Cystic Fibrosis Gene and Idiopathic Pancreatitis

[Guest guest]

Cystic Fibrosis Gene and Idiopathic Pancreatitis

The cystic fibrosis transmembrane conductance regulator (CFTR) functions as

a cyclic-AMP­regulated chloride channel essential in maintaining luminal

hydration in the ducts of many organs. Hence, mutations in the channel's

gene can lead to dysfunction in lungs, exocrine pancreas, sweat glands, and

Wolffian ducts, as manifestations of cystic fibrosis. Although the

pancreatic involvement usually does not resemble pancreatitis clinically,

several observations suggest that CFTR mutations may be responsible for some

cases of chronic pancreatitis. In both cystic fibrosis and chronic

pancreatitis, the earliest pathologic changes consist of ductal obstruction.

Moreover, sweat tests may be abnormal in patients with either condition.

The relation between CFTR mutations and idiopathic pancreatitis was explored

in 22 women and five men referred for evaluation of idiopathic pancreatitis

at Duke University and the University of North Carolina. The investigators

tested for 17 CFTR gene mutations and also for the 5T CFTR allele, whose

presence markedly reduces the level of functional gene product. Ten patients

(37%) had at least one such abnormality, for a mutation frequency 11-fold

greater than expected. In three patients, both CFTR alleles were affected,

exceeding the expected frequency 80 fold. In another report, investigators

in Manchester, England, studied 134 consecutive patients with chronic

pancreatitis--53% of the cases were alcohol-related and 45% were idiopathic.

Testing for 22 CFTR mutations, the researchers identified a mutation

frequency nearly 2.5 times the expected figure. The frequency of the 5T

allele was twice as high as expected. The mutations were associated with

idiopathic rather than alcohol-related disease. In both the Manchester and

North Carolina studies, none of the patients had cystic fibrosis.

Cohn JA et al: Relation between mutations of the cystic fibrosis gene and

idiopathic pancreatitis. N Engl J Med 339:653, 1998; Sharer N et al: Mutatio

ns of the cystic fibrosis gene in patients with chronic pancreatitis.

Ibid:645; Durie PR: Pancreatitis and mutations of the cystic fibrosis gene

(editorial). Ibid:687

The info below is much more complicated, but thought it worth passing on

SIGNIFICANCE OF HETEROZYGOUS CYSTIC FIBROSIS GENE (CYSTIC FIBROSIS

TRANSMEMBRANE CONDUCTANCE REGULATOR MUTATIONS) IN IDIOPATHIC PANCREATITIS.

CP. Choudari, AC. Yu, TF. Imperiale, EL. Fogel, S. Sherman, GA. Lehman.

Indiana University Medical Center, Indianapolis, IN.

Between 5-15% of patients with recurrent pancreatitis have no identified

etiology after routine investigations and advanced endoscopic evaluation.

The majority of the patients with cystic fibrosis (CF) homozygous disease

suffer from chronic pancreatitis and pancreatic insufficiency. This study

evaluated whether idiopathic pancreatitis is associated with the

heterozygous state of CE

Methods: Two hundred twenty five patients with pancreatitis and 210 controls

(patients without pancreatitis) undergoing ERCP were tested for 13

CF-causing CFTR mutations by DNA probe analysis. Sixty four patients had a

known cause for pancreatitis (excess alcohol intake in 39; gallstone in 15;

hypertriglyceridemia in 4; hereditary pancreatitis in 5; and trauma in one

patient). Fifty-one patients had a potentiel cause for pancreatitis after

endoscopic evaluation (pancreas divisum in 38; tumor in 9; anomalous

pancreatobiliary junction in 3; and choledochal cyst in one). Six patients

with homozygous cystic fibrosis were excluded. The remaining 104 patients

with " idiopathic pancreatitis " (IP) were compa.red to 210 control patients.

Results: The frequency of CFTR mutations (heterozygous) were:

IP n = 104 Controls n=210 P. Divisum n = 38 Et OH n = 39 Miscellaneous n

= 38

Caucasians 19/96 7/198 8/37 2/31 0/36

Afro-Amer 0/4 0/12 -- 0/8 0/1

Asian 0/4 -- 0/1 -- 0/1

Total 19/104 7/210 8/38 2/39 0/38

Nineteen Caucasian patients (19%) with IP were heterozygous (carried a

single CFRT mutation) compared to the local population carrier rate of 3.53%

(p < 0.00001). Patients with IP have a relative odds of carring a CFTR

mutation of 6.7 (95% CI 2.8-16.3). Twenty-one percent (8/38) of patients

with pancreas divisum were also heterozygotes (p < 0.0001). In

heterozygotes, sweat chlorides were normal in all tested patients (n = 7).

Summary: Caucasian idiopathic pancreatitis patients have a statistically

significant increase in CF heterozygous frequency.

Conclusions: The heterozygous state of the CF gene appears to predispose

Caucasians to pancreatitis probably by defective CFRT chloride function in

pancreatic duct similar to the homozygous state.