory task of increasing complexity [40, 95]. It is done by randomly displaying a series of 72 sorted pairs of numbers for 3 s on a computer screen. Patients are instructed to press the appropriate number on a keyboard if they identify a common digit in the sequence of numbers presented. The mean reaction times and the percentage of errors are recorded, and the results are evaluated

using the reaction times weighted by the number of errors [96].

**14**

cirrhosis [93].

**Figure 6.**

*6.3.2.4 The Stroop test*

*6.3.2.5 The SCAN test*

was predictive of the progression to OHE [94].

*inhibited if an X is followed by an X, or a Y is followed by a Y.*

Treatment of minimal hepatic encephalopathy with lactulose, probiotics, or l-ornithine-l-aspartate was seen to be effective in reducing abnormal tests and delay or eradicating risky motor car accident [47, 98–103]. It is therefore rational, especially if the patients or their family/caregivers report symptoms/signs compatible with MHE, to introduce treatment specially in patients who are at particular risk of the consequences of MHE, such as falls, impaired, and driving ability.

### **7.1 Rifaximin**

Rifaximin is an orally administered, non-absorbable, semi-synthetic antibiotic with a broad spectrum of effect on both Gram-positive and Gram-negative bacteria [11, , 104]. It was found that patients with MHE treated with rifaximin for an 8-week period showed significantly greater improvements in driving and cognitive performance and in the psychosocial dimension of the Sickness Impact Profile than those given a placebo [67]. Recently, a randomized controlled trial compared the efficacy of rifaximin with lactulose in reversal of MHE and improvement in HRQoL in cirrhotic patients with MHE. The study concluded that both drugs improve HRQoL equally well, in cirrhotic patients with MHE [105].

#### **7.2 Non-absorbable disaccharides**

The recommended standard of care for people with hepatic encephalopathy includes use of the non-absorbable disaccharides (lactulose and lactitol) [106, 107]. It was found that cirrhotic patients with MHE had improvement in health-related quality of life and psychometric performance after lactulose therapy [108]. Lactulose and lactitol, both, have effects on gut flora and are regarded as intestinal prebiotics. Adding lactulose to food can produce a bifidogenic effect connected to a favorable effect on colonic ammonia metabolism [109]. However, a recent meta-analysis evaluating the role of non-absorbable disaccharides in patients with MHE failed to show clear evidence in improving cognitive function and HRQoL [110].

### **7.3 LOLA (l-ornithine-l-aspartate)**

Ammonia scavengers, including l-ornithine-l-aspartate, are agents that reduce blood ammonia concentration by enhancing the metabolism of ammonia to glutamine [111–113]. Bai et al. assessed eight RCTs (646 total patients, 46% diagnosed with MHE), evaluating the efficacy of LOLA compared to placebo in patients with cirrhosis. He found that treatment with LOLA diminished serum ammonia levels [114]. Evidence of important benefit of LOLA was also described in RCTs of patients with MHE assessed by psychometric testing or critical flicker frequency analysis. The oral formulation of LOLA was determined to be particularly effective for the treatment of OHE or MHE [115].

#### **7.4 Probiotics**

Prebiotics are non-digestible food ingredients that selectively stimulate the growth and/or activity of the bacteria in the colon. Probiotics are live microbes that alter the intestinal balance of the microflora. The combination of prebiotics and probiotics is named synbiotics. The meta-analysis of nine studies showed substantial evidence for the efficacy of prebiotics, probiotics, and synbiotics in the treatment of MHE [116]. A Cochrane Review examining the use of probiotics in the treatment of HE included seven trials and presented an advantage of probiotics to no treatment in all-cause mortality, number of adverse events, and QoL. Findings included reduced plasma concentrations of ammonia [117].

