Cognitive Impairment After Resolution of Hepatic Encephalopathy: A Systematic Review and Meta-Analysis

Abstract

Hepatic encephalopathy (HE) is one of the most disabling metabolic diseases. It consists of a complication of liver disease through the action of neurotoxins, such as excessive production of ammonia from liver, resulting in impaired brain function. Its prevalence and incidence are not well known, although it has been established that up to 40% of cirrhotic patients may develop HE. Patients with HE episodes display a wide range of neurological disturbances, from subclinical alterations to coma. Recent evidence suggests that the resolution of hepatic encephalopathy does not fully restore cognitive functioning in cirrhotic patients. Therefore, the aim of this review was to evaluate the evidence supporting the presence of lingering cognitive deficits in patients with a history of HE compared to patients without HE history and how liver transplant affects such outcome in these patients. We performed two distinct meta-analysis of continuous outcomes. In both cases the results were pooled using random-effects models. Our results indicate that cirrhotic patients with a history of HE show clear cognitive deficits compared control cirrhotic patients (Std. Mean Difference (in SDs) = −0.72 [CI 95%: −0.94, −0.50]) and that these differences are not fully restored after liver transplant (Std. Mean Difference (in SDs) = −0.72 [CI 95%: −0.94, −0.50]).

The neurogliovascular unit in hepatic encephalopathy

“…Endothelial cells line the vasculature of the brain, with tight junctions (TJs) in between linking them firmly together, limiting bulk paracellular transport and preventing the uncontrolled influx of pathogens, cells and circulating water-soluble neurotoxins. TJs are made up of transmembrane proteins like claudins (CLDN) 1 , 3 , 5 , 12 and occludin (OCLN), which are linked to cytoskeletal fragments through zonula occludens (ZO-)1, 2, and 3. 18 Additionally, endothelial cells express transport proteins that tightly regulate the in- and outflow of substances into the brain.…”

“…However, evidence is mounting that HE episodes are associated with residual cognitive deficits after resolution or even liver transplantation. This suggests that certain alterations are irreversible, possibly through neurodegeneration (3,4). Obviously, HE poses an important health care challenge and therefore novel therapeutic strategies are wanted.…”

“…This suggests that certain alterations are irreversible, possibly through neurodegeneration. 3 , 4 Obviously, HE poses an important healthcare challenge and therefore novel therapeutic strategies are needed.…”

Neurofilament light chain plasma levels are associated with area of brain damage in experimental cerebral malaria

“…Furthermore, we cannot rule out that parasitemia-induced anemia or peripheral organ involvement may contribute to increased NfL levels as damage to the central nervous system and neurocognitive impairment have been described in e.g. anemia, kidney or liver failure 46 – 48 . One further limitation of this study is that we did not assess CSF levels of NfL, which would have been potentially higher in mice with irreversible edema compared to mice with reversible edema.…”

Hepatitis C eradication improves cognitive function in patients with or without cirrhosis: A prospective real‐life study

“…Not surprisingly, the factors that were related in our cohort to baseline cognitive impairment were prior overt HE, arterial hypertension, HADS anxiety, and years of education. Overt HE is a manifestation of decompensated cirrhosis, which has been associated with persistent cognitive impairment [31,32] even after a successful liver transplantation [32]. Arterial hypertension is a leading cause of age-related cognitive impairment in the general population [33], which also may affect HCV patients.…”