key: cord-0861289-4bhcfdht authors: Mei, Xue; Li, Hai; Deng, Guohong; Wang, Xianbo; Zheng, Xin; Huang, Yan; Chen, Jinjun; Meng, Zhongji; Gao, Yanhang; Liu, Feng; Lu, Xiaobo; Shi, Yu; Zheng, Yubao; Yan, Huadong; Zhang, Weituo; Qiao, Liang; Gu, Wenyi; Zhang, Yan; Xiang, Xiaomei; Zhou, Yi; Sun, Shuning; Hou, Yixin; Zhang, Qun; Xiong, Yan; Zou, Congcong; Chen, Jun; Huang, Zebing; Li, Beiling; Jiang, Xiuhua; Zhong, Guotao; Wang, Haiyu; Chen, Yuanyuan; Luo, Sen; Gao, Na; Liu, Chunyan; Li, Jing; Li, Tao; Zheng, Rongjiong; Zhou, Xinyi; Ren, Haotang; Yuan, Wei; Qian, Zhiping title: Prevalence and clinical significance of serum sodium variability in patients with acute-on-chronic liver diseases: a prospective multicenter study in China date: 2022-01-17 journal: Hepatol Int DOI: 10.1007/s12072-021-10282-8 sha: 2c53f71873e67b04ff3fcb76c52734876666a7af doc_id: 861289 cord_uid: 4bhcfdht BACKGROUND: No reports exist regarding the prevalence of different Na levels and their relationship with 90-day prognosis in hospitalized patients with acute-on-chronic liver disease (AoCLD) in China. Therefore, the benefit of hyponatremia correction in AoCLD patients remains unclear. METHODS: We prospectively collected the data of 3970 patients with AoCLD from the CATCH-LIFE cohort in China. The prevalence of different Na levels (≤ 120; 120–135; 135–145; > 145) and their relationship with 90-day prognosis were analyzed. For hyponatremic patients, we measured Na levels on days 4 and 7 and compared their characteristics, based on whether hyponatremia was corrected. RESULTS: A total of 3880 patients were involved; 712 of those developed adverse outcomes within 90 days. There were 80 (2.06%) hypernatremic, 28 (0.72%) severe hyponatremic, and 813 (20.95%) mild hyponatremic patients at admission. After adjusting for all confounding factors, the risk of 90-day adverse outcomes decreased by 5% (odds ratio [OR] 0.95; 95% confidence interval [CI] 0.93–0.97; p < 0.001), 24% (OR 0.76; 95% CI 0.70–0.84; p < 0.001), and 42% (OR 0.58; 95% CI 0.49–0.70; p < 0.001) as Na level increased by 1, 5, and 10 mmol/L, respectively. Noncorrection of hyponatremia on days 4 and 7 was associated with 2.05-fold (hazard ratio [HR], 2.05; 95% CI, 1.50–2.79; p < 0.001) and 1.46-fold (HR 1.46; 95% CI 1.05–2.02; p = 0.028) higher risk of adverse outcomes. CONCLUSIONS: Hyponatremia was an independent risk factor for a poor 90-day prognosis in patients with AoCLD. Failure to correct hyponatremia in a week after admission was often associated with increased mortality. (ClinicalTrials.gov number: NCT02457637, NCT03641872). CLINICAL TRIAL NUMBERS: This study is registered at Shanghai www.clinicaltrials.org (NCT02457637 and NCT03641872). SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s12072-021-10282-8. With the development of the global economy and the popularization of antiviral drugs, chronic hepatitis B and C have been gradually controlled; however, the incidence of fatty liver disease and drug-induced liver injury is increasing annually [1] . Chronic liver disease (CLD) remains a frequent cause of death. In 2017, 1.32 million people died directly because of liver cirrhosis, which accounts for 2-4% of deaths annually [2, 3] . During the coronavirus disease 2019 (COVID- 19) pandemic, mortality was also significantly higher in patients with CLD than in those without CLD [4] . To improve the prognosis of cirrhotic patients, the model for end-stage liver disease (MELD) score has been used since 2002 to rank and prioritize liver transplantation (LT) candidates [5, 6] . Since then, some researchers have found that hyponatremia was an independent prognostic factor in cirrhotic patients [7] [8] [9] . Therefore, more optimized prediction tools, such as the Model for end-stage liver disease-sodium (MELD-Na) and United Kingdom Model for end-stage liver disease (UKELD) scores, have been developed [9] [10] [11] . Most previous studies confirm that serum sodium (Na) is closely associated with the severity and complications of liver cirrhosis and affects a patient's health-related quality of life (HRQOL) and perioperative mortality after transplantation [12, 13] . Hyponatremic