British Mahal BaDctm (1992) \W 4S, No 4, pp823-M7 O The British Council
Nutrition PR Dune P B Pencharz Divisions of Gastroenterology and Nutrition, Department of Paediatrics, and the Research Institute, The Hospital for Sick Children, and from the Departments of Paediatrics, and Nutritional Sciences, University of Toronto, Ontario, Canada
There has been renewed interest in examining the multiple causes of undernutrition and growth failure in cystic fibrosis. It is now recognized that undernutrition is caused by unfavourable energy balance rather than an inherent component of the disease. Furthermore, there appears to be a direct association between the degree of undernutrition and the severity of pulmonary disease, which in turn affects overall prognosis. Energy imbalance may be caused by three main factors: increased energy loss because of nutrient maldigestion; reduced energy intake due to an improper diet and/or anorexia from respiratory disease, abdominal symptoms or clinical depression and increased energy expenditure with advanced lung disease. Most patients are capable of compensating for these factors; provided energy intake is sufficient, normal growth velocity and nutritional status is maintained. However, in a minority of older patients, when advanced lung disease supervenes, energy expenditure rises resulting in an energy deficit. Undernutrition, with loss of energy stores and lean tissue may in turn contribute to progressive deterioration of lung function. When this occurs, long-term invasive methods of nutritional support can restore energy balance.
In previous years, chronic undernutrition with significant weight retardation and linear growth failure, has been recognized as a generalized problem of most large patient populations with Cystic Fibrosis (CF). Chronic malnutrition was felt, by some, to be an inherent consequence of the disease while others have argued that malnutrition resulted from physiologic adaptation to advanced pulmonary disease. A number of early studies of CF patients, however, showed a good correlation between the degree of malnutrition and the severity of pulmonary dis-
824
CYSTIC FIBROSIS
ease which in turn adversely affected overall survival.1- 2 It has been speculated that these two factors are casually associated, but it is not clear whether prevention of malnutrition and growth failure would ameliorate the rate of progression of lung disease and improve survival. In the past decade there has been renewed interest in evaluating the multiple interdependent variables giving rise to chronic malnutrition and growth failure. In most CF centres worldwide, nutritional support is now viewed as an integral part of the multidisciplinary care of patients with cystic fibrosis and aggressive programmes have been instituted to prevent malnutrition. Table 1 "Characteristics of CF clinic populations in Boston and Toronto (1982) Boston Number of patients Male/Female (%) Age: Mean ± SD (yr) Range (yr) Median Survival (50%) in yr
Toronto
499
534
57/43 15.9 ± 9.6 0-45
58/42
21
15 2 ± 8.3 0-43 30
* Adapted from Corey et al 6
It is now recognized that growth retardation in patients with cystic fibrosis are due to unfavourable energy balance rather than to an inherent factor of the disease itself. Over 10 years ago, in contradistinction from studies elsewhere in the world, reports from Toronto indicated that the majority of patients attending their CF clinic closely conformed to the normal distribution of growth in the general population.3*5 Crosssectional growth data from the Toronto clinic showed a normal distribution of height percentiles in males and females.5 In females, however, particularly after adolescence, weight distribution was skewed towards the lower centiles, but weight retardation was far less evident than similar data reported from other centres. In a comparative study of two CF clinic populations of similar size and age distribution (Toronto and Boston), Corey et al. 6 found a marked difference in median age of survival between the two centres (Table 1). Median survival in Boston (21 years) was markedly worse than in Toronto (30 years); furthermore, after 10 years of age there was a dramatic separation in survival curves between the two centres. Pulmonary function was no different in the two clinic populations. Males and females attending the Toronto clinic, however, were taller than those in the Boston clinic, and males in Toronto were heavier. It is noteworthy, that with the exception of nutritional management of their patients, the general approach to patient care, particularly pulmonary care, was similar in the two clinics. It
