Food triggers and inherited metabolic disorders: a challenge to the pediatrician

Several disorders should be considered in the case of newborns and infants experiencing acute or recurrent symptoms after food ingestion. Immune-mediated adverse food reactions are the most frequent and always to be considered. Nevertheless, in the extensive differential diagnosis, clinicians should also include inherited metabolic disorders (IMDs). This review reports clinical features and diagnostic aspects of the most common IMDs that may present with acute manifestations triggered by food intake. Major focus will be amino acid and protein metabolism defects and carbohydrate disorders. Nowadays, for many of these disorders the risk of an acute presentation triggered by food has been decreased by the introduction of expanded newborn screening (NBS). Nevertheless, clinical suspicion remains essential because some IMDs do not have still reliable markers for NBS and a false negative screening result may occur. The aim of this review is to help pediatricians to take these rare inherited disorders into account in the differential diagnosis of acute or recurrent gastrointestinal symptoms related to food intake, which may avoid delayed diagnosis and potentially life-threatening consequences.


Background
Several disorders should be considered in the case of newborns and infants experiencing acute or recurrent symptoms after food ingestion: motility disorders or anatomic abnormalities of the gastrointestinal tract, infections, systemic diseases and adverse food reactions are the most frequent and always to be considered [1].
Adverse reactions to food, excluding toxic reactions, are distinguished on the basis of the pathogenetic mechanism and may be either immune-mediated or non-immunemediated (Fig. 1). Immunological food reactions are the most common, including IgE-mediated and non-IgEmediated food allergies, and coeliac disease. Nevertheless, non-immunological food reactions, such as secondary food sensitivities and food intolerances, may also play an important role [2][3][4].
Adverse food reactions due to secondary food sensitivities occur with or after the effects of other conditions (e.g., secondary to gastrointestinal disorders or secondary to drug treatment) [4].
Food intolerances can originate from the pharmacological effects of vasoactive substances present in foods (e.g., histamine) or from enzymatic or transport defects. In rare cases, the pathogenetic mechanism remains undefined, and the reactions are classified as idiosyncratic [3,5].
Enzymatic or transport food intolerances can occur due to defects of enzymes or transporters specifically located in the digestive system (e.g., carbohydrate intolerances) [5] or due to systemic defects of enzymes or transporters of specific metabolic pathways (inborn errors of metabolism) [6].
Inherited metabolic disorders (IMDs) are a complex and heterogeneous group of rare monogenic disorders, usually resulting from a deficient activity in a single pathway of intermediary metabolism [7].
Although the most severe forms present usually in the neonatal period, late-onset presentations may represent an important cause of morbidity and mortality in the pediatric age [10].
Food may be a specific trigger of metabolic decompensation at any age.
This review reports clinical features and diagnostic aspects of the most common IMDs that may present with acute manifestations triggered by food intake. Major focus will be amino acid and protein metabolism defects and carbohydrate disorders.
The aim of this review is to help pediatricians to take these rare inherited disorders into account in the differential diagnosis of acute or recurrent gastrointestinal symptoms related to food intake, which may avoid delayed diagnosis and potentially life-threatening consequences.

Disorders triggered by proteins Case presentation 1
The patient was born at term after an uneventful pregnancy from two unrelated parents. The baby was exclusively breast-fed until six months of age. Soon after the start of weaning, between the ages of 6 and 12 months, he experienced repetitive vomiting and episodes of diarrhea, approximately within 1 to 3 h after the consumption of meat, chicken, fish, and egg. Since symptoms always recurred after the administration of the same foods, an allergic problem was suspected. Food protein-induced enterocolitis (FPIES), a non-IgE-mediated gastrointestinal disorder, was diagnosed. Protein-rich foods related to the symptoms were eliminated from his diet and were not subsequently reintroduced because the patient manifested a severe aversion to these foods. At 7 years, clinical examination revealed short stature, mild language retardation and hepatosplenomegaly. Laboratory tests showed high serum ferritin (770 ng/ml), and lactic dehydrogenase (LDH) values (1007 UI/L) with normal white blood cell, erythrocyte and platelet counts.
Other laboratory tests (including blood gases and ammonia) were all in the normal range.
Bone marrow aspirate examination revealed evidence of erythrophagocytosis (HP).
Then, due to the clinical features and the dietary history of recurrent vomiting and spontaneous protein-rich food aversion, plasma and urinary amino-acid analysis were performed.
We found lower than normal plasmatic levels of lysine, ornithine, and arginine, and higher than normal urinary levels of the same amino acids. Based on the results, we diagnosed lysinuric protein intolerance (LPI). The diagnosis was confirmed by molecular analysis of SLC7A7 gene. The patient started a controlled low-protein diet and an oral treatment with sodium benzoate and citrulline [11].

