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Intolerance of gluten containing cereals (wheat, rye, and barley) is an etiopathogenetically heterogeneous and relatively common problem of modern man. It occurs as an adverse immune-mediated condition in genetically predisposed individuals. According to the pathogenetic mechanism of intolerance to the components of these cereals, it is classified into celiac disease as an autoimmune disease, wheat allergy as an allergic disease, and non-celiac gluten sensitivity as a non-autoimmune and non-allergic disease. Each of these disorders is characterized by specific intestinal and/or extraintestinal manifestations, which resolve on a gluten-free diet. This review article presents the basic characteristics of these disorders in accordance with modern knowledge.

Celiac disease is a multisystemic autoimmune disease induced by gluten in wheat, rye, and barley. It is characterized by polygenic predisposition, prevailing prevalence in members of the white population (1%), especially in close relatives (5–15%), very heterogeneous expression and frequent association with other autoimmune diseases (3–10%), as well as selective deficiency of IgA and Down, Turner, and Williams syndromes. The basis of the disease and the key finding in its diagnostics is gluten-sensitive enteropathy, i.e., non-specific inflammation of the small intestinal mucosa which resolves by gluten-free diet. In addition to enteropathy, whether symptomatic or asymptomatic, the disease is also characterized by various extraintestinal manifestations, and even very serious complications. Therapy is based on a lifelong glutenfree diet, so that the disorder, if diagnosed in time and treated consistently, has an excellent prognosis.

Introduction/Objective. Celiac disease (CD) is the result of a polygenic predisposition and gluten-containing diet. The aim of this study was to determine the prevalence and clinical forms of CD in siblings of children with verified disease. Methods. The study included 83 siblings, aged 1.5–27 (11.77 ± 6.2) years, of 64 children with CD diagnosed according to ESPGHAN criteria (1990/2012). In addition to a detailed history and clinical examination, serum levels of IgA and antibodies to tissue transglutaminase (AtTG) IgA and IgG classes were determined in all subjects. All with elevated AtTG levels underwent multiple duodenal enterobiopsy. The diagnosis of CD was confirmed by the finding of characteristic histological changes. Results. The diagnosis of CB was made in 13 of 83 subjects (15.67%). Nine of them had an asymptomatic form of the disease, while in the others the disease was clinically manifested – in three the form was classical, in one it was accompanied by severe malnutrition (-26.80%), and in one the manifestation was nonclassical (only short stature). Except for sideropenia and hypoferritinemia in four patients, of which two with hemoglobin below the reference value, standard laboratory findings were within normal limits. Conclusion. Our research shows that the prevalence of CD in siblings of children with verified disease is 15.67%. It is mostly detected in its asymptomatic form. In accordance with this, routine application of serological screening for CD in this population group is necessary for its timely diagnosis and treatment.

Anemia is a common and etiologically heterogeneous health problem both during the period of growth and development and in other phases of life. It is most often caused by a deficiency of iron, primarily due to inadequate nutrition, and less often as a consequence of various diseases. Particularly risk groups for the occurrence of anemia due to iron deficiency are children in the stages of rapid growth and development, i.e., in the first years after birth and during puberty. In accordance with the fact that it is better to prevent than to treat, in this article are given basic guidelines related to the prevention of this type of anemia in children and adolescents.

Gluten-related disorders are a heterogeneous group of clinical entities caused by intolerance to wheat, rye, and barley flour components. They occur in 3–5% of genetically predisposed persons and, based on pathogenic and clinical features, are classified into celiac disease, non-celiac gluten sensitivity, and wheat allergy. There are also specific entities such as dermatitis herpetiformis or gluten ataxia, which can occur either within the celiac disease or independently. This article based on the current knowledge shows the basic details of the pathogenesis, clinical expression, diagnosis, and treatment of these disorders.

