2025 Volume 266 Issue 4 Pages 311-317
Serum butyrylcholinesterase (BChE) levels are positively correlated with serum albumin levels and are influenced by inflammation. Heterozygous BChE deficiency in patients on dialysis may be overlooked as malnutrition owing to dialysis-associated low BChE and albumin levels. In this study, we aimed to clarify a method for identifying low BChE levels due to hereditary causes. This single-center, retrospective, observational study included 1,104 patients undergoing dialysis and 1,716 patients not undergoing dialysis. Patients on dialysis with available data of high-sensitivity C-reactive protein (hsCRP) levels were divided into three groups according to the hsCRP level: low (< 1 mg/L), average (1-3 mg/L), and high (> 3 mg/L), and the association of serum hsCRP level with BChE and albumin levels was investigated. We compared intercept values (y value at x = 0) of the regression formula obtained from repeated measurements between patients on dialysis and those with a known hereditary heterozygous BChE deficiency. Serum BChE and albumin levels in patients on dialysis were significantly lower, and a positive correlation was observed. The hsCRP level and the BChE and albumin levels were negatively correlated. BChE and albumin levels were highest in the low hsCRP group and lowest in the high hsCRP group, and a significant positive correlation was observed in all groups. The intercept values of the regression formula obtained from repeated measurements of BChE and albumin levels in patients on dialysis and a patient with hereditary heterozygous BChE deficiency were 0.383 and –102.730, respectively, which may be useful in distinguishing hereditary causes.
There are two types of cholinesterases in the human body: acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) (Patocka et al. 2004; Das 2007). AChE is an important enzyme in the central and peripheral nervous systems that plays a key role in the transmission of nerve impulses. The physiological role of BChE remains unknown. In humans, BChE is synthesized in many tissues, such as the liver, heart, and brain (Patocka et al. 2004). The half-life of BChE is approximately 12 days, and its reference interval is 240-486 U/L in male, and 201-421 U/L in female, respectively (Ichihara et al. 2016). Serum BChE levels decrease under various conditions such as acute and chronic liver injury, cirrhosis, malnutrition, inflammation, renal failure, and malignancy (Lampon et al. 2012).
Along with external factors, genetic factors are also involved. Hereditary BChE deficiency is a pharmacogenetic disease with an autosomal recessive inheritance (Lockridge 2015). We recently reported the case of a 52-year-old male patient on dialysis with hereditary heterozygous BChE deficiency (Tokunaga et al. 2024). His serum BChE levels fluctuated between 76 and 170 U/L; however, it was not investigated. He was diagnosed when his older sister was diagnosed. Identifying patients on dialysis with heterozygous BChE deficiency is challenging because BChE activity is not completely absent in heterozygotes, and it may be overlooked as malnutrition. There are currently no specific studies. Therefore, in this study, we aimed to clarify a useful method for identifying low BChE levels due to hereditary causes in patients undergoing dialysis. We hope that this report provides new clues for the identification of genetic factors.
This single-center, retrospective study enrolled 1,104 patients undergoing dialysis and 1,716 patients not undergoing dialysis. The major inclusion criteria were patients who visited our hospital between April and September 2022, those whose laboratory visit data for BChE, and albumin on the same day were complete. Furthermore, one patient with hereditary heterozygous BChE deficiency was included (Tokunaga et al. 2024). This study was approved by the Ethics Committee of our institution (approval no. 1117) and was conducted in accordance with the principles of the Declaration of Helsinki and Japanese ethical guidelines. Because of the retrospective study design and the anonymity of the patients studied, the requirement for written informed consent was waived by posting opt-out information.
Data collectionBaseline demographic information and laboratory data, including serum BChE, albumin, and high-sensitivity C-reactive protein (hsCRP) levels, were collected by reviewing patients’ medical records.