patients have longer hospital stays and higher hospitalization rates [14] . The subsequent mortality of patients with hyponatremia is also significantly increased, regardless of accompanying diseases [15] . An abnormal Na level seems to be a common electrolyte disorder in clinical practice, but it often indicates a risk of other complications. However, there was insufficient information regarding the prevalence of different Na levels and their relationship with 90-day prognosis in hospitalized patients with acute-on-chronic liver disease (AoCLD) in areas with a high prevalence of hepatitis B virus (HBV) in China [16] . The benefit of hyponatremia correction at 4-7 days after admission in patients with AoCLD remains unclear. Therefore, this study aimed to describe the prevalence and clinical significance of Na variability in this population. In total, 3970 patients with AoCLD were included in this study from the CATCH-LIFE cohort [16] [17] [18] , which was a multicenter prospective cohort study conducted by the Chinese Chronic Liver Failure (CLIF) Federation (comprising 15 tertiary hospitals in a high HBV epidemic area) conducted from 2015 to 2016 and from 2018 to 2019. The ethics committee of Ren Ji Hospital, School of Medicine, Shanghai Jiaotong University (Shanghai, China) approved the study and registered it at Shanghai www. clini caltr ials. org (NCT02457637, NCT03641872). The study was performed in accordance with the standards of the Declaration of Helsinki. Written informed consent was obtained from all patients. All authors have access to the study data and reviewed and approved the final manuscript. AoCLD is a nonmalignant CLD with acute decompensation (AD) or acute liver injury (ALI). CLD is considered cirrhotic or noncirrhotic liver disease with a history of liver dysfunction lasting > 6 months. Cirrhosis was diagnosed based on findings of computed tomography/magnetic resonance imaging (CT/MRI) scans and laboratory tests, clinical symptoms, and history of liver disease. A diagnosis of AD requires individuals to have at least one acute decompensation event, which includes gastrointestinal hemorrhage, hepatic encephalopathy, overt ascites, bacterial infection (e.g., spontaneous peritonitis and pneumonia), or jaundice [i.e., total bilirubin (TBIL) > 5 mg/dL] within 1 month before enrollment. ALI was defined as alanine aminotransferase or aspartate aminotransferase levels three times more than the upper limit of the normal range (ULN) (but < 40 IU/L) or a total bilirubin level two times more than the ULN (but < 1 mg/dL) within a week. The definition of 90-day adverse outcomes or poor prognosis was death or LT. Based on the definition of hyponatremia [19] [20] [21] , all patients were classified into four groups as follows: severe hyponatremia (Na level, ≤ 120 mmol/L), mild hyponatremia (Na level, > 120 and < 135 mmol/L), normal serum sodium (Na level, ≥ 135 and ≤ 145 mmol/L), and hypernatremia (Na level > 145 mmol/L) groups. The exclusion criteria were as follows: (1) age < 15 years or > 80 years, (2) pregnancy, (3) severe chronic extrahepatic disease, and (4) hepatocellular carcinoma or other liver malignancies before or during admission, and extrahepatic malignancies. Data pertaining to demographics, medical history, biochemical indicators, and imaging data were prospectively recorded at each center. After admission, all patients were followed up for 90 days, and the outcomes were recorded (endpoint events included LT or death). Data were summarized using the appropriate descriptive statistics (i.e., median and interquartile range for continuous variables and frequency and percentage for categorical parameters). The Mann-Whitney U test was used for nonparametric pairwise comparisons, and the Chi-square test or Fisher's exact test was used for categorical variables. For more than three variables, non-normal continuous variables were analyzed using the Kruskal-Wallis test. We estimated the potential confounding factors that impact the prognosis of AoCLD patients by univariate and subgroup analyses, which showed a statistically significant interaction (p < 0.05). When Na level was used as a