**3.1 The role of ammonia**

*Liver Disease and Surgery*

Description \* Absence of

**Table 1.**

**Classification Covert HE Overt HE**

recognizable clinical symptoms and signs \* Impairments only measurable with psychometric tests (psychomotor speed/ executive functions or neurophysiological alterations)

*New classification combining covert and overt HE.*

patient should be treated [3, 9].

**2. Prevalence of MHE**

**3. Physiopathology**

cation of ammonia [19].

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].

\* Minor lack of awareness \* Euphoria or anxiety \* Shortened attention span \* Altered sleep rhythm

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

Minimal hepatic encephalopathy may have a bad impact on quality of life, risk of

**MHE Grade I Grade II Grade III Grade IV**

\* Fatigue, apathy, or lethargy \* Slight disorientation for time and place \* Obvious personality change \* Inappropriate behavior \* Asterixis

\* Somnolence to semi-stupor \* Confused \* Marked disorientation to time and place \*Aggression

\* Coma \* Signs of increased intracranial pressure

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

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 detoxifi-

incidence varies from 20 to 80% of cirrhotic patients [12–15].

**4**

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,

#### **Figure 1.**

*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%).*

#### **Figure 2.**

*Pathogenesis of hepatic encephalopathy. In normal conditions, gut release of ammonia results in high portal vein ammonia levels. Microbiota is also responsible for the formation of ammonia, endotoxins. In liver cirrhosis, the liver extracts portal venous ammonia poorly. The subsequent increase of arterial ammonia levels leads to increased disposition of ammonia in other tissues. Both the brain and muscle lack a complete urea cycle and rely on the formation of glutamine. Thus, the brain and muscle become ammonia-uptake and glutaminereleasing organs. In the brain, astrocytes metabolize ammonia through glutamine synthetase, converting glutamate and ammonia to glutamine which is osmotically active and promotes water shift into the astrocyte, thus producing intracellular swelling and edema.*

thereby contributing to the cerebral dysfunction seen in HE [17]. The high-energy consumption by this process leads to oxidative stress which is accompanied by cellular dysfunction and disruption of neurotransmission predominantly of glutamate and γ-aminobutyric acid [24]. In the brain, NH3 produces inactivation of neuronal chloride extrusion pumps; these processes result in inhibition of both axonal conduction and excitatory postsynaptic potentials, subsequently suppressing inhibitory postsynaptic potential formation and depolarizing neurons [25, 26].

#### **3.2 Inflammation**

Studies demonstrated that, severity of MHE might not correlate with severity of liver disease or the level of ammonia, proposing the existence of other pathogenic

**7**

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

more decompensated the cirrhosis [35].

**4. Natural history of MHE**

to those without MHE [40–43].

**5. Clinical significance**

**3.3 Microbiota**

stimuli. Inflammation is one such stimulus that may add to the advancement of MHE and its progression to overt HE [27]. The studies suggested that, inflammation plays a synergistic role with ammonia in producing and modulating MHE [27–29]. Studies in patients with cirrhosis have documented higher levels of proinflammatory cytokines like tumor necrosis factor (TNF)-α, interleukin (IL)-1β and IL-6. This reflects the possibility of developing a systemic inflammatory response that alters the blood-brain barrier (BBB) permeability and allows diffusion of ammonia moreover [30, 31].

Studies suggested that, many interactions with gut microbiota can play an active role in MHE (**Figure 2**). Microbiota changes have been linked with impaired cognition, endotoxemia, and inflammation. With the progression of cirrhosis, there is dysbiosis (unfavorable change in the composition of the microbiome) with decreased levels of autochthonous taxa (native Firmicutes) bacteria and increased levels of other taxa (Bacteroidetes, Actinobacteria). The native bacteria are important for the harmony of the gastrointestinal flora and for the well-being of the entire body. The autochthonous bacteria produce short-chain fatty acids that feed the colonic mucosal cells and reduce local colonic inflammation, and produce anti-bacterial peptides [32]. In patients with minimal HE, stool microbiota studies demonstrated an increase in *Streptococcus salivarius* [33]. Zhang et al. found worse dysbiosis in all cirrhotic patients versus healthy controls and also found overrepresentation of two bacterial families, Streptococcaceae and Veillonellaceae, in cirrhotic patients with and without MHE as compared with controls. Moreover, patients with MHE had an overabundance of *Streptococcus salivarius*. This dysbiosis could increase ammonia production due to its urease activity, and its count positively correlated with ammonia levels and cognitive testing in patients with MHE [34]. The cirrhosis dysbiosis ratio (CDR) is the ratio of autochthonous to nonautochthonous taxa in cirrhosis. The lower the CDR the more the endotoxemia and

The incidence of MHE increases with progression of liver disease. With time, MHE may improve or progress to OHE [36, 37]. The rate of progression to overt HE was much higher in patients with MHE and Child-Pugh score > 6 than in those with MHE and Child-Pugh score ≤ 6 [38]. Moreover, MHE in patients with large portalsystemic shunts had a better outcome due to preserved hepatocytes [39]. Real probability of OHE at 3 years was 56% in patients of liver cirrhosis in the presence of MHE and 8% for those without MHE [37]. In addition, existence of MHE in cirrhosis associated with shorter survival time and increased mortality rate compared

MHE has a significant impact on daily activities. It decreases patients' quality of life (QoL) [43, 44] and driving impairment due to the attention and visuomotor coordination deficits [45–47]. The Sickness Impact Profile was studied in a group of patients with cirrhosis to evaluate QoL indicators such as sleep, rest, eating, work, home management, recreation, ambulation, daily care, movement, and emotional behavior. All scales were significantly decreased in patients with MHE compared

stimuli. Inflammation is one such stimulus that may add to the advancement of MHE and its progression to overt HE [27]. The studies suggested that, inflammation plays a synergistic role with ammonia in producing and modulating MHE [27–29]. Studies in patients with cirrhosis have documented higher levels of proinflammatory cytokines like tumor necrosis factor (TNF)-α, interleukin (IL)-1β and IL-6. This reflects the possibility of developing a systemic inflammatory response that alters the blood-brain barrier (BBB) permeability and allows diffusion of ammonia moreover [30, 31].