Statistical analysisAll data are expressed as mean ± standard deviation. Continuous variables were compared using Student t-test or Mann-Whitney U test, as appropriate. Simple linear regression analyses were used to assess the relationships between serum BChE and albumin levels, BChE and hsCRP levels, and albumin and hsCRP levels. We investigated the association of serum hsCRP level with BChE and albumin levels in patients on dialysis (n = 1,000) and divided them into three groups according to the hsCRP level (Lampon et al. 2012): low (< 1 mg/L), average (1-3 mg/L), and high (> 3 mg/L). The differences in BChE and albumin levels among the three groups were analyzed using analysis of variance (ANOVA). When the group difference was statistically significant, Bonferroni tests were used for the post hoc analysis.
Then, we compared intercept values (y value at x = 0) of the regression formula obtained from repeated measurements of BChE and albumin levels. Patients on dialysis with one measurement of BChE and albumin levels were excluded (n = 23). We investigated longitudinal datasets in 1,081 patients on dialysis (n = 6,259) and in a patient with known hereditary heterozygous BChE deficiency (Tokunaga et al. 2024) (n = 57). All statistical analyses were performed using EZR (Version 1.61). p < 0.05 was considered to be statistically significant.
This study included 1,716 patients not undergoing dialysis (1,114 male, 602 female; average age, 66.7 years) and 1,104 patients undergoing dialysis (723 male, 381 female; average age, 69.9 years). The serum BChE and albumin levels in patients on dialysis were significantly lower than those in patients not undergoing dialysis (227.2 ± 70.4 U/L vs. 293.6 ± 81.4 U/L; p < 0.001, 3.2 ± 0.4 g/dL vs. 4.0 ± 0.5 g/dL; p < 0.001) (Fig. 1A,B).
Serum BChE and albumin levels in patients undergoing and not undergoing dialysis.
Serum (A) BChE and (B) albumin levels in patients undergoing dialysis (n = 1,104) were significantly lower than those not undergoing dialysis (n = 1,716). ***p < 0.001. BChE: butyrylcholinesterase.
We evaluated the relationship between serum BChE and albumin levels in all patients. Serum BChE and albumin levels were positively correlated (R2 = 0.204, p < 0.001; R2 = 0.162, p < 0.001, respectively) (Fig. 2A,B). The regression formula to calculate the serum BChE and albumin levels in patients not undergoing dialysis and those undergoing dialysis were BChE = 78.921 (albumin) – 24.297 and BChE = 70.494 (albumin) + 1.087, respectively (Fig. 2A,B).
Relationship between serum BChE and albumin levels in patients (A) not undergoing dialysis and (B) undergoing dialysis.
Serum BChE and albumin levels were positively associated in each group. BChE: butyrylcholinesterase, R2: Coefficient of determination.
In patients undergoing dialysis with available data on hsCRP levels (n = 1,000), a significant negative correlation was observed between serum BChE and hsCRP levels (R2 = 0.052, p < 0.001) (Fig. 3A). A significant negative correlation was also observed between serum albumin and hsCRP levels (R2 = 0.178, p < 0.001) (Fig. 3B). Next, we divided the 1,000 patients into three groups according to hsCRP levels: low (< 1 mg/L; n = 892), average (1-3 mg/L; n = 81), and high (> 3 mg/L; n = 27), and investigated the BChE and albumin levels according to hsCRP concentrations. There was a group difference in BChE and albumin levels (p < 0.001, ANOVA). A post-hoc analysis showed that BChE and albumin levels were highest in the low hsCRP group (233.5 ± 68.0 U/L, 3.3 ± 0.3 g/dL) and lowest in the high hsCRP group (151.6 ± 56.3 U/L, 2.5 ± 0.6 g/dL) (Fig. 4A,B). Serum BChE levels were positively correlated with albumin levels in patients in the low hsCRP group (R2 = 0.092, p < 0.001) (Fig. 5A), average hsCRP group (R2 = 0.199, p < 0.001) (Fig. 5B), and high hsCRP group (R2 = 0.556, p < 0.001) (Fig. 5C). The serum hsCRP level was negatively correlated with BChE and albumin levels in the low hsCRP group (R2 = 0.016, p < 0.001; R2 = 0.060, p < 0.001, respectively) (data not shown). The correlations between serum hsCRP levels and BChE and albumin levels were not significant in the average and high hsCRP groups (data not shown).
