Diet Therapy Approach

There are 3 conceptual frameworks to dietary manipulation of CODE disorders: elimination, supplementation, and restriction (Figure 2). Dietary elimination refers to removing a specific nutrient from the diet, which in turn leads to the cessation of injury and the improvement in the severity of diarrhea. In diet supplementation, pharmacologic therapy with electrolytes, minerals, or vitamins can either lead to cession or improvement of diarrhea or provide needed supplements to prevent further nutritional deficiencies. In the restrictive approach, diet per se does not improve diarrhea but provides an important tool for promoting enteral autonomy and minimizing PN complications. An overlap between diet approaches may be present in a specific disease, but the dietary effect on the degree of the diarrhea is usually restricted to one approach.

 Figure 2

 

Lactase Deficiency 

Lactose intolerance is a chronic or transient condition resulting from significantly reduced lactase-phlorizin hydrolase (LCT) activity. The LCT gene encodes the β-galactosidase enzyme, located on the apical membrane of enterocytes. Reduced LCT activity impairs lactase breakdown of lactose into glucose and galactose, which results in diarrhea if the consumed lactose load exceeds lactase capacity [[2], [3], [4]].

Chronic lactose intolerance. The most common cause of chronic lactose intolerance is lactase non persistence (hypolactasia), an inherited phenotype (MIM #223100) common in children of African, Hispanic, and Asian descent that typically develops in early to mid-childhood. In contrast, the rarest form of chronic lactose intolerance is primary lactase deficiency (MIM# 223000), which presents clinically during the first several days of life and persists indefinitely. Biallelic loss-of function mutations in LCT result in primary lactase deficiency, whereas hypolactasia results from the more moderate, age-dependent monoallelic reduction of LCT expression [[2], [3], [4]].

Dietary Management

Management is tailored to the severity of symptoms and consists of dietary lactose restriction, including breast milk, in congenital primary lactase deficiency [2,5–10]. Supplementing patients with lactase enzyme replacement preparations when consuming lactose-containing foods may also be helpful in symptom management in hypolactasia [11,12]. The role of enzyme replacement therapy in congenital primary lactase deficiency is unknown due to lack of reported data. Removing most lactose-containing products from the diet should resolve the diarrhea and associated symptoms. Children who avoid dairy products should be monitored and supplemented to ensure adequate calcium and vitamin D intake [2,5–10].

Products containing lactose include cow milk and related by products, including milk solids, milk powder, cheese and cheese flavoring, curd, whey, cream, butter, and margarine containing milk solids. Products containing lactic acid, lactalbumin, and lactate do not contain lactose and can be consumed. Some patients with lactase deficiency may tolerate fermented products, such as yogurt and kefir because added bacteria assist in the digestion of lactose. Butter and hard cheeses contain trace lactose and are generally well tolerated (Supplemental Tables 2 and 3) [2,5–7,10].

Sucrase-Isomaltase Deficiency

Congenital sucrase-isomaltase deficiency (CSID; MIM#222900) is a biallelically inherited loss-of-function mutation in the sucrase isomaltase (SI) gene, which encodes a localized enzyme in the enterocyte apical membrane. SI hydrolyzes sucrose, maltose, α-4glucose oligomers, branched1-6 linked dextrins, and starch into glucose. In CSID, sucrase and isomaltase activity is significantly reduced or undetectable [13–16].

Consumption of sucrose or starch in CSID is associated with the typical symptoms observed in carbohydrate malabsorption [15,17]. The severity of symptoms is influenced by enzymatic capacity and the dietary load of sucrose and starch [15,17]. Five clinical phenotypes have been described in CSID—A, B, C, D, and F [18]—with differences based on the degree of enzymatic activity, tolerance of starch and maltodextrin, and resolution of symptoms.

Dietary Management

The management of CSID involves the dietary restriction of sucrose and starch. Initial phases involve limiting sucrose and starch, with step wise liberalization of type and amount of food based on tolerance and clinical course [16,19]. In some infants with CSID, a formula containing starch (e.g., corn maltodextrin or corn syrup solids) or lactose may not be tolerated, and a carbohydrate-free formula is advised [ 16,19]. Sucrose can be found in fruits, vegetables, legumes, and in many food products, listed as sucrose or sugar in an ingredient list. It is recommended to choose foods low in sucrose initially, then gradually increase sucrose consumption by increasing the variety of food choices and being mindful of portion size.

Individuals with CSID have varying enzymatic activity affecting starch tolerance [19–21]. The SI enzyme hydrolyzes~70% of starch in the small intestine, whereas the residual is hydrolyzed by the maltase-glucoamylase enzyme. Sources of starch in the diet include grains such as wheat, corn, rice, and starch-rich foods, such as banana, plantain, carrot, potato, tubers, and pulses (chickpeas, green peas, beans, and lentils). Higher fiber varieties of starches are often better tolerated among individuals with CSID. Starch-restricted diets maybe limited in energy and micronutrients, affecting growth, development, and quality of life. Thus, they must be personalized to the patient with the support of a registered dietitian [19,22] (Supplemental Tables 4–7). In addition to sucrose and starch eliminations, sacrosidase (Sucraid), a yeast-derived enzyme replacement therapy, is associated with improved symptoms [23–25]. Over-the-counter Saccharomyces cerevisiae or Saccharomyces boulardii may be an alternative for patients with limited access to Sucraid [13,23,25]. Sucraid can be given to all patients with a confirmed diagnosis and taken with each meal or snack.

