B Complex Vitamins Profile in Patients with Hepatic Glycogen Storage Disease and its Possible DeterminantsAbstract
Hepatic glycogen storage diseases (GSD) are a group of rare hereditary metabolic diseases characterized by abnormalities in enzymes that regulate glycogen synthesis or degradation. Treatment is essentially dietary, with frequent administration of raw uncooked cornstarch (UCCS) to avoid hypoglycemia, in addition to the restriction of sucrose, fructose, and lactose. Nutritional deficiencies in these patients are believed to result from dietary restrictions that exclude key sources of essential vitamins. This study aimed to investigate serum levels and adequacy of dietary intake of B vitamins in patients with GSD. This is a cross-sectional study, with patients over 5 years old, diagnosed with GSD and undergoing treatment with UCCS. Clinical data were collected, in addition to the dosage of B vitamins and a 3-day food record. Fifteen patients were included, six of them reported daily use of multivitamins. Serum dosage showed that all B complex vitamins, except for vitamin B2, were within reference values. The adequacy of dietary intake of vitamins was at least 78%, except for vitamin B9. There was no correlation between dosage and vitamin intake.
Keywords:
Inborn errors of metabolism; glycogen storage disease; complex B vitamins; dietary intake; supplementation; serum levels
Introduction
Glycogen storage diseases (GSD) are a group of genetic diseases that result in changes in glycogen metabolism, which can affect its synthesis (glycogenesis) or degradation (glycogenolysis) and are usually classified as hepatic and/or muscular GSD [1,2]. The global incidence is estimated at 1 case for every 20,000-43,000 live births, with types I, III, and IX representing around 80% of diagnoses [3].
The primary manifestations of hepatic GSD subtypes 0, I, III, VI, IX, and XI are fasting intolerance associated with hypoglycemia and hepatomegaly. Furthermore, patients with GSD types III and IX present, in most cases, myopathic symptoms and progressive form of cardiomyopathy [4,5] GSD I is caused by deficient glucose-6-phosphatase activity [6]; GSD III results from a deficiency of the glycogen debranching enzyme and GSD IX is caused by phosphorylase kinase deficiency [7]. Table 1 shows the classification of hepatic GSD, as well as the affected gene and inheritance pattern.
Treatment for GSD is basically nutritional, with recommendations for restricting simple carbohydrates and frequent and individualized use of uncooked cornstarch (UCCS) in order to maintain normoglycemia and avoid glycogen accumulation [9,10]. In GSD I, restriction of sucrose, fructose, and lactose is widely used. Unlike the diet used to treat patients with GSD I, the diet used to treat GSD III and IX is high-protein and the intake of fructose and galactose is allowed [6,11,12].
B complex vitamins participate in the production of energy and biosynthesis of vital molecules for cells. As these vitamins are classified as water-soluble, they are not stored in the body, so intake must be daily [13].
The dietary restrictions imposed by the treatment, as well as the large consumption of UCCS, can lead to nutritional deficiencies in these patients. Due to their wide distribution in foods, deficiency of most of these vitamins is uncommon. Little is known regarding the profile of B complex vitamins presented by these patients, however case reports indicate that individuals with this group of diseases may be associated with vitamin deficiencies, especially in complex B [14,15]. In the study by Hinkel et al. [16], however, it was observed that patients with GSD had increased serum vitamin B12 values when compared to healthy patients.
This study aims to evaluate the levels of B vitamins presented by patients with hepatic GSD and their association with clinical and treatment variables.
Methods
A cross-sectional study was carried out with the following inclusion criteria: patients over 5 years old due to the difficulty in performing blood collection in children younger than that age; confirmed diagnosis of GSD (type Ia, Ib, III, IXa, IXb, and IXc) by enzymatic assay or genotyping. Additionally, participants were required to have undergone treatment with UCCS for a minimum of one year while under the clinical supervision of the Medical Genetics Service at Hospital de Clínicas do HCPA (SGM-HCPA).
The present study obtained approval from the Ethics and Research Committee of the Hospital de Clínicas de Porto Alegre (Approval Number: 2019-0256; CAAE: 13353419100005327). The sample was selected using convenience sampling, comprising patients or their legal guardians who voluntarily agreed to participate in the research and formalized their consent by signing the Informed Consent Form.
