Eficiența și siguranța terapiei enzimatice în managementul malnutriției la copii

Introduction

Pediatric malnutrition represents a major public health issue, characterized by a complex and multifactorial etiology, with significant impact on growth, neurocognitive development, and long-term prognosis. According to the estimates of the World Health Organization (WHO), approximately 149 million children under the age of 5 years old present stunting, and over 45 million suffer from acute malnutrition, which contributes to almost 45% of global child mortality^(1,2).

In Europe, although the severe forms are relatively rare, malnutrition associated with chronic diseases, especially digestive ones, remains a relevant problem, being reported in approximately 5-10% of hospitalized children^(3,4).

From a pathophysiological point of view, malnutrition in children frequently results from the interaction between insufficient food intake, increased metabolic requirements and the disturbance of digestion and absorption of nutrients^(3,5). In this context, maldigestion and malabsorption syndromes occupy a central role, being involved in numerous gastrointestinal conditions, including enteropathies, hepatobiliary diseases, and exocrine pancreatic insufficiency^(5,6).

The impairment of intraluminal digestion is not determined exclusively by the quantitative deficiency of digestive enzymes, but also involves complex functional mechanisms, such as the inactivation of enzymes in an acidic environment, their dilution in the intestinal lumen, accelerated intestinal transit, or the disturbance of mixing with the food chyme⁽⁵⁾. In pediatric practice, secondary exocrine pancreatic insufficiency is more frequent than the primary form, being associated with various chronic digestive pathologies, which explains the increased prevalence of maldigestion in this category of patients^(6,7).

The functional interdependence of the segments of the digestive tract represents another essential element. Disorders of gastric secretion and motility can influence pancreatic and intestinal function, contributing to the appearance of dyspeptic symptoms and nutritional imbalances. Studies show that symptoms of functional dyspepsia can affect up to 20-50% of children, being frequently associated with functional gastrointestinal disorders⁽⁸⁾.

In this context, digestive enzyme therapy (PERT) represents an essential therapeutic strategy, with both substitutive and adjuvant roles. ESPGHAN and NASPGHAN guidelines recommend the use of enzyme replacement therapy in exocrine pancreatic insufficiency, especially in cystic fibrosis, but also in other conditions associated with maldigestion^(6,7). Modern preparations contain combinations of lipase, amylase and proteases, their activity being expressed in lipase units, considered the main determinant of clinical efficacy⁽⁶⁾.

Recent data suggest that certain enzyme preparations, especially those of plant origin (papain) and fungal origin (derived from Aspergillus oryzae), present increased stability to pH variations and an extended enzymatic spectrum, contributing to the degradation of proteins, lipids and carbohydrates, which makes them useful in the context of the multifactorial etiology of maldigestion⁽⁹⁾.

A major advantage of enzyme therapy consists of the favorable safety profile, most preparations not being systemically absorbed, which determines a reduced incidence of adverse reactions. Modern pharmaceutical forms, such as gastroresistant microgranules, allow the optimal release of enzymes at the intestinal level and increased clinical efficacy^(6,7).

However, important clinical challenges persist, including the lack of complete standardization of indications, dosage and duration of therapy, especially in cases without confirmed pancreatic insufficiency. International guidelines underline the necessity of an individualized approach, based on the clinical and paraclinical evaluation of digestive function^(6,7).

Digestive enzyme therapy represents an important pillar in the management of pediatric malnutrition associated with digestive disorders, and its integration into a complex therapeutic strategy can contribute significantly to the improvement of nutritional status and prognosis of pediatric patients.

Aim of the study

The present study aims to evaluate the efficacy and safety of pancreatic enzyme replacement therapy (PERT) in the management of malnutrition in children, by analyzing its impact on weight gain and exocrine pancreatic function in patients with moderate and severe malnutrition, according to the criteria of the World Health Organization, in the absence of an associated chronic pathology.

Materials and method

The study was designed as a prospective, randomized, controlled study, conducted within the Department of Gastroenterology and Hepatology of the IMSP Mother and Child Institute, Chişinău, Republic of Moldova, during the period 2023-2025. The study design was developed in accordance with the CONSORT recommendations for randomized clinical trials⁽¹⁰⁾.