Glucose-galactose malabsorption

Glucose-galactose malabsorption (GGM; MIM #606824) is an autosomal-recessive disorder that affects the absorption of the monosaccharides glucose and galactose across the apical border of the intestinal epithelium. Loss-of-function mutations of the sodium-glucose/galactose cotransporter (SGLT1/SLC5A1) result in GGM [26–28]. Symptoms including diarrhea and dehydration are seen in the first days of life following milk consumption. The lactose in milk is hydrolyzed to glucose and galactose, which are exclusively absorbed across the enterocyte’s apical membrane by SLC5A1. If the severity of diarrhea is not detected promptly, prolonged milk consumption can result in early mortality. All subjects with GGM can thrive on a completely fructose-based diet. The monosaccharide fructose is selectively transported across the apical membrane via the facilitated transporter (GLUT5/SLC2A5), and its function is retained in GGM.

Management

Patients with GGM require a lifelong glucose/galactose-depleted diet [29]. This includes all sources of glucose and galactose, complex carbohydrates such as starch (glucose polymers), and disaccharides such as maltose (glucose/glucose), sucrose (glucose/fructose), and lactose (glucose/galactose). The diet is, therefore, high in fat, protein, and fructose [29]. Patients should continue a fructose-based formula through the first year of life. Weaning foods introduced by 4 to 6mo should be depleted of galactose-glucose, such as vegetables and some fruits. Symptoms appear to marginally improve with age. Close nutrition follow-up should be maintained, and parents should be educated that management of GGM is a lifelong restriction to all sources of glucose and galactose (Supplemental Tables 8–10).

Abetalipoproteinemia 

Abetalipoproteinemia (ABL; MIM# 200100) is an autosomal recessive disorder resulting from abnormal lipoprotein metabolism due to mutations in the MTTP gene. MTTP encodes microsomal triglyceride transfer protein, the ApoB chaperone protein. MTTP is required to transfer triglycerides (TGs) and cholesterol in the endoplasmic reticulum to the Golgi apparatus and to package chylomicrons and VLDL in the intestine and liver, respectively [32]. Consequently, the defect leads to chronic fat malabsorption with almost absent plasma TG, significantly decreased TC, nearly absent LDL, VLDL, and ApoB (both ApoB-100 and ApoB-48), and FSV deficiency. Gastrointestinal (GI) manifestations present in early infancy. The diarrhea may improve later in life through adherence to a fat-restricted diet [30]. Other later symptoms may evolve due to a deficiency of FSVs in unsupplemented individuals, particularly vitamin E [33]. The accumulation of large lipid droplets has been described in hepatocytes, leading to fatty liver disease, and in enterocytes, leading to the characteristic pale mucosa.

Management

 A minimal-fat diet is recommended for patients with ABL with <10% of the total calories from fat [34]. Consumption of llong-chain fatty acids is particularly discouraged [35]. Fat restriction increases the risk of growth failure, essential fatty acid (EFA) deficiency, and micronutrient deficiency, including fat-soluble vitamins (FSVs). In infants, diet enrichment with medium-chain triglycerides (MCTs) can help in nutritional recovery [36,37]. To ensure adequate intake of EFAs, patients may be advised to consume 2teaspoons olive or soybean oil/d or similar oils rich in PUFAs (Supplemental Tables 11–18, Supplemental Note 1).

FSV replacement is a cornerstone in the dietary management of ABL. The transport of FSVs depends heavily on the integrity of the ApoB lipid transport pathway, almost exclusively for vitamin E and partially for the other FSVs. Thus, high-dose vitamin E supplementation is necessary, but this only results in a partial increase in serum vitamin concentrations to no >30% of the lower limits of normal [38, 39]. Early initiation of vitamin E therapy at <16mo of age may prevent neurologic and retinal consequences. However, improvement in neurologic dysfunction is seen even in those diagnosed as young adults [37,39,40]. Orally administered, high-dose vitamins are thought to bypass the intestinal chylomicron assembly pathway via the MCT pathway through the portal circulation. High doses of oral vitamin E are typically administered as α-tocopherol supplementation at 50–200mg/kg/d [41]. Plasma vitamin E concentrations might not accurately reflect the whole-body content of vitamin E. Thus, vitamin replacement and dosing adequacy is difficult to assess from serum concentrations. However, serum vitamin E concentrations, although diminished, can still be used to monitor compliance. Recently, some investigators have suggested that supplementation of vitamin E in the form of tocofersolan (synonym: α-tocopherol glycol succinate; oral load of 100 IU α-tocopherol acetate/kg and then 50 IU/kg daily), a commercially available water-soluble derivative of RRR-α-tocopherol [42], may be a promising enteral supplement in fat malabsorptive conditions [43]. However, if oral supplementation fails, intramuscular (IM) injection of vitamin E once to twice weekly can be used as an alternative to correct serum concentrations and replenish stores [44].

