**Abstract**

Despite significant recent breakthroughs, with rapid discoveries provided by the twentieth century, hepatic encephalopathy remains an ancestral enigma that accompanies the history of mankind. Much of this is due to the reductionist view that a single process would have primacy over others, with the emphasis on hyperammonemic theory being its greatest example. Since other factors, such as the intestinal microbiota composition, the synergism with neuroinflammation, and the role of glutamatergic and GABAergic tonus balance have been discovered, it has become clear that the traditional and linear view of scientific research allows the understanding of the initial state of multiple dysfunctional systems, but is unable to predict the overall behavior of the disease. As consequence, there is a lack of innovative interventions for controlled clinical trials, making its therapeutic management very limited. The objective of this chapter is to provide a general theoretical overview of the most relevant hypotheses and findings in the neurobiology of hepatic encephalopathy, and how its toxic, metabolic and immunological alterations affect the cellular metabolism and neurotransmission dynamics, causing its characteristic cognitive and motor manifestations.

**Keywords:** cirrhosis, hepatic encephalopathy, cognition, minimal hepatic encephalopathy, motor, neurotransmission

### **1. Introduction**

Since ancient Babylonian times (1894–1595 B.C.), people have been aware of the influence of liver dysfunction on cognition [1]. In the Ancient Orient, the liver was considered the center of life and mental activity. Hippocrates (460–370 B.C.) and Celsus (25 B.C.–50 A.D.) were pioneers in the description of behavioral disorders associated with the hepatic failure. In the *Corpus Hippocraticum*, there is the report of a patient with jaundice who "barked like a dog, could not be contained, and said nothing understandable" [2]. Galenus (129–199 A.D.), physician of the Roman centurions, considered the liver responsible, alongside the heart and the brain, for the triple control of the natural, animal and vital spirits. In his theory, he imagined that these spirits were derived from food processing and routed through the bloodstream to the cerebral ventricles [3]. In the Modern Age, especially in the eighteenth century, several records of neuropsychiatric disorders in cirrhotic patients have been described. It is from that time that Giovanni Battista Morgagni (1682–1771 A.D.) detailed the progressive nature of the disease in the famous *De Sedibus et Causis* 

*Morborum Per Anatomen Indagatis* (1761). In the Contemporary Age, Friedrich Theodor von Frerichs (1819–1885 A.D.) carried out an extensive documentation of the cognitive and motor changes found in cirrhosis [2]. In the twentieth century, especially since the 1930s, several publications have enumerated the typical alterations in the disorder known as hepatic encephalopathy, with particular emphasis on the hypothesis that its pathophysiology would be caused, in some way, by the reduction of ammonia clearance produced in the gut [4].

The mechanisms of hepatic encephalopathy, however, remain far from being fully elucidated. No significant breakthrough occurred simultaneously in clinical and basic research in the second half of the twentieth century. Indeed, up to the present moment, in the twenty-first century, it seems unlikely that any new paradigm will emerge in a short term. In consequence, there is a lack of innovative interventions for controlled clinical trials, making its therapeutic management very limited [5].

The American and European Associations for the Study of the Liver (AASLD and EASL) define hepatic encephalopathy as "a brain dysfunction caused by liver insufficiency and/or portosystemic shunt" and add that "it manifests as a wide spectrum of neurological or psychiatric abnormalities ranging from subclinical alterations to coma" [6]. Such a definition encompasses the need for detection, quantification, and differentiation of other conditions that affect cognition, regardless of insufficiency and shunt. Unfortunately, little attention has been paid to the importance of the differential diagnosis of secondary causes of cognitive deficits in patients with cirrhosis [5]. In the practice of a reference unit in Brazil, 84% of the studied population had a concomitant condition that justified or aggravated the cognitive dysfunction, such as interferon use, major psychiatric illness (mainly depression), diabetes mellitus, neoplastic disease, use of psychotropic drugs, hypothyroidism, visual impairment, use of illicit drugs, chronic obstructive pulmonary disease, heart failure, HIV seropositivity, and vitamin B12 deficiency [7].

Approximately 30–50% of patients with chronic liver diseases, such as cirrhosis, have minimal hepatic encephalopathy, with decreased information processing speed, attention deficits, and motor incoordination. There is evidence that even minimal cognitive deficits can have a major impact on quality of life, with decreased learning and driving ability, as well as increased caregiver overload [5]. The 2014 Practice Guideline on Hepatic Encephalopathy describes minimal hepatic encephalopathy as a condition in which there are "psychometric or neuropsychological alterations of tests exploring psychomotor speed/executive functions or neurophysiological alterations without clinical evidence of mental change" [6]. This definition has a primary requisite that patients do not present any clinically evident manifestations of cerebral dysfunction in the clinical evaluation. The Guideline Development Group suggests that the operational criterion for the diagnosis of this condition should be "abnormal results of psychometric and neuropsychological tests without any clinical manifestations", although it is clear that there are no universal diagnostic criteria and that, therefore, local testing standards are necessary [8].

