10
Growth failure in gastrointestinal diseases ELEONORE MAYER MARTIN STERN
Is growth failure in gastrointestinal disease merely a consequence of nutritional deficiency? High interindividual variability in terms of manifestation and response to nutritive therapy does not support this. In most cases of gastrointestinal disease, however, malnutrition offers a reasonable partial explanation for growth retardation. These children with gastrointestinal disease do not receive the appropriate quantity and/or quality of nutrients to meet the needs for normal growth. This chapter therefore first presents general aspects of growth failure in malnutrition before describing specific gastrointestinal diseases. GROWTH FAILURE IN MALNUTRITION
Manifestation The term 'growth' incorporates both linear growth and weight gain. With regard to the general context of this chapter we will concentrate on the topic of linear growth failure. Nevertheless, linear growth failure due to malnutrition is mostly associated with retarded weight gain so that a consequent distinction between both features of growth failure can hardly be made. Rather, statural growth is often only affected after a considerable period of malnutrition and inadequate weight gain for 1-2 years (Figure 1 shows the typical pattern of growth retardation in a patient with chronic malnutrition). Over time, the patient with long-standing gastrointestinal disease becomes a 'nutritional dwarf'. It is therefore desirable to evaluate changes in body weight in a child presenting with short stature. Retrospectively, first-year weight measurements may serve as a good predictor for the degree of stunting at preschool age (Simondon et al, 1991).
Aetiology and pathophysiology Malnutrition can be due to inadequate nutrient intake, maldigestion, realabsorption or enteral loss of nutrients. (Table 1 lists possible pathophysiological mechanisms in different gastrointestinal diseases.) On the other hand, malnutrition can also result from increased nutritive demands stemming from underlying gastrointestinal disease, e.g. as a consequence of Baillibre's Clinical Endocrinology and Metabolism-645 Vol. 6, No. 3, July 1992 ISBN 0-7020-1620-9
Copyright © 1992, by Bailli6re Tindall All rights of reproduction in any form reserved
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Figure 1. Weight deficit in a male patient with chronic malnutrition due to cystic fibrosis is seen over a period of several years before linear growth retardation follows. Top curve, height; bottom curve, weight.
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GROWTH FAILURE IN GI DISEASES Table 1. Digestive tract causes of malnutrition. Condition
Causes
Inadequate ingestion
Dysphagia
Anorexia
Orofacial anomalies Achalasia Oesophagitis Oesophageal stenosis Gastritis Hepatitis Inflammatory bowel disease
Defective digestion or absorption
Pancreatic insufficiency
Bile salt abnormalities Intestinal mucosal defects
Cystic fibrosis Shwachman syndrome Chronic pancreatitis Cholestasis Liver cirrhosis Infectious/postinfectious Coeliac disease Food protein allergy Congenital intestinal enzyme deficiency (lactase/sucrase/enterokinase) Microvillus atrophy Bacterial overgrowth Short bowel syndrome Intestinal lymphangiectasia Hirschsprung's disease
Excessive losses
Regurgitation, emesis
Diarrhoea, faecal loss Decreased transit time
Gastro-oesophageal reflux Gastritis Bowel obstruction See malabsorption above Protein losing enteropathy Short bowel syndrome Vipoma
stimulated metabolism in chronic inflammatory processes, Such as inflamm a t o r y bowel disease, or of additional energy needs for respiratory work and anaerobic metabolism, such as in cystic fibrosis. Insufficient utilization of nutrient substances in liver failure is another example. W h a t are the effects of malnutrition on endocrinology and metabolism? (Figure 2.) R e d u c e d dietary intake of protein and/or energy leads to relative hypoglycaemia and depressed levels of amino acids in the plasma. This causes a decrease of serum insulin levels (Becker et al, 1975). Free cortisol concentrations in the serum are elevated in malnutrition, secondary to a u g m e n t e d adrenocorticotrophic h o r m o n e ( A C T H ) output, a b n o r m a l diurnal rhythm of secretion, slowed clearance of exogenous cortisol and decreased production of cortisol binding proteins (Alleyne and Young, 1967).
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Figure 2. Endocrinology of malnutrition: pathogenetic pathways.
In short-term protein-calorie malnutrition, in kwashiorkor and marasmus, serum growth hormone concentrations were shown to be elevated. This appears to be related mainly to dietary protein deprivation. Long-term malnutrition and calorie deprivation can cause variable growth hormone response (Pimstone et al, 1973; Ho et al, 1988; Bruno et al, 1991). With respect to insulin-like growth factors (IGF) in malnutrition, one finds depressed levels of IGF-I correlating with negative nitrogen balance and the nutritional status (Hintz, 1978; Phillips et al, 1988). IGF-II serum concentrations are normal or slightly decreased (Soliman et a1,1986). Studies on cultured rat hepatocytes indicate that altered availability of certain amino acids might regulate hepatic release of IGF-I, independent of hormonal feedback (Harp et al, 1991). How nutritional deficiency is able to influence mechanisms of IGF in detail is unclear, but it appears evident that IGF-I reduction is a primary effect of malnutrition. A reduction of IGF-I independent of growth hormone levels is explained by a potential postreceptor defect in growth hormone action. Loss of growth hormone receptors has also been demonstrated (Baxter et al, 1981; Maes et al, 1988; Maiter et al, 1988; Harp et al, 1991).
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A hypothyroid-like state is induced in the malnourished patient: there is a diminished rate of triiodothyronine (T3) production by inhibition of deiodination of thyroxine (T4), as well as reduced synthesis of plasma thyroxine binding proteins. Thyroid stimulating hormone (TSH) is found mostly normal, but may be elevated in chronic malnutrition (Beas et al, 1966). This change of the hormonal and metabolic situation can be interpreted as an adaptive response to malnutrition in order to provide the energy for basic metabolic demands by shifting the energy stored as fat or structural proteins to the viscera; it is attained by inducing a lipolytic, protein saving state. The resulting lack of growth promoting hormones and effector substances and accumulation of growth "inhibitor proteins combined with peripheral shortage of nutrients lead to growth retardation. In this situation, lack of growth factors and nutrient substrates cannot be mutually compensated as they can be under physiological circumstances (McKeehan and McKeehan, 1981). Consequent alterations of the bone, the main target tissue concerned with linear growth, are: impairment of endochondral and appositional bone growth; a selective decrease in fat content with concomitant increase in water; and a reduction of organic matrix. As a result, bone age is mostly retarded in children with malnutrition (Maniar et al, 1974; Belli et al, 1990). Bone mineralization is not always affected (Himes, 1978; Davies et al, 1990b). Management and outcome
In general, growth retardation due to malnutrition should be reversible in a prepubertal child even if nutritional deprivation has existed over a period of several years. As shown in protein deprived rats, additional growth hormone administration did not promote growth, although a shght increase of IGF-I was observed (Harp et al, 1991). The key for treatment of growth retardation due to malnutrition is nutritional sufficiency (Thissen et al, 1990). However, it must not be forgotten that extra calories are needed for compensation of energy deficits, and for improved growth velocity. The total energy for catch-up growth can be estimated by the formula of Forbes (1974): Energy (total) = energy (maintenance) + energy (growth) + energy (deficit) Children recovering from malnutrition may have an increased appetite, thus providing the necessary energy intake, e.g. in coeliac disease (see below). In other diseases, such as marasmus or chronic inflammatory bowel disease, alternative diets and/or alternative routes of ingestion must be used to overcome the bad nutritional status (see below). High growth hormone levels in malnutrition favour catch-up growth once protein and calories become available. Responsiveness to nutritional therapy is best during periods when growth is physiologically accelerated and thus the risk of malnutrition is high (infancy, puberty) (Lutter et al, 1990). Rapid restoration of nutritional status does not interfere with restitution of the physiological body composition (Fjeld et al, 1989). Short-term therapeutic success can be well monitored by IGF-I levels, which are now known to be of higher
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specificity than traditional parameters like transferrin, albumin or total protein (Donahue and Phillips, 1989; Minuto et al, 1989). Since copper and zinc deficiencies are known to impair growth, supplementation of these trace elements may be useful in addition to general (hyper)alimentation (Castillo-Duran and Uauy, 1988; Khanum et al, 1988). GROWTH FAILURE IN SPECIFIC GASTROINTESTINAL DISEASES Growth failure in inflammatory bowel disease
Growth failure in Crohn's disease and ulcerative colitis is caused by multifactorial mechanisms. Inflammatory bowel disease is a good model for illustrating the relationship of gastrointestinal disease, malnutrition and impairment of growth.
Incidence and manifestation In 1970, McCaffery et al firstly published the results of a study of a group of patients with inflammatory bowel disease and growth retardation. Retrospectively, they found 22 of 130 children with inflammatory bowel disease showing impaired growth; 19 of these patients had Crohn's disease and three had ulcerative colitis. In eight patients, growth failure was the first evident symptom of the bowel disease. Further publications confirmed growth retardation as a common feature of inflammatory bowel disease. It was more often seen in Crohn's disease than in ulcerative colitis (Kirschner et al, 1978; Chong et al, 1984; Kanof et a1,1988). The great variation of the reported frequency of growth failure in inflammatory bowel disease (15-88%) may be explained by the fact that there are relevant differences in the definition of growth failure between the various studies; moreover, the investigations were done in different age groups.