Vitamin Dosage
B complex vitamins, including B1, B2, B3, and B6, were quantified using the High-performance Liquid Chromatography (HPLC) method, while B7 was assessed via Enzyme Linked Immunosorbent Assay (ELISA), B9 through chemiluminescence, and B12 via gas chromatography. Specifically, vitamins B1, B2, B6, and B9 were analyzed in red blood cells and B3 and B7 in serum. These specific vitamins were selected due to their widespread determination capabilities in specialized laboratories and their representation of various food source classes. No fasting time was stipulated prior to blood collection. Subsequently, the samples were sent to a specialized laboratory for analysis, with the reference values established by the laboratory itself.
Collection of Clinical and Treatment Data
Data regarding clinical variables (type of GSD, age, anthropometric data, presence of hypoglycemia, signs, and symptoms related to possible nutritional deficiencies) and nutritional variables (use of alternative feeding route, amount of UCCS) were obtained through review of the medical and food records. The data collected referred to the last twelve months prior to the date of blood collection.
Body mass index (BMI) was calculated as weight (kg) divided by height in meter square (m²) and classified as underweight, normal weight, overweight, or obese, per the World Health Organization (WHO) criteria [17,18]. In patients aged <19 years, nutritional status was calculated using BMI for age Z-scores calculated in WHO Anthroplus version 1.0.4 [19]. It is important to note that BMI may not accurately reflect nutritional status in pediatric patients, particularly those with short stature. To address this limitation, BMI-for-age Z-scores were calculated to better account for age- and height-related variations.
Nutrient Intake
Dietary intake of macronutrients and micronutrients, including consumption of vitamin B1 (thiamine), B2 (riboflavin), B3 (niacin), B6 (pyridoxine), B9 (folic acid), and B12 (cobalamin), was assessed through was assessed using 3-day food records 1 weekend day and 2 working days, these being the same week as the blood collection. Vitamin B7 (biotin) was not calculated because the software used did not measure this vitamin in question.
The calculation of total daily nutrient intake was performed using Nutribase™ software (NB16Cloud, CyberSoft, Inc., Phoenix, AZ, USA). Adequacy of dietary intake was classified according to the Recommended Dietary Allowances (RDA) established by the Dietary References Intakes (DRIs) [20]. When RDA values were not available, Adequate Intake (AI) cutoff points were used. The intake of nutrients from supplements used by patients were also considered.
Statistical Analysis
Categorical variables will be presented as frequencies and percentages and continuous variables as means and/or medians and standard deviation. Continuous variables were compared using the Wilcoxon test, and the association between variables was assessed using Spearman correlation.
Statistical analysis was performed using version 29.0 Statistical Package for Social Sciences (SPSS Inc. Chicago, IL). P value <0.05 was considered statistically significant.
Results
Fifteen patients were included, ten of whom were male, with a mean age of 16.4±7.9 years, diagnosed with the following types of GSD: Ia: 8, Ib: 4, IXa: 1, IXb: 1, IXc: 1. The characterization of the included patients is shown in Table 2.
Seven patients were classified with body mass index (BMI) as eutrophic, four as overweight and four as obese (Figure 1). BMI-for-age Z-scores findings were consistent with those derived from the standard BMI classification.
All patients were being treated with UCCS, in accordance with the recommendations established for the type of GSD (recommendation range: I=1.6 g/kg/dose; IX=0.6 to 2.5 g/kg/dose) [8]. Median UCCS intake was 315 grams per day (g/day) (IQR: 233-396 g/day). Eight patients (Ia: 4; Ib: 3 and IXc: 1) reported at least 1 episode of hypoglycemia due to forgetting the UCCS dose (n=7) or after physical activity (n=1) in the last month. Four patients (Ia: 4 and IXc: 1) had previously used gastrostomy, with 2 (Ia and IXc) patients requiring the alternative route due to reports of food aversion. At the time of data collection, all patients had an exclusive oral route. Episodes of hematochezia (n=1), diarrhea (n=2), vomiting (n=1), itching (n=1) were reported in outpatient consultations. No signs or symptoms have been reported that are related to B vitamin deficiencies.
Ten patients use vitamin supplements daily and regularly (calcium, vitamin A, C, and D), of which 6 use multivitamins that include vitamins from the B complex, which were included in the calculation of dietary intake. Data regarding serum food intake levels are described in Table 3.
