PEI and Cystic Fibrosis

About

Cystic fibrosis is an autosomal recessive genetic disease which causes faulty chloride and bicarbonate secretion in epithelial cells in many parts of the body. This affects the water content of epithelial cells, giving rise to many clinical symptoms including progressive damage to the respiratory and digestive system. In the pancreas, secretions become viscous with a high salt content¹ which together with thick mucus blocks the release of enzymes, causing pancreatic exocrine insufficiency (PEI).^1,2 Although treatment for cystic fibrosis in recent years has extended life expectancy, patients still suffer a premature death.¹

Epidemiology

Cystic fibrosis affects up to 1 in 2,500-3,000 live births.¹ PEI is present to some degree in 55-100% of cystic fibrosis patients,² with 85-95% of children showing symptoms at one year of age.

The Canadian prevalence of PEI in patients with cystic fibrosis is more than 4100 with 120 new diagnoses in 2014.⁹ The prevalence of severe PEI has been reported in more than 80% of people with cystic fibrosis.²

Causes

PEI in cystic fibrosis results from the presence of highly concentrated, thick pancreatic secretions which obstruct the pancreatic ducts. The consequent reductions in the volume and concentration of pancreatic enzymes and bicarbonate reaching the gut result in fat and protein maldigestion and malabsorption. These are exacerbated by impaired gastrointestinal motility and increased gastric acid secretion. In addition, bicarbonate secretion from the pancreas is reduced which can cause delayed gastric emptying and gastro-oesophageal reflux.³

Furthermore, the persistence of highly concentrated enzymes with the acinar and ductile structures results in local cellular damage, acinar atrophy, fibrosis and fatty replacement of normal organ structures. ³

Pathophysiology

Cystic Fibrosis is caused by mutations in the gene coding for the cystic fibrosis transmembrane conductance regulator (CFTR) protein. As a result of these mutations, there is functional loss of the CFTR protein which decreases secretion of chloride at the apical surface of epithelial cells and increases re-absorption of sodium and water across these cell surfaces.^1,3

Impairment of cellular chloride ion transport affects intracellular water levels and has the effect of reducing the volume and increasing the viscosity of the exocrine secretions of the pancreas. This leads to obstruction of the pancreatic ducts, acinar cell destruction, fibrosis and PEI.³

The presence of thick, high-salt fluids occurs in many organs as well as the pancreas, including the lungs, giving the other classic cystic fibrosis symptoms of recurrent respiratory infection with bronchiectasis.¹

The chance of developing PEI in patients with cystic fibrosis depends on the gene mutations they carry. In general, the vast majority have two ‘severe’ gene mutations and so develop PEI. About 10% of cystic fibrosis patients carry at least one ‘mild’ mutation and usually do not show symptoms of PEI (they remain pancreatic sufficient) and grow normally, although they may develop PEI in adult life.²

Fact

More than 95% of people with severe CFTR mutations are pancreatic insufficient in childhood or progress to PEI.

PEI should be considered in individuals with a newly diagnosed pancreatic disease predisposing to PEI, including cystic fibrosis.

Durie P, et al. 2018⁹

Signs and symptoms

In general, PEI causes malabsorption and maldigestion, resulting in symptoms of:^1,4

Symptoms

WEIGHT LOSS

ABDOMINAL PAIN

FATIGUE

DIARRHEA

STEATORRHOEA

FLATULENCE

For some infants with cystic fibrosis the amylase and lipases in maternal breast milk may compensate for PEI to some degree, so may not show weight loss until after they are weaned. Older children may compensate for loss of nutrients in the stools by increased appetite and food intake, only presenting with sudden weight loss after intercurrent infections during which feeding has decreased.³

A small proportion of patients with cystic fibrosis (<10-20%) who are homozygous or heterozygous for the less severe mutations may have enough pancreatic function to grow normally throughout childhood. Such patients may develop the symptoms of PEI during adulthood, along with bouts of pancreatitis.³

Steatorrhoea is characterized by foul-smelling, greasy stools, and is usually the most classical clinical manifestation of PEI.⁵ Steatorrhoea may be associated with deficiencies of fat soluble vitamins: A, D, E and K, leading to osteoporosis and other complications.²

Complications

Complications from maldigestion and malabsorption may have a progressive and detrimental effect on a patient’s wellbeing and increase morbidity and mortality.^4,6,7 For further information on the complications of PEI,CLICK HERE.