Introduction/Objective. Nonclassical celiac disease (CD) is characterized by a very heterogeneous and non-specific clinical presentation. The aim of this study was to determine the basic symptoms and clinical signs of this CD subtype in children and adolescents Methods. The study was based on a sample of 58 children and adolescent, 38 female and 20 male, ages 1.75 to 17.75 (10.01±4.62) years with a nonclassical CD diagnosed according to the European Society for Pediatric Gastroenterology, Hepatology and Nutrition criteria from 1990 and 2012. Results. Except four patients who were between the ages of 1.75 to 2.50 years, all others were older than three years. The main clinical symptoms and signs suggestive of non-classical CD were anemia caused by iron deficiency (48.28%), short stature (34.48%), and intermittent abdominal pain (18.97%), anorexia with stagnation or weight loss (13.79%), and chronic constipation (6.9%). Thirty patients had one symptom or sign of the disease, 15 had two and 13 had three. In addition, 12 patients had dental enamel hypoplasia, 18 sideropenia without anemia and five mild isolated hypertransaminasemia. A gluten-free diet, apart from the dental enamel hypoplasia, has resulted in the withdrawal of all indicators of the disease. Conclusion. The main symptoms and clinical signs of nonclassical CD in children and adolescents were iron deficiency anemia, short stature and intermittent abdominal pain, and less frequently anorexia with stagnation or weight loss and chronic constipation. Excluding dental enamel hypoplasia, a gluten-free diet leads to a complete recovery of the patient.

Introduction. Celiac crisis is a rare and life-threatening complication of celiac disease. Although it occurs in all ages, the most common affects children within the first two years. Outline of cases. We report three infants (two female, one male, age range 9–12) with celiac crises as an initial presentation of celiac disease precipitated with rotavirus gastroenteritis. Celiac crisis was preceded by failure to thrive caused by anorexia, occasional vomiting and frequent abundant stools for 4–8 weeks, and 1–2 days before admission with fever, frequent vomiting and profuse watery diarrhea. They were admitted in a very severe general condition, severely dehydrated, markedly malnourished, with an enormously distended abdomen, edema of the lower legs and feet, and perianal erythema. After correction of dehydration and hypoalbuminemia, they were placed on a gluten- and disaccharide-free diet and within the first two weeks on additional parenteral nutrition. The applied therapeutic measures resulted in stabilization and further rapid improvement of the patient’s condition. In all three patients the latex agglutination test for rotavirus was positive, IgA anti-TTG antibodies elevated (58.6–78 U/ml) and all three were homozygous carriers of the HLA DQ2 gene. Enterobiopsy was performed two weeks after the admission and total villous atrophy (Marsh IIIc) was registered in all three patients. In the further course, the complete recovery of the patient was accomplished by a strict gluten-free diet. Conclusion. Our experience indicates that rotavirus gastroenteritis in timely unrecognized classical celiac disease in infants can lead to celiac crisis.

Introduction/Objective. Benign transient hyperphosphatasemia (BTH) is a pathogenetic insufficiently clear clinical entity that is mostly seen in infants and young children. The objective of this paper is to present our experience regarding the age of occurrence, the conditions of the discovery, and the length of duration of BTH in children. Methods. The study was realized on a sample of 18 children, nine boys and nine girls, aged 10–42 (21.06 ± 9.35) months with BTH. The diagnosis of BTH is based on the absence of bone and hepatobiliary diseases, and its spontaneous disappearance over the course of several months. Results. One patient was in the first year, 13 in the second, three in the third, and one in the fourth. Isolated high activity of serum alkaline phosphatase, which was 2.04–21.9 (8.05 ± 5.31) times above the upper reference value for the corresponding age, in 14 cases it was found during the acute diarrhea, and in four with acute rhinopharyngitis, of which in two complicated with otitis media. The cause of diarrhea in six cases was rotavirus, in two Campylobacter, and in one adenovirus, and otitis media in one case was caused by Streptococcus pneumoniae, while in others, etiologic factors of infection were not identified. Spontaneous normalization of serum alkaline phosphatase activity was recorded between one and three months after the onset. Conclusion. BTH is a harmless biochemical disorder that spontaneously subsides within three months after initial observation. It is found randomly as a routine laboratory finding most often within the treatment of acute gastrointestinal and respiratory infections.