The study included a total of 64 children, aged between 1 and 10 years old, diagnosed with moderate and severe malnutrition according to the criteria of the World Health Organization^(1,11). The inclusion criteria were: the presence of malnutrition, the absence of severe acute pathologies at the time of evaluation, and obtaining informed consent signed by the parents or legal representatives. Patients with associated severe chronic diseases (cardiac, renal, neurological), oncological pathologies, genetic diseases with major impact on nutritional status, as well as patients with low compliance with the monitoring protocol were excluded.

Moderate malnutrition was defined by Z-score values between -2 and -3 standard deviations for weight-for-age and/or Body Mass Index-for-age and severe malnutrition by Z-score < -3 standard deviations for the same anthropometric parameters, according to WHO standards⁽¹¹⁾. The evaluation of nutritional status was performed using standardized anthropometric indicators (weight, height and Body Mass Index reported to age and sex), in accordance with the ESPGHAN recommendations regarding nutritional assessment in children⁽⁶⁾.

The patients were randomly assigned into two groups: the PERT group (n=32), which received pancreatic enzyme replacement therapy in association with hypercaloric enteral supplements, and the control group (n=32), which received exclusively hypercaloric enteral supplements (Table 1). Randomization was performed through standard random allocation methods to reduce selection bias⁽¹⁰⁾.

Enzyme therapy consisted of the administration of a pancreatin preparation (Sanzyme®), used as pancreatic enzyme replacement therapy. The doses were individualized according to body weight and the severity of the nutritional deficit, being expressed in lipase units/kg/meal, according to the recommendations of the ESPGHAN and NASPGHAN guidelines for enzyme therapy^(6,7). Administration was performed concomitantly with the main meals, and dose adjustment was carried out according to clinical evolution and anthropometric parameters during the intervention period.

Sanzyme® represents a polyvalent digestive enzyme preparation of microbial origin (fungal and/or bacterial), used in the management of functional or secondary (transient) digestive disorders. From a pharmacodyna­mic point of view, this enzymatic complex is characterized by stability and catalytic activity across a broad pH spectrum, including the acidic gastric environment, which allows the early initiation of macronutrient hydrolysis processes at the gastric level, with their continuation in the small intestine.

Compared with pancreatic enzyme replacement preparations (e.g., pancreatin of porcine origin), whose activity depends on enteric release and an adequate intestinal pH, Sanzyme® exerts an enzymatic action less dependent on duodenal pH conditions, providing a theoretical advantage in the context of functional dyspepsia or mild maldigestion, in which there is no severe pancreatic enzyme deficiency, but rather a functional inadequacy of digestive processes. It contains a complex of digestive enzymes of microbial origin, papain, pepsin, amylase, protease and lipase, sometimes associated with cellulase and lactase, which act synergistically in the digestion of macronutrients; amylase hydrolyzes starch into oligosaccharides, reducing fermentation and meteorism, protease degrades proteins into peptides and amino acids, facilitating protein digestion, while lipase cleaves triglycerides into fatty acids and monoglycerides, optimizing lipid digestion; cellulase contributes to the degradation of plant fibers, reducing gas production, and lactase allows the hydrolysis of lactose in the context of secondary enzyme deficiency; through its luminal activity over a broad pH range, the preparation improves digestive processes and reduces dyspeptic symptoms.

Sanzyme® is available in several pharmaceutical forms adapted for pediatric use, mainly including oral syrup and capsules, which allows an easy administration and flexible dosing according to age and clinical needs, while in certain regions, solid forms, such as chewable tablets, may also be available. The administration is carried out according to the patient’s age, with dilution of the preparation in boiled water, administered during meals or immediately postprandially, 2-3 times per day, as described below.

Infants (3 months – 1 year old): 0.5 g (½ small teaspoon) dissolved in 15 ml of water.

Children (1-3 years old): 1.25 g (½ large spoon) dissolved in 50 ml of water.

Children (3-7 years old): 2.5 g (one large spoon) dissolved in 50 ml of water.

Children ≥7 years old and adults: 5 g (two large spoons) dissolved in 100 ml of water or one capsule three times per day.

Duration of administration: approximately 14 days or according to medical indication.