NUTRITIONAL DEFICIENCIES IN CYSTIC FIBROSIS
825
was suggested that the improved survival in the Toronto CF population could be attributed to superior nutritional status. An examination of existing dietary practices in the two clinics revealed a striking difference in philosophy. The approach in Boston7 closely resembled the existing approach in most centres throughout the world, which involved prescribing a low-fat, carbohydrate-rich diet It was reasoned that reduction in dietary fat improve bowel symptoms and reduce stool bulk. Recognizing the problem of maldigestion and poor absorption of long-chain triglycerides many centres advocated use of artificial diets with protein hydrolysates and substitution of long-chain fat with medium-chain triglycerides (MCT).8 However, other reports showed no long-term benefits to growth when protein hydrolysates and MCT were used as supplements or substitutes.9 Fortunately, these supplements are now hardly ever advocated through reasons of cost, poor compliance and unpalatability. The net effect was to provide the CF patient with a restrictive, unpalatable diet and to exclude them from the many energy-rich foods that comprise some of the more tasty choices in a 'normal' western diet. Chronic malnutrition from reduced energy intake appears to have been an unfortunate, yet deliberate iatrogenic effect in most CF programmes worldwide. Since the early 1970s, the Toronto group advocated a calorically enriched diet by encouraging rather than restricting dietary fat and encouraging additional enzyme supplements to enhance digestion. 'O-11 Because fat is the most energy rich, economical and appetizing energy source, patients were encouraged to eat larger portions than their peers; to add fat in the form of butter or untrimmed meat, and to have high calorie snacks between meals and before bed. Fat malabsorption occurred, but with additional pancreatic enzyme supplements, net absorbed energy improved, resulting in better growth. In recent years it is gratifying to see that most CF caregivers worldwide have accepted a similar philosophy for the nutritional care of their patients. Coincidentally, it is generally accepted that the primary objective of nutritional management is to achieve normal nutrition and growth for children of all ages. This view is reflected in a statement from a Consensus Conference on the Nutritional Assessment and Management in Cystic Fibrosis which states 'There is no reason to accept nutritional failure and/or impaired growth in any individual with C F . 1 2 PATHOGENESIS OF ENERGY IMBALANCE Multiple, complex related and unrelated factors may give rise to energy imbalance in patients with cystic fibrosis. The net effect on growth po-
826
CYSTIC FIBROSIS
tential varies considerably from patient to patient, according to marked differences in disease expression, and with disease progression. In simple terms, an energy deficit results from an imbalance between energy needs and energy intake (Table 2). In patients with CF, energy balance is determined by three factors: energy losses, energy expenditure, and energy intake. Table 2
Energy unbalance in CF
Increased needs • Increased Intestinal Losses - Pancreatic insufficiency - Bile salt metabolism - Hepatobiliary disease - RegurgitaUon from
Reduced intake • Reduced intake - latrogenic fat restriction - Anorexia - Feeding disorders reflux - Depression - Esophagins
• Increased Unnary losses - Diabetes mellitus • Increased energy expenditure - pulmonary disease - primary defect?
Energy losses Faecal nutrient losses from maldigestion/malabsorption are known to contribute to energy imbalance. Only 1 to 2% of total pancreatic capacity for secreting enzyme is required to prevent maldigestion, 13 and yet in the majority of CF patients (approximately 85%) evidence of pancreatic failure is present at diagnosis. In those who exhibit maldigestion, very good correlations exist between residual pancreatic function (colipase secretion) and the severity of fat malabsorption (Fig. 1). Patients with documented steatorrhea, therefore, have variable but very limited residual pancreatic function. This observation partially explains why some patients with pancreatic insufficiency digest nutrients better than others when given pancreatic enzyme supplements with meals. Despite improvements in the enzymatic potency and intestinal delivery of ingested pancreatic enzyme supplements, many patients continue to have severe steatorrhea and azotorrhea, even when they receive adequate amounts of enzyme supplements. In the absence of adequate pancreatic bicarbonate secretion,14 gastric acid entering the duodenum may lower intestinal pH until well into the jejunum. The acid-resistent coating of the newer enzyme preparations may not dissolute in the proximal intestine. Pancreatic lipase is readily denatured below pH 2 and even if