Additionally, general recommendations are for oral vitamin A at 100–400 IU/kg/d with the dose adjusted according to plasma concentrations. High doses of vitamin A therapy can achieve normal serum concentrations, suggesting that the transport of vitamin A by retinol-binding proteins in serum is intact in ABL.

Oral vitamin D at 800 to 1200 IU/d is recommended, although vitamin D deficiency is not always found in ABL. Although there is scant evidence supporting the use of vitamin D analogs to treat vitamin D deficiency in ABL or other fat malabsorption CODE, there may be a persistent deficiency that suggests the need for other vitamin D-based interventions. Other oral preparations include calcifediol (25-hydroxy vitamin D3) and calcitriol (1,25-hydroxyvitamin D3; active form of vitamin D; Rocaltrol). Recent reviews of calcifediol suggest it is more effective at treating and maintaining vitamin D status in malabsorption than cholecalciferol (vitamin D3) and ergocalciferol (vitamin D2), as it is more polar and thought to be more readily absorbed [45]. Calcitriol can be used to treat metabolic bone disease and has been well studied in children with chronic kidney disease and hyperparathyroidism [46]. IM ergocalciferol may be considered when oral preparations have failed at treating vitamin D deficiency. IM ergocalciferol has been used with success at treating rickets in biliary atresia when 25-hydroxyvitamin D3 and 1,25-dihydroxyvitamin D3 have failed [47]. Future studies of fat CODE may consider the applicability and efficacy of doxercalciferol (1-hydroxyvitamin D2; Hectorol), an injection currently used to treat secondary hyperparathyroidism and metabolic bone disease. 

Although bleeding is not often reported, abnormal coagulation parameters are frequently reported. Thus, oral vitamin K supplementation at 15 mg/wk or 5 mg per os daily is recommended, with dosing adjusted according to international normalized ratio levels. Although plasma PIVKA-II (protein induced in vitamin K absence) is a more sensitive marker of vitamin K deficiency, it is not routinely available [48]. Supplementation of other nutrients, such as iron, can also be considered.

Familial hypobetalipoproteinemia

Familial hypobetalipoproteinemia (FHBL; MIM #615558) is an autosomal-recessive disorder usually due to mutations in the APOB gene. It is characterized by very low plasma LDL and ApoB concentrations. FHBL is due to truncation mutations leading to loss-of function mutations in APOB or infrequently, in mutations in the PCSK9 gene. The PCSK9 gene encodes a protein, mainly expressed in the liver, that regulates the LDL-receptor degradation and the number of receptors available on the cell surface [49]. The clinical phenotype of FHBL is variable, depending on the zygosity of the affected individual, with homozygous patients quite similar to those with ABL, whereas heterozygotes have a mild clinical phenotype [50]. The clinical phenotype severity in homozygotes varies and depends on the mutation and the degree of the truncated ApoB function [51]. Those with PCSK9-related FHBL do not appear to have fatty liver disease [52].

Management

The dietary management will depend on the severity of clinical symptoms, but severe cases would be managed similar to those with ABL as outlined previously.

Chylomicron retention disease

Chylomicron retention disease (CMRD; MIM #246700) is an autosomal-recessive disorder resulting from mutations in the SARA2 gene, which controls the production of the Sar1b protein, involved in the control of intracellular trafficking of chylomicrons from the endoplasmic reticulum to the Golgi apparatus. This results in the accumulation of prechylomicron transport vesicles in the cytoplasm and formation of lipid droplets within the enterocytes. The gene defect leads to chronic fat malabsorption with normal plasma TG (unlike ABL), and low TC, LDL, and ApoB (ApoB-48 completely absent) to ~25% to 40% of normal concentrations [53]. Digestive symptoms improve significantly within weeks of initiating a minimal-fat diet. The adaptation and improvement of diet fat tolerance over time is variable [53,54]. Hepatomegaly and macrovesicular steatosis are present in <20% of children, starting in infancy or late childhood, but are not associated with cirrhosis [53]. Neurologic, muscular, and retinopathy complications related to FSV deficiencies in CMRD are typically less pronounced than in ABL or homozygous FHBL but may occur during infancy.

Management

DGAT1 deficiency

Intestinal lymphangiectasia

Intestinal lymphangiectasia is a rare form of protein-losing enteropathy characterized by dilatation of intestinal lacteals, resulting in lymph leakage into the small bowel lumen [61]. Significant amounts of protein, fat, and immune cells are lost in the lymph, resulting in severe hypoproteinemia, hypoalbuminemia, lymphopenia, hypogammaglobulinemia, loss of other essential proteins, edema, and diarrhea [62]. 

