The Genetic Disease Cystic Fibrosis Health Essay

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Cystic fibrosis (CF) is a genetic disease that is common in the Caucasian (white) population in Western countries. It occurs in about 1 in 3,200 Caucasian newborns, whereas it is less common in other ethnic groups (Parker, 2007).

Cystic fibrosis is an inherited, life- threatening genetic disease caused by a mutation, or a flaw, of a single gene called the CFTR gene which is, the cystic fibrosis transmembrane

conductance regulator gene. The flawed gene is inherited, from parent to child. This mutated gene causes the body's mucous glands, to produce thick, sticky mucus that blocks the lungs and obstructs the pancreas. Blocked lungs can lead to dangerous lung infections that often repeat themselves throughout a patient's life (Giddings, 2009). Other complications of cystic fibrosis affect the endocrine, gastrointestinal and the reproductive system (Parker, 2007).

Newborn screening for cystic fibrosis offers the chance for early medical and nutritional intervention that can lead to improved outcomes. The focus of the nutritional management is on maintaining the health of the individual by preventing nutritional and respiratory complications such as failure to thrive, stunting, wasting, vitamin and mineral deficiencies, recurrent pulmonary infections associated with decreased lung function, and recurrent hospitalizations (Borowitz, & Robinson, 2009).

Patients with cystic fibrosis show inevitable physical symptoms such as growth failure and weight loss, caused by many factors that are associated with poor nutrition and also drug therapy. Lung diseases are the major problem that requires a heavy nutritional intervention (UK cystic fibrosis Trust Nutrition Working Group, 2002).

Malnutrition has been associated with increased morbidity and mortality in CF, (Corey et al, 1988). The maintenance of energy balance is thought to be challenged by a combination of factors. Energy deficits may arise as a consequence of CF-related increases in energy expenditure, increases in gastrointestinal losses and decreases in oral intake. Advances in pancreatic enzyme replacement therapy (PERT) and dietary recommendations have resulted in significant increases in the fat and absorption of individuals with CF, but numerous issues continue to limit the overall intake of children, such that elevated requirements are rarely met(Borowitz, & Robinson, 2009).

The life expectancy of those with Cystic fibrosis has increased in many countries, probably as the result of increased availability of medication and nutrition medical therapy (Shaw, 2007). In western countries the life expectancy can reach 35 years, in Lebanon it can reach up to 13 years only (Teebi, 2010).

Chapter 1

Understanding cystic fibrosis

1.1 Definition of cystic fibrosis

Cystic fibrosis is a recessively inherited genetic disease that consists of a dysfunction of exocrine glands along with disturbances of ion and fluid movements that leads to abnormally thick and dehydrated secretions.

The trigger for this dysfunction is a mutation located on the chromosome 7q (fig.1), where the gene responsible for a membrane-associated protein named the Cystic Fibrosis transmembrane conductance regulator (CFTR) is present.

The role of the CFTR is to regulate chloride and sodium transport across apical membranes of epithelial cells (Shaw, 2007) (Mahan, & Stump, 2008).

C:\Documents and Settings\G. Farah\Desktop\chromosome.jpg

Fig. 1: Representation of the CFTR gene located on the chromosome 7q and its mutation., adapted from understanding cystic fibrosis, Retrieved from

1.2 Etiology of cystic fibrosis

Although there are hundreds of possible causes for the CFTR mutation, 70% of patients have the same defect: F508, the depletion of 3 bases on the chromosome 7q that causes the loss of a phenylalanine.

Gene defects are also classified in different categories depending on the functioning of the gene. "Typical clinical manifestations of cystic fibrosis usually do not occur in patients who have 10% or more CFTR function", in patients with1% or less functioning of the gene, the patients' cells have very defective CFTR; therefore, chloride, sodium,

and water flow is faulty.(Table. 1) Most patients have parents that are heterozygotes or carriers of the disease (Grossman, 2005).

Table 1: Types of errors in production of the protein cystic fibrosis transmembrane regulator (CTFR) in patients with cystic fibrosis (adopted from Grossman, 2005).




Zero CFTR is produced


CFTR is not processed correctly, so no protein gets to the cell membrane


The CFTR chloride pathway is regulated differently than normal, but transfer of CFTR occurs


The chloride current is not conducted properly, so the transfer of CFTR is slowed


Synthesis of CFTR is abnormal, however CFTR is transferred

1.3 Pathophysiology of cystic fibrosis

Since cystic fibrosis is a disease of the exocrine glands affecting mainly the Gastro-Intestinal and the respiratory systems, it can lead to chronic lung disease, exocrine pancreatic deficiency and abnormally high sweat electrolytes. Nearly all exocrine glands are affected in varying distribution and degree of severity (Farell et al, 2008).

