Sweat Chloride
Cystic fibrosis is the most common lethal genetic disorder of Caucasians in the United States, occurring with a birth rate of 1 in 2000. It is less common in African American and Asians. Cystic fibrosis is an autosomal recessive genetic disease that is caused by mutations in both alleles of the CFTR gene. This gene encodes the cystic fibrosis transmembrane conductance regulator (CFTR) protein which is an anion channel that transports chloride and bicarbonate across the epithelial membranes of many organs. Mutations in CFTR disrupt sodium absorption, chloride secretion, and water transport, leading to the development of viscous mucus that adheres to the airway and impairs bacterial clearance. Nearly 2000 CFTR mutations have been discovered, and each one confers a different degree of diminished chloride ion transport.
The diagnosis of cystic fibrosis is based on clinical presentation, family history, a positive newborn screening test, sweat chloride test or genetic tests for CFTR mutations. Because of the large number of CFTR mutations, confirmation of diagnosis by genetic testing is limited. The sweat test remains the mainstay of diagnosis. The Cystic Fibrosis Foundation consensus statement includes an elevated sweat chloride concentration in its diagnostic criteria.
The CFTR protein facilitates chloride resorption from the ductal lumen of sweat glands into the epithelium. CFTR mutations result in decreased chloride resorption and elevated sweat chloride concentrations. Sweat chloride testing should be performed by experienced technologists following international guidelines. The preferred site for testing is the volar surface of the forearm. The sweat test involves iontopheresis of pilocarpine, a cholinergic drug, into the skin to induce sweating in a localized area. Sweat is collected into a Macroduct coil and sent to the clinical laboratory for measurement of chloride concentration. Results are interpreted as follows:
| Chloride | Interpretation |
| 0-29 mEq/L | Negative |
| 30-59 mEq/L | Indeterminate |
| 60 mEq/L or greater | Consistent with CF |
Approximately 99% of patients with cystic fibrosis have a sweat chloride concentration greater than 60 mEq/L. Sensitivity is 99% and specificity is 96%. Indeterminate results require additional diagnostic testing such as CFTR genetic analysis.
Sweat electrolyte concentration increases with age and healthy adults can have sweat chloride concentrations greater than 60 mEq/L. Elevated levels can also be caused by eczema, skin rash, malnutrition, dehydration and many other diseases listed below.
Metabolic Disorders
- Fucosidosis
- G6PD deficiency
- Glycogen storage disease type 1
- Mucopolysaccharidosis type 1
- Malnutrition
Endocrine Disorders
- Adrenal insufficiency, untreated
- Hypothyroidism, untreated
- Hypoparathyroidism
- Mauriac syndrome
- Pseudohypaldosteronism
- Nephrogenic diabetes insipidus
Immunologic Disorders
- Atopic dermatitis
- Hypogammaglobulinemia
Genitourinary Tract Disorders
- Klinefelter syndrome
- Nephrosis
Neuropsychiatric Disorders
- Anorexia nervosa
- Autonomic dysfunction
False negative results can occur if the patient is edematous, is receiving mineralocorticoid therapy or an inadequate volume of sweat is collected.
Patients with borderline and positive results should be retested. Duplicate tests should agree within 10 mEq/L for chloride concentrations less than 60 mEq/L and within 15 mEq/L for chloride concentrations greater than 60 mEq/L.
Children with a positive newborn screen for cystic fibrosis who have an indeterminate sweat test and one or no cystic fibrosis-causing mutations, are classified as having cystic fibrosis related metabolic syndrome (CRMS), This diagnosis is also applied to children who have a positive newborn screen, a sweat test result less than or equal to 29 mmol/L, and two CFTR gene mutations, with at least one that does not cause any physical cystic fibrosis symptoms.
Full-term babies usually produce enough sweat by 2 weeks of age. The test should be done as soon as possible between 10 days and, at the latest, 4 weeks of age for babies who have had a positive newborn screen. Approximately 7% of cystic fibrosis diagnoses are made in adults with relatively mild symptoms.
Specimen requirement is 25 uL of sweat.
References
Farrell PM et al. Diagnosis of cystic fibrosis: consensus guidelines from the Cystic Fibrosis Foundation. J Pediatr. 2017;181S:s4-s15.
Castellani C. et al. ECFS best practice guidelines: the 2018 revision. J Cyst Fibros. 2018:17(2)153-178.
McCarthy C, Clancy JP and Brewington J. Sweat Chloride Testing. JAMA (published on line January 30, 2019) doi:10.1001/jama.2018.21998.