To overcome all difficulties related to the understanding of hepatic encephalopathy, it is essential to establish a common language among the several research areas related to the disease. The aim of this chapter is to provide a general theoretical overview of the most relevant hypotheses and findings in the neurobiology of hepatic encephalopathy, in order to contribute to the construction of an integrated approach to the subject.

#### **2. The role of intestinal microbiota and enterocytes**

Since the 1930s, ammonia has been known to play an important role in the pathophysiology of hepatic encephalopathy [4]. However, hyperammonemia can be

**39**

*The Neurobiology of Hepatic Encephalopathy DOI: http://dx.doi.org/10.5772/intechopen.86320*

logical profile [15].

found in patients without hepatic encephalopathy, and normal levels of ammonia can be seen in patients with advanced hepatic encephalopathy [9]. Serum ammonia dosage is also not a good parameter for evaluating the severity of the disease [10]. In addition, studies have demonstrated that hyperammonemia is not a sufficient condition to produce cognitive deficits in minimal hepatic encephalopathy [11]. Ammonia is produced in the body from the metabolism of intermediate amino acids, and its concentration is increased by the action of intestinal bacteria. In adults, approximately 1000 mmol (17 g) of ammonia is produced per day [12]. In cirrhotics, its serum concentration increases two to three times, an increase that is also exacerbated by the induction of glutaminase expression by enterocytes, which hydrolyzes the amino acid glutamine into glutamate and ammonia to obtain energy [9]. At least one haplotype of the glutaminase gene appears to be related to a higher propensity to develop clinically symptomatic encephalopathy, demonstrating that

the constitutive activity of this enzyme undergoes genetic variations [13].

**3. The role of hepatocytes and endothelial cells**

The small and large intestines are colonized by a massive variety of microorganisms, collectively known as microbiota. About two-thirds of the gut microbiota is unique to each individual, being composed of more than a thousand species of bacteria, although less than 170 commensals predominate, such as *Bacteroides* and *Firmicutes* [14]. Some studies have shown that the composition of the intestinal microbiota affects the severity of hepatic encephalopathy by modulating its toxico-

Recently, the concept of intestinal dysbiosis has been highlighted as a risk factor for the development of hepatic encephalopathy [5]. It refers to changes in bacterial composition, with a decrease in the rate of potentially beneficial autochthons and an increase in the rate of pathogens such as *Staphylococcaceae*, *Enterobacteriaceae*, and *Enterococcaceae* [9]. Such alterations potentiate ammonia synthesis and a proinflammatory systemic environment, contributing to neuroinflammation [14]. One of the major obstacles in assessing the impact of these changes, however, is that the composition of the microbiota varies according to geographic differences, making it practically impossible to compare individuals from different cultures and environments [9]. The use of non-absorbable disaccharides (e.g., lactulose and lactitol) remains the mainstay for the treatment and secondary prevention of hepatic encephalopathy. Although widely known for their laxative properties and their capacity to inhibit glutaminase activity, they have the ability to modify positively the intestinal microbiota, inducing the growth of commensal microorganisms. The 2014 Guideline on hepatic encephalopathy does not recommend its use for the treatment of minimal hepatic encephalopathy, but states that exceptions can be made on a case-by-case basis if there is impairment in driving ability, work performance, or quality of life [16].

Ammonia reaches the liver through the portal circulation and is purified by periportal hepatocytes, which incorporate it into urea synthesis, or by perivenular hepatocytes, which catalyze the condensation of glutamate and ammonia into glutamine by the action of glutamine synthetase [9]. The ammonia concentration in the portal vein ranges from 300 to 600 μmol, dropping to 20–60 μmol in the hepatic veins [12]. The liver, thus, plays a central role in the regulation of its levels and, in healthy individuals, removes it almost completely: small amounts of escaping ammonia are metabolized in the skeletal muscle (which also expresses glutamine synthetase), and in the kidneys (where more than 70% of it is reabsorbed). In case of hepatic failure and portosystemic shunt, ammonia escapes this detoxification process, increasing its serum concentration [9]. This leads the skeletal muscle to play an important role

#### *The Neurobiology of Hepatic Encephalopathy DOI: http://dx.doi.org/10.5772/intechopen.86320*

*Liver Disease and Surgery*

*Morborum Per Anatomen Indagatis* (1761). In the Contemporary Age, Friedrich Theodor von Frerichs (1819–1885 A.D.) carried out an extensive documentation of the cognitive and motor changes found in cirrhosis [2]. In the twentieth century, especially since the 1930s, several publications have enumerated the typical alterations in the disorder known as hepatic encephalopathy, with particular emphasis on the hypothesis that its pathophysiology would be caused, in some way, by the