1.3.1 Respiratory diseases

Lung disease is manifested in almost all CF patients by recurrent episodes of infection and inflammation that lead to tissue destruction, fibrosis and eventually respiratory failure. Pulmonary disease is the primary cause of death in about 90% of CF patients, but the severity of lung disease and the rate of decline in lung function are highly variable (Cutting, 1997; Kraemer et al.,2000; Rantjen and Döring, 2003).

The lungs of patients with CF develop adherent, viscous secretions that cause poor airways clearance, dilatation of acinar and duct lumens of sub mucosal glands, leading to mucous obstruction of bronchioles accompanied by bronchiolar wall inflammation (Cutting, 1997). As obstruction of the airway increases, it becomes more difficult for air to pass during exhalation. This leads to expansion of alveoli, where air trapping occurs and, slowly, causes the barrel shaped chest (Grossman, 2005) (Shaw, 2007). The most commonly encountered obstructions are assumed to be caused by a number of factors (Table 2) (Brand, 2000).

Table.2 Mechanisms involved in airways obstruction in cystic fibrosis, (Brand, 2000)

The next phase of the disease is local and generalized chronic bacterial infection with pathogens such as Staphylococcus aureus, Haemophilus influenzae and Pseudomonas aeruginosa (Cutting, 1997; Rantjen and Döring, 2003).

A typical sign of pulmonary disease associated with cystic fibrosis, is decreased levels of interleukin-10, which is a cytokine with anti-inflammatory properties, especially in the lungs, the reason being the decreased Chloride secretion due to the defective CFTR (Shmarina et al., 2001) (Soltys et al., 2002).

1.3.2 Hematopoietic system

Lungs of the cystic fibrosis patient are more than often colonized or infected during infancy. Chronic infection with Pseudomonas aeruginosa is the main reason for lung dysfunction.P. aeruginosa colonizes the airway tract and start using iron for its own growth.Microcytic anemia, or iron deficiency are a result of chronic hemoptysis caused by the colonization (Reid et al. 2009).

1.3.3 Pancreatic disease

The CFTR mRNA, is present in the centroacinar cells of the intercalated duct in the pancreas, an obstruction of the pancreatic ducts will limit the blood flow into the pancreatic tissue, which causes damage and death of β cells ( Fig.2) and later α cells.

The prevalence of diabetes mellitus in patients with cystic fibrosis is high, and increases with age. The damage will slowly decrease insulin production combined with insulin resistance.

Fig. 2: A visual representation of the progressively deteriorating beta cell function (insulin deficiency) that precedes the diagnosis of cystic-fibrosis-related diabetes, (Dobson et al., 2004).

The same glycemic thresholds have been adopted as the standard for the diagnosis of Cystic Fibrosis Related Diabetes (CFRD) since no equivalent have been made.

The American Diabetes Association diagnostic criteria have been used (Table. 2)

Table. 2 Diagnostic criteria for diabetes mellitus (adopted from American Diabetes Association, 2010)

The exocrine secretions of the pancreas are also affected by the mutation of CFTR, Damage begins in utero with ongoing destruction and eventual replacement of the acini

with fibrous tissue and fat.

Secretion of digestive enzymes and bicarbonate is altered, resulting in malabsorption of fat, protein, bile, vitamin B12 and fat soluble vitamins. Pancreatic insufficiency usually presents with symptoms of malabsorption, malnutrition, vitamin deficiencies, and weight loss (or inability to gain weight in children) and is often associated with steatorrhea (loose, fatty, foul-smelling stools). As estimation, 90% of patients have pancreatic insufficiency, (Shaw, 2007).

1.3.4 Gastrointestinal system

Diseases of the gastrointestinal tract are usually less prominent in CF patients. However, about 10 to 15% of CF newborns suffer from obstruction of the small intestine, called meconium ileus (MI), due to reduced water secretion and sludging of intestinal contents (Davis et al., 1996, Welsh et al., 1995). The accumulation of undigested proteins (e.g albumin), when mixed with intestinal mucus, produces an impervious and hyperviscid meconium substance (Quinton, 1999). Dehydration of the intestinal contents can already be detected in utero by ultrasonography as hyperechogenic fetal bowel (Scotet et al., 2002). Later in life, recurrent episodes of bowel obstruction called distal intestinal obstruction syndrome or the equivalent of MI are also characteristic for CF, and are encountered by about 20% of CF patients. Complete obstruction is associated with failure to pass stool, abdominal distension and vomiting, whereas partial obstruction is accompanied only by intermittent abdominal pain (Welsh et al., 1995). Tenacious intestinal residue may serve as a lead point for intussusception or cause recurrent rectal prolapse. In childhood, rectal prolapse in CF patients is a common complication (occurrence about 20%), but is an infrequent event for adults with cystic fibrosis (Cutting, 1997; Welsh et al., 1995).

1.3.5 Sweat glands

The most consistent functional alteration in CF has been elevated concentrations of chloride ion and sodium ion in sweat, which are the basis for the principal diagnostic test for the disease (Davis et al., 1996). The number of sweat glands is normal and there are no structural abnormalities in the eccrine sweat glands in CF (Welsh et al., 1995).

