ORIGINAL ARTICLE Year : 2023  |  Volume : 14  |  Issue : 2  |  Page : 93-96

Study of serum zinc level in liver cirrhosis and its correlation with stages of hepatic encephalopathy

Suraj Ramesh Hiwarkar, Madhuri Prashant Holay, Bhiwagade Rahul, Patil Prashant
Department of General Medicine, Government Medical College and Hospital, Nagpur, Maharashtra, India

Date of Submission27-Jan-2023Date of Decision22-Feb-2023Date of Acceptance09-Mar-2023Date of Web Publication04-Jul-2023

Correspondence Address:
Dr. Suraj Ramesh Hiwarkar
MARD Hostel, Medical Square, Nagpur, Maharashtra
India

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/injms.injms_9_23

Background: Zinc increases the natural defense of reactive oxygen radicals; Zinc also acts as an antioxidant, an anti-apoptotic agent, a cofactor for DNA synthesis, and an anti-inflammatory agent. Hence, deficient zinc levels seem to have an effect in the pathogenesis of hepatic encephalopathy (HE). Aims: This prospective observational study was done to assess serum zinc levels in cases of liver cirrhosis with decompensated liver disease (DCLD) and to see the correlation of serum zinc levels with stages of HE and patients' outcome. Materials and Methods: This prospective observational study was conducted at a tertiary care institution in Central India. Total 66 cases of liver cirrhosis with DCLD were studied. Fifty healthy controls were enrolled. All cases were evaluated for serum zinc levels, and all were divided further according to the class of liver cirrhosis and stages of HE. The association between serum zinc level and stages of HE and outcome was studied. The data were analyzed with SPSS software version 22. Results: The mean age of the cases at presentation was 45.67 ± 8.73 years. The M: F ratio was 10:1. The mean serum zinc level in controls was 104.16 ± 22.60 μg/dl, while in cases, it was 47.68 ± 16.72 μg/dl. It was significantly low in cases as compared to the controls, P < 0.0001. An inverse correlation was observed between serum zinc and West Haven classification grading of HE. There was found a direct correlation between serum zinc level and serum albumin. The lesser the serum albumin, the lesser the serum zinc level. P <0.0001 was highly significant. The mean serum zinc level was 57.67 μg/dl in survivors 40 cases (60.61%) as compared to 32.30 μg/dl in nonsurvivors 26 (39.30%). Low serum zinc level was associated with high mortality. P <0.0001 was statistically highly significant. Conclusion: Low serum zinc is associated with cirrhosis of the liver, DCLD, and high incidence of HE. Hence, all patients of cirrhosis liver with hypoalbuminemia and HE should be evaluated for low serum zinc. Low serum zinc in HE was associated with high mortality. The present study could not establish a causal relationship between low serum zinc and liver cirrhosis with DCLD having HE. Whether correction of zinc in these cases can prevent worsening, HE needs further evaluation.

Keywords: Cirrhosis liver, decompensated liver disease, hepatic encephalopathy, serum zinc level

How to cite this article:
Hiwarkar SR, Holay MP, Rahul B, Prashant P. Study of serum zinc level in liver cirrhosis and its correlation with stages of hepatic encephalopathy. Indian J Med Spec 2023;14:93-6
How to cite this URL:
Hiwarkar SR, Holay MP, Rahul B, Prashant P. Study of serum zinc level in liver cirrhosis and its correlation with stages of hepatic encephalopathy. Indian J Med Spec [serial online] 2023 [cited 2023 Jul 4];14:93-6. Available from: http://www.ijms.in/text.asp?2023/14/2/93/380399   Introduction 

Liver disease affects millions of people worldwide every day. Cirrhosis is a consequence of chronic liver diseases.

In India, the most common causes of cirrhosis are alcohol abuse and viral hepatitis. Diffuse fibrosis causes architecture distortion with regenerative nodule formation resulting in decreased liver cell mass and reduced blood flow to the liver.[1] The majority of the patients remain symptom free until the advanced stage called decompensated cirrhosis, characterized by ascites, spontaneous bacterial peritonitis, hepatic encephalopathy (HE), or variceal bleeding from portal hypertension.

HE is a life-threatening complication that can occur in acute or chronic liver failure. About 30% of patients with cirrhosis die due to hepatic coma.[2] HE in a patient with liver failure is an indication of poor prognosis, in a cirrhotic patient. HE is probably precipitated due to gut-derived neurotoxins such as ammonia.

Zinc is an essential trace element and zinc is associated with more than 300 enzymatic systems.[3] It is an important cofactor in the urea cycle and has a great role in the conversation of ammonia to urea. Zinc increases the natural defense of reactive oxygen radicals, and zinc also acts as an antioxidant, an anti-apoptotic agent, a cofactor for DNA synthesis, and an anti-inflammatory agent. Hence, deficient zinc levels seem to have an effect in the pathogenesis of HE. Zinc deficiency in cirrhotic patients appears to be due to anorexia and reduced intake of animal proteins, increase in cytokines or hormones that may affect zinc metabolism, increases in renal loss, and poor absorption of nutrients due to portal hypertension.

