{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T01:13:04Z","timestamp":1760058784896,"version":"build-2065373602"},"reference-count":37,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2025,4,28]],"date-time":"2025-04-28T00:00:00Z","timestamp":1745798400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Japan Agency for Medical Research and Development Sciences Research","award":["23HC2001"],"award-info":[{"award-number":["23HC2001"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Covert hepatic encephalopathy (CHE) can worsen the quality of life and prognosis of patients with cirrhosis. We analyzed the risk factors of CHE and identified patients at high risk for overt hepatic encephalopathy (HE) who would benefit from therapeutic interventions. We included 145 patients without a history of or treatment for overt HE. Patients were divided into the CHE and no-CHE groups (n = 91 and 54, respectively). CHE had a score above the age-based cutoff value of one of the neuropsychological tests, such as the Stroop and number connection tests. CHE prevalence was 62.8% (n = 91). Compared with the no-CHE group, the CHE group had significantly lower serum zinc and albumin levels. Multiple logistic regression analysis identified serum zinc levels at a cutoff value of 74 \u00b5g\/dL. Subclinical zinc deficiency showed a diagnostic performance of 55.6% sensitivity and 81.5% specificity for CHE. Blood ammonia levels and liver functional reserves were not predictive of CHE. Compared with patients with zinc levels &lt; 74 \u00b5g\/dL (n = 102), those with \u226574 \u00b5g\/dL (n = 43) had significantly lower CHE prevalence and better hepatic functional reserve. Subclinical zinc deficiency was associated with CHE occurrence in patients with cirrhosis without a history of or treatment for overt HE. Measurement of zinc levels facilitates early detection of CHE by neuropsychological testing.<\/jats:p>","DOI":"10.3390\/ijms26094184","type":"journal-article","created":{"date-parts":[[2025,4,29]],"date-time":"2025-04-29T05:17:12Z","timestamp":1745903832000},"page":"4184","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Clinical Significance of Marginal Zinc Deficiency as a Predictor of Covert Hepatic Encephalopathy in Patients with Liver Cirrhosis"],"prefix":"10.3390","volume":"26","author":[{"given":"Takuya","family":"Matsuda","sequence":"first","affiliation":[{"name":"Department of Gastroenterology, Nara Medical University, 840 Shijo-cho, Kashihara 634-8522, Nara, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3158-5318","authenticated-orcid":false,"given":"Tadashi","family":"Namisaki","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Nara Medical University, 840 Shijo-cho, Kashihara 634-8522, Nara, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Akihiko","family":"Shibamoto","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Nara Medical University, 840 Shijo-cho, Kashihara 634-8522, Nara, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shohei","family":"Asada","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Nara Medical University, 840 Shijo-cho, Kashihara 634-8522, Nara, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fumimasa","family":"Tomooka","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Nara Medical University, 840 Shijo-cho, Kashihara 634-8522, Nara, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takahiro","family":"Kubo","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Nara Medical University, 840 Shijo-cho, Kashihara 634-8522, Nara, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aritoshi","family":"Koizumi","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Nara Medical University, 840 Shijo-cho, Kashihara 634-8522, Nara, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Misako","family":"Tanaka","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Nara Medical University, 840 Shijo-cho, Kashihara 634-8522, Nara, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3575-5609","authenticated-orcid":false,"given":"Satoshi","family":"Iwai","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Nara Medical University, 840 Shijo-cho, Kashihara 634-8522, Nara, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takashi","family":"Inoue","sequence":"additional","affiliation":[{"name":"Department of Evidence-Based Medicine, Nara Medical University, 840 Shijo-cho, Kashihara 634-8522, Nara, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuki","family":"Tsuji","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Nara Medical University, 840 Shijo-cho, Kashihara 