Two types of intestinal lymphangiectasia have been described: primary and secondary. Primary intestinal lymphangiectasia (PIL) most commonly occurs in infants and children and is generally diagnosed before the third year of life [63,64]. PIL is caused by congenital abnormalities of the chest and/or intestinal lymphatics. It involves hypoplasia, agenesis, or stenosis in the thoracic duct and mesenteric lymph nodes, leading to increased pressure, expansion, and rupture of intestinal lymphatic vessels [62]. Secondary intestinal lymphangiectasia is caused by various diseases, such as lymphoma, scleroderma, pericarditis, and sarcoidosis, that induce lymphatic obstruction [62,65]. Treatment of the primary disease usually corrects the secondary intestinal lymphangiectasia. Therefore, this section will focus on PIL.

PIL is characterized by bilateral lower limb edema, ascites, pleural and pericardial effusion, lymphedema, abdominal pain, fatigue, anemia, FSV deficiency, diarrhea, hypocalcemia, and metabolic bone disease [63,66]. The primary nutritional deficiencies in this group include FSV deficiency, particularly vitamin D, poor calcium absorption, negative calcium balance, and zinc deficiency.

Management

The goal of nutrition management in PIL is to reduce the formation and minimize the loss of lymph and its constituents into the intestinal lumen (Table 2). This can be achieved through a diet high in protein and low in long-chain fats with adequate amounts of EFAs to prevent EFAD. A total of ~3% of total energy should come from linoleic acid and ~0.5% from α-linolenic acid to prevent EFAD [67,68]. The principles of a minimal-fat diet are similar to those in fat malabsorption (Supplemental Tables 11–18, Supplemental Note 1). The amount of fat required should be calculated based on total energy needs (calculated using the Schofield equation or through indirect calorimetry) to prevent EFAD. MCT oil should comprise the highest proportion of fats in the diet. FSV supplements should be in water-soluble form. In addition, calcium, zinc, and iron supplements are needed while monitoring patients’ blood concentrations. These diet modifications are lifelong, as liberalization of diet or noncompliance leads to relapse of clinical symptoms [69,70]. In extensive disease, some patients do not respond to a high protein, minimal-fat diet therapy, and PN is required. PN is often used for in-hospital management during the initial diagnosis, after which some patients are discharged and maintained on home PN for 3–5 nights per week as a complementary therapy to the minimal-fat diet [64,71].

Acrodermatitis enteropathica

Acrodermatitis enteropathica (AE; MIM #201100) affects zinc uptake and can be inherited (congenital) or acquired [72]. AE is associated with zinc deficiency. Clinical symptoms vary, reflect the consequences of zinc deficiency, and range in severity from mild to severe [72,73]. Common signs and symptoms of AE include diarrhea, dermatitis, poor growth, anorexia, dysgeusia, mood changes, neurologic and cerebral disturbances, alopecia, nail deformity, recurrent infections, and rarely, ophthalmic and hepatic abnormalities [72,74]. If left untreated, AE can be fatal; however, symptoms can reverse with enteral zinc supplementation [72,73].

The congenital form of AE results from SLC39A4/ZIP4 mutations and impairs the active transport of zinc across the duodenal mucosa [72,73,75]. A mutation in SLC30A2, a gene encoding the zinc transporter ZnT2, can lead to a decreased zinc secretion in breast milk and transient AE, such as in breastfed neonates [76]. Acquired forms of AE are variable and include zinc deficient breast milk [77] or concurrent conditions such as malabsorptive disorders (e.g., cystic fibrosis, celiac disease, cholestatic liver disease) or in cases in which the duodenal surface area is bypassed (e.g. surgery, postpyloric/jejunal nutrition support) [73,74].

Management

Treatment of AE is 1 to 3 mg zinc/kg/d [73], divided twice or thrice daily. Zinc supplements exist in different forms, including zinc sulfate, gluconate, or acetate. Each form contains a different percentage of elemental zinc that needs to be considered when calculating treatment doses. To date, there is very little evidence assessing the bioavailability, absorption, and tolerability of the different forms of zinc in AE or other conditions. In addition, there are known zinc-drug and zinc-nutrient interactions to consider as part of monitoring response to zinc therapy for AE [74,78]. Antibiotics (e.g. quinolone and tetracycline), penicillamine, and diuretics can interact with zinc [74]. Zinc can also interfere with the absorption of iron, copper, and calcium [74]. As such, zinc supplements should be taken apart from certain medications and iron, copper, or calcium supplements. Zinc toxicity, which has only been documented to occur from supplementation, is also a risk, thus zinc concentrations need to be monitored in patients treated for AE [74,78]. Beyond supplementation, there is no special diet to follow for congenital or inherited AE.

Congenital chloride diarrhea

Congenital chloride diarrhea (CCD; MIM #214700) is a disorder of the intestinal Cl /HCO3 exchange transporter, resulting in high fecal Cl loses, hypochloremia, hypokalemia, and metabolic alkalosis [79, 80]. It is an autosomal-recessive disorder caused by mutations in the SLC26A3 gene [81–83].