The reason is that even though CFTR is an apical epithelial chloride channel, but irregular sodium transports also take place at the same time. It was shown that a reduced rates of reabsorption of Cl- and Na+ in the sweat glands was behind the sodium loss (Donaldson, & Boucher, 2007).

1.3.6 Reproductive system

Infertility is a very common among men with cystic fibrosis, because of the absence or a malformed vas deferens (a duct in the male reproductive system that transports sperm from the epididymis before the ejaculation).

Women on the other hand, present a better fertility but requires more time to become pregnant, due to Mucus plugs in the oviduct and thicker cervical mucus that

decreases sperm movement. Puberty seems to be delayed for both men and women with cystic fibrosis (Moskowitz et al, 2008).

1.4 Diagnosing cystic fibrosis

Screening for cystic fibrosis in newborn children is increasing, because early detection gives access to specialized medical care and improves outcomes.

Sweat chloride test is currently the gold standard for diagnosing cystic fibrosis, but isn't always conclusive. Genotype analysis doesn't give a certain answer since many mutations can occur to the CFTR gene (Farell et al, 2008). While screening is mandatory in some states in the United States of America, it remains an elective test everywhere else around the world (Massie et al, 2010).

1.4.1 Sweat chloride test

It measures the electrolytes in the sweat, and generally chloride is the most affected. Universal definitions of normal (≤39 mmol/L), intermediate (40 to 59 mmol/L), and abnormal (≥ 60mmol/L) sweat chloride values have been applied to all patients.

If sweat chloride is ≥60 mmol/L, a second, confirmatory sweat chloride test is recommended unless mutation analysis identifies the presence of 2 Cystic Fibrosis causing mutations.

If sweat chloride is in the intermediate range (30 to 59 mmol/L for infants under age 6 months; 40 to 59 mmol/L for older individuals) should undergo extensive CFTR mutation analysis.

If sweat chloride is under 39mmol/L in individuals over the age of 6 months, cystic fibrosis is a very unlikely diagnosis, unless mutations are found. (Farell et al, 2008)

1.4.2 DNA analysis

When the sweat chloride test is in the intermediate range, DNA analysis is performed to help establishing a diagnosis. Checking for the faulty cystic fibrosis gene can reduce the risk of clinical errors at the time of sweat chloride testing, (Farell et al, 2008).

1.4.3 Antenatal testing

During pregnancy, a test can be done to see if the unborn baby has cystic fibrosis.

The test uses chorionic villus sampling (CVS). Antenatal testing for cystic fibrosis is generally only offered to mothers who are considered to be at high risk of having a child with CF such as consanguineous parents that are carriers of the CF gene (Farell et al, 2008).

1.5 Treatment of cystic fibrosis

There are many approaches available for treating patients with cystic fibrosis:

1.5.1 Physiotherapy

It is a way of clearing the built up mucus in the lungs. This can help on preventing infections and lung damage. The duration of treatment sessions varies according to every patient need. Daily physiotherapy is usually required and in case of a chest infection you may need to increase the amount of airway clearance. If secretions are fewer, treatment sessions may only need to last 10-15 minutes. If there are many secretions, it could take as long as 45-60 minutes. The physiotherapy should start since the diagnosis of the infection, and it is better for parents to learn how to administer physiotherapy on their children, and adolescents can become independent doing it (Papadopoulo, & Tsanakas, 2007).

1.5.2 Medication

Infections can be cleared or controlled by a variety of drugs. The most commonly used medication for people with Cystic Fibrosis are the following:

In case of lungs complications, airway obstruction is commonly encountered in patients with CF. Bronchodilator drugs are used to open the airways by relaxing the surrounding muscles. This will relieve the feeling of tightness and short of breath.

In order to be fully effective, short-acting β2 agonists should be inhaled at least four times daily, (brand, 2000). Preliminary studies are looking at the efficacy of long acting β2 agonist being superior to short acting drugs (fig.3), (Hordvik et al, 1999).

Fig. 4 Mean changes in FEV1 caused by chest physiotherapy in cystic fibrosis patients hospitalized with a pulmonary exacerbation. Patients were treated before chest physiotherapy sessions at 7:00 am and 7:00 pm with inhaled salbutamol (solid bars)

or salmeterol (hatched bars) (Ref 13). FEV1=Forced expiratory volume in 1 s, (Hordvik et al, 1999).

Antibiotics are also used to help treat or control any infection. Since pseudomonas aeruginosa is the most opportunistic pathogen to affect the lungs of the CF patients, various antibacterial agents have been used to control or fight this pathogen.

Depending on the mode of action of the antibiotic, resistance can occur especially when the drug is given for a prolonged period of time (Doring et al, 2000). The recommended dosages of antibiotics used in the management of cystic fibrosis are listed in Appendix 1,

Respiratory distress in CF can be attributed to the buildup of mucus in the airways.