Relationship between serum hsCRP level with (A) BChE and (B) albumin levels in patients on dialysis (n = 1,000).
A significant negative correlation between serum BChE and hsCRP levels, and serum albumin and hsCRP levels was obtained. hsCRP: high-sensitivity C-reactive protein, BChE: butyrylcholinesterase, R2: Coefficient of determination.
Serum (A) BChE and (B) albumin levels according to hsCRP concentrations in patients on dialysis.
The 1,000 patients were divided into three groups according with the hsCRP ranges: < 1 mg/L (n = 892), 1-3 mg/L (n = 81), and > 3 mg/L (n = 27). Higher levels of hsCRP were associated with lower levels of BChE and albumin. ***p < 0.001. hsCRP: high-sensitivity C-reactive protein, BChE: butyrylcholinesterase.
Relationship between serum BChE and albumin levels in patients on dialysis in three groups according to the hsCRP ranges: (A) < 1 mg/L, (B) 1-3 mg/L, and (C) > 3 mg/L.
A significant positive relationship was found between serum BChE and albumin levels in each group. hsCRP: high-sensitivity C-reactive protein, BChE: butyrylcholinesteras, R2: Coefficient of determination.
Finally, we compared intercept values (y value at x = 0) of the regression formula obtained from repetitive measurements in patients on dialysis and in a patient with known hereditary heterozygous BChE deficiency (Tokunaga et al. 2024). Fig. 6A shows the regression formula obtained from the longitudinal datasets (n = 6,259) of patients on dialysis (n = 1,081): BChE = 70.583 (albumin) + 0.383 (R2 = 0.158, p < 0.001). The number of patients with repetitive measurements (two, three, four, five, six, seven, and eight) are 19, 20, 28, 60, 930, 23, and 1, respectively. Fig. 6B shows the regression formula obtained from the longitudinal datasets (n = 57) of a patient with known hereditary heterozygous BChE deficiency: 73.006 (albumin) –102.730 (R2 = 0.643, p < 0.001).
Relationship between serum BChE and albumin levels obtained from repetitive measurements in (A) patients on dialysis (n = 6,259) and (B) the patient with a hereditary heterozygous BChE deficiency (n = 57).
The intercept of the regression formula obtained from repetitive measurement in patients with hereditary heterozygous BChE deficiency may decrease. R2: Coefficient of determination.
The intercept of the regression formula between serum BChE and albumin levels obtained from repetitive measurements may decrease in patients on dialysis with hereditary heterozygous BChE deficiency. To the best of our knowledge, this is the first report of a novel method for differentiating patients on dialysis with hereditary heterozygous BChE deficiencies. Our findings provide a reference equation for their identification. When the slope of the regression equation is close to 70, the intercept value may be reliable regardless of the number of plots. The far negative intercept obtained may suggest a genetic disorder, and in the clinical practice of dialysis, careful repetitive measurement can inform a suspected genetic alteration.
