Published online Sep 28, 2026. doi: 10.5528/wjtm.124154
Revised: July 7, 2026
Accepted: July 28, 2026
Published online: September 28, 2026
Processing time: 87 Days and 14.8 Hours
Hepatic encephalopathy (HE) is a complex neurological process that is seen in advanced liver disease. The onset of HE in patients with liver disease is a critical indicator of decompensation and is associated with poor outcomes. Many studies have shown a fall in serum zinc with advancing chronic liver disease (CLD) and higher grades of HE. There are, however, conflicting results on the benefit of zinc supplementation in HE.
To determine the association between serum zinc, HE, and liver disease severity in decompensated CLD (DCLD) patients in Kano.
We conducted a comparative cross-sectional study at a Nigerian tertiary hospital. Eighty DCLD patients with HE and 80 matched controls (16 per HE grade) were recruited. The diagnosis of DCLD combined clinical, laboratory, and ultrasound assessments. We graded liver disease severity with the Child-Pugh score and staged HE using the West Haven classification. Serum zinc was measured using atomic absorption spectrophotometry. Spearman’s correlation explored associations, with P < 0.05 considered significant. The study adhered to standard ethical principles.
The median serum zinc level in CLD patients was 0.381 mg/L [interquartile range (IQR) = 0.16]. This value was lower than that of the controls, which was 0.89 mg/L (IQR = 0.09). Serum zinc decreased with increasing HE grade, and this was found to be statistically significant (correlation coefficient, r = -0.601; P value < 0.001). There was a significant negative correlation between serum zinc levels in CLD subjects and the Child-Pugh class (r = -0.547; P value < 0.001). Serum bilirubin, prothrombin time (PT), and international normalized ratio (INR) also had a statistically significant negative correlation with serum zinc levels.
Serum zinc levels are significantly reduced in CLD and show inverse correlations with the severity of HE, Child-Pugh class, bilirubin, PT, and INR.
Core Tip: Zinc deficiency is frequently seen in patients with decompensated chronic liver disease (DCLD) and appears to worsen as liver disease progresses. In this study, serum zinc levels were significantly lower in DCLD patients and were inversely related to both hepatic encephalopathy (HE) and Child-Pugh class. This suggests that low serum zinc may reflect worsening liver dysfunction. Recent guidelines recommend serum zinc assessment in HE patients not responding to standardized treatment, and a conditional recommendation for zinc supplementation in those found deficient. This reflects the evolving role of zinc both as a biomarker and therapeutic target.
- Citation: Manzo MGA, Audu N, Musa Y, Muktar AA, Samaila AA, Borodo MM. Serum zinc levels, hepatic encephalopathy, and liver disease severity in decompensated chronic liver disease patients in Kano, Nigeria. World J Transl Med 2026; 12(3): 124154
- URL: https://www.wjgnet.com/2220-6132/full/v12/i3/124154.htm
- DOI: https://dx.doi.org/10.5528/wjtm.124154
The American Association for the Study of Liver Disease and the European Association for the Study of the Liver (EASL) joint practice guideline defines hepatic encephalopathy (HE) as “A brain dysfunction caused by liver insufficiency and/or portosystemic shunts that manifests as a wide spectrum of neurological or psychiatric abnormalities ranging from subclinical alterations to coma[1]”.
The precise pathophysiological pathways causing HE remain unclear despite much scientific research. The notion that nitrogenous compounds originating from the gut negatively affect cerebral function is among the most widely accepted mechanisms. Ammonia is the key component involved. Current HE management strategies focus on reducing elevated ammonia levels.
The development of subclinical or overt HE in a patient with chronic liver disease (CLD) has been considered one of the adverse events of decompensation and carries significant morbidity. HE was incorporated into early prognostic tools, including the Child-Turcotte-Pugh score, based on clinical experience at the time. The prognosis related to HE varies significantly depending on the decompensation status of the underlying liver cirrhosis[2].