continuous variable and a categorical variable, multiple covariates (i.e., potential confounding factors) were gradually introduced to analyze the influence of unadjusted and multivariate-adjusted Na level on 90-day adverse outcomes using the backward stepwise (likelihood ratio) method of binary logistic regression. Furthermore, a generalized additive model and smooth curve fitting were used to describe the relationship between Na level and 90-day adverse outcomes. Survival curves were estimated using the Kaplan-Meier method and compared using the log-rank test. The main objective of this study was to assess the effect of Na level on the risk of 90-day adverse outcomes. All statistical tests were two-tailed, and bilateral α of < 0.05 was statistically significant. SPSS 25 (IBM, Seattle, WA, USA) and R version 4.0.4 software (http:// www.rproje ct. org) were used for statistical analysis and plots. Finally, 3880 patients were analyzed in this study according to the inclusion and exclusion criteria (Fig. 1) . We determined not more than 5% missing data for each variable used on admission ( Supplementary Fig. 1 ). The prevalence of different Na levels (i.e., hyponatremia, normonatremia, hypernatremia) in patients with AoCLD and their characteristics are summarized in Table 1 . The incidence of alcoholic liver disease and chronic hepatitis B were significantly different between the Na level groups (p < 0.05). The lower the Na level, the higher the proportion of liver cirrhosis and the worse the liver function score, including MELD, sequential organ failure assessment (SOFA), Child-Pugh, and other related scores (p < 0.05). At admission, patients in the hyponatremic groups had a higher frequency of AD events (e.g., ascites, hepatic encephalopathy, infection, and jaundice, but not gastrointestinal bleeding; p < 0.05). Moreover, TBIL, international normalized ratio (INR), serum creatinine (CR) level, blood urea nitrogen, and white blood cell (WBC) counts were also higher in the hyponatremic groups (p < 0.05) ( Table 1 ; Supplementary Fig. 2 ). Among the 3880 patients, 712 (18.35%) had 90-day adverse outcomes (498 deaths and 214 LT). The severe hyponatremia group had the highest incidence of adverse outcomes (50.0%, p < 0.05) and LT-free mortality (48.2%, p < 0.05) ( Table 1 ; Supplementary Fig. 3a ). Interactions between Na level and 90-day adverse outcomes were observed in subgroups with different TBIL levels, INR, CR levels, age, and incidence of cirrhosis, ascites, infection, and hepatic encephalopathy (p < 0.05), but not for sex and etiology ( Supplementary Fig. 3b ). Among patients with hepatitis B, regardless of receiving nucleotide/nucleoside analogs (NUCs) before admission, Na level remained an independent risk factor for 90-day adverse outcomes. We constructed four models (i.e., 1 unadjusted and 3 adjusted) to evaluate the relationship between Na level and 90-day adverse outcomes. Univariate and multivariate analyses showed that Na levels were inversely associated with the incidence of 90-day adverse outcomes (for trend, p < 0.001) ( Table 2 ). After adjusting for all confounding factors that may affect the outcomes, the severe hyponatremia group had the highest risk of 90-day adverse outcomes (odds ratio [OR] 2.36; 95% confidence interval [CI] 0.98-5.67; p = 0.056). Therefore, hyponatremia was an independent risk factor for 90-day adverse outcomes in patients with AoCLD. When Na level was analyzed as a continuous variable, the risk of 90-day adverse outcomes decreased by 5% (OR 0.95; 95% CI 0.93-0.97; p < 0.001), 24% (OR, 0.76; 95% CI 0.70-0.84; p < 0.001), and 42% (OR 0.58; 95% CI 0.49-0.70; p < 0.001) for Na level increasing by 1, 5, and 10 mmol/L, respectively, after adjusting for all confounding factors. Similar results were obtained for the cirrhosis subgroup (Table 3 ). In the noncirrhotic population, hyponatremia increased the risk of 90-day adverse outcomes; however, no significant difference existed after adjusting for all confounding factors (Table 4 ). Finally, we found that the results were consistent with the original data, based on sensitivity analysis of multiple imputation missing