One patient (8) had low dietary intake for all vitamins; six (1, 2, 4, 11, 12, 13) had adequate intake of all vitamins, except for vitamin B9 and two patients (5, 6) achieved adequate dietary intake equal to or greater than 80% of recommendations. Patient 3 had low intake of vitamins B1, B6, B9, and B12; patient 7 for vitamins B2, B6 and B9; patient 9 for vitamins B1 and B9; patient 10 for vitamin B6 and finally, patient 15 for vitamins B1, B2, B9, and B12.
Nine patients had low serum levels of vitamin B2 (Ia: 5, Ib: 1, IXa: 1, IXb: 1, IXc 1), six patients did not have low levels of B vitamins (Ia: 3, Ib: 3). Only one patient presented more than one possible vitamin deficiency, with values below the established reference for vitamin B2 and vitamin B12 (IXa). In general, vitamins B1, B7, B9, and B12 were within the reference value and vitamins B3 and B6 were slightly above the upper level.
There was a moderate correlation between UCCS consumption and BMI (rs -0.625; P 0.013) and there was no correlation with age. There was a correlation between the dosage of vitamin B9 and the amount per g/kg/day of UCCS (rs -0.652; P 0.011). Correlation data are presented in Table 4.
Discussion
A diet rich in carbohydrates and with several dietary restrictions, as in the case of patients with hepatic GSD, may be deficient in some B vitamins [13,21]. It is known that vitamin deficiencies manifest after many months of vitamin deprivation [21], however, when reviewing the clinical data and medical history of the study patients, no related signs or symptoms were reported.
The status of vitamin B1, thiamine, can be assessed by determining the activity of erythrocyte transketolase, through blood or serum concentrations of thiamine and also by urinary excretion of thiamine. Whole grains are the most important source of vitamin B1, and it is also found in foods of animal origin, such as pork [22]. In the present study, the serum B1 level was within the reference value, while consumption represented 78.8% of adequacy, showing no correlation between them. In the study by Idris et al. [15], the case of a 16-year-old patient with type Ia GSD, with symptoms related to Wernicke's encephalopathy, is described. The diagnosis of thiamine deficiency was based on symptoms and laboratory tests, with no data provided regarding dietary intake.
In the present study, patients had low serum vitamin B2 levels. This vitamin is abundant in foods with yellow pigments (vegetables and fruits), as well as milk and dairy products [23], and these foods are restricted for patients with hepatic GSD, especially patients with subtypes Ia and Ib. Cereal processing significantly decreases riboflavin levels in the food, around 38-73% in wheat flour is lost when compared to whole meal flour and around 33-57% in rice when compared to brown rice [24]. Analysis of diet records showed that the majority of patients do not consume whole foods, nor milk and dairy products, making the availability of this vitamin low. However, if the patient takes supplementation as prescribed, the levels reach the recommended recommendations. Riboflavin plays an important role in converting macronutrients into energy usable by the body, and therefore, patients with vitamin B2 deficiencies may experience feelings of fatigue and weakness. After analyzing the medical records, no patient included in the study complained about any characteristic sign and/or symptoms of vitamin B2 deficiency. Regarding the assessment of vitamin B2 status, the meta-analysis by Hoey et al. [23] - which aimed to identify the most reliable biomarkers of riboflavin - indicated that erythrocyte glutathione reductase activity coefficient (EGRac) is an effective biomarker for evaluating vitamin B2 intake. In contrast, plasma or erythrocyte riboflavin concentrations, which were the methods used in the present study, were found to be inconsistent.
Vitamin B9 intake was low in most patients (13/15), with an adequacy of dietary intake of 26%. This vitamin is widely present in dark green leafy vegetables (spinach, asparagus, broccoli), as well as beans and peas. The body absorbs about 100% of folic acid from supplements and fortified foods, but only two-thirds of folate is naturally present in foods [25]. Additionally, there is a loss of 50 to 90% of folate during storage, cooking or processing at high temperatures [22]. In Brazil, the National Agency for Food Surveillance and Safety (ANVISA) regulated the addition of folic acid to wheat and corn flour (0.15 mg/100g) in 2004, citing the difficulty in ingesting this vitamin only with a normal, balanced diet [26]. Although regulations exist, patients with GSD rarely consume flour products (breads, cookies, pasta), mainly because some products contain added sugar. Another explanation for the low adequacy of dietary intake is due to the complexity of analyzing food sources of folate, in addition to the fact that the values of this vitamin in food composition tables are generally very low [22]. Even though there was no correlation between dosage and intake, serum folic acid values were in line with reference values (≥151 ng/dL), thus ruling out the possibility of nutritional deficiency.
