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Repeated admission to hospital with unexplained pancreatitis will prompt close questioning on alcohol consumption. In a teetotal patient, this can be particularly disagreeable.
A woman aged 54 had in the past 4 years experienced several episodes of acute pancreatitis, two of them requiring admission to the intensive therapy unit. Endoscopic retrograde cholangiopancreatography showed biliary sludge but no gallstones. Eventually she had undergone cholecystectomy. A teetotaller, she objected to the repeated inquisitions about her alcohol intake. She had never been asked about her family history.
Her sister had lost three children to cystic fibrosis (CF) at young ages. In her parents' generation there had been two childhood deaths from 'pneumonia'. Her three children and four grandchildren are all well. The patient was born at term and her motor development was normal, but deafness until age 7 resulted in speech delay. At this age a surgical procedure (probably the insertion of grommets) restored her hearing to normal. She had also suffered badly from sinusitis since she was a child, and had a chronic productive cough. Urinary frequency and dribbling predated her pregnancies.
Suspecting that the pancreatitis might be linked with the family history of CF, her general practitioner referred her for genetic assessment and, at her request, her DNA was analysed for mutations in the CF transmembrane conductance regulator (CFTR). She was found to be a compound heterozygote, with one ΔF508 mutation and one R117H mutation. Subsequent investigation by an adult CF specialist included sweat chloride measurement, which was normal.
The principal causes of recurrent pancreatitis are gallstones and alcohol, with the 'small print' including autoimmune disease, hypertriglyceridaemia, hyperparathyroidism, tumours, trauma, infections, drugs, parasitic infiltrations, scorpion bites and cystic fibrosis.1 In some series nearly a third of cases are classed as 'idiopathic'.
CF is a common disorder, inherited in an autosomal recessive manner, in which the defective protein is CFTR. This is a cAMP regulated chloride channel with multiple functions in epithelial cells. The CFTR gene is located on chromosome 7q31, and the most common mutation found in northern Europeans is ΔF508, which causes a severe phenotype when present in both copies of the gene. Over a thousand mutations in the CFTR gene have been found so far, and they can be divided into 'mild' and 'severe' on the basis of clinical phenotype.2 Examples of severe mutations are R553X, ΔF508 and G551D. Mild mutations include R117H and R347P.
The CF Genotype-Phenotype Consortium Study indicated that patients such as ours, with ΔF508/R117H mutations, tended to be older than others and pancreatic-sufficient when first diagnosed as having CF.3 Other genes involved in the pathogenesis of chronic pancreatitis include serine protease 1 and a trypsin inactivator Kazal type 1.4 The exact pathogenic mechanism driven by mutations in CFTR, PRSS1 and SPINK 1 is poorly understood.
In the present case it was the recurrent acute pancreatitis that caused the general practitioner to consider the family history of CF. In fact the patient had several other recognized features—sinusitis and urinary frequency and dribbling.5 She was relieved at having the CF diagnosis—not least because, if her pancreatitis recurs, she will no longer have to cope with the stigmatizing suggestion that she is a covert abuser of alcohol.