Int J Clin Exp Med 2016;9(5):8264-8271 www.ijcem.com /ISSN:1940-5901/IJCEM0020913

Original Article sodium, potassium, , and chlorine for predicting the in-hospital mortality in cirrhotic patients with acute upper gastrointestinal bleeding: a retrospective observational study

Zheng Ning1,2*, Xingshun Qi1*, Feifei Hou1,3, Jiancheng Zhao1,3, Ying Peng1,2, Hongyu Li1, Jing Li1,2, Han Deng1,2, Xintong Zhang1,4, Xiaozhong Guo1

1Liver Cirrhosis Study Group, Department of Gastroenterology, General Hospital of Shenyang Military Area, Shenyang, China; 2Postgraduate College, Dalian Medical University, Dalian, China; 3Postgraduate College, Liaon- ing University of Traditional Chinese Medicine, Shenyang, China; 4Postgraduate College, Fourth Military Medical University, Xi’an, China. *Equal contributors. Received December 1, 2015; Accepted March 29, 2016; Epub May 15, 2016; Published May 30, 2016

Abstract: Background and aims: The association of with the outcomes of acute upper gastrointestinal bleeding (AUGIB) in liver cirrhosis remains unclear. A retrospective observational study aimed to explore whether or not serum sodium, potassium, calcium, and chlorine could predict the in-hospital mortality in such patients. Meth- ods: All consecutive patients with liver cirrhosis and AUGIB admitting to our hospital between January 2011 and June 2014 were retrospectively included in this study. Serum sodium, potassium, calcium, and chlorine concentra- tions were collected. Their prognostic values were evaluated by receiver operating characteristic (ROC) curve analy- ses. Areas under curve (AUCs) with 95% confidence intervals (CIs), sensitivity, and specificity were reported. Results: Overall, 713 cirrhotic patients with AUGIB were included. ROC curve analyses demonstrated that serum sodium, potassium, and chlorine, rather than calcium, could significantly predict the in-hospital death (AUC=0.619, 95% CI: 0.508-0.729, P=0.023; AUC=0.615, 95% CI: 0.502-0.728, P=0.028; AUC=0.605, 95% CI: 0.475-0.735, P=0.045; AUC=0.423, 95% CI: 0.248-0.597, P=0.296, respectively). The best cut-off value of serum sodium, potassium, and chlorine was 140.5 mmol/L (sensitivity: 56%; specificity: 71%), 4.34 mmol/L (sensitivity: 53.1%; specificity: 74.4%) and 112.9 mmol/L (sensitivity: 37.5%; specificity: 92.9%), respectively. The in-hospital mortality was significantly different between patients with sodium >140.5 mmol/L and ≤140.5 mmol/L (8.7% vs. 2.1%, P<0.001), between patients with potassium >4.34 and ≤4.34 mmol/L (8.5% vs. 3.4%, P=0.005), and between patients with chlorine >112.9 and ≤112.9 mmol/L (20.7% vs. 3.2%, P<0.001). Conclusion: Higher serum sodium, potassium, and chlo- rine concentrations were positively associated with increased in-hospital mortality of cirrhotic patients with AUGIB.

Keywords: , liver cirrhosis, hepatic, prognosis, death

Introduction family members about who is at a high risk of early death. Although this issue has been Liver cirrhosis is the end stage of chronic liver explored by numerous studies [3], few studies diseases [1], which can lead to portal hyperten- have focused on the role of electrolyte balance sion-related complications and liver failure. in predicting the outcomes of AUGIB in liver cir- Acute upper gastrointestinal bleeding (AUGIB) rhosis. By comparison, the impact of serum is one of the most lethal complications of liver sodium on the outcome of cirrhotic patients cirrhosis. Most of AUGIB events originate from with ascites has been widely identified [4, 5]. the rupture of gastroesophageal varices [2]. It Additionally, as we have known, model for end is clinically important to predict the early mor- stage liver disease (MELD) score is an impor- tality (e.g. in-hospital mortality) of cirrhotic tant index for assessing the prognosis of liver patients with AUGIB. The knowledge is useful to cirrhosis [6]. Notably, the incorporation of alert the physicians, patients, and patients’ serum sodium into the MELD score (i.e., MELD- Electrolyte and AUGIB in cirrhosis

