(Butyrylcholinesterase dficiency, Pseudocholinesterase deficiency)

The plasma pseudocholinesterase (also known as butyrylcholinesterase or plasma cholinesterase and nonspecific cholinesterase) is a glycoproteolytic enzyme synthesized in the liver, able to break the ester bonds of choline in foreign proteins:

-         succinylcholine, hydrolyzed in succinyl monocholine then in succinic acid,

-         mivacurium, 

-         amino-esters type local anesthetics such as procaine and cocaine. 

The decrease in its activity prolongs the action of these drugs.

This enzyme is found in the blood and most tissues of the body except red blood cells. Its half-life is about 8 to 16 hours.

A quantitative or qualitative modification of its activity can be caused by:

• genetic causes : 
  prevalence: 1/2,800. Plasma pseudocholinesterase deficiency are mostly genetic in origin, with a greater frequency in Caucasian populations than in Asian populations. An Indian population (Arya Vysyas) presents a considerable prevalence of the anomaly (4000 times higher than Caucasian populations). The synthesis of plasma pseudocholinesterase is controlled by 2 alleles, noted 'Eu', at the level of the locus BCHE1 of the long arm of the gene on 3q26.1-q26.2. In 96 % of cases, the population is homozygous for these 2 alleles (genotype Eu-Eu). The remaining 4 % present, at the BCHE1 locus, either homozygously or heterozygously, one or more of the 4 main atypical alleles of the gene:

- allele Ea (or atypical form): mutation of the Eu gene responsible for the resistance to dibucaine; the most common atypical genotype, Eu - Ea, occurs in 2.5 % of the population and causes only a modest prolongation (which can be unnoticed) of the duration of action of succinylcholine. Ea - Ea homozygosity, much rarer, causes a prolongation of the curarization  beyond 1 hour. 

- allele Ef: mutation of the gene responsible for Eu's resistance to fluoride; even in the homozygous form Ef - Ef, the prolongation of curarization is moderate, usually less than 1 h

- alleles Es: these 12 different alleles are characterized by the presence of a stop-codon responsible for of the "silent" variant. In the absence (genotype Es-Es) or near-total absence of pseudocholinesterase, which is exceptional (prevalence: 1/100.000), neuromuscular paralysis after a dose of succinylcholine may extend up to 8 h.

- alternative K: this is the most common variant. It leads to a reduction of approximately 30 % of the anticholinesterasic activity and therefore does not interfere with the clinical effect unless it is associated with atypical form or an acquired or iatrogenic cause of deficiency of acetylcholinesterases.

There is also a rare allele, the C5 allele, which induces a increased production of pseudocholinesterase (with an increased plasma level), resulting in a relative resistance to succinylcholine.

The majority of the 4 % patients not having the genotype Eu - Eu carry a single atypical allele (heterozygosity Eu - Ea or Eu - Ef) and develop a partial pseudocholinesterase deficiency resulting in a moderately prolonged curarization by succinylcholine (> 5 min but < 1 h). A severe decrease in plasma pseudocholinesterasique activity  caused by the presence of 2 atypical alleles It is present in less than 0.1 % of the population 

• physiological variations :

-        neonatal period: 40-50 % of adult levels

- pregnancy

-        during strenuous exercise

-        in case of significant malnutrition

• acquired causes

-        hepatic failure

-        kidney disease, especially in case of chronic hemodialysis

-        cancer: response to some chemotherapy (cyclophosphamide)

-        severely burned, proportionally to the burned surface

-        hypothyroidism (myxedema)

-        organophosphate poisoning

• iatrogenic causes

-        plasmapheresis

-        neostigmine: competitive inhibition

-         echothiophate containing eyedrops

-        oral contraception

-        neuromuscular blocking drugs: pancuronium, vecuronium and rocuronium

-        metoclopramide

-        L.A.: bupivacaine, dibucaine, chloroprocaine

-        antidepressant: MAOI's

Diagnosis : 3 biological tests can be performed:

-         determination of the plasma pseudocholinesterasique activity;

-         test of inhibition with dibucaine to define the "dibucaine number";

-         inhibition test with fluoride, to define by analogy with the previous test, the "fluoride number".

