occult celiac disease: a common cause of short stature - GGH Journal

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Occult Celiac Disease continued from page 1 No clinical or laboratory clues enabled the investigators to differentiate between the cases of short stature due to occult CD and those due to other causes. Equally unhelpful in differential diagnosis was the age at diagnosis, length of follow-up prior to referral to the GIservice, and degree of bone-age retardation. Although abnormal stool-fat excretion was found only in children with CD, sensitivity waslow, and abnormal results were found in only four of nine patients tested. However, testing for the presence of microcytic anemia revealed that all of the children with CD, but none without the disease, were anemic. A positive history of past GI problems, particularly diarrhea, during early childhood also was very helpful. The prevalence of CD is low in some studies (1.8%,7 8%,9 and 5% 1°) but high in others (24%8 and 48%11). This disparity may indicate that CD can be recognized and treated in some areas of the world at a younger age, when the malabsorption symptoms are more clear-cut and before severe stunting of growth occurs; in other regions, however, it tends to be diagnosed later, when short stature is the more obvious problem. This varying prevalence may also reflect a real disparity between the incidence of CD and its mode of presentation. Is CD-Induced Short Stature Occult? Detecting occult CD as a cause of short stature is a function of professional alertness insofar as the clinician considers this condition in a differential diagnosis. Data in the medical literature. as well as from our own experience, show that many CD patients with short stature have a history of diarrhea at an early age and/or have microcytic anemia. Other diagnostic clues that may indicate CD include increased stool fat, antigliadin and antiendomysial antibodies. and low folate and serum ferritin levels.3-S In a few cases, however, there may be no clue to CD other than abnormal intestinal mucosa diagnosed by an orally obtained jejunal biopsy. Pathogenesis of Growth Retardation The cause of growth failure in children with CD has been the focus of many investigations. Initial studies suggested secondary hypopituitarism might be the basis for the retarded growth.1, 12-14 Subsequent assessments, however, failed to substantiate growth hormone (GH) deficiency in most growth-impaired children with CD. On continued investigation, it became increasingly evident that a gluten-free diet could reverse this complication. This finding further emphasized the importance of adequate and appropriate nutrition in maintaining normal linear growth. The effect of gluten ingestion on the growth pattern of CD patients is still unresolved. Is growth retardation induced by the effect of the disease on the general nutritional status? That is, does malabsorption lead to malnutrition, which, in turn, leads to a decrease in weight and failure to gain height? Or, in addition, is there a direct effect of gliadin peptides on the GH-secreting apparatus, as well as on other hormones affecting growth, such as somatomedin? GH and CD Inadequate response of serum GH levels to insulin stimulation was reported by Hamilton in 1969 in one of five CD patients examined. 1 We have examined the plasma GH levels in response to insulin stimulation in CD patients on a normal gluten diet, in patients on a glutenfree diet, and in normal children of comparable age who served as controls (Figure).12 The CD children showed a lower GH response, as a group, than the normal controls. Also, serum GH response to insulin stimulation in the CD group consuming a normal gluten diet was significantly lower than in the CD group on the glutenfree diet. Similar results have been reported in other studies.1,7,13,14 Somatomedin-C (Sm-C), a GHdependent growth factor modulated by nutrient status, is variable in CD patients.1s-17 We were unable to find a correlation between serum Sm-C levels in CD children and the diet consumed. As would be expected, some CD patients who had low Sm-C levels while on the normal gluten diet had increased levels while on a glutenfree diet. On the other hand, other patients had normal serum Sm-C levels while consuming a normal gluten diet. Data are accumulating to suggest that Sm-C may be a useful marker of nutritional adequacy in patients with inflammatory bowel disease 18,19 but not in patients with CD. Enhanced Enteric Losses and Nutritional Dwarfism Anyone or a combination ot the nutritional alterations may lead to nutritional dwarfing in CD patients.This may occur even in patients
who have an increased body weight/height ratio (i.e., short and plump patients). The basic defect in CD is destruction of the intestinal epithelial cell layer, with reactive production of intestinal cells up to seven times the normal rate. The net result is flattening of the intestinal mucosa; immature and damaged epithelial cells cover the surface. This blunting of the villi is instrumental in decreasing the absorptive surface of the intestine and producing malabsorption and malnutrition.3-s The nutritional status of these patients is further impaired by the defects in the intestinal epithelium that cause protein-losing enteropathy, and is aggravated by the desquamation of the epithelial cells and shedding of lymphocytes. The resultant loss of protein, DNA, and lymphocytes leads to hypoproteinemia and lymphopenia. CD patients also experience intestinal loss of zinc. There is a tendency toward lower serum zinc levels in the CD patients. but these levels are not low enough to produce clinical symptoms. Children with CD have impaired iron balance as well. Serum ferritin levels in CD patients are often significantly lower than in controls, and a gluten-free diet produces a definite rise toward normal levels. The low ferritin levels reflect impairment of iron absorption, as well as increased iron losses in the desquamating epithelial cells and lymphocytes. Additionally, the serum folate levels are significantly lower in the untreated CD patients and may result from a decrease in the folate absorption caused by the impairment of the deconjugase enzyme present in the brush border of the intestinal epithelial cells. This enzyme facilitates absorption by splitting glutamic acid residues from the folate heptaglutamate in foods and reducing them to monoor diglutamates. However, it is well known that there is a sevenfold increase of cell turnover and in DNA synthesis in patients with CD. This regenerative effort by the crypt cells in active CD requires folic acid, an essential component of the enzymes involved in the synthesis of DNA. Thus, there is a decrease in folic acid absorption that parallels an increase in folic acid requirements for DNA synthesis in patients with active CD. The net result is decreased serum folate levels. 3 Diagnosis of CD Two factors are important to remember when considering occult CD in the differential diagnosis of short stature: 1) Studies show an increased incidence of CD among children hospitalized for examination of short stature; and 2) CD may be present even in the absence of GI symptoms. A small-bowel bi-opsy, "the gold standard" for the diagnosis of CD, should be performed in all children examined for short stature who show a decrease in the body weight/height ratio, have a history of diarrhea during the first year of life, or present with hematologic abnormalities such as anemia. Summary CD is more common than idiopathic GH deficiency as a cause of short stature. Thus, it is important to rule out this disease in children in whom there is no endocrinologic cause of short stature. CD should be suspected in patients who 1) fail to grow at normal rates and have a bone age that is delayed, particularly if by more than 4 years; or 2) have a bone age below that expected for height. Because abnormal absorption may not be detected by common tests even in known CD patients, an intestinal biopsy may be needed for diagnosis. Confirmation of CD as the cause of delayed growth should come from documentation of catch-up growth in weight and height after institution of a glutenfree diet, the only treatment"-now available for CD. The original work was supported by a grant from DFG, West Germany. Editor's comment-One of the greatest enigmas in pediatrics today is why celiac disease is so prevalent in Europe and the Middle East (Israel, for example) but not in North America. There are many descendants of Europeans in North America, but the disease is rare. Readers who have a tenable theory, particularly one with supporting data, are encouraged to write to the editors of Growth,Genetics, and Hormones. continued on page 4
Page 1: Vol. 5 No.2 June 1989 Asaria Ashken

occult celiac disease: a common cause of short stature - GGH Journal

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