Pathophysiology Growth impairment in inflammatory bowel disease seems to be mainly a consequence of malnutrition. The following factors are best documented in growth impaired children with Crohn's disease. First of all, there is reduced nutrient intake caused by anorexia: intake is in general only 50-80% of the recommended daily allowance for age and height (Kirschner et al, 1978, 1981; Kelts et al, 1979). Fat malabsorption due to mucosal injury, bacterial overgrowth and bile salt loss was described as a substantial cause of calorie loss in about 40% of Crohn's disease patients (Kelts and Grand, 1980). Other studies, however, point out that malnutrition in inflammatory bowel disease cannot be sufficiently explained by steatorrhoea alone (Kelts et al, 1979; Kirschner et al, 1981). Carbohydrate malabsorption, shown for D-xylose (Kelts et al, 1979; Kirschner et al, 1981) and lactose (Kelts and Grand, 1980), can be excluded
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as a relevant pathogenetic factor. Protein losing enteropathy is seen in most children with active disease (Kirschner et al, 1981), leading in at least 50% to hypoalbuminaemia (Kelts and Grand, 1980). However, not all the studies show a negative nitrogen balance (Layden et al, 1976; Kirschner et a1,1981; Motil et al, 1982). Correlating with hypoalbuminaemia is magnesium and zinc deficiency, which may also contribute to growth failure (Nishi et al, 1980). Energy expenditure in inflammatory bowel disease is not generally increased as far as we can learn from limited studies measuring oxygen consumption (Kelts et al, 1979; Kirschner et al, 1984b). Fever and chronic inflammation may raise the energy needs of the body (Hamilton, 1981; Chan et al, 1986). Although corticosteroids given to induce remission of the disease initially improve growth, they exert a negative long-term effect on growth velocity (Tenore et al, 1977; Kelts et al, 1979; Hyams et al, 1988). In contrast to earlier assumptions (McCaffery et al, 1970), basal and stimulated serum growth hormone levels are within normal ranges (Tenore et al, 1977; Chong et al, 1984). There are no abnormalities in thyroid function tests that could explain growth failure (Kirschner et at, 1978; Kelts et al, 1979). IGF-I was found to be low in the serum of patients with inflammatory bowel disease, especially in those with impaired growth (Kirschner and Sutton, 1986). Management and outcome
From a therapeutic viewpoint, procedures to be discussed are those that are most relevant to growth failure, again with emphasis on Crohn's disease. In principle, any type of adequate treatment of the underlying inflammatory disease (e. g. salicylates, metronidazole, etc.) will mitigate all the symptoms, including retardation of growth. Since growth failure in inflammatory bowel disease is chiefly the result of insufficient nutrient intake, nutritional restitution is mandatory. Successful therapeutic efforts have been described using both enteral and parenteral alimentation in paediatric patients with Crohn's disease. Kirschner et al (1981) describe the outcome in seven patients whose caloric intake was increased on average from 56 to 91% of the recommended daily allowance by oral supplementation (including formula diet). After an observation period of about 4 years, five of the seven patients were again within 5% of their preillness height percentile. After an 8-week period of combined oral and parenteral nutrition resulting in a caloric supply of a mean of 136% of the recommended daily allowance, a group of seven patients, whose principal manifestation was growth failure, showed gain of weight, followed by accelerated linear growth extending up to 1 year after dietary treatment; catch-up growth was not seen (Kelts et al, 1979). Seventeen patients followed up by Strobel et al (1979) were put on total or partial parenteral nutrition for a period of 1.5 to 11 months. All had a marked improvement in symptoms, including accretion of body mass. Of
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Years Figure 3, Clinical course of a male patient with Crohn's disease. (1) marks the beginning of parenteral nutrition over a 6 week period after medical (eorticosteroids, sulphasalazine, metronidazole) treatment alone had failed to improve the patient's nutritional status. Weight gain and increased linear growth was seen then. At (2) the patient stopped therapy. Five years later (3), when the patient (aged 17 years) presented again, now with considerable linear growth failure, he was put on elemental diet and sulphasalazine. A remarkable increase in growth velocity was achieved. Top curve, height; bottom curve, weight. (We are grateful to Dr R, M. Bertele-Harms, University Children's Hospital, Munich, who provided us with this data.)
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the 14 prepubertal patients, ten demonstrated catch-up growth and the other four had appropriate growth velocity. Recent reports point out the advantage of elemental diet in Crohn's disease (Sanderson et al, 1987; Belli et al, 1988): If the small bowel in particular is affected, disease activity usually decreases, so that corticosteroid dosage can be reduced. Thus, in addition to improved nutritional supply, growth-retarding side-effects of corticosteroids can be avoided. Figure 3 illustrates the effect of nutritive therapy on the growth pattern of a patient with Crohn's disease. Although improved growth has been described in growth-retarded children despite high doses of corticosteroids (Kelts et al, 1979), the latter should be applied on an alternate-day basis as soon as remission of inflammatory bowel disease is achieved. Thus, disease activity can often be held at a low level (Whitington et al, 1977), while growth rate is not impaired by medication (Blodgett et al, 1956). Growth measurements of the lower leg in a child with Crohn's disease who receivedalternate-day steroids showed that growth was accomplished on the steroid-flee days (Wales and Milner, 1988). Recent research indicates that dietary supplements such as polyunsaturated fatty acids, nucleotides or certain amino acids (e.g. arginine) might be of benefit by modulating the mucosal immunity (Seidman et al, 1991). The effects of gut resection in localized inflammatory bowel disease are controversial (Frey et al, 1972; Homer et al, 1977). Disease location and the type of primary operation performed in Crohn's disease seem to influence the outcome, including growth (Davies et al, 1990a). Best results were observed in patients with disease confined to the small bowel and ileocaecal region, while patients with panenteric disease mostly relapsed. In colitis, patients who underwent subtotal colectomy with ileostomy remained in better condition than patients with staged colonic resection and primary anastomosis or loop ileostomy. In Crohn's disease, improved growth mainly appears to be an early benefit of surgery. In a recent study of 13 patients, the combination of surgical intervention and high energy intake in the postoperative period was successful (McLain et al, 1990). Twelve patients exhibited catch-up growth after resection while having a prolonged symptom-flee period, or at least a time of substantially improved general health. In ulcerative colitis, however, surgery may be curative, so that a more durable effect on growth can be expected (Becker, 1983). The timing of surgery appears to be critical. The studies mentioned so far describe the outcome for patient groups differing in age, maturity, disease activity and therapeutic efforts so that general conclusions cannot readily be drawn. Kirschner et al (1984a) report the follow-up to maturity of 25 patients with Crohn's disease and five patients with ulcerative colitis. These patients received intensive combined treatment for their inflammatory disease. Nine patients did not reach the fifth height percentile, but eight of these nine patients had familial short stature. The results indicate that prognosis for height in growth-impaired children with inflammatory bowel disease is generally good if adequate treatment is applied prior to bone maturation, provided there is no concomitant additional defect.
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Recently, good correlation has been shown between serum concentrations of collagen propeptides and growth velocity (Hyams et al, 1989, 1991). Thus, regular measurements of collagen propeptides might help to monitor therapy with respect to the current growth activity. Growth failure in coeliac disease
Incidence and manifestation Growth failure appears in 30-50% of patients with coeliac disease, mostly in combination with considerable bone age retardation (Young and Pringle, 1971; Exner et al, 1978; Maki et al, 1988). Short stature is more frequently seen in patients diagnosed beyond toddler age. In a retrospective study of 110 patients, 60% who were diagnosed over 4 years of age presented with growth failure, while only 28% of those under 4 years of age had retarded growth (Young and Pringle, 1971). Impaired linear growth may be the only symptom of the disease, even preceding gastrointestinal complaints, so that the diagnosis of coeliac disease may be delayed (Young and Pringle, 1971; Exner et al, 1978; Verkasalo et al, 1978; De Luca et al, 1988; M~ki et al, 1988). However, the degree of stunting does not differ between overt and silent cases. Thus coeliac disease has to be considered as a possible differential diagnosis in patients with growth failure, even if gastrointestinal symptoms are absent. Various studies showed that coeliac disease is the reason for unexplained growth retardation in 5 to 24% (Groll et al, 1980; Stenhammar et al, 1986; Radzikowski et al, 1988). In an unselected group of 60 short children, 8% were found to have underlying coeliac disease. Growth hormone deficiency was shown in only 5% (Cacciari et al, 1983). In another study (Exner et al, 1978), five of 172 children investigated for retarded growth had coeliac disease, and 11 patients had growth hormone deficiency. Screening for coeliac disease is therefore mandatory in short children. Measurement of antigliadin antibodies and antiendomysium antibodies is useful, even if a low or absent titre does not allow coeliac disease to be definitely ruled out (Btirgin-Wolff et al, 1991).