Most children are born prematurely with hydramnios and absence of meconium, suggesting an intrauterine onset of diarrhea [79,84,85]. Similar to congenital sodium diarrheas, the condition can go undiagnosed in the early neonatal period due to high-volume stool output resembling urine. During the first days of life, patients usually have a large, distended abdomen, and the neonatal weight loss is unusually high [79]. Dehydration is common and can lead to death, particularly during the early neonatal period [86].   

Clinical symptoms include failure to thrive and high output of very watery stool containing high chloride, >90 mmol/L. However, stool chloride may be low in patients with chronically depleted serum chloride. Urine chloride is dependent on serum chloride, and in cases in which the serum chloride is <95 mmol/L, urine testing is associated with an absence of chloriduria [79].

Management

During the early neonatal period, patients are treated with IV fluids aiming to replace stool losses of fluids, NaCl, and KCl. Oral salt substitution therapy is an effective diet therapy as the child ages, with a gradual introduction of oral feeding with the addition of oral electrolyte solutions containing 0.7%–0.9% NaCl (120–154 mmol/L) and 0.3%–0.2% KCl (15–20 mmol/L) solutions. Doses are adjusted to maintain normal serum electrolytes, as well as some urine chloride [79], aiming for urine concentrations of 10–50 mmol/L [87].

In the neonatal period, chloride and potassium needs are 6–10 and 3–4mmol/kg/d, respectively, and as the child grows, the needed amount slightly drops or may remain the same [79]. Oral salt substitution therapy administered 3–4 times/d [86,87] should meet these targets. Older patients are prescribed 1.8% NaCl (300 mmol/L) and 1.9%–2.2% KCl (130–150 mmol/L) 3–4 times daily with meals [79]. Beyond the maintenance therapy, acute exacerbations should be treated with aggressive IV rehydration to correct the electrolyte abnormalities that tend to worsen during such episodes. The treatment of CCD is lifelong as the high chloride and voluminous stools persist, although a decrease in stools has been reported with age [87]. Over time, most patients can be maintained on oral supplements and will not require PN or IV support [85].

Congenital sodium diarrhea

Congenital sodium diarrheas (CSD) are a group of diseases with a similar diarrheal phenotype caused by impaired intestinal Na+ absorption and characterized by high-fecal sodium loss, serum hyponatremia, and metabolic acidosis [88,89]. CSD is a heterogeneous group of disorders, and this heterogenicity is observed genetically and clinically. Biallelic mutations in NHE3/SLC9A3 (MIM #616868), a sodium hydrogen antiporter, and gain of function autosomal dominant mutation in GUCY2C (MIM #601330), an apical receptor activating cGMP, cause nonsyndromic CSD, whereas syndromic CSD results from SPINT2 mutations (MIM #270420) [89,90].

Patients with CSD have watery electrolyte transport diarrhea, abdominal distension, and dilated fluid-filled bowel loops [90]. The condition can go undiagnosed initially because the stools are voluminous and resemble urine. The large stool volume is responsible for progressive weight loss and dehydration [88,90]. Stool sodium is very high, and the acid-base aberration in CSD is metabolic acidosis as opposed to the metabolic alkalosis in CCD [89]. Chloride fecal loss, in addition to sodium losses, can be found in patients with GUCY2C mutation due to the downstream effect of the mutated protein on NHE3 and CFTR [91,92]. Urine sodium will be low when body fluid status is uncorrected. Fractional sodium excretion is a more accurate marker of sodium status because it is independent of urine flow [93–95]. Progressive weight loss and dehydration are common at disease onset, and acute renal failure may develop in patients with delayed diagnosis [96]. Inflammatory bowel disease has been sporadically reported in patients with GUCY2C and NHE3 mutations [89].

Management

Oral supplementation of NaHCO3 and potassium citrate has been reported to lead to clinical recovery in some cases [97]. In addition, loperamide has also been described as a successful treatment for increasing intestinal sodium absorption in patients with CSD [98]. However, the evidence for these approaches is limited, and they do not significantly affect diarrhea or electrolyte balance in most cases. Total home PN has been the mainstay of treatment in patients with CSD, mainly in patients carrying NHE3 and SPINT2 mutations, whereas the minority of patients with GUCY2C mutation require PN. Patients require up to 22 and 10 mmol/kg/d of sodium and acetate, respectively, with a total IV fluid intake of 160–180 mL/kg/d. The variation in the effectiveness of the different treatments likely lies in the heterogeneous nature of the disease. Most patients with NHE3 and GUCY2C mutations and the minority with SPINT2 [99] mutation may be able to reduce their PN requirements over time and tolerate enteral feeding.