Table 1. Patient characteristics Na score) has further improved the No. Pts prognostic significance [7]. Thus, we Variables Results available hypothesized that serum sodium and Age-years 713 56.17 ± 12.00 other electrolytes might be also as- sociated with the prognosis of AUGIB Sex (Male/Female), n (%) 713 479 (67.2)/234 (32.8) in liver cirrhosis. The aim of our study Causes of liver diseases, n (%) 713 was to explore whether or not serum HBV 204 (28.6) sodium, potassium, calcium, and ch- HCV 46 (6.5) lorine could predict the in-hospital HBV+HCV 4 (0.6) mortality of cirrhotic patients with Alcohol 185 (25.9) AUGIB. HBV+Alcohol 37 (5.2) HCV+Alcohol 9 (1.3) Patients and methods HBV+HCV+Alcohol 3 (0.4) Patient selection Autoimmune 46 (6.5) Drug 20 (2.8) In this retrospective observational Cholestatic 13 (1.8) study, all patients who were consecu- Others 5 (0.7) tively admitted to our hospital bet- ween January 2011 and June 2014 Unknown 141 (19.8) were eligible. Inclusion criteria should Ascites, n (%) 711 be as follows: 1) a diagnosis of liver No 378 (53.2) cirrhosis; and 2) AUGIB, regardless of Mild 79 (11.1) variceal and non-variceal bleeding. Moderate and severe 254 (35.7) AUGIB was defined as a new episode HE, n (%) 711 of upper gastrointestinal bleeding No 666 (93.7) within 5 days before our admission. Grade I-II 37 (5.2) Malignancy was excluded. Because Grade III-IV 8 (1.1) only the in-hospital death was obs- RBC (1012/L) 709 2.69 ± 1.51 erved, repeated admission was not excluded. Some patients had been Hb (g/L) 709 74.35 ± 22.17 included in our previous studies WBC (109/L) 709 6.27 ± 5.42 [8-11]. This study protocol was ap- 9 PLT (10 /L) 709 98.36 ± 88.58 proved by the Ethic Committee of our TBIL (μmol/L) 686 28.23 ± 35.20 hospital (number k [2015] 18). Due DBIL (μmol/L) 686 13.95 ± 23.89 to the study objective and design, the IBIL (μmol/L) 686 14.31 ± 13.88 patients’ informed consent was wai- ALB (g/L) 683 30.27 ± 6.51 ved. ALT (U/L) 686 32.71 ± 50.22 Data collection AST (U/L) 686 50.31 ± 102.64 ALP (U/L) 685 92.08 ± 81.19 All patients’ medical charts were ret- GGT (U/L) 685 81.03 ± 131.22 rospectively reviewed to collect the BUN (mmol/L) 662 9.02 ± 5.87 following baseline data: age, sex, Cr (μmol/L) 662 71.13 ± 63.96 cause of liver cirrhosis, AUGIB, asci- Potassium (mmol/L) 684 4.11 ± 0.55 tes, hepatic encephalopathy, and ro- Sodium (mmol/L) 684 138.48 ± 4.53 utine laboratory data. AUGIB was Calcium (mmol/L) 360 2.04 ± 0.22 independently evaluated by two in- vestigators, and finally validated by Chlorine (mmol/L) 683 106.84 ± 5.85 another investigator. The discrepan- PT (second) 652 17.19 ± 5.30 cy was resolved after their discus- APTT (second) 647 41.65 ± 10.20 sions. Grade of ascites and hepatic INR 647 1.44 ± 0.66 encephalopathy were established Child-Pugh score 618 7.54 ± 1.88 according to the relevant criteria [12, Child-Pugh class, n (%) 13]. The laboratory data primarily