634-8522, Nara, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2402-574X","authenticated-orcid":false,"given":"Yukihisa","family":"Fujinaga","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Nara Medical University, 840 Shijo-cho, Kashihara 634-8522, Nara, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6295-3283","authenticated-orcid":false,"given":"Norihisa","family":"Nishimura","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Nara Medical University, 840 Shijo-cho, Kashihara 634-8522, Nara, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3049-3443","authenticated-orcid":false,"given":"Shinya","family":"Sato","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Nara Medical University, 840 Shijo-cho, Kashihara 634-8522, Nara, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5794-1512","authenticated-orcid":false,"given":"Koh","family":"Kitagawa","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Nara Medical University, 840 Shijo-cho, Kashihara 634-8522, Nara, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kosuke","family":"Kaji","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Nara Medical University, 840 Shijo-cho, Kashihara 634-8522, Nara, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6666-5633","authenticated-orcid":false,"given":"Akira","family":"Mitoro","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Nara Medical University, 840 Shijo-cho, Kashihara 634-8522, Nara, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4515-6047","authenticated-orcid":false,"given":"Kiyoshi","family":"Asada","sequence":"additional","affiliation":[{"name":"Clinical Research Center, Nara Medical University, Nara Medical University, 840 Shijo-cho, Kashihara 634-8522, Nara, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hiroaki","family":"Takaya","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Nara Medical University, 840 Shijo-cho, Kashihara 634-8522, Nara, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4559-7600","authenticated-orcid":false,"given":"Ryuichi","family":"Noguchi","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Nara Medical University, 840 Shijo-cho, Kashihara 634-8522, Nara, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6675-0475","authenticated-orcid":false,"given":"Takemi","family":"Akahane","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Nara Medical University, 840 Shijo-cho, Kashihara 634-8522, Nara, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hitoshi","family":"Yoshiji","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Nara Medical University, 840 Shijo-cho, Kashihara 634-8522, Nara, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,4,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1757","DOI":"10.1038\/ajg.2014.264","article-title":"Covert hepatic encephalopathy is independently associated with poor survival and increased risk of hospitalization","volume":"109","author":"Patidar","year":"2014","journal-title":"Am. J. Gastroenterol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1007\/s40265-018-1018-z","article-title":"Hepatic encephalopathy: Definition, clinical grading and diagnostic principles","volume":"79","author":"Weissenborn","year":"2019","journal-title":"Drugs"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1828","DOI":"10.1016\/j.cgh.2014.05.011","article-title":"Validation of encephalapp, smartphone-based stroop test, for the diagnosis of covert hepatic encephalopathy","volume":"13","author":"Bajaj","year":"2015","journal-title":"Clin. Gastroenterol. Hepatol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1016\/j.cgh.2021.12.047","article-title":"Quickstroop, a shortened version of encephalapp, detects covert hepatic encephalopathy with similar accuracy within one minute","volume":"21","author":"Acharya","year":"2023","journal-title":"Clin. Gastroenterol. Hepatol."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Matuszczak, M., Kiljanczyk, A., Marciniak, W., Derkacz, R., Stempa, K., Baszuk, P., Bry\u015bkiewicz, M., Sun, P., Cheriyan, A., and Cybulski, C. (2024). Zinc and its antioxidant properties: The potential use of blood zinc levels as a marker of cancer risk in BRCA1 mutation carriers. Antioxidants, 13.","DOI":"10.3390\/antiox13050609"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Matuszczak, M., Kiljanczyk, A., Marciniak, W., Derkacz, R., Stempa, K., Baszuk, P., Bry\u015bkiewicz, M., Cybulski, C., D\u0119bniak, T., and Gronwald, J. (2024). Antioxidant properties of zinc and copper-blood zinc-to copper-ratio as a marker of cancer risk BRCA1 mutation carriers. Antioxidants, 13.","DOI":"10.3390\/antiox13070841"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1016\/j.taap.2018.12.018","article-title":"The Interaction of zinc and the blood-brain barrier under physiological and ischemic conditions","volume":"364","author":"Qi","year":"2019","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"662","DOI":"10.1111\/hepr.13601","article-title":"Zinc Deficiency predicts overt hepatic encephalopathy and mortality in liver cirrhosis patients with minimal hepatic encephalopathy","volume":"51","author":"Miwa","year":"2021","journal-title":"Hepatol. Res."