Definitions and Epidemiology
Pancreatic insufficiency (PI) is a term used to define patients who have lost a significant amount (usually >95%) of pancreatic exocrine function and therefore their ability to digest and assimilate nutrients normally.1 Cystic fibrosis (CF) is by far the most common form of PI in children and the focus of this chapter.
CF is the most common life-threatening autosomal recessive disease in the United States. The prevalence is higher in populations of northern European descent (~1 in 2500 births) compared to people from Hispanic (1 in 4000–10,000), African American (1 in 15,000–20,000), or Asian (1:30,000) ethnic backgrounds. The carrier rate is estimated to be around 3.5% for Caucasians; heterozygotes show no clinically relevant phenotypes.2
CF is caused by a mutation in the gene that encodes CF transmembrane conductance regulator (CFTR) protein. CFTR is expressed in many epithelial cells (sweat duct, airway, pancreatic duct, intestine, biliary tree, and vas deferens) and functions as an apical membrane anion channel, mainly involved in chloride and bicarbonate secretion.3–5 It is proposed that the lack of CFTR leads to acidic, dehydrated, and protein-rich secretions, which then plug the lumen and cause the destruction of the organ.4 Pulmonary involvement causes the most significant morbidity and mortality in patients with CF. With substantial improvement in the medical care of CF patients, the projected life expectancy has now increased to ~37 years of age.6
Although >1500 CFTR mutations have been identified, the functional importance is known only for a small number of mutations. CFTR mutations can be classified into six types of defects (class I–VI mutations) (Table 32–1)2: absence of protein synthesis (class I); defective protein maturation and premature degradation (class II); disordered regulation (class III); defective chloride (Cl) conductance or channel gating (class IV); a reduced number of CFTR transcripts due to a promoter or splicing abnormality (class V); and accelerated turnover from the cell surface (class VI) (Figure 32–1).4,7,8CFTR function is virtually absent with class I–III and VI mutations while class IV and V mutations allow some residual CFTR function.6 Pancreatic function appears to correlate well with the gene mutations at the CFTR locus. Exocrine pancreatic dysfunction is seen almost exclusively in association with class I–III and VI mutations.7 Patients with at least one mutation belonging to class IV or V generally present with symptoms in late childhood or adulthood.
|Protein production (no CFTR made)
|621 + G–T
|Processing (defect in protein trafficking leads to degradation)
|Regulation (CFTR not activated by ATP or cyclic AMP)
|Conduction (reduced anion transport through CFTR)
|Splicing defect (reduced production of normal CFTR)
|3849 + 10 kb C → T
|1811 + 1 · 6 kb A → G
|IVS8-5T, 2789 + 5G → A
Classes of CFTR mutations. Classes of defects in the CFTR gene are: absence of protein synthesis (class I); defective protein maturation and premature degradation (class II); disordered regulation, such as diminished ATP binding and hydrolysis (class III); defective Cl– conductance or channel gating (class IV); a reduced number of CFTR transcripts due to a promoter or splicing abnormality (class V); and accelerated turnover from the cell surface (class VI).
The absence of phenylalanine at position 508 (ΔF508, a class II mutation) constitutes two-thirds of CFTR mutations in northern European and North American populations. No other single mutation accounts for >5% of CFTR mutations worldwide.2 Among the various gastrointestinal organs affected by CF, the exocrine pancreas shows the strongest association between genotype and phenotype. In most cases, considerable destruction of the pancreas starts in utero and functional loss of the exocrine pancreas develops at birth or in early infancy.2
The pancreas is commonly involved in patients with CF, and CF is the most frequent cause of exocrine PI in childhood. Eighty-five percent of CF patients have PI; 50–65% have PI at birth, and 20–30% of pancreatic sufficient (PS) patients become rapidly insufficient during the first few months and years of life.9 The 15% of CF patients who are PS have a markedly improved prognosis and lung disease of later onset. Although it has “sufficient” function, pancreas is never normal in CF patients with PS. Pancreas does not manifest failure until >95% of its exocrine portion is lost.
There are four potential mechanisms that could explain pancreatic damage and PI in CF: (1) obstruction of pancreatic ducts by inspissated plugs, (2) inhibition of endocytosis in acinar cells, (3) inflammation, and (4) imbalance in membrane lipids. Any of these abnormalities alone or in combination may explain the development of pancreatic lesions in CF.10
In healthy mammals, pancreatic juice is first secreted as protein and pancreatic enzyme-rich fluid by acinar cells. As it passes through the pancreatic ducts, the fluid composition is changed by the secretion of fluid and HCO3– into the lumen, a function regulated mainly by CFTR in the ductal epithelial cells. Patients with CF have low-flow pancreatic secretions with a high protein concentration that presumably precipitates in the duct lumen causing obstruction, damage, and atrophy. Inspissated secretions may also be due to increased mucus production and alterations of proteins through proteolysis or modification of the milieu in which these proteins reside.
It appears that blunted ductal bicarbonate (HCO3–) secretion is the initiating event in CF pancreatic disease. Acidification of the acinar and duct lumen may cause defective endocytosis of the zymogen granule membranes and decreases solubilization of the pancreatic secretory proteins, resulting in precipitation and formation of lamellar plugs.