values (Supplementary Tables 1-3) . The generalized additive model showed that, when the Na level was < 135 mmol/L, the relationship between the Na level and the incidence of 90-day adverse outcomes was approximately linear and negatively correlated, regardless of the correction of the confounding factors (Fig. 2a,b) . However, when the Na level was > 135 mmol/L, the risk of 90-day adverse outcomes did not significantly increase. Therefore, a Na level of 135 mmol/L could be used as the cut-off value. The risk of 90-day adverse outcomes in patients with hyponatremia (Na level < 135 mmol/L) was significantly higher than that in patients without hyponatremia (Na level ≥ 135 mmol/L) (hazard ratio [HR], 3.01; (Fig. 2d, e) . On day 4, the MELD, SOFA, and Child-Pugh scores, baseline WBC, and baseline TBIL, INR, and CR levels in the uncorrected group were significantly higher than those in the corrected group. The corrected group had a lower incidence of cirrhosis, ascites, and infection than the uncorrected group (p < 0.05) (Supplementary Table 4 ). Dynamic observation revealed that the Na levels on days 4 and 7 were significantly lower in patients with 90-day adverse outcomes after admission than in patients in the survival group (p < 0.05). However, in the 90-day adverse outcomes group, changes in Na level were not significantly different between days 4 and 7 (p = 0.851) (Fig. 2f ). Our study population represents most inpatients with liver disease in areas with a high prevalence of HBV in China. Therefore, despite the fact that hyponatremia is a well-recognized complication of cirrhotic patients, a specific analysis of hyponatremia in patients with AoCLD had so far not been reported. The investigation of this relationship is clinically relevant, given the important physiological effects of low serum Na levels and the well-demonstrated relationship between hyponatremia and survival in a Chinese population with CLD. To the best of our knowledge, this study is the first to describe the prevalence of hyponatremia, normonatremia, and hypernatremia and their relationship with 90-day prognosis in hospitalized patients with AoCLD. We confirmed that hyponatremia is an independent risk factor for 90-day adverse outcomes in this population, which is independent of other indicators reflecting liver dysfunction, regardless of the etiology of chronic liver disease and whether patients with hepatitis B have received NUCs before admission. The risk of 90-day adverse outcomes decreased by 5%, 24%, and 42% for Na levels increased by 1, 5, and 10 mmol/L, respectively. These patients whose hyponatremia could be corrected on days 4 or 7 had a better prognosis than those whose hyponatremia could not be corrected. In the past few decades, major studies [7, [9] [10] [11] [12] have confirmed that hyponatremia is an independent risk factor for poor prognosis in cirrhotic patients. The European CANONIC cohort study in 2014 indicated that hyponatremia was also an independent risk factor for 90-day poor prognosis in patients with acute-on-chronic liver failure [22] . As expected, our study showed similar results in hospitalized patients with AoCLD. The LT-free mortality of patients with severe hyponatremia in our study (48%) was higher than that reported in a previous study [23] . In advanced cirrhosis, renal free water clearance function is impaired, serum Na balance is not maintained, and diluted hyponatremia occurs and is reasonably considered present; however, due to its unique human physiopathological mechanisms of systemic vasodilatation, clinicians often ignore it in daily practice [12] . Previous research showed that hyponatremia is usually accompanied by various complications in cirrhotic patients, which somewhat reflect the severity of portal hypertension [19, 24] . In our study, the incidence of liver cirrhosis, ascites, infection, hepatic encephalopathy, and jaundice in hyponatremic patients was also significantly higher, especially in patients with severe hyponatremia. Patients with severe hyponatremia tended to have a poorer liver function and higher 90-day mortality. Thus, LT should be actively considered for this