Albumin is the major plasma carrier of zinc, and the amount of zinc transported in the blood depends not only on zinc but also on the availability of serum albumin.[4],[5] The excess use of diuretics also increases the urinary secretion of zinc. Frequent bowel wash and lactulose also increase gastrointestinal (GI) loss of zinc.[6] Mostly zinc in the body present in bound form, it may be loosely bound with albumin and tightly bound with α2-globulin, albumin level is significantly low in CLD patients, patients who have low serum albumin concentration also prone to more zinc deficiency. Low albumin level is one of the most important causes of low zinc level in CLD, and another cause of low zinc levels in CLD patients is loss of appetite.

There are fewer data available in India regarding the association between serum zinc and cirrhosis liver with HE. Therefore, this study was undertaken to know serum zinc level in cirrhosis liver (decompensated liver disease [DCLD]), its correlation with grades of HE, and patients' outcome.

  Materials and Methods 

This prospective observational study was conducted from November 2019 to October 2021 at tertiary care institution, Nagpur, in Central India.

After taking institutional ethics committee clearance, total 116 subjects (66 cases and 50 healthy controls) were enrolled in the study. Total 66 cases of more than 18 years of age attending hospital outdoor or indoor with symptoms and signs suggestive of chronic hepatocellular dysfunction (decompensated liver cirrhosis) with or without HE were included in the study.

Fifty healthy controls without having clinical and ultrasonographic evidence of liver cirrhosis were also included to know serum zinc status.

Cases having encephalopathy of other metabolic causes, head injury, stroke, psychiatric disorders, alcohol withdrawal state, and acute alcohol intoxication were excluded. Written informed consent was taken from each subject after explaining the purpose of the study.

Diagnosis of cirrhosis (decompensated chronic liver disease) and HE was entirely based on clinical examination additionally supported by USG abdomen and serum ammonia level.

A complete physical examination was done for signs of chronic liver failure (jaundice, spiders, pedal edema, palmar erythema, and ascites), flapping tremors, and Neuropsychiatric manifestation (altered sensorium) for HE.

HE cases were clinically graded according to West Haven classification (WHC).[7] All cases were classified according to Child–Pugh class 4, and the severity of liver cirrhosis was assessed by Child–Pugh score.[8] For serum zinc, venous blood sample was collected. All the cases and controls were subjected to serum zinc level by absorption spectrophotometry. Other laboratory tests such as complete blood count (CBC), serum electrolytes, liver function test, renal function test, coagulation profile, and serum albumin were done. Serum ammonia was estimated in HE cases only.

Data were analyzed in two groups: cirrhosis liver with HE and without encephalopathy.

The statistical analysis was done by SPSS software version 22. All values were expressed in percentages and as mean ±standard deviation. To find out significant change in continuous variables, a 2 paied student t test was used and for noncontinuous variable chi square test was used. The difference was considered to be statistically significant with P ≤0.05.

  Results 

Out of 66 cases of liver cirrhosis, the mean age at presentation was 45.67 ± 8.73 years. There was male preponderance, 60/66 (90.91%); only 6 cases were female with a M: F ratio of 10:1. For controls, 42/50 (84%) were male while only 8/50 (9.09%) were female.

Among etiological factors for cirrhosis, alcohol intake (89.39%) was the most common risk factor observed in the present study. The most common presenting symptom was ascites (100%), and the next common were constipation (84.85%), pedal edema (78.79%), vomiting (71.2%), and GI bleeding (66.67%).

Upper GI (UGI) bleeding (75.76%) was observed as the leading precipitating factor for HE. Other precipitating factors were constipation (71.21%), infection (9.09%), and dyselectrolytemia (6.06%).

The mean serum zinc level in cases was significantly low 47.68 ± 16.72 μg/dl as compared to 104.16 ± 22.60 μg/dl in controls. P <0.0001 was highly significant [Table 1].

Table 1: Comparison of mean serum zinc level in cases and controls (n=116)

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The mean serum zinc level in cases as per Child–Pugh class A was 65.41 ± 4.87 μg/dl; in class B, it was 54.07 ± 7.93 μg/dl, and in class C, the mean serum zinc was 40.46 ± 16.38 μg/dl, P < 0.001, which was statistically highly significant [Table 2]. Child–Pugh class had an inverse correlation with mean serum zinc level.

Table 2: Correlation of mean serum zinc level in relation to Child–Pugh class in cases of liver cirrhosis (n=66)

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There was found a direct correlation between serum zinc level and serum albumin. The lesser the serum albumin, the lesser the serum zinc level. P <0.0001 was highly significant [Table 3].

In subgroup analysis out of 66 cases of cirrhosis liver, 50 cases were in HE while 16 cases were without HE.

Hence, in intergroup analysis, the mean serum zinc in 50 cases out of 66 with HE was 42.24 ± 15.50 μg/dl as compared to 64.68 ± 4.46 μg/dl in cases (16/66) without HE. P <0.0001 was statistically significant.

An inverse correlation was observed between serum zinc and WHC grading. As the grade of WHC increases, serum zinc level decreases [P < 0.0001, [Table 4]].

