European Journal of Cardiovascular Medicine

Cirrhosis is the most common cause of liver-related death worldwide.1 It is the advanced stage of progressive liver fibrosis, in which the hepatic architecture is distorted.2 Cirrhosis is compensated in the early stages. Most patients are asymptomatic at this point and may present occasionally with the stigmata of liver disease. Decompensation in compensated cirrhosis patients is usually defined as the first occurrence of ascites, oesophageal variceal bleeding, and hepatic encephalopathy.3,4 Many of the complications of cirrhosis require specific therapy. Once decompensation occurs, cirrhosis-related mortality and morbidity dramatically increase, with the 1-year case-fatality rate reaching as high as 80% depending on the cause of decompensation.5,6 Frequent medical attention and increasing titration of medications are required as the disease progresses. Recurrent hospitalizations are needed, and this contributes to a poor quality of life. It poses a major burden on the patient, the health care system, and the country. Cirrhosis like many other diseases such a HIV, Cancer and mental illness is associated with perceived stigma.  The most common cause in India includes alcohol and viral hepatitis. Life span is shortened in case of decompensated cirrhosis.7 In 2010, deaths due to liver cirrhosis in India was accounted for nearly one-fifth (18.3%) of  all Liver Cirrhosis deaths worldwide.8

In multiple previous studies which were done to detect good predictors of mortality and morbidity in liver patients, Child - Pugh score and MELD scores were found to be effective.9,10 The Child-Pugh score uses variables such as serum bilirubin, albumin, prothrombin time, hepatic encephalopathy, and ascites.11 It has been widely used in the clinic for about 50 years because of its simplicity. Zinc plays a major role in this, and its deficiency can cause abnormal taste, dermatitis, hair loss, anemia, stomatitis, male sexual dysfunction, susceptibility to infection, and osteoporosis.12,13 Zinc deficiency is caused by a variety of factors, including changes in zinc metabolism and liver diseases.14 Its absence can disrupt the reduction mechanism of reactive oxygen species, causing problems with cell function, propagation, and survival.15 And also zinc deficiency in Chronic liver disease is associated with decreased albumin levels, reduced absorption, increased levels of IL-6 which may interfere with the zinc transporters, and increased excretion in the urine which may be related to the use of diuretics in cirrhosis.16,17 Furthermore, the impact of the Child-Pugh scoring system on the prognosis of liver cirrhosis patients and serum Zn levels is less known. The present study was planned to solidify the correlation between serum zinc level and severity of cirrhosis by studying the prevalence of zinc deficiency in patients with cirrhosis and by assessing its association with hepatic encephalopathy, ascites, and alcohol intake and the other parameters such as albumin, prothrombin time, bilirubin, hemoglobin and creatinine, etc; which will help the better management of hepatic cirrhosis patients in our set up.

The setting of the study was at Department of General Medicine, Mahatma Gandhi Medical College and Research Institute, Pondichery. A one-year observational study was conducted during the period from October 2022 to September 2023. All the cases of clinically diagnosed and as per the the standard case definitions admitted in the ward during the above period up to reach the required sample size were included in the study after duly following the inclusion and exclusion criteria as indicated below. Inclusion criteria: 1. Symptoms and Signs suggestive of Hepatic Cirrhosis and confirmed by Abdominal Ultrasound report 2. Patients who were given consent and have a permanent address in Pondichery. Exclusion criteria: 1. Patients who did not give consent and not staying in Pondichery. Objectives: 1. To know the socio-demographic profiles of the study subjects 2. To study the Serum zinc levels and their correlation & association with the Child-Plugh score and other biochemical, pathological, and epidemiological risk factors. After receiving the Ethical committee clearance from the institution the study began and the required data was collected by using a pretested proforma pertaining to their socio-demographic profiles, Child-Plugh score and associated biochemical, pathological, and epidemiological risk factors and assessing the degree of severity and prognosis in association with risk factors etc; and all the cases (study subjects) of the study were managed and followed until discharge. Chil-Pugh score was used to classify the severity of Hepatic Cirrhosis and also the risk factor profile of each patient was evaluated during the stay in hospital.

