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than two million people suffer from MHE in USA, in the in cirrhotic patients by ingestion of an amino acid
European Union and even more in the rest of the world. mixture induces neuropsychological impairment
during inflammation, but not after its resolution. The
[31]
Minimal hepatic encephalopathy has important contribution of inflammation and hyperammonemia to
consequences on daily life of patients with chronic the neurological impairment in different pathological
liver diseases. Attention, mental processing speed, situations with different grades of inflammation and
visuomotor and bimanual coordination are necessary hyperammonemia was assessed by Felipo et al., [32] who
for many daily tasks such as driving cars or dressing. showed that the joint presence of inflammation and
Patients with MHE have impaired driving ability, hyperammonemia, is enough to induce mild cognitive
which is associated with peripheral inflammation, with impairment, even in the absence of liver failure. The
[31]
[32]
increased levels of interleukin-6 (IL-6) and IL-18. [23-25] studies by Shawcross et al. and Felipo et al. support
They also have increased risk of traffic, home and work the idea that, as occurs in other chronic diseases, in
accidents and more falls, fractures, and hospitalizations, chronic liver diseases, peripheral inflammation is
which pose a high economic burden to health systems. involved in the induction of the cognitive and motor
In addition, MHE predisposes patients to clinical HE alterations associated to MHE and to overt HE.
with more serious neurological impairment that can
lead to coma and death and reduces life span. Early Peripheral inflammation may lead to neuroinflammation
diagnosis and treatment of MHE would improve the by different mechanisms. The presence of
quality of life and survival of patients and economic neuroinflammation in patients with chronic liver
burden. [26-29] diseases has not been thoroughly studied. One of the
main methods to assess neuroinflammation is to assess
INFLAMMATION AND NEUROINFLAMMATION IN by positron emission tomography (PET); the binding
THE NEUROLOGICAL ALTERATIONS IN PATIENTS of ligands to the translocator protein (18 kDa) (TSPO),
WITH CHRONIC LIVER DISEASE AND MHE previously known as peripheral type benzodiazepine
receptor. Cagnin et al. showed using PET techniques
[33]
[34]
Inflammation is a main contributor to the changes in that cirrhotic patients with HE show increased binding
11
cognitive and motor functions found in MHE patients of [ C](R)-PK11195 to TSPO in brain. [34] Moreover, the
suffering from chronic liver disease. For example, the patient with the most severe cognitive impairment
11
serum levels of the pro-inflammatory cytokines IL-6 had the highest increases in regional [ C](R)-PK11195
and IL-18 are increased in cirrhotic patients with MHE binding. The authors suggested that an altered glial
compared with cirrhotics without MHE. Moreover, the cell state might be causally related to impaired brain
levels of IL-6 and IL-18 correlate with the grade of MHE functioning in HE. These data suggest the presence of
evaluated using psychometric tests. [30] neuroinflammation in patients with HE, correlating
with the grade of cognitive impairment. [34]
Hyperammonemia plays a synergistic role with [35]
inflammation in the induction of the neurologic In support for the role of microglia, Dennis et al.
impairment [Figure 1]. Hyperammonemia developed performed immunohistochemistry studies and cytokine
assays in fixed postmortem brain tissue from chronic
alcoholics with cirrhosis and HE, alcoholics without
HE and controls. About half of the patients with HE
showed what they called “proliferative HE (pHE)”
and the other half did not. [35] The microglia in pHEs
displayed an activated morphology with hypertrophied
cell bodies and short, thickened processes. These
patients also showed increased levels of IL-6. In
contrast, the microglia in white matter regions of
the non-proliferative HE cases were less activated
and appeared dystrophic. The authors suggest that
microglial proliferation may form part of an early
neuroprotective response in HE that ultimately fails
to halt the course of the disease because underlying
etiological factors such as high cerebral ammonia and
systemic inflammation remain. In support, Zemtsova
[35]
Figure 1: Hyperammonemia and inflammation act synergistically to induce
neurological alterations in chronic liver disease. Chronic liver failure induces both et al. [36] also analyzed markers of neuroinflammation in
hyperammonemia and peripheral inflammation, leading to microglial activation postmortem brain tissue from patients with cirrhosis
and neuroinflammation, which alters neurotransmission, leading to cognitive
and motor impairment that presented with and without HE and noncirrhotic

Neuroimmunol Neuroinflammation | Volume 2 | Issue 3 | July 15, 2015 139