More than 30 years ago, it was suggested that the large amount of DNA in mucus secretions is responsible for its viscosity. In fact, lung secretions incubated in vitro with partially purified bovine pancreatic DNase I show a large reduction in viscosity of the mucus, (Chernick et al, 1961).

Based on that, bovine DNAse I have been approved as safe and effective for treating the CF patients, although severe adverse respiratory distress did occur occasionally, as a consequence of allergic reactions to a foreign protein.

Nowadays, human DNase is used to reduce the viscosity of sputum in CF patients, (Shak et al, 1990).

1.6 Cystic Fibrosis and malnutrition

Malnutrition occurs when nutrients fail to meet the body's nutritional requirements; this imbalance results either from inadequate food intake, absorption and/or assimilation, or from excess needs despite good nutritional intake.

Malnutrition is a common problem among patients with cystic fibrosis, (Huichuan, & Shoff, 2008).

Nutritional failure is currently defined according to the 2002 Cystic Fibrosis Foundation (CFF) criteria:

Height < 5th percentile

%Ideal Body Weight (%IBW) < 90% percentile

BMIp < 50th

However studies showed that the use of %IBW by the CFF is flawed because it misclassifies underweight in short and tall children, (Zhang et al, 2002).

Chapter 2

Medical nutrition therapy in cystic fibrosis

2.1 Assessing nutritional status

Growth monitoring in infancy and childhood has been part of preventive child health programs for more than a century in both developed and underdeveloped countries. It is a popular tool for defining health and nutritional status of children. At the individual level, growth monitoring consists of measuring the individual's height, weight and head circumference and plotting these measurements on a growth chart. The position of the measurements on such a growth chart shows whether the growth pattern of the child deviates from that of the reference population, (Walker et al, 2004).

2.1.1 Assessing height, weight and head circumference

Several studies have compared the growth pattern of CF-patients with that of healthy children. Many cases show FTT for weight, length and body mass index (BMI).

The presentation of growth charts differs between countries. Some countries present

their growth charts in percentiles, while others use Standard Deviation Scores (SDS).

Additional care must also be taken when interpreting head circumferences centiles as young children with CF have been shown to have smaller head circumferences than well children, (Ghosal et al, 1995). In addition, genetic short stature must be taken into consideration as well as delayed puberty. The delayed puberty is the reason why an overestimation might occur in the adolescent age group.

The body mass index (BMI), is a tool used to assess whether weight is in proportion to height. In 1998, it has been validated for children, (Prentice, 1998).

An alternative method using the percentage of ideal body weight (%IBW) was adopted in 2001 by the cystic fibrosis foundation as a better assessment tool.

Recent studies compared the use of both percentage of ideal body weight and BMI percentiles (BMIp) (fig.6). As a conclusion, results showed that among children with average stature (ie, height between the 25th and 75th percentiles), %IBW and BMIp yields similar estimates of ideal weights and good agreement in classifying malnutrition. However, among children with short stature (ie, height < 25th percentile), %IBW underestimates the severity of malnutrition when compared with BMIp. Among children with tall stature (ie, height > 75th percentile), %IBW overestimates the severity of malnutrition when compared with BMIp, (Zhan g & Lai, 2004).

Fig.6 Comparison of the nutritional status as reflected by ideal body weight recommended by the Cystic Fibrosis Foundation (%IBWCFF) with that indicated by body mass index percentile (BMIp) in children with CF who were reported to the 2000 CFF Patient Registry, (Zhan g & Lai, 2004).

2.1.2 Assessing body composition

Determining body composition offers a more accurate assessment of nutritional

status by evaluating the nature of malnutrition.

The possibility that ongoing sub-normal growth in CF is due low stores of fat and/or sub-optimal lean body mass, suggests that monitoring of body composition may enable deteriorations in nutritional status to be detected early, and nutrition interventions to be implemented immediately, before any stunting in height, inadequate weight gain or deterioration in pulmonary function occurs, (Lai et al, 1998).

There are numerous methods of assessing body composition, but most are invasive, expensive and not suitable for general use with children or infants. These measurements, which enable us to assess whether, weight loss or gain is mainly attributable to lean tissue, water or fat mass would affect the method of nutritional support chosen and also the type of nutrients delivered to the patient.

Methods include total body potassium (TBK), total body electrical conductivity (TOBEC), bioelectrical impedance analysis (BIA), total body water by isotope dilution and dual energy x-ray absorptiometry (DEXA), (UK cystic fibrosis Trust Nutrition Working Group, 2002).

Simpler methods of body composition assessment include simple anthropometric measurements, specifically mid-upper arm circumference (fig. 7) and arm muscle area (derived from mid-arm skinfold and girth measurements). Skinfold thickness measurements are thought to be useful as they indicate the level of subcutaneous fat and are considered to be an index of stored energy. Girth measurements are also useful for assessing nutritional status as they can be used to estimate muscularity.