Zinc, a cofactor in the urea cycle that enhances the activity of the enzyme ornithine transcarbamylase, is essential in ammonia detoxification. Studies have demonstrated that people with cirrhosis have zinc deficiency and that there is a negative link between serum zinc levels and the severity of liver disease and the degree of HE[3,4]. The improvement of HE with zinc supplementation has also been documented in several studies[5-9]. Some researchers have found no appreciable improvement in HE with zinc supplementation[10,11].
There is a paucity of data on the serum level of zinc among decompensated CLD (DCLD) patients in Nigeria, with even fewer attempting to correlate serum zinc with HE and the severity of liver disease. This knowledge gap highlights the necessity for additional research to explore these relationships.
Zinc deficiency is also more prevalent in low-resource countries like Nigeria. This is because the diet is predominantly based on cereals and legumes, which are rich in phytates, a substance known to impair zinc absorption[12]. Furthermore, the commonest etiology of CLD in Nigeria is hepatitis B, unlike developed nations, in which metabolic dysfunction-associated liver disease is the leading cause[13,14]. Finally, most of the patients with CLD present late in Nigeria, with advanced hepatic dysfunction and, as such, are more predisposed to zinc deficiency due to inadequate intake, malnutrition, or the presence of infections. Accordingly, due to these contextual differences, studies from more developed countries would not be an ideal representation of low-income countries, including Nigeria.
This study aimed to determine the correlation between serum levels of zinc, degree of liver disease, and grades of HE among DCLD patients in Kano.
The study was conducted in Aminu Kano Teaching Hospital (AKTH), a tertiary referral health care center situated in the North-Western geopolitical zone of Nigeria with a bed capacity of 750. The medical wards have a total bed capacity of 80. Study participants were recruited from patients admitted to the medical wards and those attending the Gastroenterology outpatient clinic. On average, 80 patients are seen weekly in the Gastroenterology Clinic.
We conducted a comparative cross-sectional study from February 2024 to October 2024. Eighty adults (≥ 18 years) with decompensated CLD in HE and eighty age- and sex-matched healthy controls were recruited in a 1:1 ratio consecutively. Controls were apparently healthy participants drawn from hospital staff, students, patients’ relatives, and persons who visited the hospital for other purposes.
(1) Patients diagnosed with DCLD secondary to all causes in HE (both overt and covert); (2) Patients aged 18 years or above; and (3) Patients who gave consent.
(1) Patients with hepatocellular carcinoma. Hepatocellular carcinoma was excluded using an ultrasound scan demon
(1) Apparently healthy adults matched for age and sex with the case; (2) No clinical or imaging evidence of CLD; and (3) Negative serology for hepatitis B surface antigen, anti-hepatitis C virus antibody, and a normal liver function test.
(1) Persons with evidence of liver disease; and (2) Those on zinc supplementation for any reason.
Sample size for the study was calculated using the formula for correlational studies below: n = [(Zα + Zβ)/C] 2 + 3. Where Zα = 1.96 at a 95% confidence level (CI), Zβ = 0.84 at 80% power, and C = 0.5 Ln [(1 + r)/(1 - r)]. The correlation coefficient (r) of 0.328 was gotten from a similar study[15]. The minimum sample size calculated was 71 which was increased to 80 to improve the power of the study.
Participants were categorized into five groups based on the severity of HE: Minimal HE, and Grades I-IV HE, with 16 patients in each group. Written informed consent was obtained from all participants; for patients with severe encephalopathy, consent was obtained from their next of kin.
DCLD was defined by the presence of clinical features of hepatic decompensation, such as ascites, variceal bleeding, jaundice, or HE, supported by biochemical abnormalities (including hypoalbuminaemia and reversal of the albumin-globulin ratio) and/or abdominal ultrasonographic findings suggestive of liver cirrhosis, such as an irregular liver outline or coarsened echotexture. The severity of HE was graded using the West Haven criteria. In patients with Grade III and IV HE, the Glasgow Coma Scale was additionally applied in accordance with the 2022 EASL guidelines.
