Pseudocholinesterase Deficiency

Updated: Dec 13, 2022
  • Author: Daniel R Alexander, MD; Chief Editor: Karl S Roth, MD  more...
  • Print
Overview

Practice Essentials

Pseudocholinesterase deficiency, also known as butyrylcholinesterase deficiency, [1] is an inherited enzyme abnormality that results in abnormally slow metabolic degradation of exogenous choline ester drugs such as succinylcholine and mivacurium. If there is a deficiency in the plasma activity of pseudocholinesterase, prolonged muscular paralysis may occur, resulting in an extended need for mechanical ventilation. A variety of pathologic conditions, physiologic alterations, and medications can lower plasma pseudocholinesterase activity. [2, 3, 4, 5, 6, 7, 8, 9]

A personal or family history of an adverse drug reaction to one of the choline ester compounds such as succinylcholine, mivacurium, or cocaine may be the only clue suggesting pseudocholinesterase deficiency. Most clinically significant cases of pseudocholinesterase deficiency are due to 1 or more inherited abnormal alleles that code for synthesis of the enzyme.

Anesthesia providers must understand the pathophysiology of pseudocholinesterase deficiency and must be prepared to safely and effectively manage patients who show signs and symptoms consistent with the disorder after indicated neuromuscular blocking drugs are used. [10]

The inherited form of the enzyme transfers in an autosomal recessive manner secondary to mutations in the butyrylcholinesterase gene, located on chromosome 3 (3q26.1-26.20). Malnutrition, pregnancy and the postpartum period, burns, liver disease, kidney disease, hemodialysis, myocardial infarction, congestive heart failure, malignancy, chronic infection, and drugs such as steroids and cytotoxic agents can decrease production of the pseudocholinesterase enzyme. Certain other medications and chemicals such as organophosphate insecticides, monoamine oxidase inhibitors, and anticholinesterase drugs can inhibit enzyme activity. [1]

This condition is recognized most often when respiratory paralysis unexpectedly persists for a prolonged period of time following administration of standard doses of succinylcholine. [11] The mainstay of treatment in these cases is ventilatory support until diffusion of succinylcholine from the myoneural junction permits return of neuromuscular function of skeletal muscle. The diagnosis is confirmed by a laboratory assay demonstrating decreased plasma cholinesterase enzyme activity.

Genetic analysis may reveal several allelic mutations in the pseudocholinesterase gene, including point mutations resulting in abnormal enzyme structure and function and frameshift or stop codon mutations resulting in absent enzyme synthesis. Partial deficiencies in inherited pseudocholinesterase enzyme activity may be clinically insignificant unless accompanied by a concomitant acquired cause of pseudocholinesterase deficiency. Clinically significant effects are generally not observed until plasma cholinesterase activity is reduced to less than 75% of normal. [3] Pseudocholinesterase deficiency is most common among people of European descent; it is rare in Asians.

The prognosis for recovery following administration of succinylcholine is excellent when medical support includes close monitoring and respiratory support measures. In nonmedical settings in which individuals with pseudocholinesterase deficiency are exposed to cocaine, sudden cardiac death can occur.

Individuals with pseudocholinesterase deficiency may also be at increased risk of toxic reactions, including sudden cardiac death, associated with recreational use of cocaine.

Patients with known pseudocholinesterase deficiency may wear a medic-alert bracelet that will notify healthcare workers of increased risk from administration of succinylcholine. These patients also may notify others in their family who may be at risk for carrying one or more abnormal pseudocholinesterase gene alleles.

Next:

Pathophysiology

Pseudocholinesterase is a glycoprotein enzyme that is produced by the liver and circulates in the plasma. It specifically hydrolyzes exogenous choline esters; however, it has no known physiologic function.

Pseudocholinesterase deficiency results in delayed metabolism of only a few compounds of clinical significance, including the following: succinylcholine, mivacurium, procaine, and cocaine. [12] Of these, its most clinically important substrate is the depolarizing neuromuscular blocking agent, succinylcholine, which the pseudocholinesterase enzyme hydrolyzes to succinylmonocholine and then to succinic acid.

Among individuals with normal plasma levels of normally functioning pseudocholinesterase enzyme, hydrolysis and inactivation of approximately 90-95% of an intravenous dose of succinylcholine occur before it reaches the neuromuscular junction. The remaining 5-10% of the succinylcholine dose acts as an acetylcholine receptor agonist at the neuromuscular junction, causing prolonged depolarization of the postsynaptic junction of the motor-endplate. This depolarization initially triggers fasciculation of skeletal muscle. As a result of prolonged depolarization, endogenous acetylcholine released from the presynaptic membrane of the motor neuron does not produce any additional change in membrane potential after binding to its receptor on the myocyte. Flaccid paralysis of skeletal muscles develops within 1 minute.

