Cholinesterase Deficiency

A disorder caused by atypical or deficiency of pseudocholinesterase (PCE) leading to prolonged paralysis after administration of succinylcholine or mivacurium.

Pseudocholinesterase Deficiency; Plasma Cholinesterase Deficiency; Butyrylcholinesterase Deficiency; Cholinesterase II Deficiency; Succinylcholine Sensitivity; Suxamethonium Sensitivity.

For homozygosity, the incidence is approximately 1:2,000-4,000, whereas the incidence for heterozygosity increases to up to 1:500. The gene for the dibucaine-resistant atypical cholinesterase appears to be widely distributed. Among Caucasians, males are affected almost twice as often as females. The frequency for heterozygosity is low among black people, Japanese and non-Japanese Orientals, South Americans, Australian aborigines, and Arctic Inuits (in general). However, there are a few Inuit populations (e.g., Alaskan Inuits) with an unusually high gene frequency for PCE deficiency. A relatively high frequency also was reported among Jews from Iran and Iraq, Caucasians from North America, Great Britain, Portugal, Yugoslavia, and Greece.

Autosomal recessive. Genes encoding cholinesterase 1 (CHE1) and CHE2 have been mapped to 3q26.1-q26.2. One gene is silent, whereas the other is responsible for the defect in cholinesterase.

The inherited defect is caused by either the presence of an atypical PCE or complete absence of the enzyme. Cholinesterases are enzymes that facilitate hydrolysis of the esters of choline. Acetylcholine, the most commonly encountered of these esters, is the mediator of the whole cholinergic system. Acetylcholine is immediately inactivated “in situ” by a specific acetylcholinesterase in the ganglions of the autonomic nervous system (preganglionic and postganglionic in the parasympathetic nervous system and almost exclusively preganglionic in the sympathetic nervous system), in the synapses of the central nervous system, and in the neuromuscular junctions. The affinity of PCE is lower for acetylcholine, but higher for other esters of choline, such as butyrylcholine, benzoylcholine, and succinylcholine, and for aromatic esters (e.g., procaine, chloroprocaine, tetracaine). Normal PCE is produced in the liver, has a plasma half-life of 8 to 12 days, and can be found in plasma, erythrocytes, glial tissue, liver, pancreas, and bowel. When succinylcholine is used for anesthesia, its high plasma concentration immediately after intravenous injection decreases rapidly in normal individuals because of the rapid action of plasma PCE. In case of an atypical PCE or complete absence of PCE, the effect of the injected succinylcholine can last for up to 10 hours.

The disorder is completely asymptomatic prior to the use of succinylcholine. The diagnosis is suspected in any patient with prolonged paralysis (>10 minutes) after succinylcholine administration. A nerve stimulator helps confirm the diagnosis by demonstrating the flaccidity of hand muscles. Laboratory tests use the property of the local anesthetic dibucaine, which can inhibit normal PCE activity in vitro, but has minimal effects on atypical enzymes. Normal PCE activity is reduced by nearly 80%, whereas the activity of atypical enzymes is reduced by only 20%. This defines the “dibucaine number” (DN), which represents the percentage inhibition of PCE by a fixed concentration of dibucaine under standardized conditions using benzoylcholine as the substrate. DN is calculated according to the following formula:

DN ranges from 70 to 83 in normal individuals, 40 to 60 in heterozygous patients, and values below 30 in homozygous patients. Variants where the atypical enzyme was inhibited by sodium fluoride, but not by dibucaine have been reported. This can be confirmed by another test measuring the fluoride resistance (expressed as “fluoride number” [FN]; the formula used for calculation of DN also applies for FN), which decreases in patients presenting with the disorder. The normal range for FN is 56 to 65. The diagnosis can also be established by electrophoretic measurement of PCE plasma concentration.

Complications most commonly occur after injection of either succinylcholine or mivacurium and present with prolonged paralysis. Two forms of clinical presentation exist: (1) depolarizing block with tetanus that can be increased by anticholinesterases and (2) nondepolarizing block with fade in the train of four and a slight tetanus associated with posttetanic facilitation (dual block), in which case anticholinesterase agents are indicated (prostigmine or neostigmine in combination with glycopyrrolate or atropine). Cardiac problems may include arrhythmia, ventricular fibrillation, and cardiac arrest as a result of succinylcholine. Neurologic manifestations include seizures, coma has been reported only following injection of procaine.

Laboratory investigations confirm reduced DN and/or decreased FN and decreased plasma PCE concentration.

Check for previous anesthesia-related problems in the patient, the parents, and relatives. In case of prolonged motor block following administration of triggering agents (succinylcholine, mivacurium), blood samples must be obtained to measure DN and FN. Keep in mind that certain physiologic situations are associated with lower plasma PCE activity (newborn period and infancy, pregnancy, and increased age). Furthermore, decreased PCE activity has been reported in association with liver disease (e.g., cirrhosis, hepatitis), plasmapheresis, acute myocardial infarction, myxedema, and acute infections.

If the disease has not been diagnosed before anesthesia and prolonged motor block occurs, the treatment of choice is mechanical ventilation. Fresh blood or fresh-frozen plasma as a source of PCE is indicated only in case of cardiac complications.

Succinylcholine, mivacurium, and amino-ester local anesthetics are contraindicated. Use of anticholinesterases must be discussed after evaluation and interpretation of the motor block (nerve stimulator). Certain drugs, such as pancuronium, metoclopramide, esmolol, chlorpromazine, bambuterol (a precursor of terbutaline), acetylcholinesterase inhibitors (neostigmine, pyridostigmine), echothiophate, steroids, and chemotherapeutic agents (cyclophosphamide), decrease PCE activity. In patients with partial deficiency of PCE, drugs that may cause an acquired decrease in PCE activity must be avoided.