Contraindications to the administration of the preparation include hypersensitivity to any of the components of the preparation and acute pancreatic pathology, especially acute pancreatitis or exacerbations of chronic pancreatitis; its use requires caution in the context of severe acute diarrhea, where it does not replace etiological and rehydration therapy, as well as in infants, where careful monitoring of digestive tolerance is required.

The therapeutic intervention was administered over eight weeks.

Patient evaluation included anthropometric parameters (weight, height, Body Mass Index and weight Z-score) and fecal elastase-1 (FE-1) level, used as a marker of exocrine pancreatic function. All parameters were determined at baseline and after eight weeks of intervention. The baseline characteristics of the study population, including distribution by age, sex, degree of malnutrition and anthropometric and biochemical parameters, are presented in Table 2, highlighting the comparability of the groups at the time of inclusion.

The statistical analysis was performed using descriptive and comparative methods. Continuous variables were expressed as mean ± standard deviation. Group comparison was performed using statistical tests appropriate to the data distribution (Student’s t-test or nonparametric tests), and the threshold for statistical significance was set at p<0.05⁽¹²⁾. The study was conducted in accordance with the ethical principles of the Declaration of Helsinki regarding biomedical research on human subjects, with informed consent obtained from the parents or legal guardians before the inclusion of patients in the study⁽¹³⁾.

Results and discussion

The study analyzed 64 children, aged between 1 and 10 years old, diagnosed with moderate and severe malnutrition according to WHO criteria, randomly assigned into two equal groups: the PERT group (n=32) and the control group (n=32).

The analysis of the results aimed at the comparative evaluation of the efficacy of pancreatic enzyme replacement therapy associated with hypercaloric nutritional support, in relation to nutritional support alone. The evaluated parameters included standardized anthropometric indicators (weight, height, Body Mass Index and weight-for-age Z-score), determined in accordance with the World Health Organization standards for the evaluation of pediatric nutritional status⁽¹¹⁾. Exocrine pancreatic function was evaluated by determining the level of fecal elastase-1, a noninvasive method validated for the diagnosis of exocrine pancreatic insufficiency^(6,14).

The interpretation of the results was performed according to internationally recognized thresholds, values below 100 µg/g indicating severe pancreatic insuffi­ciency, while values between 100 and 200 µg/g suggesting moderate pancreatic insufficiency^(6,14).

The determinations were performed at the initial moment (baseline) and after eight weeks of intervention, for the evaluation of the dynamics of nutritional status and pancreatic function under treatment.

The results are presented comparatively between groups, highlighting the dynamic changes and intergroup differences at the end of the study period.

The baseline characteristics of the patients included in the study are presented in Table 2. These highlight a comparable distribution between the PERT group and the control group, without clinically significant diffe­rences between the evaluated variables.

The distribution of malnutrition in the analyzed group confirms current epidemiological data, highlighting a clear age dependence, with predominance of cases in the first years of life. Thus, most patients included in the study were in the age group 1-2 years old (n=38), corresponding to the critical period of nutri­tional transition, followed by the age group 3-4 years old (n=15). A smaller number of cases was recorded in children aged 5-7 years old (n=7) and 8-10 years old (n=4) – Figure 1.

This distribution supports the concept that the 6-24-month interval represents a critical period for the development of malnutrition, in the context of nutritional transition determined by dietary diversification, increased susceptibility to infections and frequently inadequate nutritional intake^(2,15). This stage coincides with the period of introduction of complementary foods, in which nutritional errors and hygiene conditions can significantly influence the nutritional status of the child⁽¹⁵⁾.

The progressive decrease in the prevalence of malnutrition with advancing age can be explained by the functional maturation of the digestive tract, the adaptation of enzymatic and immunological mechanisms, as well as by the diversification and stabilization of food intake^(5,16). Also, repeated exposure to food factors and the development of digestive tolerance contribute to improving the efficiency of digestion and absorption processes⁽⁵⁾.

The gender distribution was balanced, with a slight predominance of the male sex in the PERT group (53.1%), and an equal distribution in the control group (50% male and 50% female).

Regarding the severity of malnutrition, most patients in both groups presented moderate malnutrition (62.5% in the PERT group and 65.6% in the control group), while severe malnutrition was identified in 37.5% and, respectively, 34.4% of patients, without significant discrepancies between groups.