Our collective experience in these rare diseases suggests a focus on PN in early infancy with restrictions on all oral fluids except for oral rehydration solution. During the weaning years, low-sugar solid foods are introduced and maintained as textures progress. The volume of oral rehydration solution is slowly increased, and stools with fluid and electrolyte balance are frequently and carefully monitored to assess tolerance. If tolerance improves, PN volume and hours of infusion are weaned. Weaning is progressed until it is determined that growth, electrolyte balance, or hydration status are compromised. Specifically for patients with GUCY2C mutation, with the improvement in diarrhea after infancy, most patients will tolerate full oral diet with a need to avoid simple sugars, fruits, and dairy products [100].

Primary bile acid diarrhea

Bile acid diarrhea (BAD) is a common but underdiagnosed cause of chronic diarrhea [101–103]. BAD is the result of impaired enterohepatic cycling of bile acids and can be subcategorized into the following 3 types: 1) ileal mucosal dysfunction; 2) excessive hepatic synthesis of bile acids; and 3) an idiopathic or primary etiology involving genetic variants [104,105]. Diarrhea associated with BAD is thought to be multifactorial. Mechanisms for the role of bile acids in BAD include stimulation of the colon to secrete fluid, sodium, or mucus; increased gastric motility and/or defecation; and a damaging effect on the intestinal mucosa [101–103]. In addition, diet will further exacerbate the diarrhea and worsen GI symptoms. Several genetic defects have been identified in bile acid metabolism and provide insights into the pathophysiology of BAD. These include variants in SLC10A2 (MIM #601295), which codes for an apical sodium-dependent bile acid transporter thought to be important in the enterohepatic circulation of bile acids, and in SLC51B, which is thought to be involved in bile acid recycling [106]. Compared to adults, pediatric cases of BAD are rare, assumed to be primary in nature, and generally present with more severe symptoms and malnutrition [107]. BAD in infancy is associated with chronic diarrhea, steatorrhea, reduced plasma cholesterol concentrations, and growth faltering [101,104,105]. 

Management

The mainstay of nutritional management of pediatric BAD parallels other forms of CODE and includes IV fluid resuscitation, correction of metabolic acidosis, correction of electrolyte abnormalities, and provision of nutrition via PN support and/or enteral nutrition support if tolerated. Hydrolyzed, extensively hydrolyzed, or amino acid formula will not ameliorate symptoms of BAD. Bile acid sequestering with anion exchange resins such as cholestyramine is integral to differentiating pediatric BAD from other CODE disorders, with improvement in the diarrhea following its introduction in many cases. Although there is no specific diet management, nutrition principles that may minimize loose, frequent bowel movements may have some therapeutic benefits in pediatric BAD. These include adding soluble fiber and limiting the consumption of simple sugars (anecdotal author experience).

Enteroendocrine defects

At least 5 monogenic disorders result in enteric endocrinopathies, including loss-of-function mutations of the NEUROG3, PCSK1, PERCC1, ARX1, and RFX6 genes. These disorders have identical consequences associated with their enteric endocrinopathies; however, all are associated with distinct systemic endocrinopathies that distinguish the disorders from one another and may influence their long-term nutritional management. The following 3 characteristics set this group of patients apart from those with other forms of CODE: 1) normal appearing small bowel mucosa; 2) inability to tolerate all forms of enteral nutrients; and 3) the requirement of PN during the first several years of life.

Patients with endocrinopathies develop dehydration, metabolic acidosis, and diarrhea during the first several weeks of life. Diarrhea is of the general malabsorptive type and worsens with the selective dietary challenges of any form of carbohydrates, amino acids, or fats, and resolves entirely during fasting.

Management

The initial dietary options for most enteric endocrinopathies rely primarily on PN, slow advancements of low osmolality enteral feeds, and loperamide. The requirement for PN is generally limited to the first several years of life, although the diarrheal symptoms never abate. Therefore, parenteral and enteral nutrition should be balanced to target the ideal body weight, but the parenteral component can be tapered over time. Anecdotally, the diarrheal symptoms improve when liquid formulas are minimized, and semisolid feeds are advanced (Table 2).

Nutritional considerations by specific endocrinopathies 

NEUROG3 

Enteric anendocrinosis is an autosomal-recessive disorder caused by mutations of the NEUROG3 gene (MIM# 610370) [108]. NEUROG3 is required for endocrine cell development in the pancreas, intestine, and portions of the hypothalamus. Unlike the other CODE endocrinopathies, this disorder results in a paucity of enteroendocrine cells. A component of the diarrheal symptoms may be related to pancreatic insufficiency in some patients. Diabetes mellitus is a common occurrence in most of these children, but the age of onset is rarely in early infancy. Severe forms of FSV deficiency have also been seen in some patients.

Measuring fecal elastase-1, chymotrypsin, and 72-h fat collection should be considered as pancreatic insufficiency can present early on. If there is evidence of pancreatic insufficiency, enzyme replacement therapy is indicated. Anticipatory guidance and management including diet for diabetes mellitus resulting from systemic endocrinopathy is indicated.

