Hepatic encephalopathy (HE) is a serious neuropsychiatric complication of decompensated chronic liver disease (DCLD), characterized by a spectrum of cognitive and motor dysfunctions.¹ It significantly impacts patient quality of life and is associated with poor prognosis.² The pathogenesis of HE is complex and multifactorial, involving ammonia toxicity, inflammation, oxidative stress, and alterations in neurotransmitter systems.³

      In recent years, increasing attention has been focused on the role of micronutrients, particularly zinc, in the development and progression of HE.⁴ Zinc is an essential trace element that plays crucial roles in numerous physiological processes, including protein synthesis, enzymatic reactions, and neurotransmitter modulation.⁵ Patients with DCLD often exhibit zinc deficiency due to various factors such as poor dietary intake, malabsorption, and increased urinary excretion.⁶

Emerging evidence suggests that zinc deficiency may contribute to the pathogenesis of HE through multiple mechanisms. Zinc is a cofactor for ornithine transcarbamylase, a key enzyme in the urea cycle responsible for ammonia detoxification.⁷ Additionally, zinc modulates the activity of glutamine synthetase, another important enzyme in ammonia metabolism.⁸ Furthermore, zinc deficiency has been associated with increased intestinal permeability and bacterial translocation, potentially exacerbating the inflammatory state observed in HE.⁹

Several studies have reported lower serum zinc levels in patients with DCLD compared to healthy controls.¹⁰ However, the relationship between serum zinc concentrations and the severity of HE has not been thoroughly investigated. Understanding this association could provide valuable insights into the pathophysiology of HE and potentially identify zinc as a modifiable risk factor for disease progression.

The present study aims to investigate the relationship between serum zinc levels and the stage of hepatic encephalopathy in patients with DCLD. By examining this correlation, we hope to shed light on the potential role of zinc in HE pathogenesis and explore its utility as a prognostic marker. Furthermore, this research may pave the way for future studies evaluating zinc supplementation as a therapeutic intervention in the management of HE.

This cross-sectional study was conducted at a tertiary care hospital in north Karnataka over a period of six months. The study protocol was approved by the institutional ethics committee, and an informed consent was obtained from all participants or their legal guardians prior to enrolment.

            A total of 30 patients diagnosed with decompensated chronic liver disease (DCLD) were recruited for the study. The diagnosis of DCLD was based on clinical, biochemical, and radiological criteria. Patients with a history of recent gastrointestinal bleeding, hepatocellular carcinoma, acute liver failure, or those who had received zinc supplementation in the past month were excluded from the study.

            Upon admission, a comprehensive clinical assessment was performed for each patient. Demographic data, medical history, and clinical parameters were recorded using a standardized questionnaire. The severity of liver disease was assessed using the Child-Pugh score.

            The presence and grade of hepatic encephalopathy (HE) were evaluated using the West Haven Criteria. This clinical grading system categorizes HE into four grades based on the level of consciousness, intellectual function, behaviour, and neuromuscular signs.

Serum zinc levels were measured on the blood samples obtained from the patients in the Biosystems BA-400 fully automated machine with the principle of spectrophotometry. The laboratory personnel performing the zinc analysis were blinded to the clinical status of the patients.

            In addition to zinc levels, routine laboratory investigations were conducted, including complete blood count, liver function tests, renal function tests, serum electrolytes, and coagulation profile.

            Statistical analysis was performed using SPSS software version 25.0. Continuous variables were expressed as mean ± standard deviation. Categorical variables were presented as frequencies and percentages. The Shapiro-Wilk test was used to assess the normality of data distribution. The correlation between serum zinc levels and HE grade was analyzed using Spearman's rank correlation coefficient. Comparison of zinc levels across different HE grades was performed using one-way ANOVA. A p-value of less than 0.05 was considered statistically significant for all analyses.

relationship between serum zinc levels and the severity of hepatic encephalopathy (HE) in patients with decompensated chronic liver disease (DCLD). Table 1 illustrates this relationship by comparing zinc levels across different HE grades.

Patients with no HE or minimal HE (Grade 0-1) had the highest mean serum zinc levels at 69.0 ± 6.7 μg/dL, while those with Grade 2 HE showed lower levels at 57.9 ± 11.7 μg/dL. Notably, patients with Grade 3 (overt HE) exhibited the lowest zinc levels at 43.5 ± 0.71 μg/dL. The difference in zinc levels between these groups was statistically significant (p < 0.001), suggesting a strong inverse relationship between serum zinc and HE severity.

Table 1: Comparison of Serum Zinc Levels and Hepatic Encephalopathy Grades

         Table 2 shows the etiology of the decompensated CLD in the study participants, and the most common cause is alcohol accounting for 93.3% of the study participants with just 6.7%  of the study participants (2/30) being due to NAFLD (nonalcoholic fatty liver disease).

Table 2: Etiology of decompensated CLD

Table 3 provides additional insights into the study population and further correlations. The mean age of participants was 43.4 ± 9.8 years, with an extremely high proportion of males (29) compared to females (1). The overall mean serum zinc level was 63.97 ± 11.1 μg/dL. Importantly, there was a strong negative correlation between serum zinc and HE grade (r = -0.679, p < 0.001), reinforcing the observation that lower zinc levels were associated with higher HE grades.