8265 Int J Clin Exp Med 2016;9(5):8264-8271 Electrolyte and AUGIB in cirrhosis

A 213 (34.5) electrolyte, and hypo-electrolyte B 309 (50.0) groups according to the of serum sodium, potassium, C 96 (15.5) calcium, and chlorine levels. The in- MELD score 620 7.09 ± 6.57 hospital mortality was compared Abbreviations: HBV, hepatitis B virus; HCV, hepatitis C virus; HE, hepatic among groups by Chi-square tests. encephalopathy; RBC, red cell; Hb, hemoglobin; WBC, white blood cell; PLT, platelet; TBIL, total ; DBIL, direct bilirubin; IBIL, indirect Receiver operating characteristic bilirubin; ALB, albumin; ALT, alanine aminotransferase; AST, aspartate (ROC) curve analysis was em- aminotransferase; ALP, ; GGT, gamma-glutamyl trans- ployed to identify the best cut-off peptidase; BUN, ; Cr, ; PT, prothrombin time; value of serum sodium, potassium, APTT, activated partial thromboplastin time; INR, international normalized calcium, and chlorine concentrations ratio; MELD, model for end stage liver disease. for predicting the in-hospital death. Areas under curve (AUCs) with 95% Table 2. Treatment options for AUGIB confidence intervals (CIs) were calcu- lated. Sensitivity and specificity were No. Pts Treatment options Results available also reported. Two-sided P value <0.05 was considered statistically Endoscopic treatment, n (%) 713 427 (59.9) significant. All statistical analyses Sengstaken-Blackmore tube, n (%) 713 19 (2.7) were performed by using SPSS Somatostatin, n (%) 713 656 (92.0) Statistics version 17.0.0. Blood transfusion, n (%) 713 451 (63.3) Hemostatics, n (%) 713 593 (83.2) Results Proton pump inhibitor, n (%) 713 698 (97.9) Splenectomy, n (%) 704 4 (0.6) During the enrollment period, a total of 713 cirrhotic patients with AUGIB were included in the study. Patient included red blood cell count, hemoglobin, characteristics were shown in Table 1. A major- white blood cell count, platelet count, total bili- ity of patients had HBV and alcohol abuse relat- rubin, direct bilirubin, indirect bilirubin, albu- ed liver cirrhosis. Among them, Child-Pugh min, alanine aminotransferase, aspartate ami- scores were available in 618 patients; 213, notransferase, alkaline phosphatase, gamma- 309, and 96 patients had Child-Pugh class A, glutamyl transpeptidase, blood urea nitrogen, B, and C, respectively. Treatment options for creatinine, prothrombin time, activated partial AUGIB were shown in Table 2. In-hospital mor- thromboplastin time, international normalized tality was 4.6% (33/713). Distribution of serum ratio, sodium, potassium, calcium, and chlo- sodium, potassium, calcium, and chlorine con- rine. In our hospital, the reference range of centrations were shown in Figure 1A-D. serum sodium, potassium, calcium, and chlo- rine was 135-145 mmol/L, 3.5-4.5 mmol/L, Serum sodium 2.2-2.5 mmol/L, and 99-110 mmol/L, respec- tively. Child-Pugh and MELD scores were calcu- Serum sodium was available in 684 patients. lated according to the relevant formulas [6, 14]. Among them, 120, 528, and 36 patients had The treatment options for AUGIB were also col- serum sodium concentration of <135 mmol/L, lected, including endoscopic treatment, Sen- 135-145 mmol/L, and >145 mmol/L, respec- gstaken-Blackmore tube, somatostatin, blood tively (Supplementary Figure 1A). The in-hospi- transfusion, hemostatics, proton pump inhibi- tal mortality was 3.3% (4/120), 4.7% (25/528), tor, and surgery. The in-hospital death and and 8.3% (3/36), respectively (P=0.456) cause of death were clearly recorded. (Supplementary Figure 1B).

Statistical analysis Serum potassium

Continuous and categorical data were expr- Serum potassium was available in 684 pa- essed as mean ± standard deviation and fre- tients. Among them, 51, 622, and 11 patients quency (percentage), respectively. The patients had a serum potassium concentration of <3.5 were divided into hyper-electrolyte, normal mmol/L, 3.5-4.5 mmol/L, and >4.5 mmol/L,

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Figure 1. Distribution of serum sodium, potassium, calcium, and chlorine.

respectively (Supplementary Figure 2A). The (28/622), and 18.2% (2/11), respectively (P= in-hospital mortality was 3.9% (2/51), 4.5% 0.100) (Supplementary Figure 2B).

8267 Int J Clin Exp Med 2016;9(5):8264-8271 Electrolyte and AUGIB in cirrhosis

Figure 2. ROC results of serum sodium, potassium, calcium, and chlorine for predicting the in-hospital mortality in cirrhotic patients with AUGIB.