NUTRITIONAL DEFICIENCIES IN CYSTIC FIBROSIS
827
not denatured, enzymatic activity is considerably reduced at a low pH. Bile acids are readily precipitated in an acid milieu,15 and duodenal bile acid concentration may fall below the critical micellar concentration, thereby exacerbating fat maldigestion. Precipitated bile salts also appear to be lost from the enterohepatic circulation in greater quantities, which reduces the total bile salt pool and alters the glycocholate:taurocholate ratio. Bile salt losses are exacerbated by the binding of bile salts to unabsorbed protein or neutral lipid. Oral taurine supplements have been reported to benefit some patients.16 Viscid, thick intestinal mucus, with altered physical properties, may have a deleterious effect on the thickness of the intestinal unstirred layer, further limiting nutrient absorption. Two other factors, more prevalent in adolescents and adult patients with CF, may contribute to energy losses. Diabetes mellitus, if not adequately controlled may increase caloric losses due to glycosuria. Advanced liver disease with multifocal biliary cirrhosis may result in inadequate bile salt secretion resulting in severe fat malabsorption. Energy intake Actual energy intakes in healthy patients with cystic fibrosis have been poorly documented. Nevertheless, it is widely accepted that energy intake should exceed normal requirements, and crude estimates have suggested that patients may require 120-150% of the Recommended Daily Allowance (RDA) for age and sex.3 When we accurately evaluated nutrient intakes of a group of healthy adolescents, we were surprised to learn mat energy intakes were close to the normal range for age, body weight and sex.17 Those with normal growth percentiles for height and weight did show higher energy intakes than the patients with growth retardation. Other CF centres, who have developed more liberal attitudes to dietary fat intake, have noted a corresponding improvement in energy intake and growth.18-19 However, in most reports nutrient intakes were found to be close to the normal range. Patients with cystic fibrosis are particularly prone to complications that might limit oral intake. Oesophagitis induced by acid reflux is quite common in patients with advanced pulmonary disease and is frequently associated with pain, anorexia and vomiting following bouts of coughing.20-21 The Distal Intestinal Obstruction Syndrome (meconium ileus equivalent), an unusual form of subacute obstruction within the distal ileum and proximal colon,22 is seen in some adolescents and adults with pancreatic failure; it frequently causes recurrent, crampy abdominal pain and patients often find that the symptoms are exacerbated by eating. Other abdominal symptomatology, including extra hepatic biliary obstruction, cholangitis, advanced liver disease and severe con-
828
CYSTIC FIBROSIS
100 -, 80 : 6040-
20-
O
10 8 6
Nutrition PR Dune P B Pencharz Divisions of Gastroenterology and Nutrition, Department of Paediatrics, and the Research Institute, The Hospital for Sick Children, and from the Departments of Paediatrics, and Nutritional Sciences, University of Toronto, Ontario, Canada
There has been renewed interest in examining the multiple causes of undernutrition and growth failure in cystic fibrosis. It is now recognized that undernutrition is caused by unfavourable energy balance rather than an inherent component of the disease. Furthermore, there appears to be a direct association between the degree of undernutrition and the severity of pulmonary disease, which in turn affects overall prognosis. Energy imbalance may be caused by three main factors: increased energy loss because of nutrient maldigestion; reduced energy intake due to an improper diet and/or anorexia from respiratory disease, abdominal symptoms or clinical depression and increased energy expenditure with advanced lung disease. Most patients are capable of compensating for these factors; provided energy intake is sufficient, normal growth velocity and nutritional status is maintained. However, in a minority of older patients, when advanced lung disease supervenes, energy expenditure rises resulting in an energy deficit. Undernutrition, with loss of energy stores and lean tissue may in turn contribute to progressive deterioration of lung function. When this occurs, long-term invasive methods of nutritional support can restore energy balance.
