Agency for Toxic Substances and Disease Registry 
Case Studies in Environmental Medicine (CSEM) 

Cholinesterase Inhibitors
Including Insecticides and Chemical Warfare Nerve Agents
Part 4: The Cholinergic Toxidrome
Section 10: Laboratory Assessment of the Cholinergic Toxidrome
Red Blood Cell (RBC) and Serum Cholinesterase

Learning Objectives

Upon completion of this section, you will be able to:

• Describe the usefulness and limitations of laboratory analysis of RBC and serum cholinesterase levels.

Misconception

Cholinesterase levels play an important role in the emergency diagnosis and treatment of cholinesterase inhibitor toxicity.

Reality

Emergency assessment and treatment should be based on the patient’s history, signs, and symptoms. (Wiener and Hoffman 2004) It should not be delayed to await the results of these laboratory tests, which are rarely available in time to guide emergency treatment! (Tareg et al. 2001)

Introduction

Circulating RBC and serum (uninhibited) cholinesterase levels are used to approximate levels in neural tissue, since the latter are impractical to obtain. (Clark 2002)

The Two Types of Cholinesterase Levels

There are two types of cholinesterase levels

• Red Blood Cell (RBC) cholinesterase (also called true cholinesterase).
• Serum cholinesterase (also called pseudocholinesterase or butyrylcholinesterase).

In general, the key differences between RBC cholinesterase and serum cholinesterase are shown in the following table.

Accuracy*

Greater**

Less

Availability

Less

Greater

Duration of depression (Reigart and Roberts 1999)

Several days to a few weeks

1-3 months

Onset of depression

Later

Early

*That is, it is thought to more closely approximate cholinesterase levels in the neurosynapse.

**Although one author contends that there is no evidence that this is the case for nerve agents. (Wiener and Hoffman 2004)

Sources of Error in the Measurement of Cholinesterase Levels (Optional Reading)

Listed below are some of the sources of error in the measurement and interpretation of cholinesterase levels.

• Normal ranges of RBC and serum cholinesterase vary widely between individuals (and even in the same individual at different times). (Karalliedde 2002; Leikin, Thomas et al. 2002; Wessels, Barr et al. 2003; Wiener and Hoffman 2004)
• Because of this, a person who usually has a “high-normal” level of cholinesterase could be significantly toxic but his or her cholinesterase level could decrease only into the “low-normal” range. (Tareg et al. 2001)
• Thus, the toxic patient would have a falsely normal test result. (Midtling, Barnett et al. 1985; Jamal 1997; Clark 2002) (One author indicates that for serum cholinesterase there is a 300% difference between the lower and upper normal values. (Erdman 2004))
• Thus, unless pre-exposure levels are available for comparison, only a level of inhibition greater than that due to interindividual variability (about 25% for RBC cholinesterase) can be considered significant. (Ray 1998)
• Errors in laboratory results can also occur if samples are stored at room temperature, because cholinesterase bound to un-aged inhibitors can undergo significant spontaneous reactivation. (Ray 1998)
• Another source of error, even with modern testing kits, is lack of experience and skill of the laboratory technician. (Wessels, Barr et al. 2003)

Case Example (Optional Reading)

In one study of 29 farm workers who were symptomatic after exposure to pesticides, none had RBC or serum cholinesterase levels below the lower limit of normal. (Midtling, Barnett et al. 1985)

Variations among Laboratories (Optional Reading)

Due to differences in techniques, the absolute cholinesterase values vary from laboratory to laboratory. (Minton and Murray 1988) Laboratories may report their findings as percentages of average or normal (in unexposed subjects) rather than as absolute values.

Levels Correlated with Toxicity (Optional Reading)

Even with the more accurate RBC cholinesterase, the point at which various authors have suggested that toxicity begins to appear ranges from 40% to 75% of normal values. (Carlton, Simpson et al. 1998) (Romano, McDonough et al. 2001; Clark 2002)

The Role of Baseline Cholinesterase Levels (Optional Reading)

Some authors suggest that, when compared to an individual’s baseline value, changes in RBC cholinesterase levels correlate well with cholinesterase inhibitor toxicity. (Tareg et al. 2001; Clark 2002) However, such baseline values are rarely available except, perhaps, in occupational settings where workers are monitored for ongoing exposures.

Other Causes of Cholinesterase Level Abnormalities

Other conditions, besides exposure to cholinesterase inhibitors can cause abnormalities in cholinesterase levels.

Low levels

• Antimalarial drugs (Clark 2002)
• Oral contraceptives (Clark 2002)
• Some anemias (Tareg et al. 2001)

• Acute infections (Tareg et al. 2001)
• Benzalkonium salts (Reigart and Roberts 1999)
• Carbon disulfide (Reigart and Roberts 1999)
• Chronic debilitating disease (Clark 2002)
• Ciguatoxins (Reigart and Roberts 1999)
• Cocaine (Clark 2002)
• Codeine (Clark 2002)
• Dermatomyositis (Reigart and Roberts 1999)
• Genetic deficiency (3% of individuals) (Tareg et al. 2001; Clark 2002)
• Hepatic parenchymal disease (Clark 2002)
• Malnutrition (Clark 2002)
• Morphine (Clark 2002)
• Pregnancy (Tareg et al. 2001)
• Oral contraceptives (Tareg et al. 2001)
• Organic mercury compounds (Reigart and Roberts 1999)
• Solanines (Reigart and Roberts 1999)
• Some anemias (Tareg et al. 2001; Clark 2002)
• Succinylcholine (Clark 2002)
• Use of gray-top blood collection tubes or those containing fluoride (Clark 2002)

High levels

• Nephrotic syndrome (Clark 2002)

Key Points

• RBC and serum (uninhibited) cholinesterase levels are used to approximate levels in neural tissue, since the latter are impractical to obtain.
• These tests are rarely available in time to guide the emergency treatment decisions. Initial emergency management should therefore be based on clinical assessment.
• When available, test results must be interpreted with caution, because of
  • Interindividual and intraindividual differences in normal cholinesterase levels.
  • Other medical conditions and substances that can alter cholinesterase levels.
  • Laboratory errors.

Progress Check