Serum calcium 2.30 mmol/L with a sensitivity of 25.0% and a specificity of 91.6%. Serum calcium was available in 360 patients. Among them, 294, 55, and 11 patients had AUC of serum chlorine concentration for pre- a serum potassium concentration of <2.2 dicting the in-hospital death was 0.605±0.066 mmol/L, 2.2-2.5 mmol/L, and >2.5 mmol/L, (95% CI: 0.475-0.735, P=0.045) (Figure 2D). respectively (Supplementary Figure 3A). The in- The best cut-off value of serum chlorine was hospital mortality was 4.1% (12/294), 5.5% 112.9 mmol/L with a sensitivity of 37.5% and a (3/55), and 9.1% (1/11), respectively (P=0.676) specificity of 92.9%. (Supplementary Figure 3B). In-hospital mortality according to the cut-off Serum chlorine value

Serum chlorine was available in 683 patients. Serum sodium concentration was > and ≤140.5 Among them, 51, 444, and 188 patients had mmol/L in 207 and 477 patients, respectively. a serum potassium concentration of <99 The in-hospital mortality was 8.7% (18/207) mmol/L, 99-110 mmol/L, and >110 mmol/L, and 2.1% (14/477), respectively (P<0.001). respectively (Supplementary Figure 4A). The in- hospital mortality was 9.8% (5/51), 2.5% Serum potassium concentration was > and (11/444), and 8.5% (16/188), respectively ≤4.34 mmol/L in 177 and 507 patients, respec- (P=0.001) (Supplementary Figure 4B). tively. The in-hospital mortality was 8.5% (15/177) and 3.4% (17/507), respectively ROC curve analysis (P=0.005).

AUC of serum sodium concentration for predict- Serum chlorine concentration was > and ing the in-hospital death was 0.619±0.056 ≤112.9 mmol/L in 58 and 625 patients, (95% CI: 0.508-0.729, P=0.023) (Figure 2A). respectively. The in-hospital mortality was The best cut-off value of serum sodium was 20.7% (12/58) and 3.2% (20/625), respective- 140.5 mmol/L with a sensitivity of 56% and a ly (P<0.001). specificity of 71%. Discussion AUC of serum potassium concentration for pre- dicting the in-hospital death was 0.615±0.058 This was a large retrospective observational (95% CI: 0.502-0.728, P=0.028) (Figure 2B). study, which aimed at evaluating the role of The best cut-off value of serum potassium was serum sodium, potassium, calcium, and chlo- 4.34 mmol/L with a sensitivity of 53.1% and a rine in predicting the in-hospital mortality of cir- specificity of 74.4%. rhotic patients with AUGIB. Their respective cut-off values were also identified by the ROC AUC of serum calcium concentration for pre- curve analyses. We found that higher serum dicting the in-hospital death was 0.423±0.089 sodium, potassium, and chlorine concentra- (95% CI: 0.248-0.597, P=0.296) (Figure 2C). tions were significantly associated with the in- The best cut-off value of serum calcium was hospital mortality of cirrhotic patients with