In previous years, chronic undernutrition with significant weight retardation and linear growth failure, has been recognized as a generalized problem of most large patient populations with Cystic Fibrosis (CF). Chronic malnutrition was felt, by some, to be an inherent consequence of the disease while others have argued that malnutrition resulted from physiologic adaptation to advanced pulmonary disease. A number of early studies of CF patients, however, showed a good correlation between the degree of malnutrition and the severity of pulmonary dis-
824
CYSTIC FIBROSIS
ease which in turn adversely affected overall survival.1- 2 It has been speculated that these two factors are casually associated, but it is not clear whether prevention of malnutrition and growth failure would ameliorate the rate of progression of lung disease and improve survival. In the past decade there has been renewed interest in evaluating the multiple interdependent variables giving rise to chronic malnutrition and growth failure. In most CF centres worldwide, nutritional support is now viewed as an integral part of the multidisciplinary care of patients with cystic fibrosis and aggressive programmes have been instituted to prevent malnutrition. Table 1 "Characteristics of CF clinic populations in Boston and Toronto (1982) Boston Number of patients Male/Female (%) Age: Mean ± SD (yr) Range (yr) Median Survival (50%) in yr
Toronto
499
534
57/43 15.9 ± 9.6 0-45
58/42
21
15 2 ± 8.3 0-43 30
* Adapted from Corey et al 6
It is now recognized that growth retardation in patients with cystic fibrosis are due to unfavourable energy balance rather than to an inherent factor of the disease itself. Over 10 years ago, in contradistinction from studies elsewhere in the world, reports from Toronto indicated that the majority of patients attending their CF clinic closely conformed to the normal distribution of growth in the general population.3*5 Crosssectional growth data from the Toronto clinic showed a normal distribution of height percentiles in males and females.5 In females, however, particularly after adolescence, weight distribution was skewed towards the lower centiles, but weight retardation was far less evident than similar data reported from other centres. In a comparative study of two CF clinic populations of similar size and age distribution (Toronto and Boston), Corey et al. 6 found a marked difference in median age of survival between the two centres (Table 1). Median survival in Boston (21 years) was markedly worse than in Toronto (30 years); furthermore, after 10 years of age there was a dramatic separation in survival curves between the two centres. Pulmonary function was no different in the two clinic populations. Males and females attending the Toronto clinic, however, were taller than those in the Boston clinic, and males in Toronto were heavier. It is noteworthy, that with the exception of nutritional management of their patients, the general approach to patient care, particularly pulmonary care, was similar in the two clinics. It
NUTRITIONAL DEFICIENCIES IN CYSTIC FIBROSIS
825
was suggested that the improved survival in the Toronto CF population could be attributed to superior nutritional status. An examination of existing dietary practices in the two clinics revealed a striking difference in philosophy. The approach in Boston7 closely resembled the existing approach in most centres throughout the world, which involved prescribing a low-fat, carbohydrate-rich diet It was reasoned that reduction in dietary fat improve bowel symptoms and reduce stool bulk. Recognizing the problem of maldigestion and poor absorption of long-chain triglycerides many centres advocated use of artificial diets with protein hydrolysates and substitution of long-chain fat with medium-chain triglycerides (MCT).8 However, other reports showed no long-term benefits to growth when protein hydrolysates and MCT were used as supplements or substitutes.9 Fortunately, these supplements are now hardly ever advocated through reasons of cost, poor compliance and unpalatability. The net effect was to provide the CF patient with a restrictive, unpalatable diet and to exclude them from the many energy-rich foods that comprise some of the more tasty choices in a 'normal' western diet. Chronic malnutrition from reduced energy intake appears to have been an unfortunate, yet deliberate iatrogenic effect in most CF programmes worldwide. Since the early 1970s, the Toronto group advocated a calorically enriched diet by encouraging rather than restricting dietary fat and encouraging additional enzyme supplements to enhance digestion. 'O-11 Because fat is the most energy rich, economical and appetizing energy source, patients were encouraged to eat larger portions than their peers; to add fat in the form of butter or untrimmed meat, and to have high calorie snacks between meals and before bed. Fat malabsorption occurred, but with additional pancreatic enzyme supplements, net absorbed energy improved, resulting in better growth. In recent years it is gratifying to see that most CF caregivers worldwide have accepted a similar philosophy for the nutritional care of their patients. Coincidentally, it is generally accepted that the primary objective of nutritional management is to achieve normal nutrition and growth for children of all ages. This view is reflected in a statement from a Consensus Conference on the Nutritional Assessment and Management in Cystic Fibrosis which states 'There is no reason to accept nutritional failure and/or impaired growth in any individual with C F . 1 2 PATHOGENESIS OF ENERGY IMBALANCE Multiple, complex related and unrelated factors may give rise to energy imbalance in patients with cystic fibrosis. The net effect on growth po-
826
CYSTIC FIBROSIS
tential varies considerably from patient to patient, according to marked differences in disease expression, and with disease progression. In simple terms, an energy deficit results from an imbalance between energy needs and energy intake (Table 2). In patients with CF, energy balance is determined by three factors: energy losses, energy expenditure, and energy intake. Table 2
Energy unbalance in CF
Increased needs • Increased Intestinal Losses - Pancreatic insufficiency - Bile salt metabolism - Hepatobiliary disease - RegurgitaUon from
Reduced intake • Reduced intake - latrogenic fat restriction - Anorexia - Feeding disorders reflux - Depression - Esophagins
• Increased Unnary losses - Diabetes mellitus • Increased energy expenditure - pulmonary disease - primary defect?
