Pseudocholinesterase Deficiency

Background

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]}

The table below outlines common agents and conditions associated with reduced pseudocholinesterase activity.

Table 1. Triggering Agents and Inhibitors of Pseudocholinesterase Activity

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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. 

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.^[7]

This condition is recognized most often when respiratory paralysis unexpectedly persists for a prolonged period of time following administration of standard doses of succinylcholine.^[8]  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.

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.

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Etiology

Pseudocholinesterase deficiency, either inherited or acquired, results in reduced or absent serum pseudocholinesterase activity, increasing sensitivity to anesthetic agents such as succinylcholine and mivacurium. These agents depend on normal enzyme function for rapid breakdown; deficiency may lead to prolonged neuromuscular blockade during general anesthesia.^[9]

Inherited causes

Inherited pseudocholinesterase deficiency is autosomal recessive and due to mutations in the butyrylcholinesterase (BChE) gene on chromosome 3 (3q26.1–26.2).^[1] It affects approximately 1 in 3200 to 1 in 5000 individuals and is typically identified when paralysis persists longer than expected after administration of succinylcholine or mivacurium. A family history of anesthesia complications may help identify at-risk patients.^[10]

Most cases are due to abnormal alleles that either reduce enzyme levels or produce dysfunctional variants. Individuals with only one abnormal allele usually have mild or no symptoms unless another acquired cause is present. Homozygotes may experience significant prolongation of neuromuscular blockade (> 1 hour).

Table 2. Atypical Gene Alleles for the Pseudocholinesterase Genotype

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*Alleles may be present in homozygous or heterozygous combinations, including with the normal allele (Eu) or other rare variants.

Key phenotypes include:

• EuEu (normal): Dibucaine number ~80%.
• EuEa (heterozygous): 2.5% of the population; modest prolongation of paralysis; dibucaine number intermediate.
• EaEa: Marked prolongation; dibucaine number ~20%.
• EfEf: Mild to moderate prolongation; fluoride number ~36%.
• EsEs (silent): Complete enzyme deficiency; paralysis may last up to 8 hours; rare (~1 in 100,000).

The C5 variant is associated with elevated enzyme activity and reduced response to succinylcholine.

Dibucaine and fluoride numbers measure percentage inhibition of enzyme activity and help identify specific variants. However, some abnormal enzymes are not detectable by standard testing. Prolonged paralysis has been reported after succinylcholine use in cesarean delivery.^[11]  

Acquired causes

Conditions that may reduce plasma pseudocholinesterase activity include:

• Physiologic states: Neonates, elderly individuals, pregnancy, and the postpartum period^{[12, 13]}
• Diseases: Liver disease, chronic infection (eg, tuberculosis), malignancy, malnutrition, uremia, burns^[14]
• Toxic exposures: Organophosphate pesticide poisoning^[15]

  • One study (N = 70) showed reduced enzyme levels in all patients with organophosphorus poisoning (mean: 3154.16 ± 2562.40 IU/L).^[15]

   

  

   

Iatrogenic causes

Medications and procedures that lower pseudocholinesterase levels include:

• Anticholinesterase inhibitors
• Bambuterol
• Chlorpromazine
• Contraceptives
• Cyclophosphamide
• Echothiophate
• Esmolol
• Glucocorticoids
• Hexafluorenium
• Metoclopramide
• Monoamine oxidase inhibitors
• Pancuronium
• Phenelzine
• Plasmapheresis
• Tetrahydroaminacrine

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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.^[16] 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.

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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.^[10]

The incidence of individuals who are homozygous for abnormal pseudocholinesterase enzyme variants is approximately 1 in 2000 to 1 in 5000. Heterozygosity for an abnormal variant occurs in approximately 1 in 500 individuals. The male-to-female ratio for atypical pseudocholinesterase enzyme expression is approximately 2:1. Populations reported to have higher prevalence of pseudocholinesterase deficiency include males of Northern European ancestry, individuals of Persian Jewish descent, and some Alaska Native groups.^[1]

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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 two 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]

In nonmedical settings in which individuals with pseudocholinesterase deficiency are exposed to cocaine, sudden cardiac death can occur.

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History

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.^[10]

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Physical Examination

Physical findings in pseudocholinesterase deficiency are typically limited to the postoperative period and may include:

• Persistent muscle flaccidity
• Absent or shallow spontaneous respirations
• Delayed return of motor function after anesthesia

Neurologic exam is otherwise normal once the anesthetic drug wears off.

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. Severe forms of inherited pseudocholinesterase deficiency may exhibit prolonged muscle paralysis for as long as 8 hours following a single dose of succinylcholine.

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Complications

Complications of pseudocholinesterase deficiency may include:

• Prolonged ventilator dependence after anesthesia
• Potential for misdiagnosis as opioid overdose, brainstem stroke, or residual sedation
• Cocaine exposure in undiagnosed individuals may cause sudden cardiac death
• Risk of adverse outcomes in emergency surgeries, such as cesarean section, where rapid paralysis and reversal are critical

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Laboratory Studies

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.^{[16, 17]}

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 3, 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 3. Reaction Times for Acholest Test Paper

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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.

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Medical Care

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.

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