Table 4: Correlation between mean serum zinc level and West Haven classification grading of hepatic encephalopathy (n=50)

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The present study tried to see further correlation of serum zinc with outcome of cases of decompensated liver cirrhosis in terms of survival.

The mean serum zinc level was 57.67 μg/dl in survivors 40 (60.61%) as compared to 32.30 μg/dl in nonsurvivors 26 (39.30%). Low serum zinc level was associated with high mortality. P <0.0001 was statistically highly significant [Table 5].

  Discussion 

Cirrhosis of the liver reflects irreversible chronic injury of the hepatic parenchyma and includes extensive fibrosis in association with the formation of regenerative nodules. HE is one of the most common serious complications in decompensated liver cirrhosis/liver disease (DCLD). The liver plays an important role in zinc homeostasis, and different zinc compartments have been recognized to explain zinc kinetics in humans; the liver represents a fast exchangeable zinc pool with an important role in the metabolism of zinc and other trace elements.[9]

In this present study, 66 cases of decompensated liver cirrhosis had a mean age of presentation of 45.67 ± 8.73 years. The majority of the cases (50/66) with HE have common precipitating factors such as UGI bleeding, constipation, and infection. UGI bleeding emerged as the most common precipitating factor for HE in the present study. The serum zinc level was significantly low in cases as compared to controls in the present study.

A plethora of articles stating low serum zinc in liver cirrhosis and its complications are available. Various authors – Triwikatmani et al.,[10] Kar et al.,[5] and Pereira MR et al.[11] – have also reported similar results, suggesting that low serum zinc level is associated with liver cirrhosis and HE.

The present study observation showed a strong association between Child–Pugh score and low serum zinc level. The mean serum zinc level revealed a declining pattern as per progression of Child–Pugh class, suggesting that as the Child-Pugh score increases, mean serum zinc level decreases.

These findings of our study are comparable with the results of studies carried out by Soomro et al.,[4] Mangray et al.,[12] and Meena et al. (2019).[13] They also showed a statistically significant association between low serum zinc level and higher Child–Pugh class.

The results of the study conducted by Ghadir et al.[14] in 76 cases of Liver cirrhosis for evaluating the relationship between serum zinc level and complications of cirrhosis revealed that the mean serum level of zinc was 78.4 ± 18.1 μg/dL, which was significantly higher in patients with Child A than patients with Child B and C classes (P = 0.007), but no significant relation was observed between serum zinc level and HE, bleeding from esophageal varices, and spontaneous bacterial peritonitis.

In the intragroup analysis, we found significantly lower serum zinc level in HE cases as compared to the cases without HE.

Moreover, patients with higher grade of HE on WHC score had more low levels of serum zinc.

According to the hypothesis given in literature the serum zinc has key role in physiological detoxification of ammonia via urea cycle in liver and as a co factor in ornithine Transcarbamylase (OTC). So low zinc level associated with decreased OTC activity and increases in the plasma concentration of ammonia. Low plasma zinc impairs nitrogen cycle in muscle and increases glutamine in blood.[15] As a result, in advanced grade of HE there is more significant drop in plasma zinc.

Short-term oral zinc supplement is very useful as an adjunct treatment in decompensated liver disease with HE.[11] However, the present study did not assess this factor.

In liver cirrhosis with complications, other factors such as malnutrition, poor oral intake, and diuretics use are also related to low serum zinc level.

It is said that the absorbed zinc is transported to the liver by portal circulation where active incorporation into metalloenzymes and plasma proteins such as albumin and α2-macroglobulin occurs. Zinc is loosely bound with albumin and tightly bound to α2-macroglobulin. Albumin level is lowered in liver cirrhosis, and zinc is mostly bound to α2-macroglobulin and became unavailable.[16]

When we tried to see the association between serum albumin and serum zinc levels, it was observed that low serum albumin was associated with low serum zinc, suggesting that low serum zinc level may be contributed by significant hypoalbuminemia. This observation of our study was comparable with the study by Meena et al. (2018).[13]

In the present study, mortality was significantly high in liver cirrhosis, with HE cases having higher grade of WHC score. Nonsurvivors had more low serum zinc levels. The mean serum zinc level was 57.67 μg/dl in survivors and 32.30 μg/dl in nonsurvivors. A study conducted by Miwa et al. (2022)[17] in 100 cases of liver cirrhosis revealed poor survival in cases of liver cirrhosis with HE having low serum zinc level. The authors concluded that zinc deficiency was associated with poor survival (P = 0.004).

Thus, the present study documented low serum zinc level in liver cirrhosis and also in HE. However causal relationship between low serum zinc level, cirrhosis, upper GI bleeding and HE could not be established.

  Conclusion 

Low serum zinc is associated with cirrhosis of the liver and high incidence of HE. Low serum zinc in HE is associated with high mortality.

Hence, all patients of cirrhosis liver with hypoalbuminemia and HE should be evaluated for low serum zinc.

Financial support and sponsorship

None.

Conflicts of interest

There are no conflicts of interest.

 

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  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]