Patients without overt HE were evaluated for minimal HE (MHE) using psychometric testing. Number Connection Test A (NCT-A) and Number Connection Test B (NCT-B) were administered, and impairment in both tests was used to define MHE. The tests were administered in a quiet room under standardized conditions. For NCT-A, participants were asked to connect sequential numbers from 1 to 25 as quickly as possible, while for NCT-B they connected alternating numbers and letters in sequence. Errors were corrected immediately and included in the total completion time. Only literate participants were enrolled; therefore, no adjustment for educational level was made. Standard published reference cut-offs were used, due to lack of local normalized values.
Blood samples from CLD patients were analyzed for liver function parameters (total and direct bilirubin, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, albumin, and total protein), hematological indices (platelet count), coagulation profile [prothrombin time (PT) and international normalized ratio (INR)], and viral serology (hepatitis B surface antigen and anti-hepatitis C virus antibody). The severity of liver disease was assessed using the Child-Pugh classification, incorporating serum albumin, total bilirubin, INR, ascites, and encephalopathy grade.
Serum zinc levels were measured in both cases and controls using atomic absorption spectrophotometry (PinAAcle 900H AA Spectrometer, PerkinElmer, United States) in accordance with the manufacturer’s protocol. Fasting venous blood samples were collected in the morning under standardized conditions. To minimize hemolysis, prolonged tourniquet application and the use of small-gauge needles were avoided. Blood samples were collected into plain tubes, allowed to clot, and centrifuged promptly to obtain serum. Hemolysed samples were discarded. The separated serum was stored at 4 °C until analysis. Calibration and internal quality control were performed before sample analysis to ensure accuracy of the assay.
Statistical analyses were performed using IBM’s SPSS software version 26 (SPSS, Chicago, IL, United States). All the variables were tested for normality using the Shapiro-Wilk normality test. Categorical data were summarized as n, proportions, and %, while continuous data were presented as mean ± SD or median ± interquartile range (IQR) for non-normally distributed data. Discrete variables, such as gender, were analyzed using Fisher’s exact test. Continuous variables were analyzed using the Student’s t-test for normally distributed data and its non-parametric equivalent, the Mann-Whitney U test, for non-normally distributed data. Correlation analysis was conducted using Spearman’s rank correlation coefficient. A P value of < 0.05 was considered statistically significant at a 95%CI. The effect size for the difference in serum zinc between cases and controls was estimated using rank-biserial correlation.
Ethical approval was obtained from the Human Research and Ethics Committee of AKTH (approval No. NHREC/28/01/2020/AKTH/EC/3546). Written informed consent was obtained from all participants. The study adhered to the principles of the Declaration of Helsinki (2013 revision).
The mean age of patients (47.66 ± 14.67 years) and controls (47.91 ± 14.73) is similar. A total of 80 comparable subjects who met the inclusion criteria were recruited as controls for the study. Fifty-seven of the CLD patients were hepatitis B surface antigen positive, accounting for 71.3% of the cases, with 17% having undetermined causes. Most patients were male (82.5%) and had at least secondary education, with tertiary education being the most common level attained. Ascites was present in 74 (92.5%) patients, with most patients having moderate ascites. The baseline socio-demographic and clinical characteristics of the study participants are shown in Table 1.
