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

Abstract

Patients with advanced liver cirrhosis and liver failure frequently experience abnormalities in their serum electrolyte levels. In such patients, hyponatremia has been identified as a predictor of poor outcomes. However, emerging evidence suggests that serum chloride may provide even better prognostic information in similar situations. Hypochloremia, characterised by low serum chloride levels, has been linked to increased mortality, exacerbated organ dysfunction, and higher requirements for renal replacement therapy and vasopressors in various critical conditions, including advanced liver diseases. The pathophysiological mechanisms underlying the association between low serum chloride levels and poor outcomes in liver disease appear to involve complex interactions among electrolyte imbalances, renal function, and systemic hemodynamics. Chloride dysregulation can influence renal salt-sensing mechanisms, disrupt acid-base homeostasis, and exacerbate complications such as hepatic encephalopathy and hepatorenal syndrome. This article aims to elucidate the prognostic significance of lower serum chloride levels in patients with advanced liver disease. By reviewing recent literature and analysing clinical data, we seek to establish serum chloride as an underutilised but valuable prognostic marker. Understanding the role of serum chloride in liver disease could enhance prognostic accuracy, refine treatment strategies, and ultimately improve patient outcomes.

Key Words: Chloride; Hypochloremia; Liver failure; Cirrhosis; Hyponatremia; Prognosis

Core Tip: Patients with advanced liver cirrhosis and liver failure frequently experience abnormalities in their serum electrolyte levels. Emerging evidence suggests that serum chloride may provide prognostic information in such patients. Hypochloremia has been associated with higher mortality, worsened liver dysfunction, and a greater need for vasopressors and renal replacement therapy. Despite its prognostic significance, serum chloride is often overshadowed by other electrolytes. Notwithstanding the limited available evidence, we believe that serum chloride is an underutilised prognostic marker in clinical practice. Thus, this article aims to elucidate the prognostic significance of lower serum chloride levels in patients with advanced liver disease.

INTRODUCTION

Fluid, electrolyte, and acid-base balance are frequently altered in critically ill patients, including those with advanced liver cirrhosis, acute liver failure (ALF), and acute-on-chronic liver failure[1-3]. Although recent advances in intensive care medicine have led to better outcomes, the mortality rates for these patients remain high[4]. Hence, the prognosis of critically ill liver disease patients must be predicted to guide and optimise treatment decisions. In this context, a fair prognostication using routinely used laboratory parameters would be of enormous clinical value. Hyponatremia has long been recognised as a significant predictor of mortality in patients with cirrhosis[5]. Furthermore, serum sodium has been incorporated into the Model for End-Stage Liver Disease (MELD) score, which is currently the most widely used prognostic marker in advanced liver disease patients[6]. However, some studies have not identified an added benefit of combining sodium with the MELD score[7]. Several studies have demonstrated that hyponatremia is not an independent predictor of mortality in patients with cirrhosis when considering various covariates[8,9]. The prognostic role of serum chloride has now been increasingly recognised in patients with various critical illnesses, including acute kidney injury, chronic kidney disease, and heart failure[10-13]. Hypochloremia has been identified as an independent predictor of mortality in critically ill cirrhosis and ALF patients[2,8,9,14]. In fact, serum chloride has been shown to confer better prognostic value than serum sodium in patients with advanced cirrhosis[9,14]. These insights underscore the broader physiological significance of chloride compared with sodium and suggest that chloride may affect the pathogenesis of cirrhosis independently of serum sodium levels.

Chloride is the second most abundant ion in the body after sodium. It is predominantly confined to the extracellular fluid compartment and accounts for approximately one-third of plasma tonicity and two-thirds of all plasma negative charges[15]. Chloride plays an important role in many physiological processes, including the maintenance of osmotic pressure, acid-base balance, electroneutrality of body fluids, muscular activity, and blood pressure regulation[16,17]. Compared with serum sodium, chloride appears to offer several advantages, as depicted in Table 1. Nevertheless, serum chloride has received relatively less attention and is an underutilised prognostic marker for patients with advanced liver diseases. Thus, this article aims to elucidate the prognostic significance of lower serum chloride levels in critically ill liver disease patients.

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.

