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Disorders of Digestion in the Neonate
Chronic and prolonged diarrhea is a symptom complex with a variety of underlying etiologies. This chapter focuses on the approach to infants with protracted diarrhea and is a review of recent literature on infantile diarrheal illnesses.
Intractable diarrhea is a term developed many years ago by Avery to describe chronic, unexplained diarrhea in young children. This phrase describes a symptom complex rather than a discrete disease entity and is not favored by many experts. Protracted diarrhea has been used more recently to describe infants with loose and frequent stools of sufficient severity to require nutritional support in the form of parenteral alimentation. This emphasis on adequate support of total caloric intake and nutritional rehabilitation has dramatically improved the survival of affected infants.
Diarrhea is classified as either secretory or osmotic; however, in several cases both mechanisms may be involved. A strategic problem in these diarrheal disorders is the presence of fluid and electrolyte secretion into one or more segments of the small intestine, large intestine, or both. Secretory diarrhea is the result of either impaired absorption of NaCl from villous enterocytes or increased chloride secretion from crypt cells, secondary to exogenous toxins from bacteria or viruses or endogenous substances (hormones, neurotransmitters, or cytokines), or from inherent defects in the sodium or chloride channels. The secretory diarrhea usually presents as a large volume of watery stools and does not improve with fasting. Osmotic diarrhea results from nonabsorbable substances in the intestinal lumen, which increases the osmolality of the luminal contents. This results in either retention of fluid or secretion of fluid into the intestinal lumen, therefore leading to diarrhea. In contrast to secretory diarrhea, osmotic diarrhea typically improves with fasting. Osmotic diarrhea can be distinguished from secretory diarrhea by measuring the electrolyte concentration in the stool and the osmotic gap. In osmotic diarrhea, there is a significant osmotic gap (>50 mOsm/kg) between the stool osmolality and twice the concentrations of sodium and potassium in the stool ( Table 83.1 ). However, in clinical practice, usually the diagnosis is made by a trial of fasting to determine if there is improvement in the stool output. Some diarrheal disorders may have a secretory and osmotic component, as is sometimes seen for example in celiac disease. In the absence of carbohydrate malabsorption in a patient with osmotic diarrhea, it is essential to determine whether steatorrhea is present ( Table 83.2 ). Although diarrhea alone may be responsible for an increase in fat excretion of up to 11 g per day (normally <7 g fat/day is excreted by persons consuming 100 g fat/day), when larger amounts of fat are found in the stool the patient should be evaluated for a disorder of fat absorption. Based on the description of diarrhea as osmotic or secretory or mixed osmotic and secretory components, infantile diarrheal etiologies can be distinguished, as shown in Box 83.1 .
TABLE 83.1
Differentiating Osmotic From Secretory Diarrhea
| Osmotic | Secretory | |
|---|---|---|
| Stool volume | Small | Large |
| Response to fasting (72 hours) | Improves | Unchanged |
| Stool sodium | <70 | >70 |
| Stool osmotic gap (290-2[stool Na+stool K]) | >50 | <50 |
TABLE 83.2
Clues to Distinguish Osmotic Diarrhea From Carbohydrate Versus Fat Malabsorption
| Isolated Carbohydrate Malabsorption | Isolated Fat Malabsorption | |
|---|---|---|
| Stool character | Loose and watery Non-foul-smelling |
Bulky large stool Foul-smelling Oil droplets visible |
| Perianal rash/skin erosion | + | + |
| Signs of fat soluble vitamin deficiency | ± | + |
| Stool pH | Acidic (usually <6) | Alkaline |
| Stool reducing/nonreducing substances | + | − |
Box 83.1
Causes of Infantile Chronic and Protracted Diarrheal Illness
Osmotic Diarrhea
-
Carbohydrate Malabsorption
-
Glucose-galactose malabsorption
-
Sucrase-isomaltase deficiency
-
Congenital lactase deficiency
-
Maltase-glucoamylase deficiency
-
-
Fat Malabsorption
-
Pancreatic insufficiency
-
Defective handling of bile acids—primary bile acid malabsorption, cholestasis
-
Defective mucosal lipid handling—intestinal lymphangiectasia, abetalipoproteinemia, chylomicron retention disease
-
-
Protein Malabsorption
-
Primary enterokinase deficiency
-
Hartnup disease
-
Secretory Diarrhea
-
Normal Villous Architecture
-