| Characteristics | Cases (n = 80) | Controls (n = 80) |
| Age (years), mean ± SD | 46.7 ± 11.5 | 46.5 ± 11.2 |
| Male sex | 66 (82.5) | 66 (82.5) |
| Educational status | ||
| Primary or less | 26 (32.5) | - |
| Secondary | 20 (25.0) | - |
| Tertiary | 34 (42.5) | - |
| Etiology of CLD | ||
| HBV | 57 (71.3) | - |
| HCV | 3 (3.75) | |
| Alcohol | 1 (1.25) | |
| Idiopathic | 17 (21.25) | |
| Others | 2 (2.5) | - |
| Ascites | ||
| Mild | 18 (22.5) | |
| Moderate | 35 (43.8) | |
| Severe | 21 (26.3) | |
| None | 6 (7.5) |
The median serum zinc level among the controls was 0.892 mg/L (IQR: 0.088; 95%CI: 0.867-0.903), while the median serum zinc level in patients with CLD was 0.381 mg/L (IQR: 0.160; 95%CI: 0.360-0.420). This difference was statistically significant (Mann-Whitney U = 14.0, P < 0.001), with a very large effect size (rank-biserial r = 0.996).
All liver function tests were deranged in DCLD patients (Table 2). There were elevations in transaminases (aspartate aminotransferase: 61.00; alanine aminotransferase: 51.50 U/L), bilirubin (30.00 µmol/L), and coagulation indices (INR: 1.97; PT: 24.80 seconds). Serum albumin was reduced (28.55 ± 5.96 g/L), consistent with impaired synthetic liver function.
| Parameter | All DCLD patients | MHE (n = 16) | Grade I (n = 16) | Grade II (n = 16) | Grade III (n = 16) | Grade IV (n = 16) |
| INR | 1.97 (2.36) | 1.28 (0.97) | 1.55 (1.34) | 2.16 (2.46) | 3.23 ± 2.26 | 3.23 ± 1.68 |
| PT (seconds) | 24.80 (29.8) | 18.00 (13.00) | 18.75 (13.50) | 25.50 (28.30) | 38.95 ± 24.19 | 38.08 ± 21.76 |
| AST (U/L) | 61.00 (67.00) | 33.00 (70.00) | 43.00 (57.00) | 70.00 (72.00) | 59.63 ± 39.53 | 99.38 ± 56.62 |
| ALT (U/L) | 51.50 (52.00) | 41.00 (65.00) | 57.56 (41.68) | 42.50 (37.00) | 50.50 (60.00) | 70.00 (74.00) |
| Total bilirubin (µmol/L) | 30.00 (44.80) | 20.30 (21.50) | 14.50 (15.80) | 44.61 ± 35.12 | 59.50 (61.30) | 40.00 (39.30) |
| Albumin (g/L) | 28.55 ± 5.96 | 30.00 (9.00) | 31.81 (5.73) | 26.44 ± 7.03 | 25.13 ± 5.21 | 27.94 ± 4.23 |
Across increasing grades of HE, there was a general trend toward worsening biochemical derangement (Table 2). However, not all parameters demonstrated a consistent stepwise progression across HE grades.
A boxplot showing the relationship between serum zinc levels and various grades of HE is depicted in Figure 1. It illustrates a trend of decreasing serum zinc with increasing HE grades: Minimal HE (0.528 ± 0.152), grade 1 (0.412 ± 0.098), grade 2 [median 0.381 (IQR 0.079)], grade 3 (0.336 ± 0.099), and grade 4 (0.297 ± 0.091). The Spearman rank test indicates that this relationship is statistically significant, with a correlation coefficient (r) of -0.601 and a P value < 0.001.
The serum zinc levels decrease with increasing Child-Pugh class (Figure 2). The mean serum zinc level was 0.516 ± 0.150 mg/L in patients with Grade A and 0.440 ± 0.845 mg/L in those with Grade B. Similarly, it was lower in Grade C patients, with a median value of 0.320 mg/L. This study found a statistically significant negative correlation between Child-Pugh class and serum zinc levels among patients with decompensated CLD, with a correlation coefficient (r) of
Further analysis was conducted to determine which components of the Child-Pugh score were associated with serum zinc levels. Spearman correlation showed that bilirubin levels were more strongly associated with serum zinc in CLD subjects, with a correlation coefficient of -0.363 (P value < 0.01) (Figure 3A and Table 3). Similarly, INR and PT also correlated with serum zinc, with correlation coefficients of -0.234 and -0.255, respectively (Figure 3B and C; Table 3).
