Hypochloremia as a Novel Adverse Prognostic Factor in Acute Liver Failure

Jiexin Wang; Po-Hong Liu; Pin Xu; Andrew Sumarsono; Jody A. Rule; S. Susan Hedayati; William M. Lee


Liver International. 2022;42(12):2781-2790. 

In This Article

Abstract and Introduction


Background and Aims: Emerging evidence has identified hypochloremia as an independent predictor for mortality in multiple conditions including cirrhosis. Acute liver failure (ALF) is frequently complicated by electrolyte abnormalities. We investigated the prognostic value of hypochloremia in a large cohort of ALF patients from North America.

Methods: The Acute Liver Failure Study Group (ALFSG) registry is a longitudinal cohort study involving 2588 ALF patients enrolled prospectively from 32 North American academic centres. The primary outcome was a composite of 21-day all-cause mortality or requirement for liver transplantation (death/LT).

Results: Patients with hypochloremia (<98 mEq/L) had a significantly higher 21-day mortality rate (42.1%) compared with those with normal (27.5%) or high (>107 mEq/L) chloride (28.0%) (p < .001). There was lower transplant-free cumulative survival in the hypochloremic group than in the normo- or hyper-chloremic groups (log-rank, χ 2 24.2, p < .001). Serum chloride was inversely associated with the hazard of 21-day death/LT with multivariable adjustment for known prognostic factors (adjusted hazard ratio [aHR]: 0.977; 95% CI: 0.969–0.985; p < .001). Adding chloride to the ALFSG Prognostic Index more accurately predicted risk of death/LT in 19% of patients (net reclassification improvement [NRI] = 0.19, 95% CI: 0.13–0.25) but underestimated the probability of transplant-free survival in 34% of patients (NRI = −0.34, 95% CI: −0.39 to −0.28).

Conclusions: Hypochloremia is a novel independent adverse prognostic factor in ALF. A new ALFSG-Cl Prognostic Index may improve the sensitivity to identify patients at risk for death without LT.


Acute liver failure (ALF) is a rare yet catastrophic disease of severe hepatocyte injury causing coagulopathy and hepatic encephalopathy (HE) in patients without preexisting liver disease.[1] The overall mortality rate was reported as high as 93% in the 1970s, which has decreased to 38% largely due to the advent of liver transplantation.[2] Currently, predicting whether a patient will recover their native liver without transplantation remains a challenge to clinicians. Several prognostic tools including the King's College Criteria (KCC) and Model for End-stage Liver Disease (MELD) have been proposed to predict mortality in ALF patients.[3–5] While the KCC is the first developed prognostic tool, it was generated prior to the wide application of liver transplantation. Subsequent validation with more contemporary databases revealed its relatively low sensitivity of 68%–69% in predicting short-term mortality,[6,7] and does not reliably predict transplant-free survival due to its low negative predictive value. The more recent ALFSG Prognostic Index proposed in 2016 was shown to be more accurate than the KCC or MELD in predicting transplant-free survival, although further external validation is needed.[8]

Emerging evidence has identified hypochloremia as a predictor for mortality in patients with congestive heart failure and chronic kidney disease.[9–12] More recently, hypochloremia was demonstrated to be an adverse prognostic factor independent of serum sodium in patients with decompensated cirrhosis.[13–16] Electrolyte derangements are frequently observed in the ALF population, with previous studies focused on hypophosphatemia and hyponatremia.[17–19] However, very little is known about the prognostic value and clinical relevance of chloride perturbations in ALF patients. This study aimed to: (i) investigate whether hypochloremia was associated with greater disease severity and poorer clinical outcome in a large cohort of ALF patients from North America; (ii) determine whether incorporating serum chloride into the ALFSG Prognostic Index may improve the prediction of transplant-free survival.