In normal persons, skeletal muscle function returns to normal approximately 5 minutes after a single bolus injection of succinylcholine is given, as it passively diffuses away from the neuromuscular junction. Pseudocholinesterase deficiency can result in higher levels of intact succinylcholine molecules reaching receptors in the neuromuscular junction, causing the duration of paralytic effect to continue for as long as 8 hours.

This condition is recognized clinically when paralysis of respiratory and other skeletal muscles fails to spontaneously resolve after succinylcholine is administered as an adjunctive paralytic agent during anesthesia procedures.

Previous
Next:

Etiology

Pseudocholinesterase deficiency is an inherited or acquired condition in which serum pseudocholinesterase levels are absent or are lower than normal. This enzyme is produced by the liver; decreased levels of the enzyme in an individual may cause increased sensitivity to anesthetic agents such as succinylcholine and mivacurium. Pseudocholinesterase deficiency is caused by mutation of the butyrylcholinesterase (BChE) gene—the gene that provides instructions for making the pseudocholinesterase enzyme. Succinylcholine is a depolarizing muscle relaxant that provides quicker onset and a brief duration of muscle relaxation during general anesthesia. [13]

Pseudocholinesterase deficiency can be inherited as an autosomal recessive trait, occurring in approximately 1 in 3200 to 1 in 5000 people. In most cases of pseudocholinesterase deficiency, no signs or symptoms of the condition are evident. This condition is first suspected after prolonged recovery from paralysis following general anesthesia in which succinylcholine or mivacurium is administered. A family history of anesthesia complications may help clinicians identify patients at risk. [14]

A personal or family history of an adverse drug reaction to one of the choline ester compounds such as succinylcholine, mivacurium, or cocaine may be the only clue suggesting pseudocholinesterase deficiency. Most clinically significant causes of pseudocholinesterase deficiency are due to 1 or more inherited abnormal alleles that code for synthesis of the enzyme. These abnormal alleles may result in failure to produce normal amounts of the enzyme or in production of abnormal forms of pseudocholinesterase with altered structure and lacking full enzymatic function, as described below.

Patients with only partial deficiencies of inherited pseudocholinesterase enzyme activity often do not manifest clinically significant prolongation of paralysis following administration of succinylcholine unless a concomitant acquired cause of pseudocholinesterase deficiency is present. Acquired causes of pseudocholinesterase deficiency include a variety of physiologic conditions, pathologic states, and medications (listed below).

Inherited causes

The gene that codes for the pseudocholinesterase enzyme is located at the E1 locus on the long arm of chromosome 3, and 96% of the population is homozygous for the normal pseudocholinesterase genotype, which is designated as EuEu. The remaining 4% of the population carry 1 or more of the following atypical gene alleles (see Table 1, below) for the pseudocholinesterase gene in a heterozygous or homozygous fashion.

Table 1. Atypical Gene Alleles for the Pseudocholinesterase Genotype (Open Table in a new window)

Ea

Atypical dibucaine-resistant variant

Point mutation

Ef

Fluoride-resistant variant

Point mutation

Es

Silent variant

Frameshift mutation

*These alleles may occur either in the homozygous form or in any heterozygous combination with each other, with the normal Eu allele, or with a number of additional rare variant abnormal alleles.

In individuals with an inherited form of pseudocholinesterase deficiency, only a single atypical allele is carried in a heterozygous fashion, resulting in a partial deficiency in enzyme activity, which manifests as a slightly prolonged duration of paralysis—longer than 5 minutes but shorter than 1 hour—following administration of succinylcholine. Less than 0.1% of the general population carries 2 pseudocholinesterase gene allele mutations that will produce clinically significant effects from succinylcholine lasting longer than 1 hour.

One rare variant allele of the pseudocholinesterase gene, designated the C5 variant, actually has higher than normal enzyme activity, resulting in relative resistance to the paralytic effects of succinylcholine.

The dibucaine-resistant genetic variant form of pseudocholinesterase is identified by percentage inhibition of hydrolysis of benzyl choline caused by adding dibucaine to the pseudocholinesterase enzymatic assay. The dibucaine number is the percentage inhibition of hydrolysis of benzyl choline by dibucaine added to the plasma sample. The normal dibucaine number for the homozygous typical genotype (EuEu) is 80%. Individuals homozygous for the atypical dibucaine-resistant genotype (EaEa) have a dibucaine number of 20%, which correlates with marked prolongation of the paralytic effects of standard doses of succinylcholine to well over 1 hour in duration. Heterozygotes (EuEa) have intermediate dibucaine numbers and modest prolongation of muscle paralysis with succinylcholine. The EuEa heterozygous genotype is found in 2.5% of the general population, making it more common than all other abnormal pseudocholinesterase genotypes combined.