Energy losses Faecal nutrient losses from maldigestion/malabsorption are known to contribute to energy imbalance. Only 1 to 2% of total pancreatic capacity for secreting enzyme is required to prevent maldigestion, 13 and yet in the majority of CF patients (approximately 85%) evidence of pancreatic failure is present at diagnosis. In those who exhibit maldigestion, very good correlations exist between residual pancreatic function (colipase secretion) and the severity of fat malabsorption (Fig. 1). Patients with documented steatorrhea, therefore, have variable but very limited residual pancreatic function. This observation partially explains why some patients with pancreatic insufficiency digest nutrients better than others when given pancreatic enzyme supplements with meals. Despite improvements in the enzymatic potency and intestinal delivery of ingested pancreatic enzyme supplements, many patients continue to have severe steatorrhea and azotorrhea, even when they receive adequate amounts of enzyme supplements. In the absence of adequate pancreatic bicarbonate secretion,14 gastric acid entering the duodenum may lower intestinal pH until well into the jejunum. The acid-resistent coating of the newer enzyme preparations may not dissolute in the proximal intestine. Pancreatic lipase is readily denatured below pH 2 and even if
NUTRITIONAL DEFICIENCIES IN CYSTIC FIBROSIS
827
not denatured, enzymatic activity is considerably reduced at a low pH. Bile acids are readily precipitated in an acid milieu,15 and duodenal bile acid concentration may fall below the critical micellar concentration, thereby exacerbating fat maldigestion. Precipitated bile salts also appear to be lost from the enterohepatic circulation in greater quantities, which reduces the total bile salt pool and alters the glycocholate:taurocholate ratio. Bile salt losses are exacerbated by the binding of bile salts to unabsorbed protein or neutral lipid. Oral taurine supplements have been reported to benefit some patients.16 Viscid, thick intestinal mucus, with altered physical properties, may have a deleterious effect on the thickness of the intestinal unstirred layer, further limiting nutrient absorption. Two other factors, more prevalent in adolescents and adult patients with CF, may contribute to energy losses. Diabetes mellitus, if not adequately controlled may increase caloric losses due to glycosuria. Advanced liver disease with multifocal biliary cirrhosis may result in inadequate bile salt secretion resulting in severe fat malabsorption. Energy intake Actual energy intakes in healthy patients with cystic fibrosis have been poorly documented. Nevertheless, it is widely accepted that energy intake should exceed normal requirements, and crude estimates have suggested that patients may require 120-150% of the Recommended Daily Allowance (RDA) for age and sex.3 When we accurately evaluated nutrient intakes of a group of healthy adolescents, we were surprised to learn mat energy intakes were close to the normal range for age, body weight and sex.17 Those with normal growth percentiles for height and weight did show higher energy intakes than the patients with growth retardation. Other CF centres, who have developed more liberal attitudes to dietary fat intake, have noted a corresponding improvement in energy intake and growth.18-19 However, in most reports nutrient intakes were found to be close to the normal range. Patients with cystic fibrosis are particularly prone to complications that might limit oral intake. Oesophagitis induced by acid reflux is quite common in patients with advanced pulmonary disease and is frequently associated with pain, anorexia and vomiting following bouts of coughing.20-21 The Distal Intestinal Obstruction Syndrome (meconium ileus equivalent), an unusual form of subacute obstruction within the distal ileum and proximal colon,22 is seen in some adolescents and adults with pancreatic failure; it frequently causes recurrent, crampy abdominal pain and patients often find that the symptoms are exacerbated by eating. Other abdominal symptomatology, including extra hepatic biliary obstruction, cholangitis, advanced liver disease and severe con-
828
CYSTIC FIBROSIS
100 -, 80 : 6040-
20-
O
10 8 6