CHLORIDE REGULATION

In humans, chloride regulation is primarily managed by the kidneys and the gastrointestinal system. Chloride is absorbed in the intestinal lumen through several mechanisms, and its excretion is largely handled by the kidneys[15]. About 99% of filtered chloride is reabsorbed along with sodium, with only a small amount being excreted. The various mechanisms that regulate sodium homeostasis in the body, including the renin-angiotensin-aldosterone system (RAAS), atrial natriuretic peptide, and the sympathetic nervous system (SNS), also regulate chloride[18,19]. The normal range of serum chloride for adults is 96-106 mmol/L. Hypochloremia is an electrolyte imbalance where chloride levels are 95 mEq/L or less. Foods high in chloride include celery, lettuce, olives, tomatoes, and rye. Nevertheless, table salt accounts for the majority of chloride intake. Studies conducted in various countries have revealed that the average person consumes about 10 g of salt per day[3]. Therefore, a decrease in oral intake causing chloride deficiency is rare.

FUNCTIONAL SIGNIFICANCE OF CHLORIDE IN ADVANCED LIVER CIRRHOSIS

Chloride is the primary ion involved in renal salt-sensing mechanisms, influencing processes such as renin release, tubuloglomerular feedback, and the activity of sodium transporters in the renal tubules[18]. The macula densa, a component of the juxtaglomerular apparatus, plays a pivotal role in regulating renal hemodynamics. By sensing the luminal concentration of chloride, the macula densa provides a critical feedback mechanism for modulating glomerular filtration rate. This sensory mechanism is primarily mediated by the apical Na-K-2Cl cotransporter. Research has shown that the macula densa exerts its effects on channel transporters through a family of WNK (With-No-Lysine) serine-threonine kinases[20,21]. Chloride binding to the catalytic site of these kinases regulates the activity of channel transporters, fine-tuning renal function in response to changes in sodium and chloride levels[21,22]. Moreover, chloride plays a pivotal role in maintaining acid-base balance, particularly in contraction alkalosis induced by diuretic therapy[23]. An essential mechanism for the electrochemical equilibrium and autoregulation of the acid-base balance is tubular chloride reabsorption. Bicarbonate alterations in cirrhosis patients considerably influence chloride levels[24,25]. Cl⁻ channels are present in the plasma membrane and in several intracellular compartments of hepatocytes[26]. Despite limited research on the alterations of Cl^- channels in patients with advanced liver disease, these channels are essential for controlling cell volume and the acidity of intracellular organelles. Additionally, there is evidence that chloride channels serve a function in modulating cell growth and apoptosis[19,27,28].

MECHANISMS OF HYPOCHLOREMIA IN ADVANCED LIVER DISEASE PATIENTS

Two primary mechanisms seem to cause hypochloremia in patients with advanced cirrhosis: Dilutional and depletive hypochloremia. The progression of cirrhosis, marked by portal hypertension and splanchnic vasodilation, results in effective arterial hypovolemia and subsequent activation of endogenous vasoconstrictor systems, including RAAS, SNS, and arginine vasopressin (AVP)[29]. This leads to disproportionate water retention, which produces dilutional hypochloremia in addition to hyponatremia. The causes of depletive hypochloremia include fluid loss with chloride due to diuretic therapy, vomiting, or diarrhoea. Hyperglycemia can also reduce serum chloride levels by causing glucose-induced osmotic diuresis. Given that patients with advanced cirrhosis frequently have diabetes mellitus, including hepatogenous diabetes, this may be an unconsidered factor[30,31]. Other factors that may contribute to hypochloremia in advanced cirrhosis patients include the infusion of excess hypotonic fluid, adrenal insufficiency, malnutrition, salt-restricted diets, and concomitant heart failure[32]. Given the higher salt intake by the general population, low salt intake is considered an uncommon cause of hypochloremia. However, patients with advanced cirrhosis are often prescribed a low-salt diet. This, along with concomitant diuretic treatment, has the potential to cause hypochloremia[3]. Laxatives, corticosteroids, and bicarbonates, which are sometimes prescribed for liver disease patients, may also contribute to hypochloremia.