The initial anthropometric parameters were comparable between groups. The mean weight was 10.8 ± 3.4 kg in the PERT group and 10.6 ± 3.2 kg in the control group, and the mean height was 83.5 ± 11.2 cm and 82.9 ± 10.8 cm, respectively. Also, the Body Mass Index presented almost identical values between groups (15.2 ± 1.8 versus 15.1 ± 1.7 kg/m²).

The weight Z-score was comparable, indicating a similar degree of nutritional impairment at baseline (-2.4 ± 0.6 in the PERT group and -2.3 ± 0.5 in the control group).

The level of fecal elastase-1 (FE-1), used as a marker of exocrine pancreatic function, was also similar in both groups (185 ± 72 µg/g in the PERT group and 190 ± 75 µg/g in the control group), suggesting a homogeneous distribution of pancreatic functional status at inclusion.

Pancreatic enzyme replacement therapy (PERT) was administered in accordance with the ESPGHAN recommendations and current international guidelines for the management of exocrine pancreatic insufficiency in children^(6,7).

The recommended initial dose was 500-1000 IU lipase/kg/meal, individually adjusted according to the severity of clinical symptoms and therapeutic response. In children who had intermediate meals (snacks), a dose equivalent to approximately 50% of the dose administered at main meals was used, respectively 250-500 IU lipase/kg^(6,7).

The maximum admitted dose did not exceed 2500 IU lipase/kg/meal, respectively 10,000 IU lipase/kg/day, in accordance with safety recommendations, for the prevention of complications associated with overdose, including fibrosing colonopathy^(6,7,17).

After eight weeks of intervention, the PERT group presented a significant improvement in anthropometric parameters and fecal elastase-1 level compared with the control group (Table 3). Intergroup differences were statistically significant for weight, Body Mass Index, Z-score and FE-1 level (p<0.05), while height did not present significant differences.

These results are in accordance with data from the specialized literature, which highlight the efficacy of enzyme therapy in improving nutrient absorption, weight gain, and normalization of pancreatic function markers in children with exocrine pancreatic insufficiency^(6,7,9).

Body weight increased significantly in the PERT group from 10.8 ± 3.4 kg to 12.6 ± 3.5 kg compared with the control group, where the increase was more modest (from 10.6 ± 3.2 kg to 11.2 ± 3.3 kg) – Table 3. Intergroup differences at the end of the study period were statistically significant (p<0.05).

The Body Mass Index followed the same trend, with a more pronounced increase in the PERT group (15.2 ± 1.8 to 16.4 ± 1.9 kg/m²), compared with the control group (15.1 ± 1.7 to 15.6 ± 1.8 kg/m²), the differences being statistically significant (p<0.05).

The weight Z-score showed a significant improvement in the PERT group, from -2.4 ± 0.6 to -1.6 ± 0.5, while in the control group, the change was more reduced (-2.3 ± 0.5 to -2.0 ± 0.5), the intergroup differences being statistically significant (p<0.05).

The evolution of body weight revealed a more pronounced increase in the PERT group compared with the control group.

The analysis of FE-1 dynamics showed favorable changes in the PERT group, where values increased from 185 ± 72 µg/g to 265 ± 80 µg/g, compared with the control group, where the change was minimal (190 ± 75 µg/g to 205 ± 78 µg/g). The differences at the end of the intervention were statistically significant (p<0.05).

Intergroup comparison at eight weeks highlighted the superiority of the PERT group in terms of improvement of anthropometric and functional parameters. Weight gain, improvement of BMI, and reduction of the degree of malnutrition (through Z-score) were significantly more pronounced in the group that received pancreatic enzyme replacement therapy.

Also, FE-1 changes were significantly more favorable in the PERT group, suggesting a positive impact of the therapy on digestive status and intestinal absorption.

The results of this study demonstrate that the administration of pancreatin-based pancreatic enzyme replacement therapy (Sanzyme®), in association with standard nutritional support, is associated with a significant improvement of nutritional status in children with moderate and severe malnutrition. The more pronounced weight gain, improvement of Body Mass Index and the favorable evolution of the weight Z-score in the interventional group suggest a superior therapeutic effect compared with isolated nutritional management.