Introduction/Objective Isolated hypertransaminasemia (IHTS) is a common, benign, and transient appearance in patients with celiac disease (CD). The aim of this study is to determine the frequency of IHTS in children up to two years old with clinically classical CD, as well as its connection with the onset of the first symptoms of the disease, the age of diagnosis, the clinical and laboratory nutritional parameters, and the degree of damage of small intestinal mucosa. Methods The study was based on a sample of 82 children, 55 female and 27 male, ages 7–24 (14.28 ± 4.41) months. The diagnosis of CD was based on the revised ESPGHAN criteria and the activity of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) by standard laboratory methods. Results IHTS was found in 39 (47.56%) patients, 27 of whom (69.23%) had elevated levels of both transaminases and 12 of only one – eight of AST and four of ALT. The increase in relation to the aforementioned reference value for ALT was 1.1–10.08 (1.67 ± 1.73), and for AST it was 1.08–7.91 (1.56 ± 1.29) times. In patients with IHTS compared to those with normal transaminasemia, the age of onset of CD was significantly lower (9.83 ± 3.69 vs. 12.95 ± 4.43 months, p = 0.001), as well as the age of diagnosis (12.97 ± 3.88 vs. 15.47 ± 4.56 months; p = 0.01), while the differences in the other observed parameters were not significant. Conclusions IHTS occurs in almost half of children up to two years old with classical CD. Hypertransaminasemia is in most cases mild and significantly more frequent in patients with earlier clinical expression of the CD.

Introduction/Objective. The classic type of celiac disease (CD) is most common in children under two years of age. The aim of this study was to investigate whether breastfeeding, particularly breastfeeding during gluten introduction, and timing of gluten introduction, influence the onset of CD at this age. Methods. We retrospectively analyzed medical records of 93 children, 40 in the first and 53 in the second year, with a classic CD diagnosed at the University Children’s Hospital, Belgrade between 2000 and 2010. The diagnosis of CD was based on the criteria of the European Society for Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) from 1989. Results. Duration of breastfeeding reduced the onset of the CD in the first year p = 0.039 (OR = 1.43 95% CI 1.019–1.899). Also, breastfeeding at the time of gluten introduction significantly delayed the age at diagnosis (F = 1.671, t = 2.39, p = 0.029). The timing of gluten introduction did not affect the age of occurrence of CD in these group of children. Conclusion. Longer breastfeeding, and breastfeeding at the time of gluten introduction, postponed the onset of classic CD in patients up to two years. The association between the occurrence of CD and the time of introduction of gluten in this age group of patients has not been established.

Introduction/Objective. Anemia is the most common extraintestinal manifestation of celiac disease (CD) in children. The aim of this study was to determine the frequency, severity and type of anemia in children with a classical CD, as well as the differences between anemic and non-anemic patients in their age, duration of illness, percentile body length or height, percentage of body weight (BW) deviation compared to ideal, and the degree of damage to the small intestine mucosa. Methods. The study was based on a sample of 90 children, 56 females and 34 males, ages 7–90 (18.23 Ѓ} 12.7) months with classical CD. The diagnosis of CD is based on the ESPGHAN criteria from 1990 and 2012, and of anemia on the 2011 WHO reference values. Results. Anemia was found in 47 (52.22%) patients, of which it was mild in 23 cases [hemoglobin (Hb) 100–109 g/L] and moderately severe in 24 (Hb 70–99 g/L), in 34 (72.34%) it was microcytic [mean cell volume (MCV) < 70 fl] and normocytic (MCV 70–87 fl) in 13 patients. Low serum iron levels (< 10.7 μmol/L) were found in 68 (75.56%), and hypoferritinemia (< 16 ng/ml) in 77 (85.56%) patients. Except for a greater deficit of BW in patients with anemia compared to those without anemia (-14.64 ± 9.60 vs. -8.56 ± 11.87%, p < 0.01), differences in other defined features were not significant. Conclusion. Mild or moderate iron deficiency anemia occurs in slightly more than half of children with a classical type CD. In anemic compared to non-anemic patients, there is a significantly higher BW deficit, while differences in other characteristics typical for this type of disease are not significant.