Case presentation 2
A male 15 months of age was admitted to the hospital after a day of persistent vomiting and somnolence alternating with periods of irritability. He had a history of recurrent vomiting by the 6 months of age. According to his parents, the child had no spontaneous aversion to proteins (daily intake 2.5 g/kg) and the episodes seemed to be more related to fructose ingestion even the child used to have a meal including fruit and meat together. Routine biochemical investigations performed in well-state showed elevated  The duration and severity of hyperammonemia strongly correlate with brain damage Variable.
The duration and severity of hyperammonemia strongly correlate with brain damage.

Late complications may be fatal
Variable.
The duration and severity of acidosis and hyperammonemia strongly correlate with brain damage.
Late complications may be fatal Variable.
The duration and severity of coma strongly correlate with brain damage Variable.
The duration and severity of hypoglycemias strongly correlate with brain damage. Increased frequency of generalized seizures transaminases (AST 300 U/L, ALT 1727 U/L), normal ammonia, lactate, amino acids and acylcarnitine profiles. Isoelectric focusing (IEF) of serum transferrin (Tf) showed an increased trisialo-Tf form, suggesting a possible diagnosis of fructosemia.
The patient was put on a low-fructose diet and molecular analysis for aldolase B gene mutation was performed.
About 4 months later, he was readmitted to the hospital with severe acute encephalopathy after a day of continuous vomiting. Vomiting was started by the ingestion of a sandwich with ham.
Brain CT scan showed severe edema. Liver transaminases were increased (AST 557 U/L, ALT 1923 U/L); ammonia reached a value of 600 μmol/L. Despite intensive treatments, the child died the following morning. Plasma amino acids and urinary organic acids performed during acute symptoms were suggestive for ornithine transcarbamylase deficiency (OTCD). OTC gene analysis confirmed the diagnosis [12].
Deficiencies of enzymes or transporters involved in amino acid and/or protein metabolism may present acutely in the neonatal period, typically after a short symptom-free interval, or later in life with acute, intermittent or progressive forms. In all cases, clinical features become apparent as a result of the accumulation of toxic compounds proximal or related to the metabolic block (intoxication type disorders) [10]. The most common acute (or recurrent) signs of "intoxication" are vomiting or feeding difficulties with lethargy, encephalopathy that may rapidly progress to coma, and liver failure [10].
Triggers provoking acute metabolic attacks are more commonly catabolic states (e.g., prolonged fasting, infections, fever, surgery, chemotherapy, high-dose glucocorticoids). Nevertheless, an increased protein intake (e.g., weaning dietary changes, a barbecue) may also be a cause of metabolic decompensation both in children and in adults [13].
Adult-onset cases unmasked by parenteral nutrition have also been described [14,15].
Based on few laboratory data (ketones, ammonia, blood gas analysis) collected at the same time during the acute attack, we propose a schematic diagnostic algorithm to guide the initial approach and the differential diagnosis of acute presentations of IMDs triggered by proteins (Fig. 2) ( Table 1).
Nowadays, for many of these IMDs the risk of an acute presentation triggered by food has been decreased by the introduction of expanded NBS.