Unlike the study sample by Hinkel et al. [16], in which patients with GSD (n=44) had high levels of B12, only 2 patients (Ib and IXc) in the present study had serum vitamin B12 levels above the reference value, the other patients maintained the dosage within the established range (187-883 pg/mL). Although previous studies correlate vitamin B12 intake with plasma concentration in healthy patients [27,28], both Hinkel's study [16] and ours, this finding was not correlated. In the study by Jacoby et al. [29], the use of vitamin supplements impacts the adequacy of dietary intake in patients with hepatic GSD. After supplementation, vitamin B6 reached >100% and vitamin B12 >150% of intake adequacy. In our study, these same vitamins had an adequacy of 76 and 96% respectively, even with the inclusion of supplements in the food record calculation. Therefore, B vitamin supplementation is important for these patients, as otherwise the intake of these vitamins could be insufficient, causing a possible nutritional deficiency.
It is noteworthy that the majority of patients in the studied sample regularly use multivitamins, which may have been an analysis bias, but demonstrates the importance of supplementation in this genetic condition of restrictive diet. For both GSD and other types of inborn errors of metabolism (IEM), poor adherence ends up being a significant factor that interferes with treatment success [30]. Daly et al. [31] considers it essential that in the long term nutritional supplements, such as glucose polymers, fat emulsions and other products, are enriched with vitamins and minerals in order to improve nutritional quality as well as adherence. In phenylketonuria (PKU), there is evidence to suggest that long-term adherence is better when vitamins and minerals are already added to protein replacement products.
The nutritional status has been extensively studied in the literature. A correlation has been suggested between the consumption of uncooked cornstarch (UCCS) and increased fat mass in these individuals. UCCS has an energy value of around 361 calories in 100g of food [32]. The patients' average UCCS intake was 1137.15 kilocalories/day, representing 44.7% of the total daily calories, that is, almost half of the daily caloric intake is due to the imposed treatment. In the present study, half of the patients included are classified as overweight or obese. This data corroborates previous studies by our research group, in which patients with GSD have a tendency to be overweight or obese [8,29,33,34,35].
Another important point to highlight is in relation to the food selectivity that children with IEM have. Eating difficulties are often considered inherent to metabolic disease, but there is little evidence describing their frequency or severity [36]. In patients with PKU, whose treatment is a diet free of the amino acid phenylalanine, Tonon et al. [37], observed that food phobia is common in this group due to the dietary restrictions imposed from the first days of life. In patients with hepatic GSD, in the study conducted by Martinez et al. [38], the prevalence of feeding difficulties in patients was 72.2% (n=32), being related to the use of alternative feeding (tube or gastrostomy), food selectivity and prolonged meals and lack of meals with the family. These findings were also found in studies by Venema et al. [39] and Bérat et al. [40]
Conclusion
Multidisciplinary care in patients with hepatic GSD is essential for successful treatment. Because the treatment is based on UCCS and this is correlated with an increase in BMI, patients are advised to ingest sufficient amounts of UCCS to maintain adequate metabolic control, avoiding excessive carbohydrate overload. Furthermore, requesting periodic tests to biochemically assess nutritional status becomes important, considering that clinical manifestations of vitamin deficiency can take months for symptoms to appear.
The study corroborates previous data in the literature on the need to indicate vitamin replacement in patients with different forms of GSD due to the nutritional restriction imposed by the treatment. It can be seen from the food record that just consuming food is not enough to meet established needs. Therefore, we recommend the practice of evaluating food intake and the use of multivitamins for patients.
More studies from our group are under development to evaluate the dietary intake profile of patients with GSD, including the fatty acid profile and its possible correlations with lipid intake and UCCS.
Acknowledgments
The authors acknowledge the Coordination for the Improvement of Higher Education Personnel (CAPES), the Postgraduate Program in Medicine: Medical Sciences at the Federal University of Rio Grande do Sul (UFRGS) and the patients for their time and willingness to participate in this study.
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Data availability
The manuscript has data included as electronic supplemental material; Additional data will be available on reasonable request.
Publication Dates
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Publication in this collection
15 Sept 2025 -
Date of issue
2025
History
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Received
03 Sept 2024 -
Accepted
19 July 2025
