**1. Introduction**

494 New Advances in the Basic and Clinical Gastroenterology

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Strictures and Benign Obstructive Disorders of the Bile Duct. [In:] Zuidema GD, Yeo ChJ, ed. Shackelford's Surgery of the Alimentary Tract. Vol III. 5th edition. WB The liver is the most important organ for the well-functioning of other organs because of its vital role in nutrition, metabolism and secretion. Any disturbance in normal homeostasis of liver as it happens in acute liver failure (ALF) and chronic liver disease (cirrhosis) will lead to extra hepatic manifestations of liver disease, among them one is encephalopathy. And this encephalopathy caused by liver abnormality is known as Hepatic encephalopathy (HE).(1) HE occurs in 50-70% of patients with chronic liver disease and this is one of the sign of decompensated chronic liver disease. Occurrence of HE associated with poor prognosis with survival of approximately 42% at 1 year.(2)

#### **1.1 Definition**

Hepatic encephalopathy(HE) is defined as a reversible and metabolically induced neuropsychiatric complication, most commonly associated with cirrhosis, but may also be a complication of acute or chronic liver disease.(3) The affected patients exhibit alterations in psychomotor functions, personality changes, cognitive impairment and disturbed sleep pattern. Although, precise pathophysiologic mechanisms are not well understood, severe liver damage or the presence of Porto-systemic shunts are thought to be the major mechanisms involved.(4)

According to the classification proposed by the working party in 1998, HE can be graded into 3 types:


Type C HE can be further divided into three categories:


Overt HE (OHE) is a syndrome of neuropsychiatric abnormalities that can be detected by bedside clinical tests in contrast to minimal HE (MHE) that requires specific psychometric tests for detection.(5) Defining type-C HE into minimal or overt, episodic or persistent and

Hepatic Encephalopathy 497

Hyper ammonia lead to abnormal cerebral blood flow and glucose metabolism and this had been seen in studies of single photon emission tomographic (SPECT) in which redistribution of blood flow form cerebral cortex to subcortical regions had been demonstrated. This

The partial credit also goes to the inflammation because majority of the cirrhotic patients in the presence of infection develop the HE. This association of markers of inflammatory response in state of systemic inflammatory response (SIRS) and HE, has been demonstrated in different studies.(21, 22) In one of the clinical study, it has been seen that HE or neuropsychological dysfunction improves after the resolution of SIRS.(23) Despite this exact mechanism of inflammation leading to HE is still not known as yet, but possibly it is hypothesized that cytokine mediated changes in blood brain barrier (BBB) permeability,

altered glutamate uptake by astrocyte and altered expression of GABA receptors.(23)

endothelial Blood-Brain barrier and increases ammonia diffusion into astrocytes. (24)

**2.3 Neurosteroids and GABA/Benzodiazepine receptor complex theory** 

TNF released in response to inflammation has been correlated to the symptoms of HE. It causes Astrocytes to release inflammatory cytokines (i-e IL-1, IL-6) which impairs the

Neurosteroids are mainly produced by myelinating glial cells in response to increased expression of peripheral type benzodiazepine receptor (Trasnslocator proteins), which are activated by ammonia, inflammation and manganese. Neurosteroids increase chloride influx and thereby enhance GABAergic tone, causing symptoms in patients with Type C

GABA mediates its action through GABA-receptor complex (GRC) and acts as an inhibitory neurotransmitter. Increased sensitivity of the trasnslocator proteins also enhances the activation of GABA-GRC complex, hence causing inhibition of neurotransmission.(14, 27) Increased GABAergic tone has been associated with the pathogenesis of HE and this was proved by the reports which had revealed the beneficial effects of benzodiazepine antagonist (Flumazenil).(28) There is an excess of benzodiazepine like compounds in HE that are derived from synthesis by intestinal flora, dietary vegetables and medications.(29, 30) Moreover natural benzodiazepines also accumulate in brain and furthermore cirrhotic patients have the poor capability of clearing the benzodiazepine like compounds.(31) These compounds bind to GABA receptor complex inducing GABA release and neuro-inhibition. A study by Stewart et al group had shown that ammonia itself bind to the GABA receptor complex.(32) It may also potentiate benzodiazepines by up regulating expression of peripheral type benzodiazepine receptor that trigger synthesis of neuro-steroids, which are

Hence GABAergic tone is more likely attributed to elevated levels of benzodiazepines like

**BCCA and false neurotransmitter theory:** Brain neurotransmission is regulated by CNS concentration of amino acids and their precursor. In cirrhotic patients, plasma concentrations of aromatic amino acids (tryptophan, tyrosine, and phenalanine) are elevated and branch

abnormality lead to different HE features.(17, 20)

**2.2 Inflammation** 

HE.(25, 26)

strong GABA agonists.(33)

compounds in patients with cirrhosis.

precipitated or spontaneous is clinically relevant since the management of each category is very different. Nowadays MHE has been recognized as the major factor in impairing the health related quality of life (HRQOL) in patients with cirrhosis.(6, 7) And MHE has prognostic significance because it predicts the occurrence of overt HE and is not useful predictor for mortality in cirrhosis.(8)
