Genotype and phenotype correlations in patients with cystic fibrosis and pancreatitis

doi:10.1053/gast.2002.37042

Gastroenterology

Volume 123, Issue 6, December 2002, Pages 1857-1864

https://doi.org/10.1053/gast.2002.37042 Get rights and content

Abstract

Background & Aims: Pancreatitis is known to occur in some patients with cystic fibrosis (CF), but the prevalence, natural history, and genotypic basis are unclear. We examined a well-defined cohort of patients with CF to answer these questions. Methods: Patients with CF were identified from a computerized database (1966–1996). Chart audit identified all patients with CF and pancreatitis. Results: Among 1075 patients with CF, 937 (87%) were pancreatic insufficient at diagnosis, 28 (3%) were pancreatic sufficient but developed pancreatic insufficiency after diagnosis, and 110 (10%) have remained pancreatic sufficient. No patients with pancreatic insufficiency developed pancreatitis. Nineteen patients (17.3%) with pancreatic sufficiency experienced one or more attacks of pancreatitis. The mean age at diagnosis of pancreatitis was 22.7 ± 10.3 years (range, 10–35 years), and pancreatitis was recognized before the diagnosis of CF in 6 patients (32%). The diagnosis of CF in pancreatic-sufficient patients, with and without pancreatitis, was established at a significantly older age than in those with pancreatic insufficiency (P < 0.0001). Genotyped patients with pancreatic insufficiency carried 2 severe mutant alleles. All genotyped patients with pancreatic sufficiency and pancreatitis carried at least one mild mutation. No specific genotype was predictive of pancreatitis. Conclusions: Patients with CF with pancreatic sufficiency carry at least one mild mutant allele and are at a significant risk of developing pancreatitis. Symptoms of pancreatitis may precede the diagnosis of CF. Pancreatitis is associated with an otherwise mild CF phenotype.

GASTROENTEROLOGY 2002;123:1857-1864

Section snippets

Patients

Clinical information on all patients with CF followed up within a regional referral center has been prospectively recorded in a computerized database. The CF database, together with an audit of all medical records, was used to identify all patients with a diagnosis of CF and acute recurrent or chronic pancreatitis over a 30-year period (1966–1996). The audit showed no new cases of pancreatitis. Because pancreatitis was only identified in patients with PS, a systematic chart review for evidence

Patient demographics

The CF database identified 1075 patients with a diagnosis of CF over the 30-year period. Table 1 compares the clinical characteristics of the 3 subgroups of patients categorized by pancreatic phenotype.

. Clinical characteristics of patients with CF in 3 subgroups categorized by pancreatic phenotype

Empty Cell	PI (n = 937)	PS → PI (n = 28)	PS (n = 110)	P^a
Age at diagnosis (yr)
Mean ± SD	2.3 ± 4.6	1.9 ± 4.4	10.1 ± 9.3	<0.0001
Median (range)	0.59 (0–45.7)	0.41 (0.14–21.9)	7.9 (0.01–40.1)	<0.0001
Mean sweat chloride (mmol/L)

Discussion

Although symptomatic pancreatitis is well documented among patients with CF, its overall prevalence is probably low. Our study shows that only 1.7% of 1075 patients with CF monitored over a 30-year period had documented evidence of pancreatitis on the basis of abdominal pain in association with a significantly elevated serum amylase level. This observation is not surprising given the severe pancreatic phenotype in most patients with CF, in whom progressive pancreatic damage is already occurring

Acknowledgements

The authors thank Louise Taylor and Anna Tsang for their assistance with the clinical aspects of the study as well as Lenny Chong for data management.

References (31)

K Gaskin et al.
Improved respiratory prognosis in patients with cystic fibrosis with normal fat absorption
J Pediatr
(1982)
M Corey et al.
Familial concordance of pancreatic function in cystic fibrosis
J Pediatr
(1989)
Z Weizman et al.
Acute pancreatitis in children
J Pediatr
(1988)
BJ Rosenstein et al.
The diagnosis of cystic fibrosis: a consensus statement
J Pediatr
(1998)
KN Jeejeebhoy et al.
Determination of faecal fats containing both medium- and long-chain triglycerides and fatty acids
Clin Biochem
(1970)
J Zielenski et al.
Identification of mutations in exons 1 through 8 of the cystic fibrosis transmembrane conductance regulator (CFTR) gene
Genomics
(1991)
PG Noone et al.
Cystic fibrosis gene mutations and pancreatitis risk: relation to epithelial ion transport and trypsin inhibitor gene mutations
Gastroenterology
(2001)
H Kopleman et al.
Impaired chloride secretion as well as bicarbonate secretion, underlies the fluid secretory defect in the cystic fibrosis pancreas
Gastroenterology
(1988)
H Kopleman et al.
Pancreatic fluid secretion and protein hyperconcentration in cystic fibrosis
N Engl J Med
(1985)
JM Rommens et al.
Identification of the cystic fibrosis gene: chromosome walking and jumping
Science
(1989)

JR Riordan et al.

Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA

Science

(1989)

B-S Kerem et al.

Identification of the cystic fibrosis gene: genetic analysis

Science

(1989)

E Kerem et al.

The relation between genotype and phenotype in cystic fibrosis-analysis of the most common mutation (ΔF508)

N Engl J Med

(1990)

Cystic Fibrosis Genetic Analysis Consortium

Correlation between genotype and phenotype in patients with cystic fibrosis

N Engl J Med

(1993)

P Kristidis et al.

Genetic determination of exocrine pancreatic function in cystic fibrosis

Am J Hum Genet

(1992)

Cited by (188)

Update in Advancing the Gastrointestinal Frontier in Cystic Fibrosis
2022, Clinics in Chest Medicine
Digestive outcomes in Cystic fibrosis
2022, Best Practice and Research: Clinical Gastroenterology
Cystic fibrosis (CF) is the most frequent life-limiting autosomal recessive disease in Caucasians, affecting the respiratory tract, but also the pancreas, gut, and hepatobiliary tract. CF is caused by variants in the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) gene. Prognosis of CF has markedly improved over the last 20 years because of the management in CF centers and recent introduction of CFTR modulators, aimed at correcting the defective CFTR protein. There are nowadays more CF adults than children, with a predicted median survival age of around 50 years in high-income countries. Around 85% of CF patients have pancreatic insufficiency present at birth. Gastroesophageal reflux disease (GERD) is more frequent in CF patients, but its role on decline in lung health is controversial. Distal small bowel obstruction syndrome (DIOS) caused by meconium-like stool plugs occurs at any age after the neonatal period, affecting up to 15–20% of CF patients. Because of increased life expectancy, most CF patients are expected to live to their fifties or beyond, when cancer is more frequent. In addition, CF is associated with a higher risk for GI malignancy as compared with the general population. Colorectal cancer represents the most significant risk, and colonoscopy-based screening is recommended from 40 years of age onwards. Other digestive outcomes in CF reviewed in this paper include meconium ileus, Clostridium difficile infection, intussusception, acute appendicitis, small intestinal bacterial overgrowth, appendiceal mucocele and rectal prolapse. Every CF Center should comprise a gastroenterologist with expertise in the care of CF patients.
A bird eye view on cystic fibrosis: An underestimated multifaceted chronic disorder
2021, Life Sciences
Citation Excerpt :
According to the KIWI study, 24 weeks of ivacaftor treatment in CFTR patients have shown a mean increase in fecal elastase-1 (from 1 < 50 to 99.8 mg/g), suggesting an enhancement of exocrine pancreatic function [145,146]. The similar effects were subsequently observed in a case report in older patients with CF [147]. Cystic fibrosis related diabetes (CFRD) is a widespread comorbidity in people with CF with an average incidence of 20% in teenagers and as age rises, up to 40–50% in adults with CF [148].
Cystic fibrosis (CF) is an autosomal recessive disease which involves the mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. CF involves in the inflammatory processes and is considered as a multisystem disorder that is not confined to lungs, but it also affects other vital organs that leads to numerous co-morbidities. The respiratory disorder in the CF results in mortality and morbidity which is characterized by series of serious events involving mucus hypersecretion, microbial infections, airways obstruction, inflammation, destruction of epithelium, tissue remodeling and terminal lung diseases. Mucins are the high molecular weight glycoproteins important for the viscoelastic properties of the mucus, play a significant role in the disease mechanisms. Determining the functional association between the CFTR and mucins might help to identify the putative target for specific therapeutic approach. In fact, furin enzyme which helps in the entry of novel COVID-19 virus into the cell, is upregulated in CF and this can also serve as a potential target for CF treatment. Moreover, the use of nano-formulations for CF treatment is an area of research being widely studied as they have also demonstrated promising outcomes. The in-depth knowledge of non-coding RNAs like miRNAs and lncRNAs and their functional association with CFTR gene expression and mutation can provide a different range of opportunity to identify the promising therapeutic approaches for CF.
Cystic Fibrosis and Congenital Anomalies of the Exocrine Pancreas
2020, Pediatric Gastrointestinal and Liver Disease, Sixth Edition
Cystic fibrosis (CF) is an autosomal recessive disease that involves multiple organ systems, most importantly the respiratory and gastrointestinal tracts. Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) are responsible for the CF phenotype, which varies according to genotype. Airway clearance, antibiotics, and exogenous pancreatic enzymes have traditionally been the mainstays of therapy. More recently, CFTR modulators have become available, which correct the underlying defect due to certain mutations. The majority of patients with CF have exocrine pancreatic insufficiency leading to malabsorption of nutrients and a variety of gastrointestinal symptoms and presentations. Nutrition support is critical for patients with CF and is complicated due to decreased caloric intake, gastrointestinal disease, and increased energy expenditure. Nutritional status correlates with pulmonary function and overall outcomes. CF-related liver disease is an important contributor to morbidity and mortality in a subset of patients with CF. While CF is the major cause of exocrine pancreatic insufficiency in children, other congenital anomalies of the pancreas syndromes may also cause exocrine insufficiency and pancreatic disease.
Total pancreatectomy with islet autotransplantation in a pancreatic-sufficient cystic fibrosis patient
2019, Journal of Cystic Fibrosis
Citation Excerpt :
These children often miss significant amounts of school, require opioids for pain control, and/or are frequently hospitalized. While there are currently no consensus guidelines for strict indications for TPIAT, our institution's general criteria include [1] the diagnosis of CP or ARP with ≥6 months of abdominal pain or debilitation, [2] failure of maximal medical or endoscopic treatment, [3] lack of a reversible cause of CP or ARP, [4] absence of physiologic or psychosocial contraindications, [5] willingness to accept the risk of lifelong diabetes, and [6] adequate islet function [6]. The primary goal of the pancreatectomy is to relieve pain and improve quality of life.
For children with Cystic Fibrosis (CF) suffering from acute recurrent pancreatitis (ARP), abdominal pain can be severe, difficult to treat, impair their quality of life, affect participation at school, and can lead to chronic opioid dependence. Total pancreatectomy with islet autotransplantation (TPIAT) is an uncommon treatment that is reserved for refractory cases of ARP. We present a case of a 4 year old female with pancreatic-sufficient CF, refractory ARP, frequent hospital admissions for abdominal pain, and continued growth failure despite gastrostomy tube and parenteral nutrition. One year after successful TPIAT, the patient is insulin-independent, growing well, and has not been re-hospitalized for abdominal pain. To our knowledge, this is the youngest patient with CF to undergo TPIAT for debilitating ARP. With CFTR modulators restoring some pancreatic function, CF clinicians should have increased vigilance for the development of ARP.
Cystic fibrosis and fat malabsorption: Pathophysiology of the cystic fibrosis gastrointestinal tract and the impact of highly effective CFTR modulator therapy
2024, Nutrition in Clinical Practice