8268 Int J Clin Exp Med 2016;9(5):8264-8271 Electrolyte and AUGIB in cirrhosis

AUGIB. This phenomenon was almost opposite rhotic patients with ascites [19]. It should be to previous findings that lower serum sodium noticed that all 22 patients with serum potas- concentration was associated with worse out- sium concentration ≥4.8 mmol/L died within 1 comes of cirrhotic patients with ascites [4, 15]. year. Similarly, our study also found that serum It might be explained by a situation that acute potassium concentration >4.34 mmol/L was bleeding events might cause pachyemia condi- significantly associated with a higher in-hospi- tions, thereby potentially elevating the electro- tal mortality of cirrhotic patients with AUGIB. lyte concentrations. If so, the elevation of elec- trolyte concentrations might be positively Although calcium was often influ- associated with the severity of AUGIB. enced by chronic liver diseases [20], especially primary biliary cirrhosis, few studies assessed Lots of studies have confirmed that hyponatre- the role of calcium levels in predicting the out- mia is significantly associated with poor prog- comes of liver cirrhosis [21]. A nested case- nosis of cirrhotic patients. Angeli et al. prospec- control study by Yin et al. demonstrated a posi- tively enrolled 997 consecutive patients with tive correlation of serum calcium level with risk liver cirrhosis and ascites between March 2003 of liver cirrhosis. Genovesi et al. also found that and August 2003 from 28 centers in Europe, lower plasma calcium levels were significantly North and South America, and Asia [15]. Low associated with longer QTc intervals, which serum sodium concentrations were associated might induce potentially lethal complications with higher frequency of severe ascites, hepat- [22]. However, our study did not find any signifi- ic encephalopathy, spontaneous bacterial peri- cant associations between calcium levels and tonitis, and hepatorenal syndrome. Recently, risk of in-hospital death. Umemura et al. also found that patients with serum sodium concentration <139 mEq/L had Until now, few studies have explored the asso- a significantly lower cumulative survival rate ciation of serum chlorine concentration with than those with serum sodium concentration the prognosis of liver cirrhosis. However, the >139 mEq/L [16]. On the other hand, in the role of chlorine in other patients has been ana- ambulatory setting, hyponatremia is significant- lyzed. Some studies favored a positive associa- ly associated with an increased risk of all-cause tion of chlorine concentration with poor out- mortality [17]. To the best of our knowledge, our come. Zhao et al. found that an increased ch- study have for the first time identified the role lorine concentration was independently associ- of hypernatremia in predicting the in-hospital ated with the presence of coronary heart dis- mortality of cirrhotic patients with AUGIB. By ease in Han Chinese population [23]. Others comparison, we found that serum sodium suggested an inverse association of chlorine >140.5 mmol/L was significantly associated concentration with poor outcome. Kimura et al. with higher in-hospital mortality. Notably, cir- compared the chlorine concentration after tho- rhotic patients with AUGIB should be regarded racic or abdominal surgery between hospital as our study population, rather than those with survivors and non-survivors. Hypochloremia ascites. It is reasonable to speculate that the was independently associated with in-hospital predictive value of serum sodium should be death (odds ratio=5.8, 95% CI=1.1-30.2) [24]. variable among the study population. Indeed, in Notably, the in-hospital mortality was signifi- one early study, Rodes et al. reported 3 cases cantly higher in patients with hypochloremia with liver cirrhosis and ascites, suggesting that than in those with normal chlorine concentra- the occurrence of gastrointestinal bleeding led tion (28.6% versus 6.0%, P=0.007). McCallum to an increase in blood urea nitrogen and plas- et al. found that serum chlorine concentration ma osmolality, thereby producing osmotic <100 mEq/L at baseline was independently diuresis and hypernatremia [18]. Presumably, associated with an increased mortality in the severity of AUGIB might be reflected by hypertensive patients during a long-term fol- serum sodium levels in liver cirrhosis. low-up [25]. Grodin et al. also found that admis- sion serum chloride level <99 mEq/L had a sig- In a Swedish prospective multicenter study, nificantly higher mortality than serum chloride serum potassium had the strongest correlation level ≥99 mEq/L in patients with acute decom- with mortality. had a significantly pensated heart failure [26]. In our study, the higher risk of death than hypokalemia in cir- ROC curve analysis demonstrated that an ele-