PCSK1 

Proprotein convertase 1/3 deficiency is an autosomal-recessive disorder caused by mutations in the proprotein convertase subtilisin/kexin type 1 (PCSK1) gene (MIM# 600955) [109]. Prohormone convertase 1/3 is a calcium-dependent serine endoprotease essential for the conversion of a variety of prohormones into their bioactive forms; it is highly expressed in endocrine cells, in the gut, in the arcuate and paraventricular nuclei of the hypothalamus, and in β cells of the pancreas, where it has a well-defined role in processing proinsulin. A uniformly common clinical feature in PCSK1 deficient infants is significant hypoglycemia that persists in the fed and fasted states, which may be related to elevated proinsulin level resulting from improper conversion to insulin. Adrenal insufficiency is common in early infancy, and diabetes insipidus generally results subsequently and needs careful anticipatory monitoring and modulations of fluids and nutrients.

As PCSK1 deficiency is associated with profound hyperphagia and moderate obesity as the infant ages, weight and total caloric intake monitoring should be continuously reviewed and modified as needed. PN support is usually limited and needed in the first few years of life.

ARX (MIM #308350/300215) and RFX6 (MIM #615710)

The usual dietary options recommended for the other enteric endocrinopathies apply to these patients as well. Similar to NEUROG3, evidence of exocrine pancreatic insufficiency should be sought, and a trial of enzyme replacement therapy should be implemented if indicated [110].

Microvillous inclusion disease

Microvillous inclusion disease (MVID) is an autosomal recessive enteropathy [111] characterized by profuse neonatal diarrhea resulting in malabsorption, dehydration, and electrolyte derangements. The most common cause of MVID results from biallelic mutations in MYO5B gene (MIM #251850) [112]. However, UNC45A and STX3 gene mutations have also been reported to cause cellular phenotype similar to MVID (MIM#619377 and #619445, respectively) [113]. Mutations in these genes lead to abnormal cytoskeletal motor proteins that in turn affect intestinal cell structure and primarily cause a loss of sodium fluid absorption, also known as electrolyte transport induced diarrhea [1].

Children with MVID commonly experience high stool volume losses between 150 and 400 mL/kg/d associated with severe dehydration, metabolic acidosis, impaired renal function, and mild/severe hyponatremia [111,114,115]. Low urine sodium with low fractional Na excretion, high urine osmolality, and hyperaldosteronism with high urine potassium are common findings. Stool output and electrolyte derangements are exacerbated by enteral intake secondary to minimal absorptive capability and lack of intestinal transporters [1]. Exacerbation of stool output with enteral intake leads to limitations to oral intake and primary dependence on parenteral support with some variation in tolerance, as in the case of STX3 gene mutation [116]. Cholestatic liver disease can be expressed among this cohort as part of the phenotype as well as secondary to intestinal failure-associated liver disease due to long-term dependence on PN [117].

There is no medical treatment capable of overcoming the intestinal failure, with the mainstay of treatment centered around parenteral support and decreasing the risk of associated comorbid conditions. Surgically, intestinal transplantation has shown promise [115,118–120], and subtotal enterectomy as a means to better control bowel losses or as a bridge to transplantation has been recently described [121].

Management

Patients with MVID are managed exclusively with PN and IV fluids. Nutritional management aims to provide adequate nutrients, promote growth, and replace fluid and electrolyte losses, with patients often requiring greater than twice the estimated maintenance fluid daily provision. Ongoing assessment of fluid balance is critical for prevention of electrolyte dysregulation and kidney injury, while cycling of PN is dependent on clinical and laboratory signs of hydration. Given intestinal loss of bicarbonate and sodium, patients often require substantial PN provision of sodium and acetate. Usually, sodium provision in PN can range between 9 and 17 mEq/kg/d, with acetate often maximized in PN and ranging between 6 and 16mEq/kg/d with additional enteral supplementation in the form of sodium bicarbonate (i.e., baking soda) to prevent acidosis (authors’ personal experience).

The lifelong dependence on PN requires close monitoring for possible multiple comorbid conditions (Supplemental Note 2). Micronutrient deficiencies can include copper and zinc due to high stool output [122], requiring periodic monitoring. Iron deficiency anemia can often be appreciated in the setting of minimal nutritional intake, varied absorption, and impaired epithelial function, often requiring IV iron supplementation [123]. Long-term PN support without enteral or dietary supplementation can lead to iodine deficiency when trace minerals do not include iodine; thus, routine screening may be prudent in identifying potential deficiencies [124]. Possible metabolic bone disease can be appreciated among patients who are on PN support secondary to compounding limitations of calcium, phosphate, and vitamin D (in multivitamin formulation) with need for additional enteral vitamin D, vitamin K, and calcium supplementation [125]. A balanced lipid emulsion with a low proinflammatory profile and cycling is recommended to reduce the risk of intestinal failure-associated liver disease. Reliance on long-term PN utilization can be associated with risk for aluminum toxicity given PN composition and requires monitoring [126]. Given patients’ predominant dependence on PN with symptoms exacerbated by enteral intake, oral aversion may be seen early in life

Tufting enteropathy

Tufting enteropathy is characterized by neonatal diarrhea with nutrient malabsorption and failure to thrive. It is an epithelial mediated disorder with disruption in cell adhesion regulation caused by mutation in the EPCAM gene (MIM #613217) leading to disorganization of villi [1] appearing with intestinal villous atrophy and “villi tufts.” Patients can present with a varied degree of malabsorption and dependence on PN, and some can be weaned off total PN over time. In one cohort in Malta and the United Kingdom, those who achieved enteral autonomy were more likely to be older, requiring less caloric support, with up to 75% of patients being fully enterally dependent by age 25 [127].