Pathophysiology Malnutrition due to malabsorption would seem to be the most obvious explanation of growth failure in coeliac disease. However, reduced height in coeliac disease is also seen in well-nourished patients, indicating that growth retardation cannot be caused by inadequate nutrition alone (Groll et al, 1980). Further, endocrinological data are not concordant with the ones observed in malnutrition, e.g. kwashiorkor, in which basal growth hormone serum levels are usually elevated. The role of the underlying endocrinological disturbances in coeliac disease remains to be elucidated. A defect of growth hormone secretion as well as an insufficient peripheral response to growth hormone could be possible. Both growth hormone deficiency (Day et al, 1973; Vanderschueren-Lodeweyckx et al, 1973) and normal growth hormone levels (Lecornu et al, 1978) have been described in growth-
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impaired coeliac patients. Studies of somatomedin levels have not been conclusive (Day et al, 1973). Recently, Karlberg et al pointed out a delay in the onset of the time at which growth hormone begins to exert a significant influence on linear growth (Karlberg et al, 1988). Treatment and outcome
Gluten withdrawal is an effective treatment for growth failure in coeliac disease. After the institution of a gluten-free diet most patients show a rapid gain of weight and height, the latter beginning after an average of 6 months of diet (Verkasalo et al, 1978; Groll et al, 1980; Cacciari et al, 1983; Auricchio et al, 1988; De Luca et al, 1988). Because of this lag period, full catch-up growth is not expected before 12 months of gluten-free diet (Auricchio et al, 1988). The majority of, but not all patients finally achieve catch-up growth (Verkasalo et al, 1978; De Luca et al, 1988). Linear growth can be limited by the dramatic acceleration of skeletal maturation under nutritive therapy (De Luca et al, 1988). Insufficient compliance, in particular during puberty, is another limiting factor (Mayer et al, 1991). The outcome in terms of height does not necessarily depend on the degree of growth failure and the age at diagnosis, as long as maturaton is not completed. Dietary treatment was shown to be successful even in cases of delayed introduction (De Luca et al, 1988), correlating with dietary compliance (Young and Pringle, 1971). However, as recently reported, adult height does not seem to be much influenced by the time of diagnosis and the duration of treatment; in general, prognosis for final height in coeliac disease is good (Bod6 et al, 1991; Cacciari et al, 1991): Comparison between patients with gastrointestinal symptoms who adhered to a glutenfree diet and non-treated patients showed that the diet led to a modest increase of final height only. In fact, treated patients reached a mean height similar to the normal population. Growth failure in cystic fibrosis
Cystic fibrosis is presented as a classic example of malnutritional growth failure due to pancreatic insufficiency and hepatobiliary and intestinal pathomechanisms. Incidence and manifestation
Growth retardation in cystic fibrosis is well known. In 1964, Sproul and Huang reported impaired linear growth after the age of 11 in boys and girls with cystic fibrosis. There was also delayed puberty and lack of pubertal growth spurt. Numerous publications thereafter described stunting as a feature of the disease (Shwachman et al, 1977; Soutter et al, 1986; Corey et al, 1988). With increasing life expectancy in cystic fibrosis, growth failure becomes more evident and psychologically important. Moreover, height seems to be a relevant prognostic factor as it reflects the patient's physical condition.
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Data from various cystic fibrosis clinics show a range of from about 10% up to over 50% of patients with height below the third percentile (Shwachman et al, 1977; Soutter et al, 1986; Corey et al, 1988). Recently, evaluation of early childhood growth patterns of Swedish children with cystic fibrosis showed that linear growth rate was retarded during the first months of life. Catch-up growth occurred after the age of 1 year, resulting in almost normal height at the age of 5 years (Karlberg et al, 1991). However, normal linear growth during the first year of life in patients with cystic fibrosis was also reported by another group (Byard, 1990). During infancy and early childhood, boys seem to be more affected. Among preadolescent and adolescent patients, growth is more often impaired in females. Linear growth parameters now appear to be better in older patients, probably due to the longer survival of well-nourished patients. Cystic fibrosis patients with different genotypes show different degrees of stunting, not necessarily correlating with weight conditions (Tiimmler et al, 1990).
Pathophysiology Although there is some evidence that growth in cystic fibrosis is also adversely affected on a genetic basis (Kerem et al, 1990; Tiimmler et al, 1990), and although not all the patients with growth retardation are in an insufficient nutritional status, numerous studies indicate that, as a general rule, linear growth velocity is substantially influenced by chronic malnutrition in cystic fibrosis. Negative energy balance and thus a chronic catabolic state in cystic fibrosis are caused by increased energy expenditure and insufficient nutrient intake (Figure 4). The majority of patients have a caloric intake of just 80-90% of the recommended daily allowance. In addition, there are excessive losses with the stool. Shepherd et al (1988) found that total energy
negative energy balance
increased energy needs insufficient nutrient supply -
anorexia pancreatic insufficiency bile acid deficiency intestinal mucosa defect
I~Z recurrent pulmonal infections increased respiratory work anaerobic metabolism essential fatty acids deficiency
Figure 4. Chronic malnutrition in cystic fibrosis: imbalance of supply and requirements.
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expenditure in young children with cystic fibrosis was on average 25 % higher than in their healthy peers. There was no correlation between energy needs and the degree of underweight, occurrence of lung disease or the degree of pancreatic insufficiency. The additional need for calories in cystic fibrosis is due to increased metabolic demands (von Ruecker et al, 1984), and recurrent pulmonary infections, hypoxia and increased respiratory work (Soutter et al, 1986) or an endogenous lack of essential fatty acids (Strandvik et al, 1981). Similar to inflammatory bowel disease, insufficient nutrient intake in cystic fibrosis is mainly a consequence of anorexia. The poor appetite may result from suppurative lung disease, gastro-oesophageal reflux or other gastrointestinal problems. It may also be a side-effect of drugs, or a consequence of electrolyte and fluid deficiencies, or result from effects on the central nervous system appetite centres related to infection or hypoxia (Editorial, 1986; Gaskin et al, 1990). Maldigestion and malabsorption lead to relevant nutritional losses with the stool. Pancreatic insufficiency causes lack of digestive enzymes such as lipase, phospholipase, trypsin, amylase, etc., thus resulting in steatorrhoea and azotorrhoea in about 85-90% of patients with cystic fibrosis (Heymans, 1989; Murphy et al, 1991). Pancreatic water and bicarbonate secretion is impaired in all cystic fibrosis patients (Weber and Roy, 1985). Consequently, pH in the duodenum is low enough to give rise to an inactivation of the remaining pancreatic enzymes and to the precipitation of glycine conjugated bile acids (Weber and Roy, 1985; Heymans, 1989). Furthermore, an isolated defect in the active absorption of bile acids is suspected (Fondacaro et al, 1982), even if the uptake of bile acids by ileal brush border membranes in cystic fibrosis was shown to be normal (De Rooij, et al, 1985). Unhydrolysed triglycerides, phospholipids and other dietary residues further impair enteral absorption by modification of the intestinal microflora. Additionally, a prolonged intestinal transit time may contribute to this problem (Shwachman and Kulczycki, 1958). In addition to the shortage of duodenal bile acids, seen particularly in patients with liver disease, there is some evidence of deficiency of mucosal lactase, enterokinase and alanylphenylalanine dipeptidase contributing to malabsorption (Morin et al, 1976; Lentze et al, 1982). There are no clear pathological endocrine data in cystic fibrosis. Levels of growth hormone, as well as of other hormones influencing growth and growth spurt, are found to be normal or elevated (Pedersen and Kastrup, 1983). Somatomedin was shown to be well functioning; levels were decreased or within normal range (Lee et al, 1980; Rosenfeld et al, 1981). In the latter case, one can assume that growth failure in cystic fibrosis may be caused by a peripheral disturbance that affects the target cells of growth. Management and outcome
Control of pulmonary disease in cystic fibrosis contributes to a decrease in the negative energy balance by improving appetite and reducing the basal energy needs of the body. Thus, physical therapy as well as antimicrobial
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treatment helps to bring the patient into an adequate nutritional status which may allow linear growth. Good results have been achieved by active hyperalimentation. Diets containing 130-150% of the mean recommended daily allowance, in combination with substitution of pancreatic enzymes, seem appropriate (Editorial, 1986; Heymans, 1989). A well-balanced, high energy and non-restricted fat diet appears to be the optimum (Corey et al, 1988; Luder et al, 1989). Earlier studies on artificial diets in cystic fibrosis did not show very convincing effects on growth; the best results were shown in preadolescent patients with mild manifestations of the disease (Yassa et al, 1978). Shepherd et al reported catch-up growth after one year of nocturnal intragastric or oral feeding of a semielemental high-nitrogen formula in nine of ten prepubertal boys and girls (Shepherd et al, 1986). In another study, all of 15 patients achieved linear catch-up growth; a lag period of up to 6 months prior to increase in linear growth velocity was observed (Soutter et al, 1986). A sevenfold increase in weight gain and doubling of linear growth velocity was described by Gaskin et al during nutritional supplementation overnight via gastrostomy tube, both in a preadolescent and adolescent patient group (Gaskin et al, 1990). Since improvement of linear growth is only sustained after a period of several months, supplementary nutrition via a parenteral route is not an alternative to oral or enteral refeeding on a long-term basis but might be the first step in counteracting general malaise (Editorial, 1986). Hyperalimentation has to be balanced with pancreatic supplementation using microcapsulated, acid-protected enzyme preparations. If steatorrhoea cannot be treated sufficiently by pancreatic enzyme supplementation, additional cimetidine or taurine can be tried (Weber and Roy, 1985; Thompson et al, 1987). Because of the difficulties of breaking the vicious circle malnutritionpulmonary disease-anorexia, it is best to start nutritional supplementation early in cystic fibrosis, before growth failure becomes evident.
CONCLUSIONS Paediatric patients with gastrointestinal disease adapt to reduced nutrient supply by slowing growth. The pathophysiology of growth failure in nutritional deficiency, particularly on the cellular level, is not yet completely understood, although many humoral and metabolic changes are quite well explored in isolated malnutrition. In gastrointestinal disorders, malnutrition alolae cannot explain growth retardation. Different gastrointestinal pathomechanisms cause growth deficit, according to the site and extent of the underlying disease. Massive inflammation (e.g. inflammatory bowel disease), genetic (e.g. cystic fibrosis) or primary endocrinological factors (e.g. coeliac disease) may contribute. Nevertheless, it transpires that nutritive therapy is the most effective approach to treatment in these diseases. Growth failure in paediatric gastrointestinal diseases seems to be
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reversible in many cases if therapy instituted before puberty.