8269 Int J Clin Exp Med 2016;9(5):8264-8271 Electrolyte and AUGIB in cirrhosis vated serum chlorine concentration might be 7603; Fax: 86-24-28851113; E-mail: 13309887- associated with the in-hospital mortality of [email protected] (HYL); [email protected] AUGIB in liver cirrhosis. Notably, the specificity (XZG); [email protected] (XSQ) of serum chlorine for predicting the in-hospital mortality was very high. In other words, serum References chlorine <112.9 mmol/L could accurately pre- [1] Tsochatzis EA, Bosch J, Burroughs AK. Liver cir- dict the probability of being alive during rhosis. Lancet 2014; 383: 1749-61. hospitalization. [2] Cremers I, Ribeiro S. Management of variceal and nonvariceal upper gastrointestinal bleed- Our study had several limitations. First, due to ing in patients with cirrhosis. Therap Adv Gas- the retrospective nature, the potential bias of troenterol 2014; 7: 206-16. patient selection should never be neglected. [3] D’Amico G, De Franchis R, Cooperative Study Not all included patients underwent the labora- G. Upper digestive bleeding in cirrhosis. Post- tory tests for electrolyte levels. Calcium levels therapeutic outcome and prognostic indica- were available in less than 50% of patients. tors. Hepatology 2003; 38: 599-612. Second, not all included patients underwent [4] Gianotti RJ, Cardenas A. Hyponatraemia and cirrhosis. Gastroenterol Rep (Oxf) 2014; 2: 21- endoscopic examinations. Thus, we did not 6. separate patients with acute variceal bleeding [5] Papadakis MA, Fraser CL, Arieff AI. Hypona- into an individual group. Third, the endpoint traemia in patients with cirrhosis. Q J Med was in-hospital death, but the long-term follow- 1990; 76: 675-88. up outcomes were not available. [6] Kamath PS, Kim WR, Advanced Liver Disease Study G. The model for end-stage liver disease In conclusion, serum sodium, potassium, and (MELD). Hepatology 2007; 45: 797-805. chlorine concentrations should be incorporated [7] Kim WR, Biggins SW, Kremers WK, Wiesner into the model for predicting the in-hospital RH, Kamath PS, Benson JT, Edwards E, Ther- mortality of cirrhotic patients with AUGIB. Co- neau TM. Hyponatremia and mortality among nsidering that their prognostic accuracy might patients on the liver-transplant waiting list. N be relatively modest, further studies should Engl J Med 2008; 359: 1018-26. validate the clinical usefulness of serum sodi- [8] Zhu C, Qi X, Li H, Peng Y, Dai J, Chen J, Xia C, Hou Y, Zhang W, Guo X. Correlation of serum um, potassium, and chlorine concentrations. liver fibrosis markers with severity of liver dys- function in liver cirrhosis: a retrospective cross- Disclosure of conflict of interest sectional study. Int J Clin Exp Med 2015; 8: 5989-98. None. [9] Qi X, Peng Y, Li H, Dai J, Guo X. Diabetes is as- sociated with an increased risk of in-hospital Authors’ contribution mortality in liver cirrhosis with acute upper gastrointestinal bleeding. Eur J Gastroenterol Zheng Ning: reviewed the literature, wrote the Hepatol 2015; 27: 476-7. protocol, collected the data, and performed the [10] Peng Y, Qi X, Dai J, Li H, Guo X. Child-Pugh ver- statistical analysis. Xingshun Qi: designed the sus MELD score for predicting the in-hospital study, wrote the protocol, performed the statis- mortality of acute upper gastrointestinal bleed- tical analysis, interpreted the data, and drafted ing in liver cirrhosis. Int J Clin Exp Med 2015; 8: the manuscript. Feifei Hou, Jiancheng Zhao, 751-7. Ying Peng, Jing Li, Han Deng, Xintong Zhang col- [11] Qi X, Li H, Chen J, Xia C, Peng Y, Dai J, Hou Y, lected the data. Xiaozhong Guo and Hongyu Li Deng H, Li J, Guo X. Serum Liver Fibrosis Mark- gave critical comments and revised the manu- ers for Predicting the Presence of Gastro- script. All authors have made an intellectual esophageal Varices in Liver Cirrhosis: A Retro- spective Cross-Sectional Study. Gastroenterol contribution to the manuscript and approved Res Pract 2015; 2015: 274534. the submission. [12] Ferenci P, Lockwood A, Mullen K, Tarter R, Weissenborn K, Blei AT. Hepatic encephalopa- Address correspondence to: Drs. Hongyu Li, Xiao- thy--definition, nomenclature, diagnosis, and zhong Guo and Xingshun Qi, Liver Cirrhosis Study quantification: final report of the working party Group, Department of Gastroenterology, General at the 11th World Congresses of Gastroenter- Hospital of Shenyang Military Area, 83 Wenhua ology, Vienna, 1998. Hepatology 2002; 35: Road, Shenyang 110840, China. Tel: 86-24-2889- 716-21.

