**1. Introduction**

Hepatic encephalopathy (HE) is a serious clinical problem of portal hypertension and cirrhosis that is characterized by neurologic and neuropsychiatric abnormalities. It is manifested by personality changes, cognitive dysfunction, and altered level of consciousness [1, 2]. Based on the severity, HE is classified into two groups: overt HE (OHE) presents episodically or continuously with obvious and clinically detectable symptoms; in contrast, covert HE (CHE) combines the two lowest grades of HE (minimal HE (MHE) and HE grade 1) [3]. Therefore, under the new classification (**Table 1**), OHE starts with grade 2 or with evidence of asterixis and disorientation. MHE is characterized by subtle cognitive and psychomotor deficits in the absence of recognizable clinical symptoms and signs of HE and is documented by neuropsychometric (NP) tests and neurophysiological tests, but HE grade 1 is defined by the presence of mild clinical alterations like euphoria, anxiety, or a shortened attention span. Although the consequences are serious, mostly CHE


**Table 1.**

*New classification combining covert and overt HE.*

is often unnoticed or even neglected in routine clinical practice due to only very mild symptoms associated with grade 1, or no diagnostics in case of MHE [4, 5].

Minimal hepatic encephalopathy may have a bad impact on quality of life, risk of road traffic accidents, and can progress to overt HE [6, 7]. Still, there are no current guidelines for the ascertained diagnosis of MHE. The Working Group on HE endorsed that, at least two of the following neuropsychologic tests should be used for diagnosing MHE: number connection test-A (NCT-A), NCT-B, block-design test (BDT), and the digit-symbol test (DST) [4]. The existing definition of MHE is built on psychometric test results that are two SDs more than normal on at least two psychometric tests [8]. Therapy for MHE is targeted toward the gut, due to the ammoniagenic role of the gut contents, which have been hypothesized to play a part in MHE pathogenesis. Guidelines for HE in chronic liver disease do not recommend routine treatment of MHE. However, they state that when a patient has clear cognitive impairment, or deterioration of quality of life (QoL), skills for driving, or ability to perform jobs that require manual labor or have high public risk, the patient should be treated [3, 9].

#### **2. Prevalence of MHE**

MHE is considered as a part of wide spectrum of typical neurocognitive alterations in liver cirrhosis, mostly involving the areas of attention, alertness, response inhibition, and executive functions [10, 11]. Depending on the population studied, patient level of education, age of the patients, and the diagnostic tool used, MHE incidence varies from 20 to 80% of cirrhotic patients [12–15].

#### **3. Physiopathology**

The pathogenesis of MHE is nearly similar to that of OHE [16]. The ammonia toxicity remains the key factor, but recently there is increased evidence that, hyperammonemia acts synergistically with systemic inflammation, oxidative stress, and gut microbiota [17, 18]. Numerous investigators suggested that, hepatic encephalopathy is a disorder of astrocyte function that plays a role in the detoxification of ammonia [19].

**5**

**Figure 1.**

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

Ammonia is a key intermediate product in the metabolism of proteins. It is manufactured by the bacterial metabolism of amino acids and purines that are consumed in the human diet [20]. Under physiological environment, about 90% of the ammonium is primarily cleared by the synthesis of urea in the liver (by the Krebs cycle) and subsequently cleared by the kidneys and to a lesser extent by the muscles (**Figure 1**). Ammonia is also consumed in the conversion of glutamate to glutamine, a reaction that depends upon the activity of glutamine synthetase [21]. In liver cirrhosis, there are two factors that contribute to hyperammonemia: the first is a decrease in the healthy hepatocytes, resulting in deficiency of NH3 detoxification; the second is the existence of porto-systemic shunting that results in shifting of NH3-rich portal blood to the systemic circulation without hepatic detoxification—subsequently, the extrahepatic metabolization of ammonia by the brain and skeletal muscle cells becomes more important [17, 22, 23]**.** The skeletal muscle plays a significant role in ammonia metabolism as it contains glutamine synthetase. However, the muscle wasting that is clear in advanced cirrhosis may increase hyperammonemia. The kidneys express glutaminase and, somewhat, play a role in ammonia production. Similarly, the kidneys express glutamine synthetase and play a key role in ammonia metabolism and excretion [20]. Ammonia crosses the blood-brain barrier and is metabolized in the astrocytes by glutamine synthetase, which converts NH3 and glutamate to glutamine [17]. Increasing glutamine in astrocytes produces an osmotic gradient (**Figure 2**), promotes water shift into astrocyte producing edema [23], and generation of reactive oxygen species,

*Ammonia is produced primarily in colon from breakdown of amino acids and urea by bacteria. The ammonia is taken up by hepatocytes and converted, in the urea cycle, to urea, which is passed into blood. Urea is* 

*primarily excreted in the kidneys (75%) and the intestine (around 25%).*

**3.1 The role of ammonia**