Fig.7 Mid-upper-arm-circumference measurement for children, (Shaw, 2007).

The reliability and reproducibility of these measurements are poor in CF and are not therefore recommended in routine clinical practice, although they are popular worldwide, (UK cystic fibrosis Trust Nutrition Working Group, 2002).

The frequency of assessment in infants should be at least every 2 weeks until appropriate growth is documented. The visit must include weight, length and head circumference and documented on the appropriate growth charts.

2.2 Factors associated with malnutrition

Various factors can result in poor nutrition for cystic fibrosis patients:

1) Anorexia and poor dietary intake: studies comparing calorie intake, between infants and toddlers with CF and healthy peers (Powers et al, 2002).; also, eating behaviors, such as meal duration, bites and sips per minute, showed that Infants and toddlers with CF would not meet the CF dietary guidelines for the percentage of RDA for calories or the percentage of calories from fat. Also Infants and toddlers with CF would have longer meal durations than healthy peers, but would not differ on the pace of eating; the number of calories consumed during the meal, or the percentage of time spent eating during the meal .

2) Increase energy loss in stool: in order to evaluate to energy requirements for cystic fibrosis, chronic fecal energy loss had to be taken into account. (Trabulsi et al, 2007) Determining fecal fat loss, was done by collecting stool samples for 72 hours from the patient, and grams of fecal fat were multiplied by 9 to determine the amount of fecal fat energy loss, due to malabsorption.

3) Increased energy demands: Increased energy expenditure arises from a combination of lung infection and inflammation (through oxidant injury and inflammatory mediators), in other words, the work of breathing and coughing and stimulation of metabolism by bronchodilator therapy, (Brand, 2000).A review of the literature on energy expenditure in CF reports that the increase in resting energy expenditure has been estimated to be between 9% and 30 % in well individuals with CF, and that a cellular defect causing greater energy utilization within the cell has been suggested, but also disputed, as the cause, (Parker, 2007). Studies investigating total daily energy expenditure in CF suggest that individuals compensate for raised energy expenditure by reducing their level of physical activity, such that those with moderate lung disease have comparable total daily energy expenditure to control, (Zemel et al, 1996).

Fig. 5 will illustrate the complexity of the inter-relationship between the CF disease process, infection, lung disease and nutrition. Recurrent chest infections, and the accompanying anorexia and increase in energy expenditure, can adversely affect nutritional status and growth. Conversely, malabsorption, specific nutritional deficiencies and protein energy imbalance may result in altered pulmonary defense mechanisms, decreased exercise tolerance and altered pulmonary muscle function, (Thomson et al, 1995).

Fig. 5 Pathogenesis of energy imbalance in cystic fibrosis, (Thomson et al, 1995).

In children with CF, the possible maintenance of adequate growth is more difficult because a positive energy balance is required to meet the energy cost of synthetizing new tissue and the energy content of the new tissue deposited.

Although it is suggested that CF patients require between 120%-150% of the normal recommended daily intake (RDI) of energy for age for gender to compensate for elevated expenditure and losses. The 2002 consensus for the nutritional management of cystic fibrosis recommends that individualized gender-and-age-specific energy requirement should be determined using basal metabolic rate, growth requirement and activity level as basis and taking into account pulmonary status and the degree of malabsorption, (UK cystic fibrosis Trust Nutrition Working Group, 2002).

In addition to inadequate energy, macro- and micronutrient deficiencies (due to decreased intake and gastrointestinal losses), lung infections and other opportunistic diseases can also affect growth and overall nutritional status. Nutrient deficiencies may inhibit growth directly or indirectly through compromising pulmonary function and immunity, (Borowtiz & Robinson, 2009).

Chronic lung infection can cause weight loss by increasing resting energy expenditure, decreasing protein synthesis and causing a secretion of hormones and immune factors such as catecholamines and tumor necrosing factor α, (Nir et al, 1996). The metabolic effects of these stress hormones and immune factors have been known to cause anorexia and increase energy expenditure (for example by mobilizing protein stores in muscle and fat stores in adipose tissue), (Shills et al, 1999).

The presence of concurrent diseases (CF-related diabetes, liver disease and gastro-oesophageal reflux) also contributes to malnutrition through additional energy losses.

2.1 Maldigestion, malabsorption and other losses

Up to 90% of individuals with CF experience maldigestion, and hence malabsorption of nutrients due to exocrine pancreatic insufficiency, reduced bile salt pool and intestinal mucus, (Borowitz el al, 2002). Pancreatic insufficiency arises because abnormal cystic fibrosis transmembrane conductance regulator processing in the pancreas causes pancreatic enzyme secretions to be obstructed and bicarbonate secretions to be reduced. Small percentages (10% to 15%) of individuals with CF have variable degrees of pancreatic dysfunction but absorb nutrients normally and are classified as having pancreatic insufficiency. The incidence of pancreatic insufficiency and pancreatic sufficiency is thought to be linked to genotype, with a majority of delta F508 homozygotes having pancreatic insufficiency and worse prognosis, (UK cystic fibrosis Trust Nutrition Working Group, 2002).