#### **7.5 Zinc**

Zinc, considered as a cofactor of urea cycle enzymes, is deficient in patients with cirrhosis, especially with malnutrition or encephalopathy [118]. Zinc is essential for the synthesis of coenzymes that mediate biogenic amine synthesis and metabolism [14]. Zinc deficiency also leads to change of neurotransmitters like γ aminobutyric acid and norepinephrine [119]. A recent RCT revealed that zinc supplementation can improve MHE in patients with liver cirrhosis associated with significant improvement in neuropsychometric tests and significantly decreased arterial ammonia level [76].

## **8. Conclusion**

The prevalence of MHE is high in liver cirrhosis. MHE is characterized by subtle motor and cognitive deficits, and impairs health-related quality of life. Detection of MHE and subsequent treatment could substantially reduce societal costs by preventing motor vehicle accident.

### **Conflict of interest**

The authors declare that there is no conflict of interest.

#### **Funding**

This research received no specific grant from any funding agency in the public, commercial, or not for-profit sectors.

**17**

**Author details**

Gamal Shiha1,2 and Nasser Mousa3

provided the original work is properly cited.

\*

2 Egyptian Liver Research Institute and Hospital (ELRIH), El-Mansoura, Egypt

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

1 Internal Medicine Department, Mansoura University, Egypt

3 Tropical Medicine Department, Mansoura University, Egypt

\*Address all correspondence to: mousa\_medic@yahoo.com

*Minimal Hepatic Encephalopathy: Silent Tragedy DOI: http://dx.doi.org/10.5772/intechopen.88231*

*Minimal Hepatic Encephalopathy: Silent Tragedy DOI: http://dx.doi.org/10.5772/intechopen.88231*

*Liver Disease and Surgery*

**7.4 Probiotics**

**7.5 Zinc**

ammonia level [76].

venting motor vehicle accident.

commercial, or not for-profit sectors.

**Conflict of interest**

**8. Conclusion**

**7.3 LOLA (l-ornithine-l-aspartate)**

for the treatment of OHE or MHE [115].

Ammonia scavengers, including l-ornithine-l-aspartate, are agents that reduce blood ammonia concentration by enhancing the metabolism of ammonia to glutamine [111–113]. Bai et al. assessed eight RCTs (646 total patients, 46% diagnosed with MHE), evaluating the efficacy of LOLA compared to placebo in patients with cirrhosis. He found that treatment with LOLA diminished serum ammonia levels [114]. Evidence of important benefit of LOLA was also described in RCTs of patients with MHE assessed by psychometric testing or critical flicker frequency analysis. The oral formulation of LOLA was determined to be particularly effective

Prebiotics are non-digestible food ingredients that selectively stimulate the growth and/or activity of the bacteria in the colon. Probiotics are live microbes that alter the intestinal balance of the microflora. The combination of prebiotics and probiotics is named synbiotics. The meta-analysis of nine studies showed substantial evidence for the efficacy of prebiotics, probiotics, and synbiotics in the treatment of MHE [116]. A Cochrane Review examining the use of probiotics in the treatment of HE included seven trials and presented an advantage of probiotics to no treatment in all-cause mortality, number of adverse events, and QoL. Findings

Zinc, considered as a cofactor of urea cycle enzymes, is deficient in patients with cirrhosis, especially with malnutrition or encephalopathy [118]. Zinc is essential for the synthesis of coenzymes that mediate biogenic amine synthesis and metabolism [14]. Zinc deficiency also leads to change of neurotransmitters like γ aminobutyric acid and norepinephrine [119]. A recent RCT revealed that zinc supplementation can improve MHE in patients with liver cirrhosis associated with significant improvement in neuropsychometric tests and significantly decreased arterial

The prevalence of MHE is high in liver cirrhosis. MHE is characterized by subtle motor and cognitive deficits, and impairs health-related quality of life. Detection of MHE and subsequent treatment could substantially reduce societal costs by pre-

This research received no specific grant from any funding agency in the public,

included reduced plasma concentrations of ammonia [117].

The authors declare that there is no conflict of interest.

**16**

**Funding**