The mechanisms of hepatic encephalopathy, however, remain far from being fully elucidated. No significant breakthrough occurred simultaneously in clinical and basic research in the second half of the twentieth century. Indeed, up to the present moment, in the twenty-first century, it seems unlikely that any new paradigm will emerge in a short term. In consequence, there is a lack of innovative interventions for controlled clinical trials, making its therapeutic management very limited [5]. The American and European Associations for the Study of the Liver (AASLD and EASL) define hepatic encephalopathy as "a brain dysfunction caused by liver insufficiency and/or portosystemic shunt" and add that "it manifests as a wide spectrum of neurological or psychiatric abnormalities ranging from subclinical alterations to coma" [6]. Such a definition encompasses the need for detection, quantification, and differentiation of other conditions that affect cognition, regardless of insufficiency and shunt. Unfortunately, little attention has been paid to the importance of the differential diagnosis of secondary causes of cognitive deficits in patients with cirrhosis [5]. In the practice of a reference unit in Brazil, 84% of the studied population had a concomitant condition that justified or aggravated the cognitive dysfunction, such as interferon use, major psychiatric illness (mainly depression), diabetes mellitus, neoplastic disease, use of psychotropic drugs, hypothyroidism, visual impairment, use of illicit drugs, chronic obstructive pulmonary

disease, heart failure, HIV seropositivity, and vitamin B12 deficiency [7].

tic criteria and that, therefore, local testing standards are necessary [8].

**2. The role of intestinal microbiota and enterocytes**

have minimal hepatic encephalopathy, with decreased information processing speed, attention deficits, and motor incoordination. There is evidence that even minimal cognitive deficits can have a major impact on quality of life, with decreased learning and driving ability, as well as increased caregiver overload [5]. The 2014 Practice Guideline on Hepatic Encephalopathy describes minimal hepatic encephalopathy as a condition in which there are "psychometric or neuropsychological alterations of tests exploring psychomotor speed/executive functions or neurophysiological alterations without clinical evidence of mental change" [6]. This definition has a primary requisite that patients do not present any clinically evident manifestations of cerebral dysfunction in the clinical evaluation. The Guideline Development Group suggests that the operational criterion for the diagnosis of this condition should be "abnormal results of psychometric and neuropsychological tests without any clinical manifestations", although it is clear that there are no universal diagnos-

Approximately 30–50% of patients with chronic liver diseases, such as cirrhosis,

To overcome all difficulties related to the understanding of hepatic encephalopathy, it is essential to establish a common language among the several research areas related to the disease. The aim of this chapter is to provide a general theoretical overview of the most relevant hypotheses and findings in the neurobiology of hepatic encephalopathy, in order to contribute to the construction of an integrated approach to the subject.

Since the 1930s, ammonia has been known to play an important role in the pathophysiology of hepatic encephalopathy [4]. However, hyperammonemia can be

reduction of ammonia clearance produced in the gut [4].

**38**

found in patients without hepatic encephalopathy, and normal levels of ammonia can be seen in patients with advanced hepatic encephalopathy [9]. Serum ammonia dosage is also not a good parameter for evaluating the severity of the disease [10]. In addition, studies have demonstrated that hyperammonemia is not a sufficient condition to produce cognitive deficits in minimal hepatic encephalopathy [11].

Ammonia is produced in the body from the metabolism of intermediate amino acids, and its concentration is increased by the action of intestinal bacteria. In adults, approximately 1000 mmol (17 g) of ammonia is produced per day [12]. In cirrhotics, its serum concentration increases two to three times, an increase that is also exacerbated by the induction of glutaminase expression by enterocytes, which hydrolyzes the amino acid glutamine into glutamate and ammonia to obtain energy [9]. At least one haplotype of the glutaminase gene appears to be related to a higher propensity to develop clinically symptomatic encephalopathy, demonstrating that the constitutive activity of this enzyme undergoes genetic variations [13].

The small and large intestines are colonized by a massive variety of microorganisms, collectively known as microbiota. About two-thirds of the gut microbiota is unique to each individual, being composed of more than a thousand species of bacteria, although less than 170 commensals predominate, such as *Bacteroides* and *Firmicutes* [14]. Some studies have shown that the composition of the intestinal microbiota affects the severity of hepatic encephalopathy by modulating its toxicological profile [15].

Recently, the concept of intestinal dysbiosis has been highlighted as a risk factor for the development of hepatic encephalopathy [5]. It refers to changes in bacterial composition, with a decrease in the rate of potentially beneficial autochthons and an increase in the rate of pathogens such as *Staphylococcaceae*, *Enterobacteriaceae*, and *Enterococcaceae* [9]. Such alterations potentiate ammonia synthesis and a proinflammatory systemic environment, contributing to neuroinflammation [14]. One of the major obstacles in assessing the impact of these changes, however, is that the composition of the microbiota varies according to geographic differences, making it practically impossible to compare individuals from different cultures and environments [9].

The use of non-absorbable disaccharides (e.g., lactulose and lactitol) remains the mainstay for the treatment and secondary prevention of hepatic encephalopathy. Although widely known for their laxative properties and their capacity to inhibit glutaminase activity, they have the ability to modify positively the intestinal microbiota, inducing the growth of commensal microorganisms. The 2014 Guideline on hepatic encephalopathy does not recommend its use for the treatment of minimal hepatic encephalopathy, but states that exceptions can be made on a case-by-case basis if there is impairment in driving ability, work performance, or quality of life [16].