},{"key":"ref_9","first-page":"e0524","article-title":"Zinc supplementation to improve prognosis in patients with compensated advanced chronic liver disease: A Multicenter, randomized, double-blind, placebo-controlled clinical trial","volume":"8","author":"Aceituno","year":"2024","journal-title":"Hepatol. Commun."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Semeya, A.A., Elgamal, R., and Othman, A.A.A. (2025). Correlation of serum zinc levels with hepatic encephalopathy severity in patients with decompensated liver cirrhosis: A prospective observational study from Egypt. Biol. Trace Elem. Res., 1\u201313.","DOI":"10.1007\/s12011-025-04544-x"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1809","DOI":"10.1111\/jgh.14635","article-title":"Prognostic significance of minimal hepatic encephalopathy in patients with liver cirrhosis in Japan: A propensity score-matching analysis","volume":"34","author":"Hanai","year":"2019","journal-title":"J. Gastroenterol. Hepatol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1518","DOI":"10.1002\/hep4.1738","article-title":"Usefulness of the stroop test in diagnosing minimal hepatic encephalopathy and predicting overt hepatic encephalopathy","volume":"5","author":"Hanai","year":"2021","journal-title":"Hepatol. Commun."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1007\/s00535-024-02160-5","article-title":"Serum Zinc Levels as Predictors of Covert Hepatic Encephalopathy in Patients with Liver Cirrhosis","volume":"60","author":"Soma","year":"2025","journal-title":"J. Gastroenterol."},{"key":"ref_14","first-page":"690","article-title":"Prevalence and characteristics of covert\/minimal hepatic encephalopathy in patients with liver cirrhosis: A systematic review and meta-analysis","volume":"119","author":"Lv","year":"2024","journal-title":"Am. J. Gastroenterol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2191","DOI":"10.14309\/ajg.0000000000002251","article-title":"Prevalence of minimal hepatic encephalopathy in patients with liver cirrhosis: A multicenter study","volume":"118","author":"Gairing","year":"2023","journal-title":"Am. J. Gastroenterol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1002\/jgh3.12468","article-title":"Association between serum albumin and cognitive dysfunction in hepatic encephalopathy: An exploratory data analysis","volume":"5","author":"Kaji","year":"2021","journal-title":"JGH Open"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"674","DOI":"10.1111\/hepr.13629","article-title":"Proposal of stroop test cut-off values as screening for neuropsychological impairments in cirrhosis: A Japanese multicenter study","volume":"51","author":"Kondo","year":"2021","journal-title":"Hepatol. Res."},{"key":"ref_18","first-page":"809","article-title":"Multifunctional role of zinc in human health: An update","volume":"22","author":"Kiouri","year":"2023","journal-title":"EXCLI J."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"849","DOI":"10.1017\/S0007114519000187","article-title":"Adaption of body zinc pools in weaned piglets challenged with subclinical zinc deficiency","volume":"121","author":"Brugger","year":"2019","journal-title":"Br. J. Nutr."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"437","DOI":"10.14740\/jocmr3374w","article-title":"The prevalence and implication of zinc deficiency in patients with chronic liver disease","volume":"10","author":"Katayama","year":"2018","journal-title":"J. Clin. Med. Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.nutres.2019.11.009","article-title":"Zinc and protein metabolism in chronic liver diseases","volume":"74","author":"Katayama","year":"2020","journal-title":"Nutr. Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"184","DOI":"10.21873\/cdp.10093","article-title":"Clinical significance of serum zinc levels on the development of sarcopenia in cirrhotic patients","volume":"2","author":"Murata","year":"2022","journal-title":"Cancer Diagn. Progn."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Kodama, H., Tanaka, M., Naito, Y., Katayama, K., and Moriyama, M. (2020). Japan\u2019s practical guidelines for zinc deficiency with a particular focus on taste disorders, inflammatory bowel disease, and liver cirrhosis. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21082941"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"78","DOI":"10.5217\/ir.2020.00124","article-title":"Effectiveness of administering zinc acetate hydrate to patients with inflammatory bowel disease and zinc deficiency: A retrospective observational two-center study","volume":"20","author":"Sakurai","year":"2021","journal-title":"Intest. Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1002\/jgf2.377","article-title":"Serum zinc concentrations and characteristics of zinc deficiency\/marginal deficiency among Japanese subjects","volume":"21","author":"Yokokawa","year":"2020","journal-title":"J. Gen. Fam. Med."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Fukushima, M., Miyaaki, H., Sasaki, R., Nakao, Y., Haraguchi, M., Takahashi, K., Ozawa, E., Miuma, S., and Nakao, K. (2024). Benefits of liver volume and serum zinc level assessment for the screening of covert hepatic encephalopathy in patients with child\u2013pugh class A cirrhosis. Diagnostics, 15.","DOI":"10.3390\/diagnostics15010023"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1186\/s12937-019-0461-3","article-title":"Zinc supplementation in patients with cirrhosis and hepatic encephalopathy: A systematic review and meta-analysis","volume":"18","author":"Shen","year":"2019","journal-title":"Nutr. J."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1038\/s41392-024-02071-0","article-title":"Homeostasis and metabolism of iron and other metal ions in neurodegenerative diseases","volume":"10","author":"Chen","year":"2025","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Muro, P., Zhang, L., Li, S., Zhao, Z., Jin, T., Mao, F., and Mao, Z. (2024). The emerging role of oxidative stress in inflammatory bowel disease. Front. Endocrinol., 15.","DOI":"10.3389\/fendo.2024.1390351"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Simicic, D., Cudalbu, C., and Pierzchala, K. (2022). Overview of oxidative stress findings in hepatic encephalopathy: From cellular and ammonium-based animal models to human data. Anal. Biochem., 654.","DOI":"10.1016\/j.ab.2022.114795"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1111\/hepr.14022","article-title":"Possible pathogenetic role of ammonia in liver cirrhosis without hyperammonemia of venous blood: The so-called latency period of abnormal ammonia metabolism","volume":"54","author":"Katayama","year":"2024","journal-title":"Hepatol. Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1584","DOI":"10.1038\/nm.3407","article-title":"Development, maintenance and disruption of the blood-brain barrier","volume":"19","author":"Obermeier","year":"2013","journal-title":"Nat. Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1002\/hep.29146","article-title":"The animal naming test: An easy tool for the assessment of hepatic encephalopathy","volume":"66","author":"Campagna","year":"2017","journal-title":"Hepatology"},{"key":"ref_34","first-page":"91","article-title":"Contemporary understanding and management of overt and covert hepatic encephalopathy","volume":"12","author":"NeSmith","year":"2016","journal-title":"Gastroenterol. Hepatol."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Crawford, A.C., Lehtovirta-Morley, L.E., Alamir, O., Niemiec, M.J., Alawfi, B., Alsarraf, M., Skrahina, V., Costa, A.C.B.P., Anderson, A., and Yellagunda, S. (2018). Biphasic zinc compartmentalisation in a human fungal pathogen. PLoS Pathog., 14.","DOI":"10.1371\/journal.ppat.1007013"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1335","DOI":"10.1111\/hepr.12864","article-title":"Updating the neuropsychological test system in Japan for the elderly and in a modern touch screen tablet society by resetting the cut-off values","volume":"47","author":"Kawaguchi","year":"2017","journal-title":"Hepatol. Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"452","DOI":"10.1038\/bmt.2012.244","article-title":"Investigation of the freely available easy-to-use software \u2018EZR\u2019 for medical statistics","volume":"48","author":"Kanda","year":"2013","journal-title":"Bone Marrow Transplant."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/9\/4184\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:23:19Z","timestamp":1760030599000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/9\/4184"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,4,28]]},"references-count":37,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2025,5]]}},"alternative-id":["ijms26094184"],"URL":"https:\/\/doi.org\/10.3390\/ijms26094184","relation":{},"ISSN":["1422-0067"],"issn-type":[{"type":"electronic","value":"1422-0067"}],"subject":[],"published":{"date-parts":[[2025,4,28]]}}}