A notable finding in this study was that hepatitis B virus infection accounted for over two-thirds of CLD cases. This aligns with findings from other studies in the country that had similar results[13,16]. These findings are consistent with the high prevalence of hepatitis B in Nigeria[17].
The median zinc level for the controls in this study was 0.89 mg/L (IQR = 0.088). This is within the normal range and aligns with the findings of a recent study by Adedeji et al[18] in South West Nigeria, which determined reference values for various micronutrients, including zinc, among Nigerians. In that study, the median serum zinc level was 0.96 mg/L (IQR = 0.3531), with a reference normal serum zinc range of 0.621-1.34 mg/L.
The median serum zinc level among patients with CLD was 0.381 mg/L (IQR: 0.160), which was significantly lower than that of the control group [0.892 mg/L (IQR: 0.088); P < 0.001]. This finding is consistent with that of an Egyptian study that also reported low serum zinc levels in cirrhotic patients with HE, with a mean serum zinc concentration of 0.315 ± 0.13 mg/L[15]. Additionally, a study by Deep et al[19] in India recorded a mean serum zinc level of 0.405 ± 0.10 mg/L in CLD patients. These outcomes are further supported by findings of a range of other studies, which have also shown reduced serum zinc levels in patients with CLD[20-23].
Several factors have been suggested as responsible for low serum zinc levels in patients with CLD. These include reduced zinc absorption in the gastrointestinal tract, increased urinary zinc excretion, nutritional deficiencies, hypoalbuminemia, portosystemic shunting, and impaired hepatic zinc uptake, all of which contribute to zinc deficiency in liver cirrhosis[24]. Additionally, the use of diuretics which is common in patients with decompensated cirrhosis is known to enhance zinc excretion in the urine by inhibiting renal tubular zinc reabsorption[24].
This study observed a decrease in serum zinc levels with increasing grades of HE, and this was found to be statistically significant (correlation coefficient, r = -0.601; P value < 0.001). Similar findings have been reported in several studies, which consistently observed lower serum zinc levels with increasing severity of HE[3,4,19,23,25]. An Egyptian study however reported a non-significant association between serum zinc and HE (r = -0.328, P = 0.232), although the direction of the association was similar to that observed in our study[15].
Evidence regarding the therapeutic role of zinc supplementation in HE remains inconsistent. Some studies have reported improvements in HE following zinc supplementation[9,26]. Earlier randomized controlled trials by Riggio et al[10] and Bresci et al[11] found no significant improvement in clinical or neuropsychological outcomes compared with standard therapy.
Consistent with these mixed findings, the most recent American College of Gastroenterology guideline recommends zinc supplementation only for patients with documented zinc deficiency whose HE persists despite optimal treatment with lactulose and rifaximin. This is a conditional recommendation based on very low-certainty evidence, underscoring the need for further well-designed clinical trials to clarify the role of zinc supplementation in HE[27].
This study showed a statistically significant negative correlation between the Child-Pugh class and serum zinc levels in patients with DCLD. These findings are consistent with those of Kamani and Shaikh[28], who also observed an inverse correlation between the Child-Pugh score and serum zinc levels (r = -0.498). Similarly, a study conducted in Japan reported a statistically significant association between serum zinc levels and the Child-Pugh score (r = -0.469, P < 0.0001)[20].
In Indonesia, a study by Yuwono et al[29] revealed a significant correlation between the severity of liver cirrhosis and serum zinc levels (P < 0.05, r = -0.583). Similar findings have been reported in other studies[21,30]. These observations are not surprising, as worsening liver dysfunction increases the likelihood of zinc deficiency due to the previously discussed mechanisms in this discussion.
However, in contrast to these findings, a study conducted in Iran found no statistically significant relationship between serum zinc and the severity of liver disease (P = 0.37)[31].
