Serum chloride concentrations and outcomes in adult patients with cirrhosis: a systematic review and meta-analysis

Abstract

Purpose: Electrolyte disturbances, including hyponatremia, are common in cirrhosis, with hyponatremia already incorporated into the MELD-Na score as a prognostic marker. However, the prognostic role of serum chloride, the main extracellular anion, remains underexplored. Emerging evidence suggests hypochloremia is independently associated with increased mortality and acute kidney injury (AKI) in cirrhotic patients. Proposed mechanisms include dysregulated activation of the renin-angiotensin, vasopressin, and sympathetic nervous systems, leading to renal vasoconstriction and impaired function. This systematic review evaluates the association between serum chloride levels and outcomes, including mortality and KDIGO-defined AKI rates, aiming to enhance understanding and inform management strategies.

Methods: This review followed PRISMA guidelines and a PROSPERO-registered protocol (CRD42024550945). Comprehensive searches of MEDLINE, EMBASE, Cochrane, Scopus, and Web of Science were conducted through June 6, 2024, without language restrictions. Controlled vocabulary and keywords were used to identify relevant studies. Two independent reviewers performed title, abstract, and full-text screening, with disagreements resolved through consensus or third-party arbitration. Inter-rater reliability was assessed using Cohen's kappa. Data extraction and risk of bias evaluations were performed using the PROBAST tool. Findings were summarized using a PRISMA flowchart.

Results: Five studies (n = 3,150) were included, primarily retrospective cohorts, with one prospective study. Hypochloremia was defined as serum chloride < 99 mEq/L in most studies, except one, which used < 107.35 mmol/L. Cirrhosis etiologies included alcohol-related liver disease (40-64%), hepatitis B (7.9-59.9%), hepatitis C (7-8.9%), and non-alcoholic fatty liver disease (7-11.7%), with fewer cases of autoimmune and cryptogenic causes. Comorbidities included diabetes mellitus (21.3%), hypertension (13.4%), and varices (72-87%), with 62-99% having a history of decompensation. Extrahepatic organ failures were prevalent, affecting 79.4% of patients, with 31.6% and 13.4% experiencing two and three organ failures, respectively.Meta-analysis showed hypochloremia was significantly associated with increased mortality (pooled OR: 2.52; 95% CI: 1.88-3.39, p < 0.0001). Individual ORs ranged from 2.08 to 17.42, with low to moderate heterogeneity (I² = 36%). Hypochloremia also correlated with elevated creatinine levels and increased AKI prevalence.

Conclusion: Hypochloremia is a strong predictor of mortality and renal dysfunction in cirrhotic patients. Early recognition and management of hypochloremia are critical to improving outcomes in this high-risk population.

Clinical trial number: Not applicable.

Keywords: Acute kidney injury; Cirrhosis outcomes; Hypochloremia; Mortality risk; Serum chloride.

Fig. 1

PRISMA Flow Diagram for Study Selection in the Systematic Review. This PRISMA flow diagram illustrates the study selection process. Out of 722 identified records, 721 were screened, with 707 excluded. After full-text assessment of 12 studies, 5 were included in the final review, while 7 were excluded due to ineligibility

Fig. 2

Etiology Distribution of Cirrhosis Across Included Studies. This bar chart illustrates the etiology distribution of cirrhosis across the included studies. The different colors represent various causes of cirrhosis, including alcohol-related liver disease, viral hepatitis (Hepatitis B and C), non-alcoholic steatohepatitis (NASH), cryptogenic causes, autoimmune liver disease, and other etiologies. The proportion of each etiology varies among studies, with alcohol being the predominant cause in most cohorts

Fig. 3

Reported Comorbidities in Patients with Cirrhosis Across Included Studies. Values represent the percentage of patients with reported cirrhosis-related complications in each study. Missing bars indicate that the variable was not reported. Semmler et al. presented separate ACLD and ICU cohorts, which are shown individually for clarity

Fig. 4

Forest Plot of the Association Between Hypochloremia and Mortality in Cirrhotic Patients. This forest plot shows the association between hypochloremia and mortality in cirrhotic patients, with an overall odds ratio (OR) of 2.52 [1.88, 3.39], indicating more than 2.5 times higher mortality risk in hypochloremic individuals. The pooled estimate (black diamond) is statistically significant (p < 0.00001), and heterogeneity is moderate (I² = 36%), suggesting consistency across studies