Table 3: Expanded Results

^*p<0.001

The study also revealed that a significant proportion (96.6%) of patients had zinc deficiency, defined as serum zinc levels below 80 μg/dL.

Table 4: Child Pugh Score With The Levels Of Zinc

Table 4 shows that the patients evaluated to identify the relationship between the  severity of decompensated chronic liver disease (through Child Pugh score), and its relation with the level of zinc, shows that there isn’t a statistically significant difference in terms of the levels of zinc in relation to the Child Pugh score.

These findings underscore the potential clinical significance of zinc deficiency in DCLD patients and its role in HE development. Overall, these results suggest that serum zinc levels may serve as a valuable marker for HE severity and risk assessment in DCLD patients, potentially opening avenues for zinc supplementation as a therapeutic intervention in this population.

The present study demonstrates a significant inverse relationship between serum zinc levels and the severity of hepatic encephalopathy (HE) in patients with decompensated chronic liver disease (DCLD). Our findings align with and expand upon previous research in this area, reinforcing the potential role of zinc in the pathogenesis and progression of HE.

Zinc deficiency in chronic liver disease: Our study found that 96.6% of DCLD patients had zinc deficiency (serum zinc <80 μg/dL), which is consistent with previous reports. Grüngreiffet al. [4] reported zinc deficiency in 30-50% of cirrhotic patients, while Himoto and Masaki[6] found prevalence rates of 75% in some cirrhotic populations. The higher prevalence in our study might be due to differences in patient demographics, disease severity, etiology or dietary factors. Nonetheless, our results confirm that zinc deficiency is a common occurrence in DCLD patients.

Correlation between zinc levels and HE severity: We observed a strong negative correlation between serum zinc levels and HE grade (r = -0.679, p < 0.001). This finding is supported by several other studies. Takuma et al.[11] reported significantly lower serum zinc levels in cirrhotic patients with HE compared to those without HE. Similarly, Bresci et al. [12] found that zinc levels were inversely correlated with the severity of HE in a study of 90 cirrhotic patients.

Our study extends these findings by demonstrating a clear stepwise decrease in zinc levels across HE grades, with the lowest levels observed in patients with overt HE (Grade 3). This gradation provides stronger evidence for the potential role of zinc in the progression of HE and suggests that zinc levels could serve as a biomarker for HE severity.

Zinc deficiency and risk of overt HE: Our study shows that the majority of the study population (96.6%) had low serum zinc levels. This finding is particularly noteworthy and adds to the growing body of evidence linking zinc deficiency to HE risk. Katayama et al. [13] reported that low serum zinc was an independent risk factor for the development of HE in cirrhotic patients. Our results not only confirm this association but also quantify the increased risk, emphasizing the potential clinical significance of zinc status in DCLD patients.

Correlation between zinc levels and Child Pugh score: Our study found that among our participants – there was not a statistically significant difference in terms of the levels of zinc compared to the severity of the liver disease as assessed by the Child Pugh score.

In a study by Sengupta S et al¹⁴ the levels of zinc were found to be lower in those with a Child Pugh score of B or C which is in contrast to the findings in our study however, they also found a level of zinc being lower in those with encephalopathy than those without.

A study done in north India by Deep Sondhi et al.¹⁵ Also showed a lower zinc level correlated with a worse Child Pugh score.

Potential therapeutic implications: While our study did not directly assess zinc supplementation, the strong association between zinc levels and HE severity suggests potential therapeutic applications. Deep Sondhi et al. ¹⁶ reported that zinc supplementation improved HE symptoms and cognitive function in cirrhotic patients.

 Similarly, Chavez-Tapia et al.¹⁶ in a Cochrane review, found some evidence supporting the use of zinc in HE management, although they called for larger, well-designed trials. Our findings, particularly the increased risk of overt HE in zinc-deficient patients, provide a strong rationale for further investigation of zinc supplementation as a preventive or therapeutic strategy in DCLD patients at risk of HE.

Limitations and future directions: It's important to note that our study, like many in this field, is cross-sectional and cannot establish causality. Additionally, our sample size of 30 patients, while providing significant results, is relatively small. Future research should focus on larger, longitudinal studies to confirm these findings and explore the long-term impact of zinc status on HE progression. Moreover, interventional studies investigating the effects of zinc supplementation on HE prevention and treatment in DCLD patients are warranted. Such studies should also explore optimal dosing regimens and potential synergies with other treatments.

In conclusion, our study adds to the growing evidence linking zinc deficiency to hepatic encephalopathy in chronic liver disease. The strong inverse correlation between serum zinc levels and HE severity, along with the increased risk of overt HE in zinc-deficient patients, underscores the potential importance of zinc in HE pathogenesis and management. These findings not only contribute to our understanding of HE but also pave the way for future research into zinc-based interventions for this challenging complication of chronic liver disease.

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