Hepatic Glycogen Storage Diseases (GSD) are a set of rare genetic disorders in which glycogen breakdown is impaired. The global incidence is estimated at 1 case per 20,000–43,000 live births [1], although some types, such as GSD type I (GSD-I), are more frequent than others [2].

GSD-I is caused by a deficiency of the glucose-6-phosphatase-α (G6Pase-α) complex, which consists of catalytic subunits and transporters. Defects on catalytic subunit G6PC causes GSD-Ia (autosomal recessive, OMIM #232200) and the impaired glucose-6-phosphate transporter activity causes GSD-Ib (autosomal recessive, OMIM #232220) [3]. The activity of those subunits is linked, so defects in this complex lead to a similar metabolic phenotype, characterized by fasting hypoglycemia, hepatomegaly, nephromegaly, hyperlipidemia, hyperuricemia, lactic acidemia, and growth retardation X3. In addition, GSD-Ib patients also have myeloid dysfunctions, inflammatory bowel disease (IBD), recurrent infections, and persistent or intermittent neutropenia, which is treated with G-CSF [4], [5], [6]. In contrast, there are reports of GSD-Ia patients with sub-clinical neutrophilia which may be a potential mechanism leading to adenoma formation [7].

GSD type III (GSD-III; autosomal recessive, OMIM #232400) and type IX (GSD-IXα; X-linked OMIM #306000) are less severe and might present with muscular involvement. In both diseases, the gluconeogenesis is intact. In GSD-III, hepatomegaly generally improves with age, but besides GSDIII/IX patients’ symptoms are usually milder than the other types [8], they may develop chronic liver cirrhosis and hepatic failure later in life [9], [10].

As result of the impaired breakdown of the glycogen, a common characteristic is fasting hypoglycaemia. To avoid those, periodic and frequent ingestion of uncooked cornstarch (UCCS) and restricted consumption of fast hydrolysis carbohydrates are recommended [11]. The doses of cornstarch are highly individualized, adjusted according to the developmental stage of each subject, using an estimation of glucose requirements in mg/kg/min [12] and on glucose and lactate monitoring, aiming glucose concentrations ˃75 mg/dL and lactate <2.2 mmol/L [2]. GSD-I untreated patients or patients with poor metabolic control have increased levels of serum lactic acid, uric acid and triglyceride. Poor metabolic control patients with GSD-III have ketotic hypoglycemia associated with increased cholesterol and triglyceride concentrations, but normal fasting blood lactate and uric acid concentrations. Triglycerides are highly increased in GSD-I, while in GSD-III and IX the increasing is milder or absent [2]. The optimum metabolic control has high clinical importance for those patients, and has the potential to delay or even prevent the complications of disease [13], as hepatocellular adenoma (HCA) [14].

Imbalance of cytokines or their downstream signaling pathways are cause of many human disorders. Cytokines are a large family of soluble factors that comprises several subfamilies, including interferons (INF), interleukins (IL), tumor necrosis factors (TNF), transforming growth factors (TGF), colony-stimulating factors (CSF), and chemokines [15]. Cytokines classical signaling is done via receptors, triggering the activation of the Janus Kinases/signal transducer and activator of transcription (JAKs/ STATs) pathway and the induction of specific gene expression programs and bioactivities, controlling virtually every aspect of mammalian physiology [16], [17], [18].

Cytokines signaling mediates several fundamental biological processes, including body growth, adiposity, lactation, hematopoiesis, as well as inflammation and immunity [19]. An imbalance of cytokines or their downstream signaling pathways are cause of many human disorders. As metabolic control can prevent or delay the complications of GSD, this study aims to evaluated the cytokine profiling of patients with aforementioned GSD compared with healthy controls and within the GSD types, also take into account triglycerides level as metabolic marker and clinical manifestations, such as anemia and HCA for GSD-Ia patients.