**14. Effects on the noradrenergic system**

In the 1970s, it was believed that hepatic encephalopathy might reflect a disturbance in catecholaminergic metabolism [31]. The main projections of noradrenaline originate in the locus coeruleus, although there are also some in the laterodorsal tegmental nuclei of the brainstem (**Figure 9**). They can be ascending or descending.

#### **Figure 9.**

*The ascending noradrenergic pathway originates in the locus coeruleus (LC) and extends to the thalamus (T), medial portion of the temporal cortex, and prefrontal cortex, while the descending pathway modulates the activity of the spinal cord. AN: accumbens nucleus, GP: globus pallidus, and S: striatum.*

**53**

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

depression and anxiety [31, 33].

encephalopathy [31].

**16. Final Considerations**

hermeneutical cycle.

**15. Effects on the adenosinergic system**

Ascending projections regulate vigilance and mood: they end diffusely throughout the brain, including many of the same sites for which serotoninergic pathways extend, although there are few noradrenergic extensions to the striatum and accumbens nucleus. The descending projections extend to the spinal cord and regulate pain [37]. Currently, it is widely accepted that changes in catecholaminergic metabolism do not precipitate hepatic coma [31]. Studies have shown that, in patients with cirrhosis, there is no decrease in norepinephrine concentration in most brain regions, with the maintenance of α1 and α2 receptor density. However, it is assumed that more subtle chronic changes may coexist with some neuropsychiatric symptoms, such as

Adenosine is a modulator of neuronal excitability, which inhibits postsynaptic potentials generated by classical neurotransmitters, such as glutamate, GABA, dopamine, and serotonin. Since 1960s, studies have shown reduced expression of adenosinergic receptors in the striatum and cortex of patients with mild hepatic

Although the mechanisms through which adenosine exerts its function are still not fully understood [36], it is known that the decrease in the expression of its receptors occurs in the early stages of the disease and contributes to an increase in glutamatergic activity, potentializing its excitotoxic effects, while increasing

The twentieth century provided the greatest scope of information on the neurobiology of hepatic encephalopathy throughout history, but failed to create an integrated theory that would allow the adoption of more effective intervention strategies. This was due to the reductionist view that a single process would have primacy over the others, with the emphasis on hyperammonemic theory being its greatest example. As other factors such as the composition of the intestinal microbiota, synergism with neuroinflammation, and the role of glutamatergic and GABAergic tonus balance were discovered, it became clear that this traditional and linear view of scientific research allows the understanding of the initial state of multiple dysfunctional systems, but is not able to predict the overall behavior of the disease. As twenty-first century progresses, it is imperative to incorporate concepts such as convergence, emergency, and complexity into research related to the theme, both in diachronic and synchronic processes, for the construction of a true dynamic and integrated vision that allows more effective therapeutic interventions, in a total

GABAergic tone, also potentializing its inhibitory effects [31].

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

*Liver Disease and Surgery*

**Figure 8.**

**52**

**Figure 9.**

*The ascending noradrenergic pathway originates in the locus coeruleus (LC) and extends to the thalamus (T), medial portion of the temporal cortex, and prefrontal cortex, while the descending pathway modulates the* 

levels have been documented in patients with hepatic encephalopathy [31]. Histamine is produced from the amino acid histidine [37]; hyperammonemia increases both the concentration of histidine and the activity of its membrane transporter into the histaminergic neurons, stimulating the synthesis of histamine [31].

*AN: accumbens nucleus, GP: globus pallidus, S: striatum, and T: thalamus.*

*The ascending histaminergic pathway originates in the hypothalamus and extends to the medial portion of the temporal cortex and prefrontal cortex, while the descending pathway modulates the activity of the spinal cord.* 

In the 1970s, it was believed that hepatic encephalopathy might reflect a disturbance in catecholaminergic metabolism [31]. The main projections of noradrenaline originate in the locus coeruleus, although there are also some in the laterodorsal tegmental nuclei of the brainstem (**Figure 9**). They can be ascending or descending.

**14. Effects on the noradrenergic system**

*activity of the spinal cord. AN: accumbens nucleus, GP: globus pallidus, and S: striatum.*

Ascending projections regulate vigilance and mood: they end diffusely throughout the brain, including many of the same sites for which serotoninergic pathways extend, although there are few noradrenergic extensions to the striatum and accumbens nucleus. The descending projections extend to the spinal cord and regulate pain [37].

Currently, it is widely accepted that changes in catecholaminergic metabolism do not precipitate hepatic coma [31]. Studies have shown that, in patients with cirrhosis, there is no decrease in norepinephrine concentration in most brain regions, with the maintenance of α1 and α2 receptor density. However, it is assumed that more subtle chronic changes may coexist with some neuropsychiatric symptoms, such as depression and anxiety [31, 33].

### **15. Effects on the adenosinergic system**

Adenosine is a modulator of neuronal excitability, which inhibits postsynaptic potentials generated by classical neurotransmitters, such as glutamate, GABA, dopamine, and serotonin. Since 1960s, studies have shown reduced expression of adenosinergic receptors in the striatum and cortex of patients with mild hepatic encephalopathy [31].

Although the mechanisms through which adenosine exerts its function are still not fully understood [36], it is known that the decrease in the expression of its receptors occurs in the early stages of the disease and contributes to an increase in glutamatergic activity, potentializing its excitotoxic effects, while increasing GABAergic tone, also potentializing its inhibitory effects [31].

## **16. Final Considerations**

The twentieth century provided the greatest scope of information on the neurobiology of hepatic encephalopathy throughout history, but failed to create an integrated theory that would allow the adoption of more effective intervention strategies. This was due to the reductionist view that a single process would have primacy over the others, with the emphasis on hyperammonemic theory being its greatest example. As other factors such as the composition of the intestinal microbiota, synergism with neuroinflammation, and the role of glutamatergic and GABAergic tonus balance were discovered, it became clear that this traditional and linear view of scientific research allows the understanding of the initial state of multiple dysfunctional systems, but is not able to predict the overall behavior of the disease. As twenty-first century progresses, it is imperative to incorporate concepts such as convergence, emergency, and complexity into research related to the theme, both in diachronic and synchronic processes, for the construction of a true dynamic and integrated vision that allows more effective therapeutic interventions, in a total hermeneutical cycle.

*Liver Disease and Surgery*
