Hypochloremia is an underutilised prognostic marker in patients with advanced liver cirrhosis and liver failure

Table 1 Significance of serum sodium and chloride in patients with advanced liver cirrhosis

Parameter	Serum sodium (Na+)	Serum chloride (Cl-)
Primary role	Osmotic balance & water distribution	Renal salt sensing & acid-base homeostasis
Pathophysiology in cirrhosis/liver failure	Affected by RAAS, AVP, splanchnic vasodilation	Involvement in renal salt-sensing mechanisms, tubuloglomerular feedback & renin release
Common disturbance	Hyponatremia (< 130 mEq/L), often dilutional	Hypochloremia (< 98 mEq/L)
Prognostic role	Hyponatremia alone or in conjunction with MELD predicts short-term mortality	Independent predictor of mortality in advanced cirrhosis/liver failure patients
Clinical outcomes	Higher risk of death, hepatic decompensation, and need for liver transplant	Strong correlation with ICU mortality, hepatic decompensation, and long-term prognosis
Scoring models	Incorporated in MELD-Na for liver transplant candidates	MELD-Cl under evaluation; not yet standardised
Associations	Linked to renal function, ascites, bilirubin, and INR	Correlates with MELD, SOFA, Child-Pugh scores, lactate, and creatinine levels
ICU prognostication	Independent impact in severe cases declines	Superior prognostic value even after adjustments
Therapeutic benefit	Correcting hyponatremia may improves outcomes	It remains to be seen if treating hypochloremia improves outcomes

RAAS: Renin-angiotensin-aldosterone system; AVP: Arginine vasopressin; MELD: Model for End-Stage Liver Disease; INR: International normalized ratio; ICU: Intensive care unit; SOFA: Sequential Organ Failure Assessment.

Table 2 Studies demonstrating prognostic role of serum chloride in advanced liver disease patients, n (%)

Ref.	Study design	Patients (n)	Incidence of hypochloremia	Results	Limitations
Sumarsono et al[14], 2020	Retrospective cohort	389 critically ill cirrhosis	157 (40.4)	Hypochloremia was associated with higher in-hospital mortality (31% vs 19%, P < 0.01) as well as 180-day mortality (45.2% vs 26.7%, P < 0.0001)	Retrospective design, limited generalizability due to inclusion of only ICU cohort, one-time chloride measurement, and selection bias as indicated by lower overall ICU mortality rates
Ji and Li[8], 2021	Retrospective cohort	1216 critically ill cirrhosis	199 (16.4)	Hypochloremic patients had a significantly higher ICU mortality rate compared to non-hypochloremic ones (34.2% vs 15.8%, P < 0.001). Every unit decline in chloride level predicted 6% increase in mortality (OR 0.94)	Retrospective design, one-time chloride measurement, confounding variable not examined in multivariate model
Cheng et al[39], 2023	Retrospective cohort	182 cirrhosis patients undergoing TIPS	Not stated	Patients with serum chloride < 107.35 mmol/L had significantly worse survival compared to those with levels ≥ 107.35 mmol/L. Each unit decline in chloride increased the mortality by 17.7%	Retrospective design, one-time chloride measurement during follow-up up to 1-year, and confounding effect of diuretics not assessed
Wang et al[2], 2022	Longitudinal cohort	2405 ALF patients	428 (17.8)	Hypochloremia group had lower 21-day transplant free survival (39% vs 50.2%, P < 0.001) and higher 28-day mortality (42.1%, P < 0.001)	Dynamic measurement of chloride not done, prior fluid and diuretic therapy might have affected serum chloride levels, and long-term prognosis not assessed
Semmler et al[9], 2023	Retrospective cohort	891 ACLD; 181 critically ill cirrhosis	138 (15) ACLD; 54 (30) critical cirrhosis	Serum chloride had a significant association with ICU mortality [OR: 0.94 (95%CI: 0.90-0.97)], even after adjusting for confounders [adjusted OR: 3.20 (95%CI: 1.20-8.82)]. Those with chloride < 100 mmol/L exhibited significantly higher odds of ICU mortality than otherwise	Retrospective design, Vomiting or diarrhea or treatment (diuretics, fluids or lactulose) prior to as well as first few hours of admission might have impacted serum electrolytes

ALF: Acute liver failure; ACLD: Advanced chronic liver disease; ICU: Intensive care unit; OR: Odds ratio; TIPS: Trans jugular Porto-systemic shunt.