population. Moreover, it is worth mentioning that 18.2% of noncirrhotic patients in our cohort still had hyponatremia and a risk of 90-day adverse outcomes. This number was only slightly lower than that in cirrhotic patients. Interestingly, after adjusting for acute decompensated events in noncirrhotic patients, the risk of 90-day adverse outcomes was statistically significant. However, the risk disappeared after the MELD score was adjusted, which suggested that Na level was not a predictor of 90-day prognosis in noncirrhotic patients. This finding was different from that in cirrhotic patients as the mechanisms of hyponatremia differ. The European Association for the Study of the Liver guidelines (Clinical Practice Guidelines for the Management of Patients with Decompensated Cirrhosis) recommends that cirrhotic patients limit fluid intake and increase the dose of diuretics or use vaptans to increase the excretion of renal solute free water and other measures to improve hyponatremia when Na level is < 130 mmol/L [25] . In fact, high-level hyponatremia (Na level, 130-135 mmol/L) is deemed unsuitable for treatment because it is always considered a frequent and harmless feature of severe liver disease [26] . In our study, there were 86 patients with Na level of 125 mmol/L and 755 patients with Na level between > 125 mmol/L and < 135 mmol/L. However, when Na level was < 135 mmol/L, the risk of 90-day adverse outcomes increased, which was stricter than the 130 mmol/L recommended by the guidelines [25] . This finding suggests the necessity of hyponatremia correction in patients with AoCLD. Na level of < 135 mmol/L should be considered for management by clinicians. Ahluwalia et al. [27] found that cirrhotic patients can benefit from hyponatremia correction, which improves cognitive function and HRQOL. Dedicated specialist input and active treatment of severe hyponatremia can effectively reduce mortality [28] . Based on experience from the European CANONIC cohort study, most of the patients will have a clear prognosis between days 3 and 7 Fig. 2 a The association between Na level and 90-day adverse outcomes in patients with AoCLD (unadjusted). b The association between Na level and 90-day adverse outcomes in patients with AoCLD (adjusted). c Survival analysis, based on the Na cut-off value, using the Kaplan-Meier method. d Kaplan-Meier curves of patients with corrected or uncorrected hyponatremia on day 4 after admission. e Kaplan-Meier curves of patients with corrected or uncorrected hyponatremia on day 7 after admission. f Dynamic changes in Na level between the survival group and adverse outcome group 7 days after admission ◂ of hospital admission, and clinical decisions, such as evaluation for liver transplant or discussion over goals of care, could be tailored using clinical scores [29] . However, there is limited information regarding whether hyponatremia correction in 1 week could improve the 90-day prognosis. Our study suggests that hyponatremia correction was associated with improvement in clinically relevant outcomes, regardless of day 4 or 7. The Na level increased continuously from day 4 to 7 in hyponatremic patients who survived; therefore, focusing on dynamic changes in Na level and managing hyponatremia in AoCLD in the first week after admission are crucial. Persistent abnormal Na level is often associated with an increased risk of death. This finding is supported by the fact that hyponatremia could not be corrected on day 4, and hyponatremic patients had a higher mortality rate, MELD score, and incidence of cirrhosis, infection, and ascites than those without hyponatremia. Therefore, managing complications associated with hyponatremia is essential. However, this needs to be further studied in patients with AoCLD and those with hyponatremia. This was a large multicenter, prospective cohort study focused on areas with a high prevalence of HBV in China. All patients were followed up for 90 days, and most data were collected to ensure authenticity and integrity. In addition to the baseline material, we similarly analyzed the dynamic Na levels on days 4 and 7 after admission. This study has some