In this meta-analysis, we included four randomized controlled trials evaluating the effect of oral zinc supplementation over hepatic encephalopathy. Three studies reported data on number connection test; all three showed an improvement in performance in the zinc group compared to placebo or standard therapy. This improvement suggests a beneficial effect of oral zinc in encephalopathy patients. Two studies reported data on encephalopathy recurrence rate. Both studies observed lower recurrence rates in the zinc groups, suggesting a beneficial effect of zinc; however, given the small sample size, confidence intervals were wide and failed to reach statistical significance.
Hepatic encephalopathy is characterized at the neurophysiological level by disturbed corticocortical and corticomuscular coupling, and at the cellular level by primary gliopathy [2, 5, 17, 18]. Ammonia is a key pathophysiological factor in hepatic encephalopathy [18, 19]. In the brain, ammonia is detoxified by astrocytes through a reaction catalyzed by glutamine synthetase; an increased brain glutamine/glutamate ratio is associated with decreased myoinositol, reflecting compensation for glial edema [20–23]. Swollen astrocytes predispose to neuronal dysfunction by impairing their regulatory activity against the increase in protein tyrosine nitration and the formation of reactive oxygen and nitrogen oxide species including nitric oxide. If not counteracted, these reactions promote RNA oxidation, which prompts gene expression and the transcription of altered proteins [2, 5, 6, 18, 19, 21, 24].
Cytokines or lipopolysaccharides could induce the formation of nitrogen oxide species and trigger zinc release from metallothioneins, the principal zinc storage protein. A fluctuation in intracellular zinc levels modulates signal transduction, transcription factor activity, and gene expression, causing hepatic encephalopathy symptoms. Zinc deficiency is associated with disturbances in learning, memory, and emotional stability and is accompanied by hyperammonemia. Zinc supplementation has shown to reduce ammonia levels in experimental animals and humans through hepatic urea synthesis stimulation and glutamine synthesis in skeletal muscle [2, 6–8, 12, 18, 19, 21, 25].
The present meta-analysis is limited by the small number and poor quality of trials included. Available trials studied heterogeneous outcomes and failed to measure critical outcomes such as quality of life. This hinders the ability to draw conclusions about the value of oral zinc supplementation in the treatment of hepatic encephalopathy. Additionally, little information regarding the clinical importance of the different zinc formulations used in the trials was available.
In conclusion, oral zinc supplementation improved performance on the number connection test, but there is no clear evidence that supplementation improves encephalopathy or encephalopathy-related quality of life. More trials are needed to evaluate the use of oral zinc supplementation in patients with liver cirrhosis and hepatic encephalopathy.