U-Shape Relationship between Plasma Leucine Level and Mortality in the Intensive Care Unit

Abstract

Patients in the intensive care unit (ICU) are at high risk of mortality which is not well predicted. Previous studies noted that leucine has prognostic value in a variety of diseases. This study investigated whether leucine concentration was a useful biomarker of metabolic and nutritional status and 6-month mortality in ICU. We recruited 454 subjects admitted to ICU (348 and 106 in the initiation and validation cohorts, respectively) with an acute physiology and chronic health evaluation (APACHE II) score ≥ 15 . We measured plasma leucine concentrations, traditional biomarkers, and calculated APACHE II and sequential organ failure assessment (SOFA) scores. Leucine levels were weakly correlated with albumin, prealbumin, and transferrin levels ( r = 0.30 , 0.12, and 0.15, p = 0.001 , 0.029, and 0.007, respectively). During follow-up, 116 (33.3%) patients died. Compared to patients with leucine levels between 109 and 174 μM, patients with leucine > 174 μ M or <109 μM had a lower cumulative survival rate. Death was also associated with age, higher APACHE II and SOFA scores, C-reactive protein, and longer stays in the ICU, but with lower albumin, prealbumin, and transferrin. Patients with leucine levels > 174 μ M had higher alanine aminotransferase levels, but no significant differences in other variables; patients with leucine levels < 109 μ M had higher APACHE II and SOFA scores, higher incidence of using inotropic agents, longer ICU and hospital stays, but lower albumin and transferrin levels. Multivariable analysis demonstrated that leucine > 174 μ M was an independent predictor of mortality, especially early mortality. However, among patients who stayed in ICU longer than two weeks, leucine < 109 μ M was an independent predictor of mortality. In addition, leucine < 109 μ M was associated with worse ventilator weaning profiles. These findings were similar in the validation cohort. Our study demonstrated a U-shape relationship between leucine levels and mortality rate in ICU.

Combining Phenylalanine and Leucine Levels Predicts 30-Day Mortality in Critically Ill Patients Better than Traditional Risk Factors with Multicenter Validation

“…It has been shown that leucine levels correlate well with the total amount of essential amino acids [ 18 ]. Recently, we noted a U-shaped relationship between leucine concentrations and ICU mortality [ 17 , 18 ]. High leucine levels represent anabolic resistance and massive endogenous release of energy in the acute phase, characterized by increased unmetabolized acylcarnitines in the circulation due to mitochondrial dysfunction with impaired beta-oxidation [ 15 , 18 ].…”

“…Stress hyperphenylalaninemia has been associated with a three-fold increase of mortality in ICU patients [ 13 , 14 ]. On the other hand, a U-shaped relationship between leucine levels and mortality in ICU patients was also noted [ 17 , 18 ]. High leucine levels may represent large endogenous release of energy and amino acids in the acute phase of critical illness and anabolic resistance, while low leucine levels may imply malnutrition.…”

Diet Is Associated with Frailty in Lung Cancer: A Possible Role of Gut Microbiota

“…In the present study, we observed that the frail patients had lower leucine intake compared to the non-frail patients, with higher plasma leucine levels. This might be attributed to the frail patients being in a state of metabolic synthesis resistance, leading to the release of more leucine to overcome the resistance and stimulate muscle protein synthesis [44].…”

The need for biomarkers to determine response to enteral nutrition during and after critical illness: an update

“…Studied biomarkers are summarized in Table 1, which needs to be interpreted with caution as none of the presented studies is able to provide definitive answers regarding the dynamics and usefulness of putative markers [4 ▪▪ ,20,21,33,34,36 ▪ ,37,39–42,53,54]. Very recently, Jenkins and colleagues have reached similar conclusions regarding both the current absence and the future necessity of biomarkers of GI dysfunction [55 ▪ ].…”

“…Blood levels of leucine (which is well represented in albumin and prealbumin) appear to have a meaningful correlation with nutritional status, and a new study in 454 ICU patients indicates that an initially high level of this amino acid is an adverse prognostic marker in critical care [36 ▪ ]. A multivariable Cox regression analysis demonstrated that concentrations >174 μM were independently predictive of early mortality after adjusting for age, disease severity and other laboratory markers, while provision of nutrition was not addressed.…”