Maldigestion in CF affects energy sources and protein. Growth may be limited by the subsequent energy and protein deficit and related increase in protein catabolism. Maldigestion of various micro-nutrients may also inhibit growth directly or indirectly through the effects of specific deficiencies on pulmonary function and immunity. Gastrointestinal problems associated with maldigestion and malabsorption, such as abdominal pain, can affect nutritional status indirectly by decreasing appetite, (Murphy et al, 1998).

Long term PERT is required by individuals with pancreatic insufficiency to improve macro-and micronutrient maldigestion. PERT aims to minimize the incidence of frequent, loose, bulky; foul smelling, greasy stools, rectal prolapse, hypoalbuminemia, edema which are commonly experienced before diagnosis, however normal fat absorption does not appear to have been achieved by the majority of individuals on PERT, (Kalivianakis et al, 1999).

Small amounts of energy an d nitrogen may be also lost from the body through the expectoration of sputum. This loss was estimated to 1% to 5% of gross energy intake, (Wooton et al, 1991).

2.2 Inadequate intake

Most of the growth problems in CF can be attributed to dietary inadequacy rather than to poor nutritional status being an inherent factor of the disease, (UK cystic fibrosis Trust Nutrition Working Group, 2002). This dietary inadequacy appears to be mostly due to unfavorable energy balance, although inadequacies of other nutrients could also contribute to poor growth. For example, protein intakes of children with CF are commonly in excess of the RDI for age and gender (similar to children in the general population), but it is not known what level is sufficient to counter the effects of the disease as RDIs are developed for the general population, which mostly includes well children, (Gordon et al, 2007).

As previously mentioned, individuals with CF are thought to require between 120% and 150% of normal energy requirements for age and gender to compensate for elevated energy expenditure and losses, (Stallings et al, 2008).

Nutrition studies conducted in the 1980s indicate that in spite of increased energy needs, dietary intakes of individuals with CF averaged at only 80% or less of the requirements for the general population and few children ever achieved the elevated energy recommendation, (Hubbard, & Mangrum, 1982)(Bell et al, 1984). However, more recently a behavioral plus nutrition education intervention has shown to be more effective on the outcomes of caloric intake. In a recent study (Stark et al, 2009) after a 24-month follow up, children maintained an estimated energy requirement of around 120%.

The validity of studies reporting dietary intakes is limited by many methodological issues (dietary data collection method, representativeness of usual intake, type of food composition tables). It is evident that many physiological, psychosocial and environmental factors cause intakes to be sub-optimal. Anorexia, dietary preferences, emotional problems, lack of knowledge about nutritional needs, poor adherence to a high fat diet and insufficient dietetic support can have an adverse influence on the oral intake of individuals, (Michel et al, 2009).

2.2.4 Concurrent diseases

Concurrent diseases may also contribute to the energy imbalance and poor nutritional status of those with CF, particularly prior to diagnosis and adequate treatment.

Pancreatic impairment is often progressive and approximately 20% of older individuals develop CF-related diabetes. If untreated, or inadequately controlled, diabetes can contribute to energy deficits through glycosuria. In addition, liver disease may exacerbate the severity of malabsorption through inadequate bile acid secretion. Other gastrointestinal complications (lactose intolerance, Crohn's disease, chronic abdominal pain, distal intestinal obstruction, gastro-esophageal reflux and esophagitis) may also make significant contributions to malnutrition in CF, (Parker, 2007).

2.3 Nutritional management

The relationship between nutrition and growth maintenance in CF is well established (Corey et al, 1988). Since symptomatic diagnosis of cystic fibrosis is associated with short- and long-term complications including failure to thrive, stunting, wasting, vitamin and mineral deficiencies, recurrent pulmonary infections and recurrent hospitalizations. Early identification of CF by newborn screening (NBS) offers the opportunity to delay and potentially prevent many of these complications through early management (Borowitz et al, 2009).

2.3.1 Nutritional requirements from birth

The goal of nutritional treatment of infants diagnosed with CF in the newborn period is normal growth. The first year of life is essential because it is a time where healthy infants double their birth weight by 4 months of age and triple it by 1 year. It is recommended that children reach a weight-for-length status of the 50th percentile by 2 years of age (Stallings, 2008). Studies indicate that higher body mass index (BMI) percentiles at 2 years of age are strongly associated with better pulmonary function later in childhood (Fig.6) (Konstan et al, 2003). Breastfeeding is the preferred type of feeding for infants with CF, a recent study (Colombo et al, 2008) executed in the largest CF center in Italy concluded that Prolonged BF is beneficial in children with CF and may protect them against decline of pulmonary function. Particular attention should be paid to promote BF in infants with CF, After multivariate analysis patients with prolonged BF showed higher values of CED expiratory volume in 1 sec (FEV-1) (p = 0.001) and a lower number of infections during the first 3 years of life (p = 0.098).