Management

The dietary goal is to minimize PN dependence by advancing enteral nutrition as tolerated [127,128]. There is no consensus on an optimal dietary regimen that leads to improvement in enteral advancement, particularly as enteral tolerance and absorption differ among patients. There are conflicting reports on the benefit of elemental formula use, with some showing good tolerance whereas others show no benefit [127]. The authors’ clinical experience has noted improvement of enteral advancement with the use of blenderized formulas, including home blends that are mainly composed of complex carbohydrates (such as rice, vegetables) mixed with other food purees based on nutritional need, in addition to commercial formulas. Utilizing rice as a base ingredient has led to enteral advancement over time, likely secondary to its binding effect with bulking of stool and longer time for digestion. Enteral access (gastrostomy tube) has been beneficial among this population as this allows slow titration of nutrients over time. In general, tolerance of dairy products can be variable and likely secondary to the degree of villous atrophy. Foods and ingredients that may cause diet-induced diarrhea are generally avoided. To optimize enteral tolerance, we recommend slowly integrating protein and vegetables, one food group at a time.

From a micronutrient standpoint, patients with tufting enteropathy maintained on PN often require supplemental enteral calcium and vitamin D due to PN-compounding limitations. Close monitoring of iron stores and zinc concentrations should be routinely monitored. Patients with large-volume diarrhea may have high fluid needs and varied need for acid-base support (Supplemental Table 19, Note 3).

Trichohepatoenteric syndrome

Trichohepatoenteric syndrome (THE) is an autosomal-recessive disorder caused by mutations in TTC37 (MIM #222470) in 60% of cases and SKIV2L (MIM #614602) with diarrheal symptoms beginning in the first few months of life [129–134]. In some cases, diarrhea improves with age, allowing for a partial or complete wean from PN to elemental feeds [135,136]. A recent systematic review showed the achievement of enteral autonomy in 50% of patients with SKIV2L mutation and 22% with TTC37 mutation [99]. Clinically common and constant symptoms include intractable diarrhea, facial dysmorphism, and hair abnormalities, and in ~90% of the reported cases, immunodeficiency, growth failure, short stature, and intrauterine growth retardation. Other symptoms with varying penetrance are frequent liver disease, skin abnormalities, platelet anomaly, or congenital cardiac defects [129,131–133,137–144]. Nutritional deficiencies are common in patients with THE and include FSV deficiencies, particularly vitamin D, and deficiencies in zinc, selenium, and iron.

Management

The main goal of treatment is to minimize PN use and advance enteral nutrition [135,145]. Patients who have been weaned off PN support often relied on a combination of an oral diet (with no reported restrictions) and formula supplementation either by mouth or via gastrostomy tube [136,146]. Most case studies report utilizing amino acid-based formulas, although there is no evidence that polymeric or semielemental formulas are not well tolerated [146,147]. Lactose-free, low MCT formulas are generally better tolerated. Oral diet recommendations include a standard high calorie, high protein diet to support adequate growth. When attempting PN weaning and use of solid foods, the authors’ practice is an initial introduction of foods low in simple sugars. Starches, meats, and low-sugar vegetables are introduced first. Fruits are added after a wide selection of vegetables are tolerated. Fruits are introduced from the lowest sugar content and progress based on tolerance. Egg, soy, and cow milk protein allergies have been described; thus, slow introduction of these feeds is recommended [136]. Patients weaned off PN may require calcium, vitamin D, zinc, and selenium supplementation, and concentrations should be closely monitored at least twice per year (Supplemental Note 4; Supplemental Tables 20–21 for THE and other CODE disorders).

Discussion and Conclusions

Infants and children with CODE diagnosis pose a clinical challenge that requires close monitoring by provider.

Diet and nutritional management remain at this stage the most effective supportive therapy for children with CODE and in specific defects it can lead to symptom resolution. Appropriate enteral or parenteral treatment allows normal growth and development and avoids electrolyte and micronutrient deficiencies. Stratification of enteral diet management to the 3 approaches—elimination, supplementation, and general restriction—provides a practical framework to the nutritional management of the various CODE groups.

Additional clinical studies and observations focusing on diet and nutrition support will provide stronger evidence to current anecdotal clinical experiences and will improve the outcome of patients with CODE.  

Link to Supplemental Tables

USDA nutrient database: https://fdc.nal.usda.gov/