(nutritive,
medical or surgical) is
REFERENCES Alleyne GAO & Young VH (1967) Adrenocortical function in children with severe proteincalorie malnutrition. Clinical Science 33: 189. Auricchio S, Greco L & Troncone R (1988) Gluten-sensitive enteropathy in childhood. Pediatric Clinics of North America 35: 157-185. Baxter RC, Bryson JM & Turtle JR (1981) The effect of fasting on liver receptors for prolactin and growth hormone. Metabolism 30: 1086-1090. Beas F, Monckeberg F, Horwitz I & Figueroa M (1966) The responses of the thyroid gland to thyroid-stimulating hormone (TSH) in infants with malnutrition. Pediatrics 38: 1003. Becker D J, Pimstone BL & Hansen JDL (1975) The relation between insulin secretion, glucose tolerance, growth hormone and serum proteins in protein-calorie malnutrition. Pediatric Research 9: 35-39. Becker JM (1983) Surgery and growth in inflammatory bowel disease. In Davidson M (ed.) Growth Retardation among Children and Adolescents with Inflammatory Bowel Disease, pp 270-291. New York: National Foundation for Ileitis and Colitis, Inc. Belli DC, Seidmann E, Bonthillier Let al (1988) Chronic intermittent elemental diet improves growth failure in children with Crohn's disease. Gastroenterology 94: 603-610. Belli L, Andreatta M, Reggiori A & Tragni C (1990) Valutazione dell'eta ossea in pazienti affetti da Kwashiorkor. Radiologia Medica (Torino) 79: 568-570. Blodgett FM, Burgin L & Jezzoni D (1956) Effect of prolonged cortisone therapy on the statural growth, skeletal maturation and metabolic status of children. New England Journal of Medicine 254: 636-641. Bod6 SH, Bachmann EH, Gudmand-HCyer E & Jensen GB (1991) Stature of adult coeliac patients: no evidence for decreased attained height. European Journal of ClinicalNutrition 45: 145-149. Bruno JF, Song JF & Berelowitz M (1991) Regulation of rat hypothalamic preprogrowth hormone-releasing factor messenger ribonucleic acid by dietary protein. Endocrinology 129: 1226-1232. Biirgin-Wolff A, Gaze H, Hadziselimovic F et al (1991) Antigliadin and antiendomysium antibody determination for coeliac disease. Archives of Disease in Childhood 66: 941-947. Byard PJ (1990) Early childhood growth in patients with cystic fibrosis. Annals of Human Biotogy 17: 483-499. Cacciari E, Salardi S, Lazzari R et al (1983) Short stature and celiac disease: a relationship to consider even in patients with no gastrointestinal tract symptoms. Journal of Pediatrics 103: 708-711. Cacciari E, Corazza GR, Salardi Set al (1991) What will be the adult height of coeliac patients? European Journal of Pediatrics 150: 407-409. Castillo-Duran C & Uauy R (1988) Copper deficiency impairs growth of infants recovering from malnutrition. American Journal of Clinical Nutrition 4"/: 710-714. Chan ATH, Fleming CR, O'Fallon WM & Huizenga KA (1986) Estimated versus measured basal energy requirements in patients with Crohn's disease. Gastroenterology 91: 75-78. Chong SK, Grossman A, Walker-Smith JA & Rees CH (1984) Endocrine dysfunction in children with Crohn's disease. Journal of Pediatric Gastroenterology and Nutrition 3: 529-534. Corey M, McLaughlin F J, Williams M & Levison H (1988) A comparison of survival, growth and pulmonary function in patients with cystic fibrosis in Boston and Toronto. Journal of Clinkal Epidemiology 41: 583-591. Davies G, Evans CM, Shand WS & Walker-Smith JA (1990a) Surgery for Crohn's disease in childhood: influence of site of disease and operative procedure on outcome. British Journal of Surgery 77: 891-894. Davies KM, Pearson PH, Huseman CA et al (1990b) Reduced bone mineral in patients with eating disorders. Bone 11: 143-147.
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Day G, Evans K & Wharton B (1973) Abnormalities of insulin and growth hormone secretion in children with coeliac disease. Archives of Disease in Childhood 48: 41-46. De Luca F, Astori M, Pandullo E et al (1988) Effects of a gluten-free diet on catch-up growth and height prognosis in coeliac children with growth retardation recognized after the age of 5 years. European Journal of Pediatrics 147: 188-191. De Rooij FWM, van den Berg JWO, Sinaasappel M e t al (1985) Bile acid malabsorption in cystic fibrosis; membrane vesicles, a tool for revealing the role of the ileal brush border membrane. Acta Paediatrica Scandinavica (SupplemenO 317: 28-30. Donahue SP & Phillips LS (1989) Response of IGF-I to nutritional support in malnourished hospital patients: a possible indicator of short-term changes in nutritional status. American Journal of Clinical Nutrition 50: 962-969. Editorial (1986) Lancet i: 249-251. Exner GU, Sacher M, Shmerling DH & Prader A (1978) Growth retardation and bone mineral status in children with coeliac disease recognized after the age of 3 years. Helvetica Paediatrica Acta 33: 497-507. Field CR, Schoeller DA & Brown KH (1989) Body composition of children recovering from severe protein-energy malnutrition at two rates of catch-up growth. American Journal of Clinical Nutrition 50: 1266-1275. Fondacaro JD, Henbi JE & Suchy FJ (1982) Intestinal bile acid malabsorption in CF: a primary mucosal cell defect. Pediatric Research 16: 494-498. Forbes G (1974) A note on the mathematics of 'catch-up' growth. Pediatric Research 8: 929-931. Frey CF, Weaver DK & Arbor A (1972) Colectomy in children with ulcerative and granulomatous colitis. Archives of Surgery 104: 416-423. Gaskin KJ, Waters DL, Baur LA et al (1990) Nutritional status, growth and development in children undergoing intensive treatment for cystic fibrosis. Acta Paediatrica Scandinavica (SupplemenO 366: 106-110. Groll A, Candy DCA, Preece MA et al (1980) Short stature as the primary manifestation of coeliac disease. Lancet ii: 1097-1099. Hamilton J (1981) Gastrointestinal disease: an important cause of malnutrition in childhood. In Suskind RM (ed.) Textbook of Pediatric Nutrition, pp 465-474. New York: Raven Press. Harp JB, Goldstein S & Phillips LS (1991) Nutrition and somatomedin. XXIII. Molecular regulation of IGF-I by amino acid availability in cultured hepatocytes. Diabetes 40: 95-101. Heymans HSA (1989) Gastrointestinal dysfunction and its effects on nutrition in CF. Acta Paediatrica Scandinavica (Supplement) 363: 74-79. Himes JH (1978) Bone growth and development in protein-calorie malnutrition. World Review of Nutrition and Dietetics 28: 143-187. Hintz RL (1978) Plasma somatomedin and growth hormone values in children with proteincalorie malnutrition. Journal of Pediatrics 92: 153. Ho KY, Valdhuis JD, Johnson ML et al (1988) Fasting enhances growth hormone secretion and amplifies the complex rhythms of growth hormone secretion in man. Journal of Clinical Investigation 81: 968-975. Homer DR, Grand ill & Coldny H (1977) Growth, course and prognosis after surgery for Crohn's disease in children and adolescents. Pediatrics 59: 717-725. Hyams JS, Moore RE, Leichtner AM et al (1988) Relationship of type I procollagen to corticosteroid therapy in children with inflammatory bowel disease. Journal of Pediatrics 112: 893-898. Hyams JS, Moore RE, Leichtner AM et al (1989) Longitudinal assessment of type I procollagen in children with inflammatory bowel disease subjected to surgery. Journal of Pediatric Gastroenterology 8: 68-74. Hyams JS, Treem WR, Carey DE et al (1991) Comparison of collagen propeptides as growth markers in children with inflammatory bowel disease. Gastroenterology 100: 971-975. Kanof ME, Lake AM & Bayless TM (1988) Decreased height velocity in children and adolescents before the diagnosis of Crohn's disease. Gastroenterology 95: 1523-1527. Karlberg J, Henter JI, Tassin E & Lindblad BS (1988) Longitudinal analysis of infantile growth in children with celiac disease. Acta Paediatrica Scandinavica 77: 516-524. Karlberg J, Kjellmer I & Kristiansson B (1991) Linear growth in children with cystic fibrosis. I. Birth to 8 years of age. Acta Paediatrica Scandinavica 80: 508-514.