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[13] Moore KP, Wong F, Gines P, Bernardi M, Ochs [21] Yin LY, Yin J, Cui JF, Liu B, Chen F, Fan JH, Chen A, Salerno F, Angeli P, Porayko M, Moreau R, W. [Association between serum calcium levels Garcia-Tsao G, Jimenez W, Planas R, Arroyo V. and the risk of liver cirrhosis]. Zhonghua Liu The management of ascites in cirrhosis: report Xing Bing Xue Za Zhi 2013; 34: 457-60. on the consensus conference of the Interna- [22] Genovesi S, Prata Pizzala DM, Pozzi M, Ratti L, tional Ascites Club. Hepatology 2003; 38: 258- Milanese M, Pieruzzi F, Vincenti A, Stella A, 66. Mancia G, Stramba-Badiale M. QT interval pro- [14] Pugh RN, Murray-Lyon IM, Dawson JL, Pietroni longation and decreased heart rate variability MC, Williams R. Transection of the oesophagus in cirrhotic patients: relevance of hepatic ve- for bleeding oesophageal varices. Br J Surg nous pressure gradient and serum calcium. 1973; 60: 646-9. Clin Sci (Lond) 2009; 116: 851-9. [15] Angeli P, Wong F, Watson H, Gines P, Investiga- [23] Zhao Y, Liu M, Wang X, Chen S, Zhou M, Li Q, Li tors C. Hyponatremia in cirrhosis: Results of a S, Huang Y, Zhao L, Wang Q, Tu X. Elevated se- patient population survey. Hepatology 2006; rum chloride is an independent risk factor for 44: 1535-42. coronary heart disease: A retrospective study [16] Umemura T, Shibata S, Sekiguchi T, Kitabatake of more than 13,000 Han Chinese. Int J Cardi- H, Nozawa Y, Okuhara S, Kimura T, Morita S, ol 2015; 198: 61-2. Komatsu M, Matsumoto A, Tanaka E. Serum [24] Kimura S, Matsumoto S, Muto N, Yamanoi T, sodium concentration is associated with in- Higashi T, Nakamura K, Miyazaki M, Egi M. As- creased risk of mortality in patients with com- sociation of serum chloride concentration with pensated liver cirrhosis. Hepatol Res 2015; outcomes in postoperative critically ill patients: 45: 739-44. a retrospective observational study. J Intensive [17] Gankam-Kengne F, Ayers C, Khera A, de Lemos Care 2014; 2: 39. J, Maalouf NM. Mild hyponatremia is associat- [25] McCallum L, Jeemon P, Hastie CE, Patel RK, ed with an increased risk of death in an ambu- Williamson C, Redzuan AM, Dawson J, Sloan latory setting. Kidney Int 2013; 83: 700-6. W, Muir S, Morrison D, McInnes GT, Freel EM, [18] Rodes J, Arroyo V, Bordas JM, Bruguera M. Hy- Walters M, Dominiczak AF, Sattar N, Padma- pernatremia following gastrointestinal bleed- nabhan S. Serum chloride is an independent ing in cirrhosis with ascites. Am J Dig Dis 1975; predictor of mortality in hypertensive patients. 20: 127-33. Hypertension 2013; 62: 836-43. [19] Wallerstedt S, Simren M, Wahlin S, Loof L, [26] Grodin JL, Simon J, Hachamovitch R, Wu Y, Hultcrantz R, Sjoberg K, Gertzen HS, Prytz H, Jackson G, Halkar M, Starling RC, Testani JM, Almer S, Oden A. Moderate hyperkalemia in Tang WH. Prognostic Role of Serum Chloride hospitalized patients with cirrhotic ascites indi- Levels in Acute Decompensated Heart Failure. cates a poor prognosis. Scand J Gastroenterol J Am Coll Cardiol 2015; 66: 659-66. 2013; 48: 358-65. [20] Luxon BA. Bone disorders in chronic liver dis- eases. Curr Gastroenterol Rep 2011; 13: 40-8.

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Supplementary Figure 1. In-hospital mortality according to the normal range of serum sodium. A. Proportion of serum sodium. B. In-hospital mortality.

Supplementary Figure 2. In-hospital mortality according to the normal range of serum potassium. A. Proportion of serum potassium. B. In-hospital mortality.

1 Electrolyte and AUGIB in cirrhosis

Supplementary Figure 3. In-hospital mortality according to the normal range of serum calcium. A. Proportion of serum calcium. B. In-hospital mortality.

Supplementary Figure 4. In-hospital mortality according to the normal range of serum chlorine. A. Proportion of serum chlorine. B. In-hospital mortality.

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