Chloride-losing diarrhea (Cl − -HCO 3 − exchanger defect)
-
Sodium-losing diarrhea (Na + -H + exchanger defect)
-
Neurogenin-3 mutation
-
-
Villous Atrophy
-
Microvillous inclusion disease
-
Tufting enteropathy
-
Acrodermatitis enteropathica
-
Trichohepatoenteric syndrome (phenotypic or syndromic diarrhea)
-
Congenital disorders of glycosylation defects (CDG1b)
-
Combined Secretory and Osmotic Diarrhea (Partial Response to Fasting With Some Decrease in Diarrhea)
-
Autoimmune Enteropathy and Infantile Onset Inflammatory Bowel Disease
-
IL10/IL10R defects
-
Hyperimmunoglobulin D from mevalonate kinase deficiency presenting as severe neonatal colitis
-
IPEX/IPEX-like syndrome
-
-
Infectious Enteropathies
-
Postinfectious Enteropathies
-
Allergic Enteropathy
-
Idiopathic
Disorders of Carbohydrate Absorption
The enterocytes in the small intestine have at their apical surface brush border various enzymes responsible for the digestion of carbohydrates. These carbohydrate hydrolases convert disaccharides and oligosaccharides into simple monosaccharides that are absorbed easily through transport proteins that exist on the intestinal surface. These proteins include maltase-glucoamylase, sucrase-isomaltase (SI), and lactase-phlorhizin hydrolase. The clinical symptoms of carbohydrate malabsorption occur either because of the deficiency of a particular enzyme (e.g., congenital sucrase-isomaltase deficiency) or because of an abnormality in a transport protein involved with the absorption of digestion product (e.g., glucose-galactose malabsorption). Obtaining a detailed feeding history may yield a correlation between the age the diarrhea started and the particular food that was introduced into the baby's diet ( Table 83.3 ) and give clues to the etiology of the diarrhea.
TABLE 83.3
Age of Onset of Different Carbohydrate Malabsorption Syndromes
| Age of Onset | Disorder |
|---|---|
| Immediate neonatal period | Glucose-galactose malabsorption Congenital lactase deficiency |
| Weaning age | Glucoamylase deficiency Congenital sucrase-isomaltase deficiency |
Patients with carbohydrate malabsorption disorders, regardless of the cause, present with severe watery diarrhea, which results from osmotic action exerted by the malabsorbed oligosaccharide (lactose or sucrose) in the intestinal lumen. The malabsorbed sugars are then fermented by colonic bacteria, producing a mixture of gases (e.g., hydrogen, methane, carbon dioxide) and short-chain fatty acids. In normal digestion, the short-chain fatty acids are absorbed via the colonic epithelium, providing energy and decreasing the colonic osmolality. In the presence of a large carbohydrate load, these protective mechanisms become overwhelmed, causing diarrhea. The increased volume associated with low pH will stimulate gut motility, decreasing intestinal transit time. In this kind of disorder, the diarrhea resolves when oral feeds are discontinued.
Disaccharidase Deficiencies
Congenital Sucrase-Isomaltase Deficiency
Congenital sucrase-isomaltase deficiency (CSID) is the most common congenital disorder of carbohydrate malabsorption. CSID is most common in native Canadians, Inuits, and Greenland Eskimo populations (3%-10%). The prevalence in North American populations is around 0.05%-0.2%.
Etiology
Congenital sucrase-isomaltase deficiency leads to reduced activity of the brush border enzyme sucrase-isomaltase and an inability to metabolize specific carbohydrates like sucrose, maltose, and starch. It is transmitted in an autosomal recessive form. However, some heterozygotes can be symptomatic. Several theories have been proposed for the pathogenesis of this enzyme deficiency, and there are at least seven known phenotypes.
Clinical Features
Patients present with diarrhea, abdominal pain, and bloating upon ingestion of sucrose, maltose, and starch, typically noticed around the age of 3-6 months when the infant is weaned from breast milk to baby foods that contain sucrose. If the baby has been switched to a sucrose-containing formula, the diarrhea will develop earlier, around the time of the dietary change. Affected infants present with severe, chronic, or intermittent watery diarrhea; abdominal distention; cramping; metabolic acidosis; and failure to thrive. Severity of symptoms is influenced by residual enzymatic activity, levels of carbohydrate intake, gut motility, and colonic fermentation. The stool pH is less than 7 as a result of fermentation of unabsorbed carbohydrates by colonic bacteria, but because sucrose is a nonreducing sugar, Clinitest or a test for stool-reducing substances is negative.