Finally, the collected data was analyzed by using appropriate statistical tools like percentages, proportions, measures of central tendency, measures of dispersion, standard error of the mean, correlation coefficient, and tests of significance, etc. with the help of computer software. The study results were compared and discussed in the light of published material of various similar studies belonging to different authors and there by conclusions and recommendations were framed.

Table 1. Age and sex-wise distribution of the study subje

Mean  ± 2 SD = 52.04± 24, 28 - 76,  P < 0.01

• Among the total study subjects 6% were male and 11.36% were female
• It was observed that the burden of the disease was more between the 41-60 years of age group (66%) and the Mean age was 52 years
• Also, it was noticed that the severity was higher among males when compared to females significantly 

Table 2: Association between serum zinc levels and Child-Pugh score

Significantly Patients with high Child-Pugh scores were associated with low serum zinc levels

Table 3: Association of Serum Zinc levels with complications and other factors

• About 16% of the study subjects developed Hepatic encephalopathy and with low serum zinc levels and also Albumin levels were directly proportional to low serum zinc levels significantly and about 75% of the cases developed ascites while having significant association with low serum zinc levels.
• Regarding alcohol consumption nearly 72% of the patients had a positive history

Table 4: Association and Correlation of Serum zinc levels with Haemoparameters and BMI

• It was observed that there was a significant correlation between serum zinc levels and total bilirubin, Prothrombin time, and Sodium levels in the blood.

In the present study out of a total of 44 study subjects 88.6% were male and 11.36% were female which was correlated with the findings of other studies like Van der rijt et al 18 and Meena et al 19 etc. It was understood that in our study the distribution of hepatic cirrhosis was more among males as was observed in the above study also. Globally the prevalence of cirrhosis is more in males than females and males also develop more complications as compared to females. The mean age of the study subjects in the present study was 52 years and a majority of the study subjects were belong to the age group between 41-60 years (60%) which was on par with the figures of a study conducted in Chennai, Tamilnadu by Meena et al 19. By observing the above figures it was understood that the problem was more distributed among middle & older age people of both sexes. It was observed that in our study about 84.1% of the study subjects had low levels of serum zinc (< 50mcg/dl) where whereas the study conducted by Meena et al showed a 100% zinc deficiency in patients of cirrhosis.19 Related to an association between serum zinc levels and Child-Pugh score, it was observed that about 75% of the study subjects with Child-Pugh score Class A cirrhosis had a serum zinc level of more than 60mcg/kg, 72% of patients among Child-Pugh score Class B had serum zinc levels in between 30-49 and Severe zinc deficiency was seen exclusively among the patients of Child class C of 11.11% had zinc levels less than 30mcg/dl. This showed that serum zinc levels were significantly lower in higher Child Pugh‘s class of cirrhosis and the findings were statistically significant and also correlated with the results obtained by Soomro et al.20 in his study. With reference to the relation between serum zinc levels and complications of hepatic cirrhosis and other risk factors causing disease in this study about 16% of patients developed hepatic encephalopathy who had low serum zinc levels and also there was a statistically significant correlation between low serum zinc levels and higher grades of hepatic encephalopathy. The Severe grade 3 hepatic encephalopathy was found in patients with serum zinc levels less than 30 mcg/dl which was similar to the findings reported by Katayama et al 21, Mohsen Maher et al from Egypt  22 and  Zergani et al 23, etc. A study conducted by Shen et al 24 showed that zinc supplementation along with lactulose improved the results of neurocognitive tests in patients with hepatic encephalopathy compared with lactulose only therapy. Usually, the onset of hepatic encephalopathy is associated with a higher degree of hospitalization and death. Ornithine transcarbamylase is an enzyme responsible for the conversion of ammonia to urea in the liver and glutamine synthase converts ammonia to glutamine in the skeletal muscle. Here Zinc acts as a co-factor for both enzymes, hence lower zinc levels would result in the accumulation of ammonia, a key player in the pathogenesis of hepatic encephalopathy.  In this study the albumin levels were directly proportional to low serum zinc levels as 70% of patients in our study with a serum albumin less than 2.5mg/dl had serum zinc levels less than 39mcg/dl which was similar to the results of Kumar et al study 25 and Kar K et al 26. The major zinc carrier in the plasma is albumin, and normally 80% of the plasma zinc is bound to albumin. Hence these results indicate hypoalbuminemia as a cause for hypozincaemia in patients with liver cirrhosis. Regarding ascites 70% of patients in our study with serum albumin less than 2.5mg/dl had serum zinc levels less than 39mcg/dl which was supported by a study conducted by Sengupta et all 27. There was no correlation between low serum zinc levels and alcohol use in our study but a study conducted by Soomro et al showed lower zinc levels in patients with alcohol ß     induced liver cirrhosis 20.  In addition to this regarding the correlation between low serum zinc levels and Laboratory haemoparameters and BMI, a significant correlation was observed with reference to increased total bilirubin, high PT/INR (Prothrombin Time/International Normalized Ratio), and mild decrease of sodium levels etc; in this study.