limitations. First, there were some missing values for the dynamic Na level. Second, owing to the nature of observational studies and various patient conditions, therapy measures of hyponatremia were not unified among the centers; however, we employed a unified standard of diagnosis and treatment for hyponatremia [30] . In conclusion, our study showed that hyponatremia is an independent risk factor for 90-day adverse outcomes in hospitalized patients with AoCLD. Elevated Na levels reduced the risk of 90-day adverse outcomes, and failure to correct hyponatremia in a week after admission was often associated with increased mortality. Therefore, clinicians should focus on hyponatremia in patients with AoCLD and actively manage its related complications in daily clinical practice for hyponatremia correction. 50-3.62; p < 0.001) (Fig. 2c), regardless of cirrhosis Causes and trends in liver disease and hepatocellular carcinoma among men and women who received liver transplants in the US Chronic liver disease: global perspectives and future challenges to delivering quality health care Collaborators (2020) The global, regional, and national burden of cirrhosis by cause in 195 countries and territories, 1990-2017: a systematic analysis for the Global Burden of Disease Study Chronic liver disease is not associated with severity or mortality in Coronavirus disease 2019 (COVID-19): a pooled analysis A model to predict survival in patients with end-stage liver disease Model for end-stage liver disease (MELD) and allocation of donor livers Hyponatremia and mortality among patients on the liver-transplant waiting list Addition of serum sodium into the MELD score predicts waiting list mortality better than MELD alone Evidence-based incorporation of serum sodium concentration into MELD Natremia and liver transplantation: the right amount of salt for a good recipe UK blood and transplant. Selection of patients for liver transplantation and allocation of donated livers in the UK Hyponatremia in cirrhosis: an update Differential impact of hyponatremia and hepatic encephalopathy on health-related quality of life and brain metabolite abnormalities in cirrhosis Prevalence, timing, causes, and outcomes of hyponatremia in hospitalized orthopaedic surgery patients Sex-specific risks of death in patients hospitalized for hyponatremia: a populationbased study Cohort profile: a multicentre prospective validation cohort of the Chinese Acute-on-Chronic Liver Failure (CATCH-LIFE) study Prevalence and clinical significance of portal vein thrombosis in patients with cirrhosis and acute decompensation Acute-on-chronic liver failure in China: rationale for developing a patient registry and baseline characteristics Disorders of plasma sodium-causes, consequences, and correction Risk factors and outcomes of rapid correction of severe hyponatremia Mortality after hospitalization with mild, moderate, and severe hyponatremia Hyponatremia influences the outcome of patients with acute-on-chronic liver failure: an analysis of the CANONIC study Prognosis of patients with severe hyponatraemia is related not only to hyponatraemia but also to comorbidities and to medical management: results of an observational retrospective study Persistent ascites and low serum sodium identify patients with cirrhosis and low MELD scores who are at high risk for early death Electronic address: easloffice@easloffice.eu; European Association for the Study of the Liver EASL clinical practice guidelines for the management of patients with decompensated cirrhosis Hyponatremia in cirrhosis: pathophysiology and management Correction of hyponatraemia improves cognition, quality of life, and brain oedema in cirrhosis Active management of severe hyponatraemia is associated with improved mortality Acute-on-chronic liver failure: an update Hyponatremia in cirrhosis: pathophysiology and management Acknowledgements We thank the following Chinese (Acute on) Chronic Liver Failure Consortium (Ch-CLIF.C) members and participants for the contributions to this study: Department The online version contains supplementary material available at https:// doi. org/ 10. 1007/ s12072-021-10282-8.