The frequency of hereditary heterozygous BChE deficiency is 1 in 150-200 individuals in Japan (Tokunaga et al. 2024). A PubMed search revealed 23 reported cases of hereditary BChE deficiency reported since 2010 (Tokunaga et al. 2024). However, none of these patients were undergoing dialysis. Considering the frequency of genetic causes, the number of patients diagnosed during dialysis may have been very small. The detection of heterozygous BChE deficiency may be difficult in patients on dialysis because of low BChE levels. However, it is worthwhile to identify the genetic factors. Patients with BChE deficiency have no risk in daily life but may have a risk of post-anesthetic apnea presenting as a prolonged coma and even death due to the delayed decomposition of succinylcholine or mivacurium used during surgery (Gätke et al. 2007). Therefore, a definitive diagnosis of BChE deficiency is important, and medical staff supporting patient care should be aware of the use of neuromuscular blocking agents (Tokunaga et al. 2024). Patients with BChE deficiency are often suspected to have hepatic dysfunction. Once diagnosed, the low serum BChE level was considered as the baseline, and unnecessary tests to determine the cause of hepatic dysfunction could be avoided. An assessment of the regression formula revealed that the intercept obtained by plotting repetitive serum BChE and albumin levels may be a useful marker for diagnosing BChE enzyme abnormalities.
Serum BChE levels serve as useful biomarkers for monitoring nutritional status because of the short half-life of BChE and ability to predict mortality from cardiovascular diseases (Calderon-Margalit et al. 2006; Santarpia et al. 2013; Sulzgruber et al. 2015). Serum BChE and albumin levels decrease in patients on dialysis (Yeun and Kaysen 1998; Garcia et al. 2008), which is consistent with our results. Because the production of BChE and albumin in the liver occurs simultaneously, albumin levels might decrease as BChE levels decrease (Lampon et al. 2012). Protein-energy wasting (PEW) is a condition that manifests as metabolic and nutritional abnormalities and is prevalent in patients on dialysis (Carrero et al. 2018). In addition to PEW, multiple factors, including anorexia and metabolic and hormonal disorders, can affect the metabolic and nutritional status of patients on dialysis (Okamoto et al. 2018; Fukushi et al. 2022). There are additional protein catabolic processes, such as the unavoidable loss of amino acids, albumin leakage due to dialysis, and inflammatory stimuli associated with the dialysis procedure (Ikizler et al. 1994; Ikizler 2013). Patients on dialysis may have decreased BChE synthesis owing to inadequate amounts of substrates and dialysis-induced catabolism (Fukushi et al. 2022).
Serum BChE levels are positively correlated with serum albumin levels and are strongly influenced by inflammation (Hubbard et al. 2008; Lampon et al. 2012). As both BChE and albumin are synthesized in the liver, their correlation is determined by their production sites, except in genetic diseases (Maekawa et al. 1997). Moreover, the monomeric form of BChE is conjugated to plasma albumin by a C2 compound (Masson 1989). Patients on dialysis have a chronic inflammatory state, as reflected by increased levels of pro-inflammatory cytokines or acute-phase proteins (Stojanov et al. 2009; Cobo et al. 2018). Here, the inflammatory state was evaluated based on the hsCRP level. Among all investigated patients on dialysis, significant negative correlations were observed among hsCRP, BChE, and albumin levels. Furthermore, when patients were classified into three groups according to their inflammatory status, higher hsCRP levels were associated with lower BChE and albumin levels. Serum BChE and albumin levels were positively correlated in all groups with the three-degree inflammation. These results suggest that BChE levels may correlate with albumin levels, regardless of the degree of inflammation.
The main limitation of this study is that it was a single-center retrospective study with a small sample size. Further prospective studies with larger sample sizes are required to confirm our findings.
In conclusion, in patients on dialysis, low serum BChE levels may be overlooked as malnutrition because of their low albumin levels. BChE deficiency should be suspected in patients with unexplained low serum BChE levels. In such cases, the intercept of the regression formula obtained by plotting serum BChE and albumin levels may be useful in distinguishing hereditary causes.
N.T. and H.S. drafted the manuscript. N.T., H.S., T.O. performed literature searches. H.S., M.M., and J.M. coordinated data analysis and critically commented on the manuscript. T.O., M.M., and J.M. helped write the manuscript. All authors participated in the discussions, and read and approved the final manuscript.
We thank Editage for technical assistance in editing a draft of this manuscript.
The authors declare no conflict of interest.