The fluoride-resistant pseudocholinesterase enzyme variant is identified by its percentage inhibition of benzyl choline hydrolysis when fluoride is added to the assay. The fluoride number (percentage inhibition of enzyme activity in the presence of fluoride) is 60% for the EuEu genotype and 36% for the EfEf genotype. This homozygous fluoride-resistant genotype exhibits mild to moderate prolongation of succinylcholine-induced paralysis. The heterozygous fluoride-resistant genotype usually is clinically insignificant unless accompanied by a second abnormal allele or by a coexisting acquired cause of pseudocholinesterase deficiency.

The most severe form of inherited pseudocholinesterase deficiency occurs in only 1 in 100,000 individuals who are homozygous for the silent Es genotype, with no detectible pseudocholinesterase enzyme activity. These individuals may exhibit prolonged muscle paralysis for as long as 8 hours following a single dose of succinylcholine. Gene mutations that produce silent alleles are caused by frameshift or stop codon mutations, resulting in no functional pseudocholinesterase enzyme synthesis.

Prolonged paralysis due to pseudocholinesterase deficiency has been reported after succinylcholine administration for emergent cesarean section. Abnormal pseudocholinesterase enzyme variants can be present but are undetectable with standard laboratory tests. [15]  

Hereditary butyrylcholinesterase (BChE) deficiency results from mutations of the BChE gene located on chromosome 3 (3q26.1-q26.2), between nucleotides 165,490,692 and 165,555,260. Hereditary low BChE activity can cause extensively prolonged apnea during general anesthesia with mivacurium or succinylcholine. [1]

Acquired causes

Neonates, elderly individuals, and pregnant women with certain physiologic conditions may have lower plasma pseudocholinesterase activity. [5, 6]

Pathologic conditions that may lower plasma pseudocholinesterase activity include the following:

  • Chronic infection (tuberculosis)

  • Extensive burn injury

  • Liver disease

  • Malignancy [16]

  • Malnutrition

  • Organophosphate pesticide poisoning

  • Uremia

One study recommended estimation of the pseudocholinesterase level to classify the severity of organophosphorus poisoning and to estimate prognosis. Pseudocholinesterase levels were reduced in all cases in this study (N = 70), with a mean level of 3,154.16 ± 2,562.40 IU/L. [17]

Iatrogenic causes

Iatrogenic causes of lower plasma pseudocholinesterase activity include plasmapheresis and medications such as the following:

  • Anticholinesterase inhibitors

  • Bambuterol

  • Chlorpromazine

  • Contraceptives

  • Cyclophosphamide

  • Echothiophate eye drops

  • Esmolol

  • Glucocorticoids

  • Hexafluorenium

  • Metoclopramide

  • Monoamine oxidase inhibitors

  • Pancuronium

  • Phenelzine

  • Tetrahydroaminacrine

Previous
Next:

Epidemiology

Pseudocholinesterase deficiency can be inherited as an autosomal recessive trait, occurring in approximately 1 in 3200 to 1 in 5000 people. In most cases of pseudocholinesterase deficiency, no signs or symptoms of the condition are noted. It is first suspected after prolonged recovery from paralysis following general anesthesia in which succinylcholine or mivacurium is administered. [14]

The incidence of patients who present as homozygotes for abnormal pseudocholinesterase enzyme is approximately 1 per 2000 to 5000 people. The incidence of heterozygotes for the abnormal enzyme is approximately 1 per 500. Male-to-female incidence for atypical pseudocholinesterase enzyme occurs at a 2:1 ratio. Populations with highest prevalence of pseudocholinesterase deficiency include Caucasian males of European descent, Persian people of the Jewish community, and a subset of Alaska Natives. [1]

Previous
Next:

Prognosis

Pseudocholinesterase deficiency is a clinical condition that is often discovered only after exposure to succinylcholine or mivacurium. Patients may be unaware that they have pseudocholinesterase deficiency if they have never had exposure to these 2 agents. Patients with diagnosed pseudocholinesterase deficiency after exposure to succinylcholine or mivacurium are expected to make a full recovery, following the spontaneous return of motor function. Mechanical ventilation and close clinical monitoring are required to prevent hypoxic respiratory failure. [1]

Previous