PATHOGENETIC MECHANISMS LINKING HYPOCHLOREMIA WITH ADVERSE OUTCOMES

Hypochloremia has a definite pathophysiological connection with advanced cirrhosis; however, how exactly chloride levels relate to outcomes remains unclear. The pathophysiological mechanisms appear to involve complex interactions among various factors, including systemic haemodynamics (Figure 1). Hypochloremia precipitates a cascade of renal and hormonal adaptations aimed at maintaining homeostatic balance. Reduced chloride delivery to the Na-K-2Cl cotransporter diminishes tubuloglomerular feedback activation, thereby preventing afferent arteriole constriction[33]. Concurrently, increased renin release from juxtaglomerular cells culminates in activation of the RAAS. Activation of RAAS results in elevated angiotensin II levels, which promote sodium retention and vasoconstriction to maintain blood pressure[34]. Furthermore, increased angiotensin II stimulates the release of AVP from the posterior pituitary gland and aldosterone from the adrenal glands, synergistically enhancing sodium retention and water reabsorption. Hypochloremia induces a decline in the functionality of Na⁺ and Cl^- channels situated in the thick ascending limb of the loop of Henle and distal convoluted tubule. This dysfunction increases sodium delivery to the distal nephron, triggering epithelial sodium channel activation and subsequent sodium reabsorption in exchange for potassium. The resultant hypokalemia and metabolic alkalosis have far-reaching consequences, including compromised myocardial contractility, arrhythmias, microcirculation abnormalities, neuromuscular irritability and, in extreme situations, seizures[35]. Furthermore, metabolic alkalosis shifts the oxygen dissociation curve to the left, impairing peripheral oxygen release. Hypochloremia has been associated with an increased risk of acute kidney injury and increased cardiovascular mortality in critical ill patients[13,36]. By causing RAAS activation and NaCl channel upregulation in the renal tubules, hypochloremia can worsen sodium retention and exacerbate diuretic resistance[37]. Studies have demonstrated that correcting hypochloremia with lysine chloride significantly enhances the efficacy of diuretics[38]. Serum chloride appears to reflect disease severity, as indicated by more severe coagulopathy, higher MELD scores, and increased need for vasopressors and renal replacement therapy in hypochloremic patients[2]. In summary, hypochloremia disrupts renal salt sensing by altering juxtaglomerular apparatus function and hormonal feedback mechanisms. This disruption leads to inappropriate sodium retention, potassium wasting, and acid-base disturbances, underscoring the critical importance of maintaining normochloremia in preserving renal and cardiovascular homeostasis.

Figure 1 Schematic diagram depicting the causes and impacts of hypochloremia in patients with advanced liver cirrhosis. ¹Increased mortality risk persists even after adjusting for Model for End-Stage Liver Disease and Sequential Organ Failure Assessment scores. RAAS: Renin-angiotensin-aldosterone system; SNS: Sympathetic nervous system; HTN: Hypertension; PCT: Proximal convoluted tubule; AVP: Arginine vasopressin; GI: Gastrointestinal; MELD: Model for End-Stage Liver Disease; SOFA: Sequential Organ Failure Assessment.

EVIDENCE SUPPORTING SERUM CHLORIDE AS A PROGNOSTIC MARKER

Several recent studies have suggested that serum chloride has significant prognostic value in critically ill cirrhosis and ALF patients (Table 2). In a study by Semmler et al[9], the prevalence of hyponatraemia and hypochloremia in an intensive care unit (ICU) cohort of 181 cirrhosis patients was found to be 47% and 30% respectively. Regression analysis revealed that serum chloride, not sodium, had a significant association with ICU mortality [odds ratio (OR): 0.94, 95%CI: 0.90-0.97]. Patients with serum chloride levels < 100 mmol/L exhibited significantly higher odds of ICU mortality than those with chloride levels > 100 mmol/L. Even after adjusting for blood pH, serum sodium, and MELD score, the association between hypochloremia and poor outcomes persisted [adjusted OR: 3.20 (95%CI: 1.20-8.82)]. Compared with MELD-Na, the combined MELD-chloride produced a slightly higher area under the receiver operating characteristic curve for ICU mortality prediction (86% vs 83%)[9]. A lower prevalence of hypochloremia compared with hyponatremia may suggest more serious disruptions of electrolyte and acid-base homeostasis in critically ill cirrhosis patients, which could explain its prognostic potential beyond sodium levels.

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.