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Kelts DG & Grand ILl (1980) Growth failure in intestinal diseases. In Lifshitz F (ed.) ClinicalDisorders in Pediatric Gastroenterologyand Nutrition, pp 349-370. NewYork: MarcelDekker. Kelts DG, Grand RJ, Shen G e t al (1979) Nutritional basis of growth failure in children and adolescents with Crohn's disease. Gastroenterology 76: 720-727. Kerem E, Corey M, Kerem BS et al (1990) The relation between genotype and phenotype in cystic fibrosis: analysis of the most common mutation (delta F 508). New England Journal of Medicine 323: 1517-1522. Khanum S, Alam AN, Anwar Iet al (1988) Effect of zinc supplementation on the dietary intake and weight gain of Bangladeshi children recovering from protein-energy malnutrition. European Journal of Clinical Nutrition 42: 709-714. Kirschner BS & Sutton MM (1986) Somatomedin-C levels in growth-impaired children and adolescents with chronic inflammatory bowel disease. Gastroenterology 91: 830-836. Kirschner BS, Voinchet O & Rosenberg IH (1978) Growth retardation in inflammatory bowel disease. Gastroenterology 75: 504-511. Kirschner BS, Klich JR, Kalman SS et al (1981) Reversal of growth retardation in Crohn's disease with therapy emphasizing oral nutritional restitution. Gastroenterology 80: 10-15. Kirschner BS, Rich BH, Sutton MM et al (1984a) Prediction of growth potential in children and adolescents with chronic inflammatory bowl disease. Gastroenterology 86:1135. Kirschner BS, Shoeller DA & Sutton MM (1984b) Measurement of energy expenditure in adolescents with Crohn's disease. Gastroenterology 86: 1136. Layden T, Rosenberg J, Nemehansky B e t al (1976) Reversal of growth arrest in adolescents with Crohn's disease after parenteral alimentation. Gastroenterology 70: 1017-1021. Lecornu M, David L & Francois R (1978) Low serum somatomedin activity in celiac disease. Helvetica Paediatrica Acta 33: 509-516. Lee JA, Dickinson LS, Kilgore BS et al (1980) Somatomedin activity in cystic fibrosis and reserpinized rats. Annals of Clinical and Laboratory Science 10: 227-233. Lentze MJ, Green JR, Sterchi EE et al (1982) Intestinal enteropeptidase deficiency associated with exocrine pancreatic insufficiency. Lancet ii: 504. Luder E, Kattan M, Thornton JC et al (1989) Efficacy of a nonrestricted fat diet in patients with cystic fibrosis. American Journal of Diseases of Children 143: 458-464. Lutter CK, Mora JO, Habicht JP et al (1990) Age-specific responsiveness of weight and length to nutritional supplementation. American Journal of Clinical Nutrition 51: 359-364. McCaffery TD, Nasr K, Lawi'ence AM & Kirsner JB (1970) Severe growth retardation in children with inflammatory bowel disease. Pediatrics 45: 386-393. McKeehan WL & McKeehan KA (1981) Extracellular regulation of fibroblast multiplication: a direct kinetic approach to analysis of role of low molecular weight nutrients and serum growth factors. Journal of Supramolecular Structure 15: 83-110. McLain BI, Davidson PM, Stokes KB & Beasley SW (1990) Growth after gut resection for Crohn's disease. Archives of Disease in Childhood 65: 760-762. Maes M, Amand Y, Underwood LE et al (1988) Decreased serum insulin-like growth factor-I response to growth hormone in hypophysectomized rats fed a low protein diet: evidence for a postreceptor defect. Acta Endocrinologica (Copenhagen) 117: 320-326. Maiter D, Maes M, Underwood L E e t al (1988) Early changes in serum concentrations of somatomedin C induced by dietary protein deprivation in rats: contributions of growth hormone receptor and post-receptor defects. Journal of Endocrinology 118: 113--120. M/aki M, Kallonen K, Lfiheaho ML & Visakorpi JK (1988) Changing pattern of childhood coeliac disease in Finland. Acta Paediatrica Scandinavica 77: 408-412. Maniar BM, Kaput PL & Seevai MH (1974) Effect of malnutrition on bones and hands in children. Indian Journal of Pediatrics 11: 2113-2126. Mayer M, Greco L, Troncone R et al (1991) Compliance of adolescents with coeliac disease with a gluten-free diet. Gut 32: 881-885. Minuto F, Barreca A, Adami GF et al (1989) Insulin-like growth factor-I in human malnutrition: relationship with some body composition and nutritional parameters. Journal of Parenteral and Enteral Nutrition 13: 392-396. Morin CL, Roy CC, Lasalle R & Bonin A (1976) Small bowel mucosal dysfunction in patients with CF. Journal of Pediatrics 88: 213-216. Motil KJ, Grand RJ, Maletskos CJ & Young VR (1982) The effect of disease, drug and diet on whole body protein metabolism in adolescents with Crohn's disease and growth failure. Journal of Pediatrics 101: 345-351.
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Murphy JL, Wootton SA, Bond SA & Jackson A A (1991) Energy content of stools in normal healthy controls and patients with cystic fibrosis. Archives of Disease in Childhood 66: 495-500. Nishi Y, Lifshitz F, Bayne MA et al (1980) Zinc status and its relation to growth retardation in children with chronic inflammatory bowel disease. American Journal of Clinical Nutrition 33: 2613-2621. Pedersen PS & Kastrup KW (1983) Somatomedin in cystic fibrosis. Acta Paediatrica Scandinavica 72: 757-758. Phillips LS, Goldstein S & Gavin III Jr (1988) Nutrition and somatomedin XVI: somatomedins and somatomedin inhibitors in fasted and refed rats. Metabolism 37" 209-216. Pimstone BL, Barbezat G, Jansen JDL & Murray P (1973) Studies on growth hormone secretion in protein-calorie malnutrition. Clinical Nutrition 21: 482-487. Radzikowski T, Zalewski TK, Kapuscinska A et al (1988) Short stature due to unrecognized celiac disease. European Journal of Pediatrics 147: 334-335. Rosenfeld RG, Landon C, Lewiston N e t al (1981) Demonstration of normal plasma somatomedin concentrations in cystic fibrosis. Journal of Pediatrics 99: 252-254. Sanderson IR, Udeen S, Davies PS et al (1987) Remission induced by an elemental diet in small bowel Crohn's disease. Archives of Disease in Childhood 62: 123-127. Seidman E, LeLeiko N, Ament M e t al (1991) Nutritional issues in pediatric inflammatory bowel disease. Journal of Pediatric Gastroenterology and Nutrition 12" 424-438. Shepherd RW, Holt TL, Thomas BJ et al (1986) Nutritional rehabilitation in cystic fibrosis: controlled studies of effects on nutritional growth retardation, body protein turnover, and course of pulmonary disease. Journal of Pediatrics 109- 788-794. Shepherd RW, Holt TL, Vasques-Valeasquez L e t al (1988) Increased energy expenditure in young children with cystic fibrosis. Lancet 1" 1300-1303. Shwachman H & Kulczycki K (1958) Studies made over a five to fourteen year period of 105 patients with CF. American Journal of Diseases of Children 96: 6-15. Shwachman H, Kowalski M & Khaw KT (1977) Cystic fibrosis: a new outlook. Medicine 56: 129-149. Simondon KB, Simondon F, Cornu A & Delpench F (1991) The utility of infancy weight curves for the prediction of linear growth retardation in preschool children. Acta Paediatrica Scandinavica 80: 1-6. Soliman AT, Gassan AEHI, Aref MK et al (1986) Serum insulin-like growth factors I and II: concentrations and growth hormone and insulin responses to arginine infusion in children with protein-calorie malnutrition before and after nutritional rehabilitation. Pediatric Research 20" 1122-1130. Soutter VL, Kristidis P, Gruca MA & Gaskin KJ (1986) Chronic undernutrition/growth retardation in cystic fibrosis. Clinics in Gastroenterology 15: 137-155. Sproul A & Huang N (1964) Growth patterns in children with cystic fibrosis. Journal of Pediatrics 65: 664-676. Stenhammar L, Ffillstr6m SP, Jansson G e t al (1986) Coeliac disease in children of short stature without gastrointestinal symptoms. European Journal of Pediatrics 145: 185-186. Strandvik B, Elfin A, Gilljam H et al (198l) Fatty acid metabolism in cystic fibrosis. In Warwick W (ed.) 1000 Years of Cystic Fibrosis, pp 304-305. Minneapolis: University of Minnesota. Strobel CT, Byrne WJ & Ament ME (1979) Home parenteral nutrition in children with Crohn's disease: an effective management alternative. Gastroenterology 77: 272-279. Tenore A, Bermann WF, Parks JS & Bongiovanni AM (1977) Basal and stimulated serum growth hormone concentrations in inflammatory bowel disease. Journal of Clinical Endocrinology and Metabolism 44: 622-628. Thissen JP, Triest S, Underwood LE et al (1990) Divergent responses of serum insulin-like growth factor-I and liver growth hormone receptors to exogenous GH in protein-restricted rats. Endocrinology 126: 908-913. Thompson GN, Robb TA & Davidson GP (1987) Taurine supplementation, fat absorption, and growth in cystic fibrosis. Journal of Pediatrics 111: 501-506. Tiimmler B, Aschendorff A, Darnedde T et al (1990) Marker haplotype association with growth in German cystic fibrosis patients. Human Genetics 84: 267-273. Vanderschueren-Lodeweyckx M, Wolter R, Molla A et al (1973) Plasma growth hormone in coeliac disease. Helvetica Paediatrica Acta 28: 349-357.
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Verkasalo M, Kuitunen P, Leisti S & Perheentupa J (1978) Growth failure from symptomless celiac disease. Helvetica Paediatrica Acta 33: 489-495. yon Ruecker AA, Bertele R & Harms HK (1984) Calcium metabolism and cystic fibrosis: mitochondrial abnormalities suggest a modification of the mitochondrial membrane. Pediatric Research 18: 594-599. Wales JK & Milner RD (1988) Variation in lower leg growth with alternate day steroid treatment. Archives of Disease in Childhood 63: 981-983. Weber AM & Roy CL (1985) Bile acid metabolism in children with CF. Acta Paediatrica Scandinavica (SupplemenO 317: %15. Whitington PF, Barnes HV & Bayless TM (1977) Medical management of Crohn's disease in adolescence. Gastroenterology 72: 1338-1344. Yassa JG, Prosser R & Dodge JA (1978) Effects of an artificial diet on growth of patients with cystic fibrosis. Archives of Disease in Childhood 53: 777-783. Young WF & Pringle EM (1971) 110 children with coeliac disease, 1950-1969. Archives of Disease in Childhood 46" 421-436.
