**2.2 Inflammation**

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)

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

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

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 HE.(25, 26)

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 strong GABA agonists.(33)

Hence GABAergic tone is more likely attributed to elevated levels of benzodiazepines like compounds in patients with cirrhosis.

**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

Hepatic Encephalopathy 499

Infection Medications (sedatives, diuretics, psychotropic,)

It has also been seen that transjuglar intrahepatic portosystemic shunt (TIPS) in some of the cases can lead to HE. Few other precipitating factors which can sometimes lead to HE, need

The clinical signs and symptoms of HE may range from mild cognitive impairment to profound coma. These include forgetfulness, alteration in sleep-wake cycle, changes in personality and emotions, hyperreflexia and drowsiness. In more severe cases disorientation, constructional apraxia , asterixis, seizures and eventually coma may develop.(43) It is very important to exclude other causes of altered mental status or

Clinically, the most commonly employed criteria used for grading is the West Haven criteria (Table 1) which defines HE semi quantitatively into four grades, based on the presence of specific clinical signs and symptoms and their severity. Further classification of comastose or unconscious patients can be done by using Glasgow Coma Scale which provides a more

Checking for Elevated Blood ammonia levels is the most commonly used parameter for assessment, but they may also be elevated due to other possible causes (i-e tourniquet use, delayed processing and cooling of sample, disorders related to ammonia and proline metabolism). In acute liver failure, arterial ammonia levels >150 mg/dl may be predictive of brain edema and herniation. However, measurement of arterial ammonia over venous

to be looked into by taking careful history and examination and shown in Box (A)

encephalopathy (Box B) in suspected patients for appropriate management of HE.

 GI Bleeding Constipation Electrolyte imbalance Hypovolemia Trauma Dehydration

Sepsis Uremia

Dietary protein Overload

**4. Clinical features** 

 Subdural Hematoma Drug or alcohol intoxication

Wernicke's encephalopathy

Box B. Differential Diagnosis for HE

objective assessment of the conscious state of the patient.(4)

ammonia offers no advantage in Chronic liver disease.(3, 44)

 Wilson's disease Hypoglycemia

Postictal Confusion

CNS Sepsis

**5. Diagnosis** 

Box A. Precipitating Factors for HE

chain amino acids (Leucine, isoleucine and valine) concentration are reduced. Aromatic as well as branch chain amino acids share a common transport mechanism into the CNS and as a consequence of increased of aromatic amino acids, neuronal levels may be increased leading to the production of false neurotransmitter subsequently leading to HE.(34)

**Serotonin theory:** Serotonin, a neurotransmitter which is widely distributed in CNS, has been implicated in the pathogenesis of HE. In cirrhotic patients it has been seen that serotonin metabolism is altered hence leading to serotonergic synaptic deficit. Serotonergic pathway in brain is important for regulation of sleep, locomotion and circadian rhythmicity.(35) Serotonin metabolism is intricately and selectively sensitive to the degree of portosystemic shunting and hyperammonaemia, therefore suggesting a role for serotonin in early neuropsychiatric symptoms of HE.(36)

**Zinc theory:** Zinc (Zn) element is a component/substrate of urea cycle enzymes. It is assumed that this element is reduced in patients with liver cirrhosis. Zn supplementation increases activities of ornithine transcarbamalyse increasing excretion of ammonia ions. Interestingly till now there is conflicting evidence for this hypothesis of Zn supplementation in He patients.(37, 38)