Fig.6 Analysis of CF Foundation Patient Registry data from 2006: Forced expiratory volume in 1 second (FEV1) in childhood in pancreatic insufficient patients with CF, stratified by their weight-for-length percentile at age 2 years (Borowitz et al, 2009).

Infants with CF can be safely breastfed. In a retrospective stud (Munk, 2010), prolonged breastfeeding for at least 4 months was associated with better pulmonary function and may protect against respiratory infections. Additional extra calories (limiting carbohydrate content up to 10-12 g/100 ml owing to the risk of decreasing the protein: energy levels and fat density 5 g/100 ml) can be added to expressed breast milk, if weight gain is poor, rather than increasing milk volumes, which might enhance the risk of gastroesophageal reflux. Patients who have had small bowel surgery for

meconium ileus, with consequent loss of small bowel surface area, may require a protein

hydrolysate (pre-digested) feed, such as Pregestimil, PeptiJunior or Prejomin (UK cystic fibrosis Trust Nutrition Working Group, 2002). Energy requirements

Elevated energy expenditure and losses (due to malabsorption) in CF patients are thought to be compensated by intakes between 120% and 150% of normal energy requirements for age and gender (Powers et al, 2006). The CF nutritional consensus (Ramsey et al, 1992) document details on how to determine approximate energy requirements using an age and gender specific estimated basal metabolic rate, growth requirements and activity level as a basis, and taking into account the patient's pulmonary status and degree of malabsorption (see appendix 2). Fat requirements

In CF, fat intake should be as high as possible within the limit of individual tolerance, as the energy cost of converting dietary fat to body fat is minimal compared with the conversion of dietary protein and carbohydrate to body fat. Nutrition guidelines have traditionally suggested that fat should provide 40% of the daily energy needs of individuals with CF if total energy intakes of more than 125% of the DRI are to be achieved (Bell et al, 1984). However, a positive association was found between fat, energy intake and growth when fat was analyzed as an absolute amount rather than as a percentage of energy intakes (Collins et al, 1997). This led to the to the alternative and more practical recommendation for individuals more than 5 years of age to consume more than 100g of fat per day (Collins et al, 1997). An important issue with high fat diets is the parental concern about the effect of dietary fat on blood lipids. It is reassuring to know that adults with cystic fibrosis and pancreatic insufficiency eating a fat intake providing 34-35% of total energy intake have lower mean plasma cholesterol concentrations than controls. It is only pancreatic sufficient patients who have lipid levels in the high normal range (Sleskinski et al, 1994) as shown by the Mean total serum cholesterol levels in men with cystic fibrosis was 3.1 mmol/L vs 4.7 mmol/L in male controls (P<.001). Mean total serum cholesterol levels in women with cystic fibrosis was 3.2 mmol/L vs 4.3 mmol/L in female controls (P<.001). Protein requirements

In addition to being used for growth and maintenance of body tissues, protein is one of the three energy-producing types of nutrients in food. Most people with CF have higher-than-usual protein requirements. People with CF who meet their increased caloric requirements by consuming a balanced diet usually meet their increased protein requirements at the same time. The current recommendations suggest that the consumption of protein should be up to 15-20% ratio of the total caloric needs (Mahan, & Stump, 2008). In outpatient clinics in the United Kingdom a large study was conducted (Geukers et al, 2006) about the stimulation of protein synthesis in stunted CF patients. 3 Groups were randomly allocated with a Isocaloric diet for age (1.5g/kg/d), Intermediate protein diet (3g/kg/d) and a High protein diet (5g/kg/d). The results showed that the net retention of nitrogen was significantly higher in the High protein group than the other two groups (P<0.001) which means that protein synthesis was definitely higher. Carbohydrate requirements

Carbohydrate intake should be as high as possible for CF patients (Daniels & Davidson, 1989). Carbohydrate intake is recommended to be between 40 and 50% of the total energy. No restrictions are to be made, except in case of CF related diabetes, parents should avoid giving sugar sweetened beverages for their kids (O'riordan et al, 2008). Fiber requirements

It has been suggested (Gavin et al, 1997) that the typically low fiber intakes of children with cystic fibrosis contribute to constipation and abdominal pain. Although that was not the experience of others. To link dietary fiber to gastrointestinal intake, a large study was conducted in Belgium (Proesmans & De Boeck, 2002) where they evaluated the fiber intake of children divided into 3 groups depending on their gastrointestinal problems: group 1, no gastrointestinal complaints; group 2, nonspecific and mild gastrointestinal complaints; and group 3, documented Distal Intestinal Obstruction Syndrome (DIOS). There wasn't a relation between fiber intake and gastrointestinal complaints or DIOS. On the contrary, in patients with DIOS, fiber intake was higher (figure.7).