Growth failure in gastrointestinal diseases ELEONORE MAYER MARTIN STERN
Is growth failure in gastrointestinal disease merely a consequence of nutritional deficiency? High interindividual variability in terms of manifestation and response to nutritive therapy does not support this. In most cases of gastrointestinal disease, however, malnutrition offers a reasonable partial explanation for growth retardation. These children with gastrointestinal disease do not receive the appropriate quantity and/or quality of nutrients to meet the needs for normal growth. This chapter therefore first presents general aspects of growth failure in malnutrition before describing specific gastrointestinal diseases. GROWTH FAILURE IN MALNUTRITION
Manifestation The term 'growth' incorporates both linear growth and weight gain. With regard to the general context of this chapter we will concentrate on the topic of linear growth failure. Nevertheless, linear growth failure due to malnutrition is mostly associated with retarded weight gain so that a consequent distinction between both features of growth failure can hardly be made. Rather, statural growth is often only affected after a considerable period of malnutrition and inadequate weight gain for 1-2 years (Figure 1 shows the typical pattern of growth retardation in a patient with chronic malnutrition). Over time, the patient with long-standing gastrointestinal disease becomes a 'nutritional dwarf'. It is therefore desirable to evaluate changes in body weight in a child presenting with short stature. Retrospectively, first-year weight measurements may serve as a good predictor for the degree of stunting at preschool age (Simondon et al, 1991).
Aetiology and pathophysiology Malnutrition can be due to inadequate nutrient intake, maldigestion, realabsorption or enteral loss of nutrients. (Table 1 lists possible pathophysiological mechanisms in different gastrointestinal diseases.) On the other hand, malnutrition can also result from increased nutritive demands stemming from underlying gastrointestinal disease, e.g. as a consequence of Baillibre's Clinical Endocrinology and Metabolism-645 Vol. 6, No. 3, July 1992 ISBN 0-7020-1620-9
Copyright © 1992, by Bailli6re Tindall All rights of reproduction in any form reserved
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Figure 1. Weight deficit in a male patient with chronic malnutrition due to cystic fibrosis is seen over a period of several years before linear growth retardation follows. Top curve, height; bottom curve, weight.
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GROWTH FAILURE IN GI DISEASES Table 1. Digestive tract causes of malnutrition. Condition
Causes
Inadequate ingestion
Dysphagia
Anorexia
Orofacial anomalies Achalasia Oesophagitis Oesophageal stenosis Gastritis Hepatitis Inflammatory bowel disease
Defective digestion or absorption
Pancreatic insufficiency
Bile salt abnormalities Intestinal mucosal defects
Cystic fibrosis Shwachman syndrome Chronic pancreatitis Cholestasis Liver cirrhosis Infectious/postinfectious Coeliac disease Food protein allergy Congenital intestinal enzyme deficiency (lactase/sucrase/enterokinase) Microvillus atrophy Bacterial overgrowth Short bowel syndrome Intestinal lymphangiectasia Hirschsprung's disease
Excessive losses
Regurgitation, emesis
Diarrhoea, faecal loss Decreased transit time
Gastro-oesophageal reflux Gastritis Bowel obstruction See malabsorption above Protein losing enteropathy Short bowel syndrome Vipoma
stimulated metabolism in chronic inflammatory processes, Such as inflamm a t o r y bowel disease, or of additional energy needs for respiratory work and anaerobic metabolism, such as in cystic fibrosis. Insufficient utilization of nutrient substances in liver failure is another example. W h a t are the effects of malnutrition on endocrinology and metabolism? (Figure 2.) R e d u c e d dietary intake of protein and/or energy leads to relative hypoglycaemia and depressed levels of amino acids in the plasma. This causes a decrease of serum insulin levels (Becker et al, 1975). Free cortisol concentrations in the serum are elevated in malnutrition, secondary to a u g m e n t e d adrenocorticotrophic h o r m o n e ( A C T H ) output, a b n o r m a l diurnal rhythm of secretion, slowed clearance of exogenous cortisol and decreased production of cortisol binding proteins (Alleyne and Young, 1967).
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I malnutrition
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Figure 2. Endocrinology of malnutrition: pathogenetic pathways.
In short-term protein-calorie malnutrition, in kwashiorkor and marasmus, serum growth hormone concentrations were shown to be elevated. This appears to be related mainly to dietary protein deprivation. Long-term malnutrition and calorie deprivation can cause variable growth hormone response (Pimstone et al, 1973; Ho et al, 1988; Bruno et al, 1991). With respect to insulin-like growth factors (IGF) in malnutrition, one finds depressed levels of IGF-I correlating with negative nitrogen balance and the nutritional status (Hintz, 1978; Phillips et al, 1988). IGF-II serum concentrations are normal or slightly decreased (Soliman et a1,1986). Studies on cultured rat hepatocytes indicate that altered availability of certain amino acids might regulate hepatic release of IGF-I, independent of hormonal feedback (Harp et al, 1991). How nutritional deficiency is able to influence mechanisms of IGF in detail is unclear, but it appears evident that IGF-I reduction is a primary effect of malnutrition. A reduction of IGF-I independent of growth hormone levels is explained by a potential postreceptor defect in growth hormone action. Loss of growth hormone receptors has also been demonstrated (Baxter et al, 1981; Maes et al, 1988; Maiter et al, 1988; Harp et al, 1991).
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A hypothyroid-like state is induced in the malnourished patient: there is a diminished rate of triiodothyronine (T3) production by inhibition of deiodination of thyroxine (T4), as well as reduced synthesis of plasma thyroxine binding proteins. Thyroid stimulating hormone (TSH) is found mostly normal, but may be elevated in chronic malnutrition (Beas et al, 1966). This change of the hormonal and metabolic situation can be interpreted as an adaptive response to malnutrition in order to provide the energy for basic metabolic demands by shifting the energy stored as fat or structural proteins to the viscera; it is attained by inducing a lipolytic, protein saving state. The resulting lack of growth promoting hormones and effector substances and accumulation of growth "inhibitor proteins combined with peripheral shortage of nutrients lead to growth retardation. In this situation, lack of growth factors and nutrient substrates cannot be mutually compensated as they can be under physiological circumstances (McKeehan and McKeehan, 1981). Consequent alterations of the bone, the main target tissue concerned with linear growth, are: impairment of endochondral and appositional bone growth; a selective decrease in fat content with concomitant increase in water; and a reduction of organic matrix. As a result, bone age is mostly retarded in children with malnutrition (Maniar et al, 1974; Belli et al, 1990). Bone mineralization is not always affected (Himes, 1978; Davies et al, 1990b). Management and outcome
In general, growth retardation due to malnutrition should be reversible in a prepubertal child even if nutritional deprivation has existed over a period of several years. As shown in protein deprived rats, additional growth hormone administration did not promote growth, although a shght increase of IGF-I was observed (Harp et al, 1991). The key for treatment of growth retardation due to malnutrition is nutritional sufficiency (Thissen et al, 1990). However, it must not be forgotten that extra calories are needed for compensation of energy deficits, and for improved growth velocity. The total energy for catch-up growth can be estimated by the formula of Forbes (1974): Energy (total) = energy (maintenance) + energy (growth) + energy (deficit) Children recovering from malnutrition may have an increased appetite, thus providing the necessary energy intake, e.g. in coeliac disease (see below). In other diseases, such as marasmus or chronic inflammatory bowel disease, alternative diets and/or alternative routes of ingestion must be used to overcome the bad nutritional status (see below). High growth hormone levels in malnutrition favour catch-up growth once protein and calories become available. Responsiveness to nutritional therapy is best during periods when growth is physiologically accelerated and thus the risk of malnutrition is high (infancy, puberty) (Lutter et al, 1990). Rapid restoration of nutritional status does not interfere with restitution of the physiological body composition (Fjeld et al, 1989). Short-term therapeutic success can be well monitored by IGF-I levels, which are now known to be of higher
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specificity than traditional parameters like transferrin, albumin or total protein (Donahue and Phillips, 1989; Minuto et al, 1989). Since copper and zinc deficiencies are known to impair growth, supplementation of these trace elements may be useful in addition to general (hyper)alimentation (Castillo-Duran and Uauy, 1988; Khanum et al, 1988). GROWTH FAILURE IN SPECIFIC GASTROINTESTINAL DISEASES Growth failure in inflammatory bowel disease
Growth failure in Crohn's disease and ulcerative colitis is caused by multifactorial mechanisms. Inflammatory bowel disease is a good model for illustrating the relationship of gastrointestinal disease, malnutrition and impairment of growth.
Incidence and manifestation In 1970, McCaffery et al firstly published the results of a study of a group of patients with inflammatory bowel disease and growth retardation. Retrospectively, they found 22 of 130 children with inflammatory bowel disease showing impaired growth; 19 of these patients had Crohn's disease and three had ulcerative colitis. In eight patients, growth failure was the first evident symptom of the bowel disease. Further publications confirmed growth retardation as a common feature of inflammatory bowel disease. It was more often seen in Crohn's disease than in ulcerative colitis (Kirschner et al, 1978; Chong et al, 1984; Kanof et a1,1988). The great variation of the reported frequency of growth failure in inflammatory bowel disease (15-88%) may be explained by the fact that there are relevant differences in the definition of growth failure between the various studies; moreover, the investigations were done in different age groups.