Disorders triggered by sugars Case presentation
A female infant was exclusively breastfed until 6 months of age. At 7 months she underwent a normal weaning, but she developed recurrent vomiting. The parents gradually eliminated from her diet several foods, in particular mousse fruits, because the patient seemed to reject them. At 12 months, the patient had resumed a predominantly milk diet and presented a growth below the 3rd percentile. Her pediatrician suggested biochemical exams and abdominal ultrasound. Blood analyses showed a mild increase of liver enzymes (ALT 98 U/L AST 75 U/L), with normal liver function and no cholestasis.
No sign of malabsorption or gastrointestinal disease was found.
The ultrasonography of the abdomen showed hepatomegaly (the lower margin was 5 cm below the lower pole of the right kidney) and hepatic steatosis.
The patient was brought to the pediatric department of a tertiary care institution for evaluation. Blood exams revealed no significant abnormalities with the exception of hypertransaminasemia (ALT 114 U/L, AST 113 U/L).
The histological analysis of liver biopsy revealed macrovesicular steatosis, mild fibrosis, and no evidence of inflammation, necrosis or bile stasis.
IEF of serum Tf was normal. Due to the dietary history suggestive for fructosemia, ALDOB gene analysis was performed. The exam revealed the homozygous mutation p.N335 K and confirmed the diagnosis.
A fructose-, sorbitol-and sucrose-free diet was immediately started and there was a complete recovery of the blood abnormalities and a significant reduction of liver size (not published).
Intoxication type disorders triggered by sugars include galactosemia and fructosemia, also known as hereditary fructose intolerance (HFI, OMIM #229600) ( Table 2). Intoxication is caused by toxic carbohydrate metabolites derived by exogenous intake of galactose and fructose, respectively [35,36].
HFI usually presents at the time of weaning, when fruits and vegetables are introduced into the diet. The patients are asymptomatic as long as they avoid foods containing fructose or any of its common precursors such as sucrose (a Fig. 3 Diagnostic algorithm to guide the initial approach to hypoglycemia, based on the liver size and the timing of hypoglycemia. Postprandial hypoglycemias of HFI and galactosemias differentiate these disorders from others characterized by fasting or unpredictable hypoglycemias. Hypoglycemias in HI/HA are induced both by fasting and by protein-rich meals (leucine sensitivity). Disorders with similar presenting features are shown as differential diagnosis. Abbreviations: CDG congenital defect of glycosylation, FAODs fatty acid oxidation defects, FBPase deficiency fructose-1,6bisphospatase deficiency, HI/HA hyperinsulinism hyperammonemia syndrome, MCAD medium-chain acyl-CoA dehydrogenase deficiency, SCAD short-chain acyl-CoA dehydrogenase deficiency, SCHAD short-chain 3-hydroxyacyl-CoA dehydrogenase disaccharide composed of fructose and glucose, also known as table sugar) and sorbitol (present in natural products, especially in dried fruits, and added to others as sweeteners). Acute symptoms include gastrointestinal discomfort, feeding difficulties, vomiting, pallor, metabolic acidosis, hepatomegaly, hypoglycemia, restlessness, lethargy and shock. Prolonged fructose ingestion can ultimately lead to an aversion towards fructose-containing foods, a strong distaste for sweet food, failure to thrive, liver failure and renal dysfunction [37,38].
In the case of galactosemia, breastfeeding or lactosecontaining formula feeding during the first days of life cause severe liver dysfunction, manifested as jaundice, hepatomegaly, hypoglycemia and coagulation disturbances, and gastrointestinal findings of poor feeding, vomiting and diarrhea. The onset of illness may be acute and fulminant and may often be confused with neonatal sepsis due to the E. coli infection [39,40].
The most prominent features of both defects in acute phase are hypoglycemia and hepatomegaly, even though late-onset forms of HFI may rarely present with isolated hypoglycemia [10].
HFI is not included in NBS panel, because of technical difficulties in screening for a condition in which there is no neonatal exposure to the offending agent.
On the contrary, most infants with galactosemia are now diagnosed through routine NBS, even if many patients may present symptoms before referral for abnormal NBS. Screening test is done primarily to detect clinically devastating classic galactosemia (CG, OMIM #230400) due to defective function of galactose-1-phosphate-uridyl transferase (GALT) and generalized forms of epimerase deficiency galactosemia (GALE deficiency galactosemia, OMIM #230350), due to defective function of UDPgalactose-4-epimerase (GALE) [39][40][41].

Conclusions
Despite the introduction of NBS for many IMDs potentially triggered by food intake, pediatricians should systematically consider these disorders in the differential diagnosis of acute or recurrent gastrointestinal symptoms related to food ingestion, in particular if they occur as a part of a systemic disorder.
Once clinical suspicion is aroused, general supportive measures and metabolic laboratory investigations must be undertaken immediately (Fig. 4). Plasma and urine samples should be promptly collected during the acute phase of illness because some tests could be normal during asymptomatic periods.