The total absence of pseudocholinesterasic activity, which is exceptional, is due to the "silent" homozygous form Es-Es.

Dibucaine has the property to inhibit the activity of pseudocholinesterase with a much stronger effect on mutant forms with the Ea allele than on the normal Eu-Eu form. The percentage of  inhibition of enzyme activity by dibucaine (0.03 mmol/L) defines the 'dibucaine number' and allows identifying three main genotypes of the disease: 

-          EU-Eu, normal dibucaine number equal to 80 %, 

-          EA - Ea, abnormal homozygous, with a dibucaine number equal to 20 %,

-         EU - Ea, heterozygous, for 2.5 % of the general population, with a dibucaine number between 20 and 80 %.

Exposure to fluoride (4 mmol/L) permits to identify the presence of the less frequent Ef allele, the consequences of which are more limited; it shows a reduction of the in vitro hydrolysis of benzylcholine by the plasma of subjects that carry it:

-         fluoride number is equal to 55-65 % in normal subjects (Eu-Eus), 

-         fluoride number is equal to 36 % in Ef - Ef homozygotes,

-         intermediate fluoride number for Eu - Ef heterozygotes.

The interpretation of the results is more difficult in young children whose plasma pseudocholinesterasic activity is greater than in adults from which the reference values have been established: that must be taken into account when iterpreting the results.

Anesthetic implications: 

NO succinylcholine, NO mivacurium, NO local anesthetic of ester (chloroprocaine) type. In case of prolonged apnea after succinylcholine or mivacurium, treatment is essentially limited to the controlled ventilation until the resumption of spontaneous ventilation and the return of normal muscle tone, which can require several hours (homozygous forms). The administration of a sufficient quantity of fresh frozen plasma (2 units in adults), providing "exogenous" pseudocholinesterases, quickly restores normal neuromuscular function, but is controversial.

References : 

-        Davis L, Britten JJ, Morgan M. 
Cholinesterase. Its significance in anaesthetic practice. 
Anaesthesia 1997; 52:244-60.

-         Sener EB, Ustun E, Kocamanoglu S, Tur A. 
Prolonged apnea following succinylcholine administration in undiagnosed acute organophosphate poisoning.
Acta Anaesthesiol Scand 2002; 46:1046-8.

-         Niazi A, Leonard IE, O'Kelly B. 
Prolonged neuromuscular blockade as a result of malnutrition-induced pseudocholinesterase deficiency. 
J Clin Anesth 2004; 16:40-2.

-         Ho VW, Osiovich H. 
A case of pseudocholinesterase deficiency of the neonate. 
Am J Perinatol 1999; 16:351-3.

-        Cerf C, Mesguish M, Gabriel I, Amselem S, Duvaldestin P. 
Screening patients with prolonged neuromuscular blockade after succinylcholine and mivacurium. 
Anesth Analg 2002; 94:461-6

-         Lejus C, Delaroche O, Trille E, Blanloeil Y, Pinaud M. 
Déficit génétique de la butyrylcholinestérase : comment interpréter l'activité cholinestérasique chez le jeune enfant? 
Ann Fr Anesth Reanim 2006; 25:657-60.

-         Soliday FK, Conley YP, Henker R. 
Pseudocholinesterase deficiency: a comprehensive review of genetic, acquired and drug influences. 
AANA Journal 2010; 78: 313-20

-        Mabboux I, Harry B, Courcell S, Ceppa F, Delacour H.
Curarisation prolongée liée à un déficit en butyrylcholinestérase.
Arch Pédiatr 2016 ; 497-500.

-        Andersson ML, Moler AM, Wildgaard K.
Butyrylcholinesterase deficiency and its clinical importance in anaesthesia : a systematic review.
Anaesthesia 2019; 74: 518-28.

Updated: April 2019