Pathophysiology Growth impairment in inflammatory bowel disease seems to be mainly a consequence of malnutrition. The following factors are best documented in growth impaired children with Crohn's disease. First of all, there is reduced nutrient intake caused by anorexia: intake is in general only 50-80% of the recommended daily allowance for age and height (Kirschner et al, 1978, 1981; Kelts et al, 1979). Fat malabsorption due to mucosal injury, bacterial overgrowth and bile salt loss was described as a substantial cause of calorie loss in about 40% of Crohn's disease patients (Kelts and Grand, 1980). Other studies, however, point out that malnutrition in inflammatory bowel disease cannot be sufficiently explained by steatorrhoea alone (Kelts et al, 1979; Kirschner et al, 1981). Carbohydrate malabsorption, shown for D-xylose (Kelts et al, 1979; Kirschner et al, 1981) and lactose (Kelts and Grand, 1980), can be excluded
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as a relevant pathogenetic factor. Protein losing enteropathy is seen in most children with active disease (Kirschner et al, 1981), leading in at least 50% to hypoalbuminaemia (Kelts and Grand, 1980). However, not all the studies show a negative nitrogen balance (Layden et al, 1976; Kirschner et a1,1981; Motil et al, 1982). Correlating with hypoalbuminaemia is magnesium and zinc deficiency, which may also contribute to growth failure (Nishi et al, 1980). Energy expenditure in inflammatory bowel disease is not generally increased as far as we can learn from limited studies measuring oxygen consumption (Kelts et al, 1979; Kirschner et al, 1984b). Fever and chronic inflammation may raise the energy needs of the body (Hamilton, 1981; Chan et al, 1986). Although corticosteroids given to induce remission of the disease initially improve growth, they exert a negative long-term effect on growth velocity (Tenore et al, 1977; Kelts et al, 1979; Hyams et al, 1988). In contrast to earlier assumptions (McCaffery et al, 1970), basal and stimulated serum growth hormone levels are within normal ranges (Tenore et al, 1977; Chong et al, 1984). There are no abnormalities in thyroid function tests that could explain growth failure (Kirschner et at, 1978; Kelts et al, 1979). IGF-I was found to be low in the serum of patients with inflammatory bowel disease, especially in those with impaired growth (Kirschner and Sutton, 1986). Management and outcome
From a therapeutic viewpoint, procedures to be discussed are those that are most relevant to growth failure, again with emphasis on Crohn's disease. In principle, any type of adequate treatment of the underlying inflammatory disease (e. g. salicylates, metronidazole, etc.) will mitigate all the symptoms, including retardation of growth. Since growth failure in inflammatory bowel disease is chiefly the result of insufficient nutrient intake, nutritional restitution is mandatory. Successful therapeutic efforts have been described using both enteral and parenteral alimentation in paediatric patients with Crohn's disease. Kirschner et al (1981) describe the outcome in seven patients whose caloric intake was increased on average from 56 to 91% of the recommended daily allowance by oral supplementation (including formula diet). After an observation period of about 4 years, five of the seven patients were again within 5% of their preillness height percentile. After an 8-week period of combined oral and parenteral nutrition resulting in a caloric supply of a mean of 136% of the recommended daily allowance, a group of seven patients, whose principal manifestation was growth failure, showed gain of weight, followed by accelerated linear growth extending up to 1 year after dietary treatment; catch-up growth was not seen (Kelts et al, 1979). Seventeen patients followed up by Strobel et al (1979) were put on total or partial parenteral nutrition for a period of 1.5 to 11 months. All had a marked improvement in symptoms, including accretion of body mass. Of
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16
17 18
Years Figure 3, Clinical course of a male patient with Crohn's disease. (1) marks the beginning of parenteral nutrition over a 6 week period after medical (eorticosteroids, sulphasalazine, metronidazole) treatment alone had failed to improve the patient's nutritional status. Weight gain and increased linear growth was seen then. At (2) the patient stopped therapy. Five years later (3), when the patient (aged 17 years) presented again, now with considerable linear growth failure, he was put on elemental diet and sulphasalazine. A remarkable increase in growth velocity was achieved. Top curve, height; bottom curve, weight. (We are grateful to Dr R, M. Bertele-Harms, University Children's Hospital, Munich, who provided us with this data.)
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the 14 prepubertal patients, ten demonstrated catch-up growth and the other four had appropriate growth velocity. Recent reports point out the advantage of elemental diet in Crohn's disease (Sanderson et al, 1987; Belli et al, 1988): If the small bowel in particular is affected, disease activity usually decreases, so that corticosteroid dosage can be reduced. Thus, in addition to improved nutritional supply, growth-retarding side-effects of corticosteroids can be avoided. Figure 3 illustrates the effect of nutritive therapy on the growth pattern of a patient with Crohn's disease. Although improved growth has been described in growth-retarded children despite high doses of corticosteroids (Kelts et al, 1979), the latter should be applied on an alternate-day basis as soon as remission of inflammatory bowel disease is achieved. Thus, disease activity can often be held at a low level (Whitington et al, 1977), while growth rate is not impaired by medication (Blodgett et al, 1956). Growth measurements of the lower leg in a child with Crohn's disease who receivedalternate-day steroids showed that growth was accomplished on the steroid-flee days (Wales and Milner, 1988). Recent research indicates that dietary supplements such as polyunsaturated fatty acids, nucleotides or certain amino acids (e.g. arginine) might be of benefit by modulating the mucosal immunity (Seidman et al, 1991). The effects of gut resection in localized inflammatory bowel disease are controversial (Frey et al, 1972; Homer et al, 1977). Disease location and the type of primary operation performed in Crohn's disease seem to influence the outcome, including growth (Davies et al, 1990a). Best results were observed in patients with disease confined to the small bowel and ileocaecal region, while patients with panenteric disease mostly relapsed. In colitis, patients who underwent subtotal colectomy with ileostomy remained in better condition than patients with staged colonic resection and primary anastomosis or loop ileostomy. In Crohn's disease, improved growth mainly appears to be an early benefit of surgery. In a recent study of 13 patients, the combination of surgical intervention and high energy intake in the postoperative period was successful (McLain et al, 1990). Twelve patients exhibited catch-up growth after resection while having a prolonged symptom-flee period, or at least a time of substantially improved general health. In ulcerative colitis, however, surgery may be curative, so that a more durable effect on growth can be expected (Becker, 1983). The timing of surgery appears to be critical. The studies mentioned so far describe the outcome for patient groups differing in age, maturity, disease activity and therapeutic efforts so that general conclusions cannot readily be drawn. Kirschner et al (1984a) report the follow-up to maturity of 25 patients with Crohn's disease and five patients with ulcerative colitis. These patients received intensive combined treatment for their inflammatory disease. Nine patients did not reach the fifth height percentile, but eight of these nine patients had familial short stature. The results indicate that prognosis for height in growth-impaired children with inflammatory bowel disease is generally good if adequate treatment is applied prior to bone maturation, provided there is no concomitant additional defect.
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Recently, good correlation has been shown between serum concentrations of collagen propeptides and growth velocity (Hyams et al, 1989, 1991). Thus, regular measurements of collagen propeptides might help to monitor therapy with respect to the current growth activity. Growth failure in coeliac disease
Incidence and manifestation Growth failure appears in 30-50% of patients with coeliac disease, mostly in combination with considerable bone age retardation (Young and Pringle, 1971; Exner et al, 1978; Maki et al, 1988). Short stature is more frequently seen in patients diagnosed beyond toddler age. In a retrospective study of 110 patients, 60% who were diagnosed over 4 years of age presented with growth failure, while only 28% of those under 4 years of age had retarded growth (Young and Pringle, 1971). Impaired linear growth may be the only symptom of the disease, even preceding gastrointestinal complaints, so that the diagnosis of coeliac disease may be delayed (Young and Pringle, 1971; Exner et al, 1978; Verkasalo et al, 1978; De Luca et al, 1988; M~ki et al, 1988). However, the degree of stunting does not differ between overt and silent cases. Thus coeliac disease has to be considered as a possible differential diagnosis in patients with growth failure, even if gastrointestinal symptoms are absent. Various studies showed that coeliac disease is the reason for unexplained growth retardation in 5 to 24% (Groll et al, 1980; Stenhammar et al, 1986; Radzikowski et al, 1988). In an unselected group of 60 short children, 8% were found to have underlying coeliac disease. Growth hormone deficiency was shown in only 5% (Cacciari et al, 1983). In another study (Exner et al, 1978), five of 172 children investigated for retarded growth had coeliac disease, and 11 patients had growth hormone deficiency. Screening for coeliac disease is therefore mandatory in short children. Measurement of antigliadin antibodies and antiendomysium antibodies is useful, even if a low or absent titre does not allow coeliac disease to be definitely ruled out (Btirgin-Wolff et al, 1991).