Vitamin D, i.e. 1,25(OH) 2D, is an essential factor, not only of homeostasis of calcium and phosphorus, but also of cell proliferation, differentiation and apoptosis, immune and hormonal regulation, as well as other body processes. Thus, its optimal presence in the body is of exceptional significance for health, both of children, as well as adults and elderly persons. Today, it is known that the lack of vitamin D, besides having negative effects on the skeleton and teeth, also contributes to the development of various malignancies, primarily of the large bowel, prostate and breasts, as well as of autoimmune and allergic diseases, diabetes mellitus type II, arterial hypertension and others. Considered from the biological aspect, physiological requirements in vitamin D are achieved by cutaneous synthesis from 7-dehydrocholesterol during sun exposure, while, except rarely, it is very scarce in food. Having in mind extensive evidence that sun exposure presents a high risk for the development of skin malignancies, primarily melanoma, it is clear that humans are deprived of the natural and basic source of vitamin D. In accordance, as well as based on numerous epidemiological studies showing the increase of diseases, in the basis of which vitamin D deficiency plays the important role, next led to the recommended dietary allowance of vitamin D, regardless of age. According to current attitudes, it is recommended that the daily dietary allowances of vitamin D. i.e. the quantity of oral intake that would safely cover the optimal body requirements should be 400 IU for ages 0-18 years, 600 IU for ages 19-70 years and 800 IU for persons aged over 70 years.

Introduction. Gluten-free diet (GFD) presents the basis of coeliac disease (CD) treatment. If strictly applied, the disorders of the small bowel mucosa and other disease signs rapidly resolve. Objective. The goal of the study was to evaluate the effect of GFD on the growth and nutritional status of children with the classical form of CD. In addition, we analyzed the differences between these parameters with the duration and the patients' compliance with GFD. Methods. The study goals were achieved on a sample of 90 children, 56 female and 34 male, aged 0.5-7.5 (1.53±1.05) years, with the classic CD diagnosed on the basis of typical pathohistological findings of the small bowel mucosa and clinical recovery of patients on GFD. The duration of the patients' follow-up was 1.08-8.75 (3.03±1.14) years, i.e. until the age of 2.5-15 (4.59±1.78) years. The initial and control values of body height (BH) in relation to matched values for age and gender were expressed in percentiles, while the deviation in body weight (BW) for the matched values of height and gender was expressed in percentages. The referent haemoglobin (Hb) rate in blood, as a laboratory indicator of nutritional status in children aged up to 5 years was ≥110 g/L, and for those aged above 5 years it was ≥115 g/L. Compliance with GFD was based on the pathohistological findings of the small bowel mucosa or determination of tissue transglutaminase. Results. Over the studied period, the effect of GFD was highly significant, both on the increase of BH percentiles (37.62±26.26 vs. 57.22±25.29; p