View all citing articles on Scopus

^☆: Address requests for reprints to: Peter R. Durie, M.D., F.R.C.P.(C), Division of Gastroenterology and Nutrition, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, Canada, M5G 1X8. e-mail: [email protected]; fax: (416) 813-6531.

^☆☆: Supported by grants in aid from the Canadian Cystic Fibrosis Foundation and National Institutes of Health (NIDDK-DK49096). C.D. was awarded a research fellowship from the Hospital for Sick Children Research Institute and Janssen Ortho (Canada) Inc.

View full text

Clinical–Liver, Pancreas, and Biliary TractGenotype and phenotype correlations in patients with cystic fibrosis and pancreatitis☆,☆☆

Abstract

Section snippets

Patients

Patient demographics

Discussion

Acknowledgements

J Pediatr

J Pediatr

J Pediatr

J Pediatr

Clin Biochem

Genomics

Gastroenterology

Impaired chloride secretion as well as bicarbonate secretion, underlies the fluid secretory defect in the cystic fibrosis pancreas

Gastroenterology

Pancreatic fluid secretion and protein hyperconcentration in cystic fibrosis

N Engl J Med

Identification of the cystic fibrosis gene: chromosome walking and jumping

Science

Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA

Science

Identification of the cystic fibrosis gene: genetic analysis

Science

The relation between genotype and phenotype in cystic fibrosis-analysis of the most common mutation (ΔF508)

N Engl J Med

Correlation between genotype and phenotype in patients with cystic fibrosis

N Engl J Med

Genetic determination of exocrine pancreatic function in cystic fibrosis

Am J Hum Genet

Clinical–Liver, Pancreas, and Biliary Tract
Genotype and phenotype correlations in patients with cystic fibrosis and pancreatitis☆,☆☆