Pseudocholinesterase Deficiency

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.

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)

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

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]

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]

Pseudocholinesterase deficiency is diagnosed by plasma assays of pseudocholinesterase enzyme activity. A sample of the patient's plasma is incubated with the substrate butyrylthiocholine, along with the indicator chemical 5,5'-dithiobis-(2-nitrobenzoic acid), which produces a colored product that is assayed by spectrophotometry. The resulting amount of spectrophotometric absorption is proportionate to the pseudocholinesterase enzyme activity that is present in the patient's plasma sample.[12, 18]

Because succinylcholine metabolites can interfere with this assay, plasma samples should be collected after muscle paralysis has completely resolved. Dibucaine and fluoride numbers can be determined by repeating this assay in the presence of standard aliquots of either dibucaine (0.03 mmol/L) or fluoride (4 mmol/L) in the reaction mixture to determine the percentage inhibition of enzyme activity caused by these agents.

A simplified screening test of pseudocholinesterase enzyme activity can be performed using the Acholest Test Paper (see Table 2, below). When a drop of the patient's plasma is applied to the substrate-impregnated test paper, a colorimetric reaction occurs. The time it takes the exposed Acholest Test Paper to turn from green to yellow is inversely proportionate to pseudocholinesterase enzyme activity in the plasma sample.

Table 2. Reaction Times for Acholest Test Paper (Open Table in a new window)

The complete DNA sequence and amino acid structure of both the normal pseudocholinesterase protein and most of its abnormal variants have now been identified. However, molecular genetic techniques such as polymerase chain reaction (PCR) amplification with allele-specific oligonucleotide probes for identifying abnormal pseudocholinesterase genotypes are currently available only in a limited number of research laboratories and are not yet available for routine clinical use.

Pseudocholinesterase deficiency is a clinically silent condition seen in individuals who are not exposed to exogenous sources of choline esters.

Patients with prolonged paralysis following administration of succinylcholine can be treated in the following ways:

• Prophylactic transfusion of fresh frozen plasma can augment the patient's endogenous plasma pseudocholinesterase activity. This practice is not recommended because of the risk of iatrogenic viral infectious complications. However, perioperative transfusion of fresh frozen plasma administered to correct a coagulopathy may mask an underlying pseudocholinesterase deficiency.

• Mechanical ventilatory support is the mainstay of treatment until respiratory muscle paralysis spontaneously resolves. Recovery eventually occurs as a result of passive diffusion of succinylcholine away from the neuromuscular junction.

• Administration of cholinesterase inhibitors such as neostigmine is controversial for reversing succinylcholine-related apnea in patients who are pseudocholinesterase deficient. The effects may be transient, possibly followed by intensified neuromuscular blockade.

Consultation with a geneticist may help identify the specific atypical genotype alleles contributing to pseudocholinesterase deficiency.

Because the DNA sequence of the pseudocholinesterase gene and its amino acid structure is known, atypical alleles now can be identified by polymerase chain reaction (PCR) amplification studies using DNA extracted from leukocytes in a blood sample.