LIMITATIONS

The study was a hospital-based and conducted in a small group of patients

As the distribution of the disease was observed more among the male and middle & older age group population, it is very important to target our intervention and preventive strategies among these groups to control the incidence and prevalence of Hepatic Cirrhosis. Also findings in the present study suggest that low serum zinc levels has a strong association with the severity of the disease, severe complications like hepatic encephalopathy  & Oesophageal varices, etc; which leads to higher morbidity and mortality of Hepatic Cirrhosis Patients, it is very important to identify the hypozincaemia as early as the diagnosis was made employing simple biochemical lab screening test and treating the patient with zinc supplementation will decrease the morbidity and prolong the survival of patients. Not only this the mere correction of zinc deficiency will indirectly control the abnormal levels of other haemo parameters like elevated total bilirubin, low sodium, decreased hemoglobin levels, etc; their morbidity will again be decreased.

1. Anthony PP, Ishak KG, Nayak NC, Poulsen HE, Scheuer PJ, Sobin LH. The morphology of Recommendations on definition, nomenclature, and classification by a working group sponsored by the World Health Organization. J Clin Pathol 1978; 31: 395–414.
2. Fleming KM, Aithal GP, Card TR, West J. The rate of decompensation and clinical progression of disease in people with cirrhosis: a cohort study. Aliment Pharmacol Ther 2010; 32: 1343–50.
3. Moreau R, Jalan R, Gines P, et al. Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of Gastroenterology 2013; 144: 1426–37.e1–9.
4. D‘Amico G, Garcia-Tsao G, Pagliaro L. Natural history and prognostic indicators of survival in cirrhosis: a systematic review of 118 studies. J Hepatol 2006; 44: 217–31.
5. Fleming KM, Aithal GP, Card TR, West J. All-cause mortality in people with cirrhosis compared with the general population: a population-based cohort Liver Int 2012; 32: 79–84.
6. Arthur MJ. Reversibility of liver fibrosis and cirrhosis following treatment for hepatitis Gastroenterology 2002; 122: 1525–28.
7. Tanaka H, Tsukuma H, Yamano H, Oshima A, Shibata H. Prospective study on the risk of hepatocellular carcinoma among hepatitis C virus-positive blood donors focusing on demographic factors, alanine aminotransferase level at donation and interaction with hepatitis B Int J Cancer 2004 Dec;112(6):1075-1080.
8. Goyal P, Goyal O, Kaur D, Chhina RS. Etiological Profile of Cirrhosis in a Tertiary Care Institute in Northern J Gastrointest Infect 2018;8(1):28-31.
9. Malinchoc, P. S. Kamath, F. D. Gordon, C. J. Peine, J. Rank, and P. C. ter Borg. A model to predict poor survival in patients undergoing transjugular intrahepatic portosystemic shunts. Hepatology 2000;31:864– 871.