FIG. 7. Distribution of fiber intake in the three patient groups. Median

values were 16.25 g, 13 g, and 21.75 g for groups 1, 2, and 3, respectively. Only in group 3 was fiber intake significantly higher compared with group 2 (P =0.049).

High fiber diets are not universally recommended in CF, because of the high satiety value of insoluble fiber, which might limit energy intake (Daniels & Davidson, 1989).

2.3.2 Pancreatic enzyme replacement therapy

Pancreatic insufficiency, seen in most individuals with CF, evolves over the first year of life. Patients with pancreatic sufficiency (PS) have a significantly longer median life-span than patients with PI. PI is present at birth in 60% of infants diagnosed with CF through new born screening and approximately 90% of infants have PI at 1 year of age (Bronstein et al, 1992). Pancreatic enzyme replacement therapy (PERT) should be introduced once there is evidence of intestinal malabsorption. Pancreatic insufficiency in new born babies is generally diagnosed by measurement of fecal pancreatic elastase-1 (Beharry et al, 2002). Since Dietary fat provides approximately 50% of the

energy intake of young infants; thus, inadequate control of fat absorption can have a devastating effect upon nutritional status (UK cystic fibrosis Trust Nutrition Working Group, 2002). A fecal elastase level of less than 200 µg/g is diagnostic of PI (Munck, 2010). Current available PERT preparations are derived from porcine pancreas. Enteric-coated preparations dramatically decrease enzyme degradation by stomach acid and improve the release of enzymes in the duodenum. However, pancreatic bicarbonate secretion is often reduced and, for some patients with poor response to PERT, H2-receptor antagonists or proton pump inhibitors may be beneficial. The effect of such drugs were studied and the conclusion was that addition of omeprazole (Heijermann et al, 1991) to the higher dose of Pancreatic enzymes significantly reduced fecal fat excretion when compared with the lower doses of Pancreatic enzymes alone (mean, 10.7%; range, 4% to 25%; P < 0.01). Satisfactory PERT should enable the patient to eat a normal or high-fat diet without unpleasant gastrointestinal symptoms and to achieve a satisfactory nutritional state (Littlewood et al, 2006). . Standard-strength enzyme preparations are recommended for infants and children. Following the occurrence, in the 1990s, of fibrosing colonopathy (Ramsden et al, 1998) in young children receiving very high doses of daily PERT and despite the rarity of this complication, the severity of the condition leaded to the 2002 consensus guidelines for PERT (Table.3) recommended not exceeding a daily dose equivalent to 10,000 IU lipase/kg/day with an upper dose limit of 250,000 IU lipase/day (500-2500 IU lipase/kg/meal) of 'standard' or 'high-strength' enzyme preparations regardless of the preparation used.

Table 3. Recommendations for pancreatic enzyme replacement therapy (IU lipase) adopted from ( Munck, 2010).


2500-3000 IU lipase/120 ml milk


500-2500 IU lipase/kg

Dietary fat

500-4000 IU lipase/g

Maximum IU/kg/day

10,000 up to 250,000 IU lipase/day

PERT should be given with breast milk and formulas, including elemental and medium chain triglyceride (MCT)-containing formulas and all foods (Caliari et al, 1996). To date, no studies have been performed in infants to determine the optimal dose of PERT (Stallings et al, 2008), until more data is available, dosing based on the historic recommendations must suffice: start PERT at a dose of 2000 to 5000 lipase units for each feeding (usually described as 120 mL; although newborn infants initially may consume less than 120 mL per feeding, PERT should still be initiated). As the infant grows and the volume of intake increases, adjust the dose to no greater than 2500 lipase units per kilogram per feeding with a maximum daily dose of 10 000 lipase units per kg per day (Borowitz, & Robinson, 2009). Enzyme dose and rate of weight gain in relation to caloric intake should be evaluated at each visit of the infant since the dose of PERT and the volume of intake will rapidly increase in the first few months of life due to the child weight gain. Doses should not be increased beyond the upper limit of the recommended range because children are at more risk of developing fibrosing colonopathy (Fitzsimmons et al, 1997). As per the recent CF Foundation Evidence-Based Practice Recommendations for Nutrition (Stallings et al, 2008) generic PERT should not be used.

Treatments failures were documented (Hendeles et al, 1990) when patients were given generic pancrelipase capsules, the in vitro tests for these products showed a decrease of lipase activity as shown in Table 4.

Table.4 Lipase Activity of Pancrease, Creon, and Generic Pancrelipase in Cold Water and After 1-Hour Exposure to Simulated Gastric Fluid at 37°C and pH 1.2* (Hendeles et al, 1990).

Currently available formulations take into account the decreased potency of enzymes over time; overfilled capsules can reach 147% of label-claimed lipase activities