It is possible that inflammation plays an important role in the development and progression of pancreatic lesions in CF. Recurrent acute and chronic pancreatitis are known complications of CF, and they may occur in ~ 20% of patients with the PS phenotype.4,11 It is not known why a subgroup of patients with CF develops pancreatitis, but preservation of acinar cells seems to be a prerequisite for this complication.
Essential fatty acid deficiency is well described in CF patients, even in the absence of other nutritional deficiencies. Plasma eicosatrienoic acid levels are high, whereas linoleic and docosahexaenoic acid levels are low in patients with CF. Docosahexaenoic acid is an important regulator of membrane fluidity and transport systems and it also down-regulates arachidonic acid incorporation into the membrane phospholipids. The imbalance between docosahexaenoic acid and arachidonic acid in CF can potentially explain the observed mucin hypersecretion, alterations in the acinar cell endocytosis, and pancreatic inflammation observed in CF. Studies are ongoing to understand the mechanisms by which mutations in CFTR lead to this membrane lipid abnormality.10
|• Persistent, productive cough
|• Obstructive airway disease
|• Chronic bronchitis with or without bronchiectasis
|• Acute exacerbations of lung disease (increased cough, tachypnea, dyspnea, increased sputum production, malaise, anorexia, and weight loss)
|• Digital clubbing
|• Colonization of the airway with pathogenic bacteria (Staphylococcus aureus, Haemophilus influenzae, Pseudomonas aeruginosa)
|• Predisposition to lung infections
|• Fat-soluble vitamin deficiencies
|• Meconium ileus (newborn period)
|• Distal intestinal obstruction syndrome (older children)
|• Focal biliary cirrhosis
|• Cholestasis (rare in infancy)
|• Cirrhosis and portal hypertension
|• End-stage liver disease (in older children, rare)
|Ear, nose, and throat
|• Chronic rhinosinusitis
|• Nasal polyps
|• Male infertility most commonly due to absence of vas deferens
|• Female infertility due to chronic lung disease and malnutrition
|• Poor weight gain or weight loss
|• Frequent, bulky, foul-smelling, sometimes greasy stools
|• Rectal prolapse
|• Abdominal pain (if pancreatitis is present)
|• Bleeding tendencies (if vitamin K is deficient)
|• Bone fractures (if vitamin D is deficient)
|• Night blindness (if vitamin A is deficient)
|• Loss of subcutaneous fat
|• Decreased muscle mass
|• Digital clubbing
|• Edema (if hypoproteinemia is present)
|• Abdominal tenderness (if pancreatitis is present)
|• Acrodermatitis (if vitamin A is deficient)
|• Neuropathy (if vitamin E is deficient)
More than half of infants with CF are pancreatic insufficient at birth; 20–30% of infants with normal pancreatic function at birth become rapidly insufficient during the first few months and years of life. The major consequences of PI are fat malabsorption secondary to decreased production of pancreatic enzymes. Fat malabsorption is defined by a fecal fat >7% of oral fat intake in a 3–5-day fat balance studies. Fat malabsorption, steatorrhea, and malnutrition are the hallmarks of CF patients with PI.
Insufficient secretion of pancreatic enzymes (proteases, amylase, lipase, and colipase) leads to malabsorption of fat and protein. Patients with CF and PI have frequent, bulky, foul-smelling, sometimes oily stools. The subsequent calorie and protein losses are usually associated with diarrhea and lead to a decrease in fat stores with loss of subcutaneous fat, decreased muscle mass, and failure to thrive within the first few months of life. In severe cases, fat malabsorption can lead to deficiencies of fat-soluble vitamins A, D, E, and K. Routine vitamin supplementation has made clinical evidence of vitamin deficiency uncommon. Nevertheless, vitamin K and D deficiencies may still occur despite supplementation. Decreased bone mineral density, increased fracture rates, and kyphosis are common in patients with CF, even among those with pancreatic sufficiency. The risk for bone disease increases with advancing age and severity of lung disease and malnutrition.
Malnutrition and poor growth are commonly found in infants with CF at the time of diagnosis, and they are more prevalent if PI is present. Among children with CF, ~15% are below the fifth percentile for weight and height. Growth parameters improve after diagnosis and appropriate treatment, but growth delay continues to be a problem in CF. Although the etiology of malnutrition is multifactorial (inadequate intake, increased losses, lung disease, and increased energy needs), PI seems to have a major impact on growth and nutrition. Infants identified with PI at diagnosis are more malnourished as evidenced by poor weight gain, depressed fat stores, low serum albumin, and BUN. These findings are noted despite an increased dietary intake in these patients.
Chronic progressive lung disease is the most prominent cause of morbidity and mortality in patients with CF. Good nutritional status has a positive impact on lung disease and patient survival, whereas malnutrition and PI are associated with more rapid decline of the pulmonary function. Patients with PS have normal growth, develop lung disease at a later age, and are less likely to have lung colonization with Pseudomonas.
Rectal prolapse and digital clubbing are common in children with CF, associated with PI and malnutrition. In older children, pulmonary symptoms dominate the picture and PI symptoms may not be elucidated unless directly asked by the examiner or investigated by laboratory testing.