PT, INR, and bilirubin showed significant correlations with serum zinc levels. Among these, bilirubin had the strongest association, with a correlation coefficient (r) of -0.363 and a P value of < 0.01. These findings are consistent with an Egyptian study that demonstrated significant correlations between serum zinc and total bilirubin (r = -0.61, P = 0.00), PT (r = -0.473, P = 0.008), and INR (r = -0.416, P = 0.022) among patients with CLD and HE[21].
The observed negative correlations between serum zinc and PT/INR, as well as bilirubin, align with the understanding that these parameters reflect worsening liver dysfunction. Elevated PT/INR and bilirubin levels are markers of hepatic impairment, making the inverse relationships between serum zinc levels and PT/INR and bilirubin levels in patients with decompensated CLD an expected finding. Since zinc has anti-inflammatory and antioxidant properties, its deficiency can exacerbate liver damage, resulting in elevated bilirubin levels and deranged PT/INR[24]. Additionally, zinc inhibits the enterohepatic circulation of bilirubin, and its deficiency may lead to higher total circulating bilirubin levels[32,33]. Notably, Zinc supplementation has even been shown to reduce bilirubin levels in infants[34].
A study by Katayama et al[20] reported that albumin had the strongest correlation with serum zinc (r = 0.587, P < 0.0001). This relationship has also been demonstrated in other studies[25,35]. Serum albumin is the major binding protein for zinc in circulation, and reductions in albumin levels can directly lead to lower measured serum zinc concentrations[24].
In addition, zinc plays a role in ammonia detoxification through its involvement in the urea cycle. Zinc deficiency may impair hepatic ammonia metabolism, leading to increased reliance on alternative pathways such as glutamine synthesis in skeletal muscle, which utilizes branched-chain amino acids (BCAAs). Depletion of BCAAs, which are important substrates for protein synthesis, may further contribute to reduced albumin production[24].
In contrast, this study did not demonstrate a significant correlation between albumin and serum zinc levels. This discrepancy may be explained by several factors. A higher prevalence of malnutrition in the study population could lead to independent depletion of both BCAAs and albumin, thereby obscuring their relationship with zinc. Furthermore, both zinc and albumin are affected by inflammation and infection. Inflammatory states reduce zinc transporter expression and lower serum zinc levels, while hypoalbuminemia is a well-recognized negative acute-phase response[36,37]. Patients with CLD are particularly susceptible to infections, which may further confound this relationship. The combined effects of malnutrition, inflammation, and disease severity may therefore have masked a clear association between serum zinc and albumin in this cohort.
This study was conducted at a single center, which may limit the generalizability of the findings. The cross-sectional design precludes inference of causality, and the subgroup sample sizes across the different grades of HE were relatively small, which may limit the precision of subgroup comparisons.
Dietary factors may also influence serum zinc levels and should be considered when interpreting our findings. Diets rich in phytate, which is present in high concentrations in grains and legumes, can impair zinc absorption. Such diets predominate in low-resource settings like ours[38]. Since dietary intake was not assessed in this study, its potential contribution to serum zinc deficiency cannot be excluded.
In addition, brain imaging was not routinely performed to exclude alternative causes of encephalopathy. Another limitation is the potential overlap between HE grade and Child-Pugh classification, as HE constitutes one of the com
Infection and inflammation are also known to reduce serum zinc levels and are well recognized precipitants of HE. In addition, detailed information on diuretic use, which may influence urinary zinc excretion and serum zinc levels, was not available[24].
Further studies in this setting are needed to clarify the relationship between serum zinc levels and HE and to validate these findings. Randomized controlled trials evaluating the role of zinc supplementation in the management of HE should also be conducted in Nigeria.
Serum zinc levels were significantly lower in patients with decompensated CLD than in healthy controls and decreased with increasing grades of HE. Serum zinc levels were also inversely correlated with Child-Pugh class; however, this association should be interpreted with caution because HE is one of the components of the Child-Pugh classification. Additionally, serum zinc levels were inversely correlated with bilirubin, PT, and the INR.
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