Diagnosis

There are several methods available for diagnosing PEI, with the indirect methods being the most frequently used in the clinical setting. Of these, the 3-5 day faecal fat balance test is recommended because it has been shown to correlate well with direct tests of pancreatic function. However the fecal elastase is a practical alternative.¹

For a detailed discussion of these techniques, CLICK HERE.

For infants diagnosed with cystic fibrosis, weight and height should be measured every month, and for children every 2-3 months. An indirect test for PEI should be carried out every 4-6 months.

The frequency of these tests should be increased if patients with cystic fibrosis are not achieving expected weight gain or develop symptoms associated with PEI such as steatorrhoea.¹

Fecal elastase-1 levels are quantified with an ELISA*1

Fecal elastase-1 levels are quantified with an ELISA*1
Measurement	Infants (0-2 years)	Children (2-18 years)	Adults (>18 years)
Height (supine/length)	1-2 weekly until thriving, then monthly	–	-
Height (standing)	–	3 monthly	Annually†
Weight	1-2 weekly until thriving, then monthly	Every clinic visit*	Every clinic visit*
Head circumference	1-2 weekly until thriving, then monthly	–	–
Plot on appropriate growth chart	✔	✔	–
% IBW	✔	✔	–
BMI	–	✔	✔
Plot on BMI centile chart	–	✔	–

Adapted from Stapleton, et al. 2006.¹

* Fortnightly if clinic visits are more frequent than this.

^†If growth has ceased; otherwise 3 monthly until cessation of growth is demonstrated (consider that growth may continue up to 20 years in males with CF).

% IBW: percentage ideal body weight, BMI: body mass index.

Adapted from APC Guidelines, 2015.¹

Treatment

Treatment of PEI in patients with Cystic fibrosis

Failure to treat PEI in patients with cystic fibrosis can result in:³

Stunted growth
Delayed puberty
Deteriorating lung function
Respiratory failure
Early death

Pancreatic enzyme replacement therapy (PERT) is essential in patients with PEl due to cystic fibrosis in order to correct malabsorption and malnutrition, reduce steatorrhoea, and achieve normal growth.³

In infants, dosing should be initiated at a dose of 2,000 to 5,000 lipase units for each feeding (usually 120 mL) and adjusted up to a dose no greater than 2,500 lipase units/kg per feeding with a maximum daily dose of 10,000 lipase units per kilogram per day.

In children less than 4 years of age, weight-based enzyme dosing should begin with 1,000 lipase units/kg body weight per meal. In children older than 4 years and in adults, the recommended initial dosing is 500 lipase units/kg body weight per meal.

Usually, half the standard dose is given with snacks. Dosage should be adjusted according to the severity of the disease, control of steatorrhea and maintenance of good nutritional status.

Fibrosing colonopathy has been reported in patients with cystic fibrosis taking in excess of 10,000 units of lipase per kilogram body weight per day. ⁸

For children of school age, taking large numbers of capsules with food may cause stigmatization, which can lead to poor adherence and consequently poor growth and/or weight loss. The consequences of suboptimal PERT management should be discussed with patients and their families.³

Doses can be titrated based on weight gain and bowel signs to find the lowest effective dose. Signs and symptoms of malabsorption such as pain, excessive gas, frequency and stool consistency are not indications for dose adjustments.¹

In addition to PERT, fat-soluble vitamins A, D, E and K should be supplemented prophylactically.¹

To learn more about the treatment of PEI with PERT, dosing of PERT, and other aspects of PEI management, CLICK HERE.

Long-term management and monitoring for PEI in patients with cystic fibrosis¹

Children should be assessed at regular intervals for height, weight and head circumference, dietary intake, biochemical assessments and a review of bowel habit and function. In very young children, dietary intake assessments should be more frequent.

Adults may lose height over time due to ageing, osteoporosis or kyphosis. A thorough assessment of dietary intake should be conducted at least once a year.

Key areas of nutritional assessment for cystic fibrosis patients:


Key areas of assessment	Purpose
Energy intake	Energy balance and affect on weight
Fat intake	Energy density and PERT adequacy
Food preferences and variety	Adequacy of micronutrient intake Fibre intake Target areas for change
PERT: dosage, adherence and gastrointestinal symptoms	Adequacy of PERT regimen
Supplements: vitamins and minerals, oral and enteral nutritional supplements	Adequacy of micronutrient intake Contribution to energy and nutrient intakes
Sodium and fluid intake	Hydration and sodium status
Nutrition-related complementary or alternative therapies	Adequacy of micro and macronutrient intake