Pathophysiology Malnutrition due to malabsorption would seem to be the most obvious explanation of growth failure in coeliac disease. However, reduced height in coeliac disease is also seen in well-nourished patients, indicating that growth retardation cannot be caused by inadequate nutrition alone (Groll et al, 1980). Further, endocrinological data are not concordant with the ones observed in malnutrition, e.g. kwashiorkor, in which basal growth hormone serum levels are usually elevated. The role of the underlying endocrinological disturbances in coeliac disease remains to be elucidated. A defect of growth hormone secretion as well as an insufficient peripheral response to growth hormone could be possible. Both growth hormone deficiency (Day et al, 1973; Vanderschueren-Lodeweyckx et al, 1973) and normal growth hormone levels (Lecornu et al, 1978) have been described in growth-
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impaired coeliac patients. Studies of somatomedin levels have not been conclusive (Day et al, 1973). Recently, Karlberg et al pointed out a delay in the onset of the time at which growth hormone begins to exert a significant influence on linear growth (Karlberg et al, 1988). Treatment and outcome
Gluten withdrawal is an effective treatment for growth failure in coeliac disease. After the institution of a gluten-free diet most patients show a rapid gain of weight and height, the latter beginning after an average of 6 months of diet (Verkasalo et al, 1978; Groll et al, 1980; Cacciari et al, 1983; Auricchio et al, 1988; De Luca et al, 1988). Because of this lag period, full catch-up growth is not expected before 12 months of gluten-free diet (Auricchio et al, 1988). The majority of, but not all patients finally achieve catch-up growth (Verkasalo et al, 1978; De Luca et al, 1988). Linear growth can be limited by the dramatic acceleration of skeletal maturation under nutritive therapy (De Luca et al, 1988). Insufficient compliance, in particular during puberty, is another limiting factor (Mayer et al, 1991). The outcome in terms of height does not necessarily depend on the degree of growth failure and the age at diagnosis, as long as maturaton is not completed. Dietary treatment was shown to be successful even in cases of delayed introduction (De Luca et al, 1988), correlating with dietary compliance (Young and Pringle, 1971). However, as recently reported, adult height does not seem to be much influenced by the time of diagnosis and the duration of treatment; in general, prognosis for final height in coeliac disease is good (Bod6 et al, 1991; Cacciari et al, 1991): Comparison between patients with gastrointestinal symptoms who adhered to a glutenfree diet and non-treated patients showed that the diet led to a modest increase of final height only. In fact, treated patients reached a mean height similar to the normal population. Growth failure in cystic fibrosis
Cystic fibrosis is presented as a classic example of malnutritional growth failure due to pancreatic insufficiency and hepatobiliary and intestinal pathomechanisms. Incidence and manifestation
Growth retardation in cystic fibrosis is well known. In 1964, Sproul and Huang reported impaired linear growth after the age of 11 in boys and girls with cystic fibrosis. There was also delayed puberty and lack of pubertal growth spurt. Numerous publications thereafter described stunting as a feature of the disease (Shwachman et al, 1977; Soutter et al, 1986; Corey et al, 1988). With increasing life expectancy in cystic fibrosis, growth failure becomes more evident and psychologically important. Moreover, height seems to be a relevant prognostic factor as it reflects the patient's physical condition.
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Data from various cystic fibrosis clinics show a range of from about 10% up to over 50% of patients with height below the third percentile (Shwachman et al, 1977; Soutter et al, 1986; Corey et al, 1988). Recently, evaluation of early childhood growth patterns of Swedish children with cystic fibrosis showed that linear growth rate was retarded during the first months of life. Catch-up growth occurred after the age of 1 year, resulting in almost normal height at the age of 5 years (Karlberg et al, 1991). However, normal linear growth during the first year of life in patients with cystic fibrosis was also reported by another group (Byard, 1990). During infancy and early childhood, boys seem to be more affected. Among preadolescent and adolescent patients, growth is more often impaired in females. Linear growth parameters now appear to be better in older patients, probably due to the longer survival of well-nourished patients. Cystic fibrosis patients with different genotypes show different degrees of stunting, not necessarily correlating with weight conditions (Tiimmler et al, 1990).
Pathophysiology Although there is some evidence that growth in cystic fibrosis is also adversely affected on a genetic basis (Kerem et al, 1990; Tiimmler et al, 1990), and although not all the patients with growth retardation are in an insufficient nutritional status, numerous studies indicate that, as a general rule, linear growth velocity is substantially influenced by chronic malnutrition in cystic fibrosis. Negative energy balance and thus a chronic catabolic state in cystic fibrosis are caused by increased energy expenditure and insufficient nutrient intake (Figure 4). The majority of patients have a caloric intake of just 80-90% of the recommended daily allowance. In addition, there are excessive losses with the stool. Shepherd et al (1988) found that total energy
negative energy balance
increased energy needs insufficient nutrient supply -
anorexia pancreatic insufficiency bile acid deficiency intestinal mucosa defect
I~Z recurrent pulmonal infections increased respiratory work anaerobic metabolism essential fatty acids deficiency
Figure 4. Chronic malnutrition in cystic fibrosis: imbalance of supply and requirements.
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expenditure in young children with cystic fibrosis was on average 25 % higher than in their healthy peers. There was no correlation between energy needs and the degree of underweight, occurrence of lung disease or the degree of pancreatic insufficiency. The additional need for calories in cystic fibrosis is due to increased metabolic demands (von Ruecker et al, 1984), and recurrent pulmonary infections, hypoxia and increased respiratory work (Soutter et al, 1986) or an endogenous lack of essential fatty acids (Strandvik et al, 1981). Similar to inflammatory bowel disease, insufficient nutrient intake in cystic fibrosis is mainly a consequence of anorexia. The poor appetite may result from suppurative lung disease, gastro-oesophageal reflux or other gastrointestinal problems. It may also be a side-effect of drugs, or a consequence of electrolyte and fluid deficiencies, or result from effects on the central nervous system appetite centres related to infection or hypoxia (Editorial, 1986; Gaskin et al, 1990). Maldigestion and malabsorption lead to relevant nutritional losses with the stool. Pancreatic insufficiency causes lack of digestive enzymes such as lipase, phospholipase, trypsin, amylase, etc., thus resulting in steatorrhoea and azotorrhoea in about 85-90% of patients with cystic fibrosis (Heymans, 1989; Murphy et al, 1991). Pancreatic water and bicarbonate secretion is impaired in all cystic fibrosis patients (Weber and Roy, 1985). Consequently, pH in the duodenum is low enough to give rise to an inactivation of the remaining pancreatic enzymes and to the precipitation of glycine conjugated bile acids (Weber and Roy, 1985; Heymans, 1989). Furthermore, an isolated defect in the active absorption of bile acids is suspected (Fondacaro et al, 1982), even if the uptake of bile acids by ileal brush border membranes in cystic fibrosis was shown to be normal (De Rooij, et al, 1985). Unhydrolysed triglycerides, phospholipids and other dietary residues further impair enteral absorption by modification of the intestinal microflora. Additionally, a prolonged intestinal transit time may contribute to this problem (Shwachman and Kulczycki, 1958). In addition to the shortage of duodenal bile acids, seen particularly in patients with liver disease, there is some evidence of deficiency of mucosal lactase, enterokinase and alanylphenylalanine dipeptidase contributing to malabsorption (Morin et al, 1976; Lentze et al, 1982). There are no clear pathological endocrine data in cystic fibrosis. Levels of growth hormone, as well as of other hormones influencing growth and growth spurt, are found to be normal or elevated (Pedersen and Kastrup, 1983). Somatomedin was shown to be well functioning; levels were decreased or within normal range (Lee et al, 1980; Rosenfeld et al, 1981). In the latter case, one can assume that growth failure in cystic fibrosis may be caused by a peripheral disturbance that affects the target cells of growth. Management and outcome
Control of pulmonary disease in cystic fibrosis contributes to a decrease in the negative energy balance by improving appetite and reducing the basal energy needs of the body. Thus, physical therapy as well as antimicrobial
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treatment helps to bring the patient into an adequate nutritional status which may allow linear growth. Good results have been achieved by active hyperalimentation. Diets containing 130-150% of the mean recommended daily allowance, in combination with substitution of pancreatic enzymes, seem appropriate (Editorial, 1986; Heymans, 1989). A well-balanced, high energy and non-restricted fat diet appears to be the optimum (Corey et al, 1988; Luder et al, 1989). Earlier studies on artificial diets in cystic fibrosis did not show very convincing effects on growth; the best results were shown in preadolescent patients with mild manifestations of the disease (Yassa et al, 1978). Shepherd et al reported catch-up growth after one year of nocturnal intragastric or oral feeding of a semielemental high-nitrogen formula in nine of ten prepubertal boys and girls (Shepherd et al, 1986). In another study, all of 15 patients achieved linear catch-up growth; a lag period of up to 6 months prior to increase in linear growth velocity was observed (Soutter et al, 1986). A sevenfold increase in weight gain and doubling of linear growth velocity was described by Gaskin et al during nutritional supplementation overnight via gastrostomy tube, both in a preadolescent and adolescent patient group (Gaskin et al, 1990). Since improvement of linear growth is only sustained after a period of several months, supplementary nutrition via a parenteral route is not an alternative to oral or enteral refeeding on a long-term basis but might be the first step in counteracting general malaise (Editorial, 1986). Hyperalimentation has to be balanced with pancreatic supplementation using microcapsulated, acid-protected enzyme preparations. If steatorrhoea cannot be treated sufficiently by pancreatic enzyme supplementation, additional cimetidine or taurine can be tried (Weber and Roy, 1985; Thompson et al, 1987). Because of the difficulties of breaking the vicious circle malnutritionpulmonary disease-anorexia, it is best to start nutritional supplementation early in cystic fibrosis, before growth failure becomes evident.
CONCLUSIONS Paediatric patients with gastrointestinal disease adapt to reduced nutrient supply by slowing growth. The pathophysiology of growth failure in nutritional deficiency, particularly on the cellular level, is not yet completely understood, although many humoral and metabolic changes are quite well explored in isolated malnutrition. In gastrointestinal disorders, malnutrition alolae cannot explain growth retardation. Different gastrointestinal pathomechanisms cause growth deficit, according to the site and extent of the underlying disease. Massive inflammation (e.g. inflammatory bowel disease), genetic (e.g. cystic fibrosis) or primary endocrinological factors (e.g. coeliac disease) may contribute. Nevertheless, it transpires that nutritive therapy is the most effective approach to treatment in these diseases. Growth failure in paediatric gastrointestinal diseases seems to be
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reversible in many cases if therapy instituted before puberty.
(nutritive,
medical or surgical) is
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