**3. Precipitating factors: (Box A)**

The Most of HE episodes are precipitated by an event rather than spontaneous, with infection anywhere in body being the common, though its frequency is decreasing. Hence careful history and examination are necessary to identify the precipitating or contributing factors for HE, most of the time these factors are evident.(42)

Gastrointestinal bleeding commonly precipitates the HE even if it is controlled or stopped bleeding. Sometimes occult chronic gastrointestinal blood loss can also lead to HE, which needs to be evaluated and treated accordingly.(42)

Dehydration is again a very common precipitating factor in cirrhotic patients leading to HE because some of the patients ascites, are diuretics. And aggressive diuresis do induce dehydration leading to metabolic alkalosis and electrolyte imbalances.

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

**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

**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

Exposure of astrocytes to ammonia, inflammatory cytokines, hyponatremia and benzodiazepines leads to enhanced production of RNS & ROS via the Calcium dependent N-methyl-D-aspartate (NMDA) pathway. RNS and ROS cause tyrosine nitration, leading to

In normal healthy individuals, Maganese is cleared by liver and excreted into the bile. Manganese is known to stimulate the Translocator proteins located on astrocytes, leading to enhanced neurosteroid synthesis. In cirrhotic patients, it accumulates in the basal ganglia because of decreased excretion of Maganese due to portosystemic shunting and promotes formation of Alzheimer's type 2 astrocytes.(41) Brain magnetic resonance imaging (MRI) in cirrhotic patients has shown changes which are due to accumulation of Maganese in basal

The Most of HE episodes are precipitated by an event rather than spontaneous, with infection anywhere in body being the common, though its frequency is decreasing. Hence careful history and examination are necessary to identify the precipitating or contributing

Gastrointestinal bleeding commonly precipitates the HE even if it is controlled or stopped bleeding. Sometimes occult chronic gastrointestinal blood loss can also lead to HE, which

Dehydration is again a very common precipitating factor in cirrhotic patients leading to HE because some of the patients ascites, are diuretics. And aggressive diuresis do induce

ganglia particularly in the palladium, putamen and caudate nucleus.(41)

factors for HE, most of the time these factors are evident.(42)

dehydration leading to metabolic alkalosis and electrolyte imbalances.

needs to be evaluated and treated accordingly.(42)

the production of false neurotransmitter subsequently leading to HE.(34)

early neuropsychiatric symptoms of HE.(36)

**2.4 Oxidative and nitrosative stress** 

**3. Precipitating factors: (Box A)** 

altered BBB permeability and astrocyte swelling. (39, 40)

in He patients.(37, 38)

**2.5 Manganese theory** 


Box A. Precipitating Factors for HE

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