Understanding Cystic Fibrosis



What is Cystic Fibrosis

Cystic fibrosis of the pancreas (or mucoviscidosis) is due to one of the many known ‘inborn errors of metabolism’ that are fundamentally the result of aberrations in the structure of the genetic material. It is classed as lethal because of the very poor prognosis afforded to sufferers. The inheritance is autosomal recessive, so that an affected child must inherit one defective gene from each of the parents to be homozygotic. Such parents must then at the least be carriers (heterozygotes). The distribution of the genetic anomaly varies with racial types. It is predominantly associated with Caucasians in whom it occurs in about 1 in every 1500 to 2000 live births.

The symptoms of the disease are manifold; however, they are not strictly specific and hence physicians often have difficulty in distinguishing CF from other childhood diseases on the basis of medical diagnosis alone. The most serious clinical features are the pulmonary problems stemming from abnormally viscous exudates in the lungs, requiring urgent physiotherapy and antibiotic treatment to offset the ever-present risk of pneumonia. The pancreas is also affected by over-viscous secretions that reduce its output of digestive enzymes; thus, the child tends to fail to thrive because the food ingested passes through the alimentary canal without the normal enzymic breakdown necessary for absorption of nutrients. Fortunately, the latter problem is relatively easily corrected by the addition of animal pancreatic extracts to the diet. The use of “pancreas” in the disease name arose because of the identification (in 1938) of pancreatic abnormalities during post-mortem examination of children that had died with a set of symptoms that were not as yet associated with a specific illness. It should be noted here that CF sufferers may differ quite widely in the degree to which they exhibit the various symptoms. Some may be relatively less affected in the respiratory airways; others may show more serious pancreatic problems. A feature of the inheritance is that carriers do not exhibit the symptoms of CF.

In 1953, it was found that children afflicted by the disease are prone to acute hyponatremia during hot weather. Investigations on the cause of the loss of sodium showed that the eccrine sweat of children with CF contains 3 to 4 times as much salt as that of unaffected subjects. Subsequent work showed that this salt increase is not observed in presumed carriers. This was the first intimation that a laboratory test for the disease was conceivable. The sweat test was born and remains to this day the principal laboratory diagnostic test for this disease. In recent years the discovery of “the CF gene” promised a new laboratory diagnostic approach. Intensive studies of this gene have revealed hundreds of variants that may, or may not, produce the typical CF symptoms.

There is no doubt that in the future, this research will illuminate the effects of different genetic abnormalities on the biochemical patterns of the individual. However, the sweat test will remain the definitive laboratory diagnostic test for some time yet.

The Evolution of Sweat Test Methods

The sweat test has traditionally involved three separate, sequential procedures — stimulation of the sweat glands, collection of their secretion, and sweat analysis. Early stimulation procedures involved total body heating followed by placing the patient in a bag, or, later by heating followed by collection from a limited area of skin covered by a hermetically sealed absorptive pad. Both of these methods endangered the infants and proved unsatisfactory.

The heating was eventually avoided by using pilocarpine iontophoresis to induce the glands to sweat maximally. Following this, the sweat was collected in a pre-weighed pad and re-weighed, eluted and analyzed.

The method is usually known as the Gibson and Cooke pad absorption sweat test or the QPIT (quantitative pilocarpine iontophoresis test). This procedure has persisted over the years and is still being performed, particularly by CF centers. It is time-consuming and tedious, requiring many manipulations where human error may intervene, and in one particular step offers technical difficulties that virtually ensure some degree of error, particularly when the sweat sample size is very small.

Laboratorians in CF centers who specialize in this method develop the requisite skill to maintain reasonably accurate results, but this is generally not the case in outlying clinics and hospitals, where the test is only occasionally requested, leading to unacceptably high risk of false results.

While the iontophoretic transport of pilocarpine into the glands has remained the universally preferred method of sweat stimulation to this day, the need for a simpler method of collection and analysis spawned the development of alternative procedures during the late 60’s and early 70’s. Principally among these were the cup-collection systems, which used electrical conductivity for analysis, and the direct skin chloride electrode system.

These methods were highly innovative, procedurally simpler than the Gibson and Cooke method, and were initially commercially successful. They nevertheless failed in their objective to eliminate false diagnostic results. The adoption of these new procedures on a wide scale exacerbated the problem, evoking a storm of criticism in the professional literature, with calls for a return to the original pad-absorption which was now regarded as the “reference method.” 2, 3, 4 In fact, CF referral centers in the United States, operating under accreditation of the Cystic Fibrosis Foundation were forbidden to use any sweat test method other than the QPIT.

These early attempts to simplify the sweat test failed for two principal reasons: (1) error intrinsic to the method of collection and beyond the control of the operator, or (2) extreme susceptibility to variations in operator technique. The direct skin chloride electrode, though offering unrivaled simplicity, was very prone to operator variability in manual skill, and gave poor results due mainly to great difficulties experienced in the control of evaporation error.

The cup collection method was examined for potential intrinsic error by Webster who found that the phenomenon of condensate formation on the walls of the plastic cups was the principal cause of the trouble. His quantitative measurements of the degree to which this occurred in unheated plastic cups showed that the error was always significant and very often reached proportions sufficient to produce false positive results. The error was avoided by using a metal collector cup that was maintained at above skin temperature throughout sweat collection, condensation was prevented, and the error disappeared.

In 1978, ELITechGroup (formerly Wescor) introduced the Model 3500 Webster Sweat Collection System that employed an electrically-heated metallic collector cup. It was the first “simplified” sweat collection system worthy of comparison with the Gibson and Cooke method, it enjoyed considerable success, and was free from any criticism by users and related professionals. It was however burdened by a problem common to all cup-collection systems, that is, the need to “harvest” the sweat accumulated beneath the cup during collection.

ELITechGroup’s determined commitment to resolve this problem eventually led to the invention of the MACRODUCT® Sweat Collector. This innovation completely supplanted the heated cup, while retaining its advantages by the use of a collector that anaerobically collected sweat by using the hydraulic pressure of the sweat glands to pump the secretion directly from the ducts into a fine-bore capillary tube. This system has been very successfully employed both in the US and internationally since 1983.

Vested in ELITechGroup’s scientific and engineering staff is a combination of many years of experience in laboratory sweat testing and in the development of modern electronic instrumentation. The ELITechGroup aim in the field of sweat testing has always been to provide quality instrumentation to meet a number of criteria.

  1. Elimination of all intrinsic sources of error concomitant to previous collection methods.
  2. Ensuring impeccable accuracy in the diagnostic result by reducing human error potential to the lowest possible level.
  3. Maximization of patient safety and comfort.
  4. Maximization of operator convenience within the strictures imposed by objectives 1, 2 and 3.

These objectives have led to considerable innovative improvements in all aspects of sweat testing, iontophoretic safety measures, collection methods and also in the analytical phase of the test. With the introduction of the Model 3600 Macroduct Sweat Collection System in 1983, all of the comprehensive objectives had been accomplished. Paramount among the system’s several unique features was the innovative Macroduct disposable sweat collector.

The Cystic Fibrosis Foundation is a great resource if you want to learn more about cystic fibrosis.Visit Here!


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