Introduction. Secondary lactose intolerance (SLI) belongs to the rarer manifestations of gluten-sensitive enteropathy (GSE). It occurs in more severe forms of the disease and its presence contributes significantly to the degree of its expression. Objective. The goal of the study was to determine the frequency of SLI in infants with clinically classic form of GSE, as well as its relationship with the duration, severity and age at the diagnosis of the basic disease and the degree of small bowel mucosa damage. Methods. The study was based on a sample of 42 infants, 30 female and 12 male, aged 7-12 months (x=9.98±1.69), with a clinically classic form of GSE. The diagnosis of GSE was established based on the characteristic pathohistological appearance of small bowel mucosa and clinical improvement of patients on gluten-free diet, while SLI on pathological lactose or milk tolerance test. The assessment of basic disease severity was based on body mass divergence in relation to the standard value, as well as on Hb and serum iron levels, while the degree of small bowel mucosa damage was determined according to the modified Marsh criteria. Results. SLI was verified in 8/42 or 19.05% of patients. In addition to the symptoms and clinical signs of GSE, all the patients with SLI also featured the problems characteristic of lactose tolerance disorders, i.e. watery diarrhoea, borborygmus and meteorism occurring after milk meals. In addition, all had perianal erythema (6 with erosive changes), as well as destructive enteropathy (5 subtotal and 3 total). The difference in the duration of the basic disease, age at diagnosis, as well as in the degree of body mass deviation from the standard value between the lactose-tolerant and lactose-intolerant infants was not found. In addition, no difference in Hb and serum iron levels or in the degree of small bowel mucosa damage was found between the two groups. Conclusion. Our findings indicate that SLI presents a relatively frequent occurrence in infants with clinically classic GSE, as well as that it occurs independently to the duration, severity and age at diagnosis of the basic disease and the degree of small bowel mucosa damage.

Introduction: Gilbert’s syndrome represents the most frequent hereditary disorder of bilirubin metabolism. It occurs in 2-7% of subjects in general population, and is manifested by mild unconjugated hyperbilirubinaemia of benign nature. Objective. The study was conducted in order to analyse our experience related to the circumstances of disclosure, age at onset and sex distribution of Gilbert’s syndrome in children. Method. The diagnosis of Gilbert’s syndrome was based on the findings of mild unconjugated hyperbilirubinaemia in the absence of haemolysis and organic liver disease, as well as significant increase of bilirubin unconjugated fraction in serum after a 3-day hypocaloric diet (400 kcal/daily). Results. Of 58 subjects with Gilbert’s syndrome, there were 40 (68.97%) boys and 18 (31.03%) girls, indicating a 2.22 fold higher incidence of boys than girls. The age at diagnosis of the disorder was similar in boys and girls, and was 12.2-18 (X=14.71±1.55) years for boys and 10.5-16.4 (X=14.38±2.10) years for girls (p>0.05). Except for 3 girls aged below 12 years, in all other patients the diagnosis was made after that age; in 20, between age 12 and 14 years and in 14, between age 14 and 16 years, while in 10 patents, it was made at age between 16 and 18 years. In 20 (34.48%) subjects, hyperbilirubinaemia was disclosed on routine paediatric examination, in 19 (32.76%) when differentiating the cause of recurrent or acute abdominal pain, in 17 (29.3%) during febrile condition and in 2 during insufficient caloric intake. The values of unconjugated bilirubinaemia, both before a hypocaloric test and after a 3-day energy deprivation, were higher in boys than girls, but this difference was statistically significant only after the 3-day hypocaloric diet in age group between 16 and 18 years (p=0.038). Also, no significant difference was found in bilirubinaemia level between the different age groups either in boys or girls. Conclusion. According to our findings, in children, Gilbert’s syndrome is manifested only in puberty, and 2.22 times more often in boys than girls. It is most frequently revealed during a routine pediatric examination, as well as when investigating the cause of abdominal pain and fever. A significantly higher level of serum bilirubin in boys as related to girls is registered only after a hypocaloric diet in age group between 16 and 18 years. .

Introduction. Human milk proteins are maximally adapted to physiological needs of a neonate. Thus, depending on the speed of the neonatal growth and development, the content of milk proteins changes, both in quantity and quality. Objective. The study was conducted in order to determine variations of total protein concentrations in milk in the first and third lactation week in lactating mothers of term and preterm neonates. Also, we analyzed the influence of the mode of delivery, neonatal Apgar score and parity on the concentration of human milk proteins in both lactation phases. Method. The study aims were evaluated on the sample of 48 women, of whom 33 were mothers of term neonates and 15 of neonates born between the 34th to 37th gestational weeks. Total protein level of the lactation milk from the middle phase was determined using the standard laboratory method (Lowry et al., 1951), and the obtained differences were analyzed by t-test. Results. Total protein concentration in term colostrum was 17.60-45.17 g/l (X=24.71±5.19), while in preterm colostrum it was 28.39-73.30 g/l (X=39.17±11.08). The total protein level of mature milk in women who had term delivery was 11.90-22.11 g/l (X=16.39±2.96), while in women who had preterm delivery it was 14.50-44.19 g/l (X=23.25±8.96). The obtained results indicated that total protein concentration in women who had preterm delivery was significantly higher than that of women who had term delivery, both in the colostral and mature phase of lactation. (p