In a study by Ji and Li[8], comprising 1216 critically ill cirrhotic patients with 16.4% having hypochloremia at baseline, the hyperchloremic group exhibited elevated levels of serum bilirubin, creatinine, international normalised ratio, and white blood cell counts compared with those without hypochloremia. Additionally, these patients received higher MELD and Sequential Organ Failure Assessment (SOFA) scores upon ICU admission. The hypochloremic group demonstrated a significantly higher ICU mortality rate than the non-hypochloremic group (34.2% vs 15.8%, P < 0.001), and it remained significant after multivariable adjustment. Moreover, patients with both hypochloremia and hyponatraemia had worse outcomes than those with either condition. Interestingly, each unit decrease in chloride was associated with a 6% relative increase in ICU mortality risk (OR = 0.94, 95%CI: 0.91-0.98, P = 0.002)[8]. In a retrospective cohort study by Sumarsono et al[14], 40% of 389 critically ill cirrhotic patients presented with hypochloremia, which was positively associated with serum sodium but negatively correlated with lactate, blood urea nitrogen, and creatinine. These patients had higher Child-Pugh classes, MELD-Na, and SOFA scores at ICU admission. In-hospital mortality was significantly higher in the hypochloremic group (31% vs 19%, P < 0.01), as were the 180-day mortality rates (45.2% vs 26.7%, P < 0.0001). Each unit decrease in chloride was linked to a 5% increase in 180-day mortality [hazard ratio (HR) = 0.95, 95%CI: 0.93-0.98, P = 0.001], with the association persisting after adjusting for MELD or SOFA scores. Again, hypochloremia was an independent risk factor for death, whereas hyponatremia was not. Kaplan-Meier analysis indicated significantly reduced survival in hypochloremic patients[14]. In a study by Cheng et al[39], serum chloride (HR = 0.823, 95%CI: 0.757-0.894, P < 0.001) was an independent predictor of one-year mortality in cirrhosis patients undergoing transjugular intrahepatic portosystemic shunt. Even patients with serum chloride < 107.35 mmol/L had significantly worse survival than those with levels ≥ 107.35 mmol/L, irrespective of ascites (P < 0.05). The prognostic significance of hypochloremia was also documented in non-cirrhotic advanced liver diseases. In a longitudinal cohort study involving 2588 patients with ALF, hypochloremia was observed in 17.8% of the subjects at baseline. Hypochloremic ALF patients presented with significantly higher MELD scores (P < 0.001) and a greater need for vasopressors and renal replacement therapy compared with those without hypochloremia (P < 0.001). The 21-day mortality rate was markedly higher in patients with hypochloremia at 42.1%, compared with 27.5% in normochloremic patients (P < 0.001). Additionally, transplant-free survival was 11% lower in the hypochloremic group compared with the normal and hyperchloremic groups (P < 0.001)[2]. Notably, serum sodium has been found to have limited prognostic value in ALF patients[40].

THERAPEUTIC IMPLICATIONS AND KNOWLEDGE GAPS

The potential role of chloride as a therapeutic target needs to be ascertained, and prospective research must seek to understand how chloride modulation affects clinical outcomes in these patients. While therapies such as adjunctive acetazolamide and hypertonic saline therapies may help with chloride imbalance, their safety and efficacy for patients with advanced cirrhosis and liver failure remain uncertain. Hypertonic saline, which contains high concentrations of sodium and chloride, can increase serum chloride levels. Theoretically, it may offer several benefits, including an osmotic shift of intracellular fluid, leading to increased intravascular volume, promoting diuresis. Combining hypertonic saline with furosemide may have synergistic effects, as hypertonic saline can decrease renin production, cause renal vasodilation, and facilitate diuresis[41]. Whereas furosemide can block tubuloglomerular feedback secondary to increased serum chloride levels[42]. Although this strategy has shown efficacy in treating heart failure, its effectiveness in cirrhosis patients remains unknown[43-45]. Notably, hypertonic saline is often recommended for managing elevated intracranial pressure in ALF patients, but it may exacerbate ascites and edema in patients with cirrhosis. Acetazolamide, a carbonic anhydrase inhibitor, acts on renal tubules to increase bicarbonate excretion and facilitate chloride reabsorption. Its role has been explored in patients with acute heart failure and volume overload, where it has been shown to alleviate congestion[46]. However, the use of acetazolamide in liver cirrhosis patients raises safety concerns, as it can reduce ammonia excretion and precipitate hepatic encephalopathy[47]. Investigating the combination of acetazolamide with ammonia-lowering agents may be a worthwhile approach to mitigate this risk.

CONCLUSION

In critically ill liver disease patients, lower serum chloride levels represent a significant but underutilised prognostic marker. In fact, hypochloremia may partially explain the mortality risk previously attributed to hyponatremia. The pathophysiological mechanisms underlying the association between low serum chloride levels and poor outcomes in liver disease appear to involve complex interactions among electrolyte imbalances, renal function, and systemic hemodynamics. Given that serum chloride is routinely tested in blood chemistry, it may be worthwhile to use its predictive value in clinical practice. While the relationship between hypochloremia and advanced liver disease prognosis is intriguing, direct evidence on how geographical and patient-specific factors influence this association is currently lacking. Interestingly, certain variants of the renal chloride channel gene have been identified as significant genetic risk factors for heart failure in Caucasian populations[48,49]. It is plausible that similar geographical variants could also influence the prognosis of liver disease patients. A significant gap in knowledge exists regarding the prognostic importance of chloride fluctuations in patients with advanced liver disease. It is unclear whether the overall prognosis is the same for hypochloremia resulting from chloride depletion or dilution. Future research should focus on integrating serum chloride measurements into prognostic models and exploring targeted interventions to address chloride imbalances, thereby potentially improving outcomes for this vulnerable patient population.