The observed effect can be explained by the physiological role of pancreatic enzyme therapy, which ensures supplementation of essential digestive enzymes (lipase, amylase, protease), thus contributing to more efficient digestion of macronutrients and to increased energetic bioavailability^(6,7,9). In this context, optimization of lipid and protein absorption has a direct impact on the energy balance and on the processes of weight recovery in the malnourished child⁽⁵⁾.

A relevant element of the study is the early clinical response, observed within eight weeks of treatment. This evolution suggests that enzymatic dysfunction, including subclinical forms of exocrine pancreatic insufficiency, can contribute to the maintenance of malnutrition and that early therapeutic intervention can determine significant benefits within a relatively short interval^(6,9).

The obtained results are in accordance with the specialized literature, which highlights the efficacy of PERT in improving malabsorption and nutritional status, especially in patients with confirmed exocrine pancreatic insufficiency, such as those with cystic fibrosis or chronic pancreatitis^(6,7). However, the use of enzyme therapy in children without a documented primary pancreatic pathology remains insufficiently studied, and current data are limited. In this context, the results of the present study support the hypothesis of the involvement of functional digestive dysfunction in the pathogenesis of pediatric malnutrition and extend the potential indications of PERT.

The use of a standardized pancreatin preparation (Sanzyme®) allowed controlled and reproducible administration of enzyme therapy, facilitating the objective evaluation of the therapeutic response. Individualization of the dose according to body weight and its adaptation according to clinical evolution are in accordance with the recommendations of international guidelines and represent determining factors for the efficacy of therapy^(6,7).

Although the observed results support the beneficial role of enzyme therapy in nutritional rehabilitation, their interpretation should be made with caution. Malnutrition is frequently associated with multiple nutritional deficiencies, including iron deficiency anemia, vitamin D deficiency, rickets and other micronutrient deficiencies, which may independently influence growth, weight gain, and recovery of nutritional status. These associated deficiencies may act as potential confounding factors and could partially contribute to the variability of therapeutic response observed among patients.

The limitations of the study include the relatively small sample size and the limited duration of follow-up, which do not allow evaluation of the long-term effects on child growth and development. Also, children with malnutrition frequently associated nutritional deficiencies, including iron deficiency anemia, vitamin D deficiency, rickets and other micronutrient deficiencies, which may independently influence growth and nutritional recovery. The study did not stratify patients according to these deficiencies or evaluate their correction during follow-up, therefore their potential confounding effect on the observed therapeutic response cannot be completely excluded. Furthermore, the absence of comprehensive biomarkers of intestinal absorption limited a detailed mechanistic assessment of the therapeutic effect.

Nevertheless, the strengths of the study consist of the comparative design, the use of standardized anthropometric parameters, and the application of a uniform therapeutic protocol.

Conclusions

Pediatric malnutrition is a multifactorial condition in which, in addition to insufficient nutritional intake, functional disorders of digestion and absorption may be involved, with a direct impact on stature-weight growth. In this study, the administration of pancreatic enzyme replacement therapy with a standardized pancreatin preparation (Sanzyme®), as an adjunct to nutritional rehabilitation, was associated with the improvement of anthropometric parameters in children with moderate and severe malnutrition. Compared with isolated nutritional support, the group that received PERT registered a more significant increase in body weight, Body Mass Index and weight-for-age Z-score during the eight-week intervention, suggesting that subclinical digestive inefficiency may contribute to the persistence of malnutrition and that its correction may accelerate the short-term nutritional recovery. The use of a standardized pancreatin preparation allowed a reproducible therapeutic intervention and individualized dose adjustment, supporting the feasibility of enzyme therapy as an adjunct in the management of pediatric malnutrition.

However, considering the exploratory character of the study, the small sample size and the limited duration of follow-up, further randomized studies with larger groups and long-term evaluation are necessary to confirm the efficacy and to clearly define the role of this intervention in pediatric malnutrition without documented exocrine pancreatic insufficiency.

Autor corespondent:   Ina Pogonea E-mail: ina.pogonea@usmf.md

CONFLICT OF INTEREST: none declared.

FINANCIAL SUPPORT: none declared.

This work is permanently accessible online free of charge and published under the CC-BY.