Introduction Breast milk jaundice occurs in 1-2% of healthy breast-fed newborns and young infants. It develops as the result of liver immaturity and the inhibitory effect of mother’s milk to the clearance of unconjugated bilirubin. Objective The paper analyzes variations in the level and length of unconjugated hyperbilirubinemia in breast-fed infants. Method The study was conducted on a sample of 29 young infants (19 male) with breast milk jaundice. All infants were born on time, by natural delivery and without complications. All were on breast-feeding only and developed optimally. None of the infants had either haemolysis or any other disease associated with unconjugated hyperbilirubinemia. Results All infants had physiological jaundice in the first week after birth, with unconjugated bilirubin level of 166-260 μmol (201.50±36.37 μmol). In the postneonatal period the highest bilirubin level was recorded in the fifth week of life and was 87-273 μmol (166.82±45.06 μmol), which then spontaneously, without interruption of breast-feeding, gradually declined. The decrease of the unconjugated fraction of serum bilirubin between the fourth and fifth week was significant, and after that highly significant. The normalization of serum bilirubin occurred in the seventh and thirteenth week (10.41±1.68 μmol). Negative consequences of hyperbilirubinemia were not noted in any of the infants. Conclusion Breast milk jaundice presents a harmless and transitory disorder of bilirubin metabolism. It occurs in healthy breast-fed neonates and young infants. Jaundice is most marked in early neonatal period, and then it gradually declines and disappears between the seventh and thirteenth week.

Introduction. The disorder of cow milk protein intolerance is characterized by a wide spectrum of clinical manifestations caused by hypersensitivity of type I, II, or IV, and occurs in 2-3% of children, mostly infants. Objective. The aim of this study was to present our experiences and observations of clinical signs and symptoms of cow milk protein intolerance in infants aged below 12 months. Method. The investigation was carried out on a sample of 55 infants, aged between 1.5-9 months (x=4.2l±1.25), who had cow milk protein intolerance. Diagnosis of illness was based on characteristic anamnestic, clinical, and laboratory parameters, as well as on an adequate patient's response to antigen elimination. Results. The clinical presentation of cow milk protein intolerance was dominated by cutaneous problems, found in 40/55 (72.73%) infants, followed by digestive disorders, found in 31 (56.36%), while respiratory tract disorders were observed least frequently (14.55%). None of the patients developed anaphylactic shock. Changes involving only one system were found in 35 (63.64%) patients; of these 20 (36.36%) were cutaneous and 15 (27.27%) digestive. Twenty (36.36%) infants displayed multisystemic changes; of these 12 were cutaneus with digestive, 4 were cutaneus with respiratory, while 4 infants had cutaneous, digestive, and respiratory disorders. Of the 55 infants with cow milk protein intolerance, 26 (47.27%) had urticaria, 22 (40.00%) perioral erythema, 21 (38.18%) diarrhoea (15 haemorrhagic, 6 non-haemorrhagic), 13 (23.64%) vomiting, 12 (21.82%) Quincke's oedema, 12 (21.82%) eczema, 5 (9.09%) obstructive bronchitis, while 3 (5.45%) infants had laryngitis. In 5 (9.09%) patients we found a significant body weight deficit and in 3 (5.45%), sideropenic anaemia, while longitudinal growth retardation was not registered in any of the patients. Conclusion. Our study showed that the disorder of cow milk protein intolerance predominantly involved cutaneous disorders as well as combinations of cutaneous and digestive disorders, while respiratory system disorders proved to be relatively rare.