10. Grungreiff K, Reinhold D, Wedemeyer The role of zinc in liver cirrhosis. Ann Hepatol 2016;15:7-16.
11. Reverter, P. Tandon, S. Augustin et al. A MELD-based model to determine risk of mortality among patients with acute variceal bleeding. Gastroenterology 2014;146:412–419.
12. Grüngrei K. Zinc in liver disease. J. Trace Elem. Exp. Med. 2002; 15:67–
13. Wastney M.E, Aamodt R.L, Rumble W.F, Henkin R.I. Kinetic analysis of zinc metabolism and its regulation in normal humans. Am. J. Physiol. 1986; 251: R398–R408.
14. Hi mot o T, Masaki Associations between Zinc Deficiency and Metabolic Abnormalities in Patients with Chronic Liver Disease. Nutrients 2018;10:88-93.
15. Takahashi M, Saito H, Higashimoto M, Hibi Possible inhibitory effect of oral zinc supplementation on hepatic fibrosis through downregulation of TIMP-1: a pilot study. Hepatol Res 2007;37:5-9.
16. Kiilerich S, Christiansen C. Distribution of serum zinc between albumin and alpha 2-macroglobulin in patients with different zinc metabolic Clin Chim Acta 1986; 154: 1–6.
17. Poynard T, Bedossa P, Opolon Natural history of liver fibrosis progression in patients with chronic hepatitis C. The OBSVIRC, METAVIR, CLINIVIR, and DOSVIRC groups. Lancet. 1997;349:825– 32.
18. Van der Rijt CC, Schalm SW, Schat H, Foeken K, De Jong G. Overt hepatic encephalopathy precipitated by zinc deficiency. Gastroenterology 1991; 100: 1114-8
19. Meena RK, Saravanan P, Ramadoss Serum Zinc Level in Decompensated Liver Disease and its Correlation with Stage of Hepatic Encephalopathy. The Journal of the Association of Physicians of India. 2019 Jan 1;67(1):30-2.
20. Soomro AA, Devarajani BR, Shaikh K, Shah SZA, Devarajani T, Bibi I ,Serum zinc level in patients with Cirrhosis, Pak J Med Sci 2009; 25:986-991
21. Katayama K, Saito M, Kawaguchi T, Endo R, Sawara K, Nishiguchi S, Kato A, et al. Effect of zinc on liver cirrhosis with hyperammonemia: A preliminary randomized, placebo controlled double-blind trial. Nutrition 2014; 30: 1409-14.
22. Maher M, Yosef TM, Sabry AI, Saleh SA, Alkady H. Hyponatremia and zinc deficiency as a risk factor for hepatic encephalopathy in cirrhotic Life Sci. 2013;10:1493-500.
23. Zergani FJ, Parsi A, Farhang The correlation of serum zinc concentration with liver cirrhosis events. Bali Medical Journal. 2017 Jan 1;6(3):655-8.
24. Shen YC, Chang YH, Fang CJ, Lin YS. Zinc supplementation in patients with cirrhosis and hepatic encephalopathy: a systematic review and meta- Nutrition journal. 2019 Dec;18(1):1-9.
25. Kumar P, Reding P, Duchateau J, Bataille C. Oral zinc supplementation improves hepatic encephalopathy. Results of a randomized controlled trial. Lancet 1984; 2: 493-95
26. Kar K, Bhattyacharya G, De J. Study of zinc in cirrhosis of liver. Ind Med Gaz 2013;75:74-8.
27. Sengupta S, Wroblewski K, Aronsohn A, Reau N, Reddy KG, Jensen D, Te H. Screening for zinc deficiency in patients with cirrhosis: when should we start?. Digestive diseases and 2015