NPD and gut biopsy

Question

Is it possible that a person has CF despite a normal gut biopsy and a normal NPD?

Answer

Thanks for this interesting question concerning two less known diagnostic tests for CF.
If clinical symptoms and signs are suggestive for CF, the first diagnostic step is a sweat test with or without genetic investigations. An abnormal sweat test result (sweat chloride above 60 mEq/l) and or two disease causing mutations in the CFTR gene revealed by genetic testing confirm the diagnosis of CF with a high certainty. If the sweat test has an intermediate value (sweat chloride between 30 and 60 mEq/l) but 2 mutations in the CFR gene are found, the term non classic CF is used. On average these patients have a milder disease course. In rare cases a sweat test may be intermediate, with only one or no mutations detected with genetic investigations. In these circumstances the function of the CFTR protein (which is a chloride channel) can be measured at the level of the nose (Nasal potential difference measurement, NPD) or in a gut biopsy (intestinal current measurement, ICM). Both tests measure the transport of salt at the mucosal level. CF is caused by decreased functioning of the chloride channel or CFTR protein.
NPD and ICM are technically difficult measurements and results obtained have to be interpreted with caution. In case of doubt repeat testing is indicated. Abnormal transport of salt detected on NPD or ICM confirms dysfunction of the CFTR protein which is diagnostic for CF. If no clear abnormalities are documented by means of NPD or ICM, the diagnosis of CF becomes very unlikely. In that case it is necessary to look for other diseases causing the complaints.
For some mutations found by genetic analysis the meaning or the clinical implication is unclear. For example the mutation R117H may cause a non classical form of CF if occurring in combination with other disease causing mutations; however R117H is also found in healthy persons. In these cases NPD can differentiate between a disturbed CFTR function or a normal function. The CFTR protein can also play a role in diseases limited to 1 organ, for example infertility. Men with sterility based on ‘bilateral absence of the vas deferens’ may have two mutations in the CFTR gene, an intermediate sweat chloride and decreased salt transport measured by NPD. In case of isolated infertility without lung or other organ disease, it is more correct to use the term ‘CFTR related disease’ or ‘CFTR dysfunction’ rather than CF. In these patients there is usually no long lung disease and evolution to severe lung disease in the future is very unlikely.
To summarize we can confirm that NPD and ICM are useful additional tests for scenarios whereby sweat test and genetic analysis cannot confirm the diagnoses of CF. In case of a normal NPD or ICM, CF is not the correct diagnosis.

With kind regards
I.Bronsveld

11.01.2011