Efficacy of Zinc Supplement in Minimal hepatic Encephalopathy: A prospective, Randomized Controlled Study (Zinc-MHE Trial)

Abstract

Background: Minimal hepatic encephalopathy (MHE) in patients with cirrhosis of the liver has a negative impact on the quality of daily life by impairing attention, memory and visuomotor coordination, and resulting in cognitive decline. Ammonia is thought to be part of the pathogenesis of hepatic encephalopathy. Zinc is an essential trace element, one of the cofactor enzymes that is essential for the conversion of ammonia to urea. Aim: To assess the effect of zinc supplementation on psychomotor performance in cirrhotic patients with MHE. Methods: This prospective, randomized, controlled trial recruited 69 cirrhotic patients (age 18-75 years) diagnosed with MHE by neuropsychometric (NP) tests comprised of the number connection test part A (NCT-A), number connection test part B (NCT-B), serial dot test (SDT), line tracing test (LTT) and digit symbol test (DST). Eligible patients were randomly assigned (1:1) by a computer-based system block of four randomizations to receive 45 mg of elemental zinc or placebo for 12 weeks. The primary endpoint was the absolute change in NP tests from baseline to 12-weeks of zinc supplement compared with placebo. The assessment of changes of the health-related quality of life (HRQOL) using the Short Form survey-36 (SF-36) questionnaire, as well as biochemical parameters including serum ammonia, was also conducted in both groups. Results: From January to December 2020, 125 eligible cirrhotic patients were diagnosed with liver cirrhosis, of whom 69 (55%) had MHE and were randomly assigned to treatment: 35 patients were assigned to receive 45 mg of elemental zinc and the others 34 patients to receive placebo. Significant improvements in NP tests were established in the zinc supplement group when compared with the placebo group (NCT-A, p = 0.029; NCT-B, p = 0.008; SDT, p = 0.002; DST, p = <0.001). A significant improvement of HRQOL assessed by the SF-36 score was only seen in the zinc group (p<0.001). In the zinc supplement group, not only was an improvement in psychomotor performance reported, but quality of life was also improved, irrespective of baseline zinc level. Conclusion: Twelve weeks of zinc supplement in cirrhotic patients with MHE not only had a positive effect on psychomotor performance but also improved HRQOL irrespective to baseline zinc level.

Nutritional Support in Acute Liver Failure

“…In addition, zinc—a microelement crucial for our immune system homeostasis—is also a cofactor for ammonia conversion to urea. Thus, zinc deficiency is strictly linked to hepatic encephalopathy [ 50 ]. Conversely, patients with ALF derived from undiagnosed Wilson disease can present with copper-driven toxicity [ 51 ].…”

Clinical Outcomes of Oral Zinc Therapy in Hepatic Encephalopathy Treatment

“…Zinc has been proposed as a potential treatment option for HE given its mechanism of action in cirrhosis and the urea cycle, and prior studies have shown potential benefit. [5][6][7][8] However, the outcomes from prior studies were improvement in NP test results, changes in ammonia levels, and healthcare quality of life scores, and none evaluated the effects of zinc on readmission rates nor were conducted in the United States.…”

“…1,2 Prior studies have evaluated zinc therapy for HE treatment, but they had various comparator groups and outcomes (Table 1). [5][6][7][8] Zinc was compared to the following: placebo, BCAAs, lactulose, and various international standard HE therapies (protein-restricted diet with lactulose, protein-restricted diet with BCAAs and lactulose), but none of the prior studies included patients on rifaximin. Therefore, these studies are not applicable to the management of HE in patients with cirrhosis already on lactulose and rifaximin.…”

Pathophysiological-Based Nutritional Interventions in Cirrhotic Patients with Sarcopenic Obesity: A State-of-the-Art Narrative Review

“…Most studies on zinc supplementation in cirrhosis focused on its effects on hepatic encephalopathy. Despite the fact that some authors demonstrated an improvement in amino acids metabolism and hepatic encephalopathy [233][234][235][236][237], while a few studies reported a better prognosis due to lower frequency of liver decompensation and HCC development in cirrhotic patients with low zinc serum levels treated with supplementation [238,239], there is still no consensus on the dose and timing of supplementation. A particular case is represented by chronic alcohol intoxication, where low levels of brain zinc have been associated with an increased sensitivity to alcohol withdrawalinduced seizures, and zinc supplementation may alleviate general alcohol withdrawal symptoms [240].…”