Diagnosis and Treatment
A detailed history will provide the correlation of the onset of diarrhea and the dietary changes. Stools are acidotic but test negative for reducing substances. Stool osmolality reveals an elevated osmolar gap (>50 mOsm), indicating the presence of malabsorbed sugars. Sucrose hydrogen breath testing is a noninvasive test to evaluate for sucrase-isomaltase deficiency, but it is not specific for a congenital deficiency and will be abnormal also if there is mucosal injury and secondary disaccharidase deficiency, for example, from bacterial overgrowth. The gold standard for diagnosis is endoscopy with biopsies analyzing the actual enzyme level. Treatment consists of strict lifelong avoidance of sucrose-containing fruits and beverages. Affected patients can try a supplemental sacrosidase when ingesting sucrose-containing foods. One study has documented a poor response to diet restriction and a good response to enzyme replacement therapy with supplemental sacrosidase at 8500 U at meal times.
Congenital Lactase Deficiency
Congenital lactase deficiency is a very rare autosomal recessive disorder. Patients usually present very soon after birth with watery diarrhea, vomiting, poor weight gain, lactosuria, aminoaciduria, and changes in the nervous system. Most of the cases reported are from Finland, where more than 42 cases have been described since the first documented diagnosis in 1959. More recently, mutations have been reported in a Japanese infant and patients from Italy and Turkey.
Etiology
Congenital lactase deficiency is caused by the deficiency of lactase in the small intestine and has been linked to chromosome 2q21. Villous architecture of the intestinal mucosa is preserved, as seen on biopsy specimens of the small intestine. Congenital lactase deficiency is different from the adult-type hypolactasia, which is very common. Usually, congenital lactase deficiency is an isolated deficiency, but Nichols and coworkers have reported it in association with other disaccharidase deficiencies such as maltase-glucoamylase.
Clinical Features
The symptoms appear when lactose-containing milk is introduced to the diet. Breast milk and other commercial formulas have lactose; therefore, the onset is usually within the first 10 days of life. As with other disaccharidase deficiencies, the stool is acidic and the diarrhea resolves after switching to a lactose-free formula, which confirms the diagnosis. Apart from diarrhea, these babies are lively and have a good appetite; they exhibit poor weight gain but no vomiting. Occasionally, they can have hypercalcemia and nephrocalcinosis. The hypercalcemia is probably secondary to the metabolic acidosis or to enhanced absorption of calcium in the ileum, facilitated by the nonabsorbed lactose. The hypercalcemia resolves after starting a lactose-free diet. As a result of metabolic acidosis, the urinary excretion of citrate decreases, producing hypocitruria, which, associated with the hypercalcemia, facilitates the development of nephrocalcinosis.
Diagnosis and Treatment
Congenital lactase deficiency can be diagnosed by obtaining a good dietary history and can be demonstrated by a lack of increase in blood sugar after a load of lactose. The blood sugar does increase after the intake of individual monosaccharides and other disaccharides. The diagnostic gold standard is quantification of the enzyme levels from duodenal biopsy specimens, but this may not be possible in all cases.
The treatment consists of avoiding lactose-containing formula and breast milk. When treated appropriately, patients have good catch-up growth with normal psychomotor development. Some patients may even tolerate supplementation with lactase as they age.
Maltase-Glucoamylase Deficiency
Maltase-glucoamylase is a brush border hydrolase that serves as an alternate pathway for starch digestion. It compensates partially for the lack of sucrase-isomaltase and vice versa. Congenital maltase-glucoamylase deficiency, first described in 1994, is very rare, with an estimated incidence of 1.8% among children with congenital diarrhea. Maltase-glucoamylase is very similar to sucrase-isomaltase (59% homology) and has two catalytic sites that are identical to those of sucrase-isomaltase. Therefore, patients may have a deficiency of both enzymes.
Clinical Features
The clinical symptoms are very similar to other disaccharidase deficiencies with diarrhea, abdominal distention, and bloating. In this disorder, the symptoms start with the introduction of starch into the infant's diet, usually at the time of weaning.
Diagnosis and Treatment
Endoscopy with biopsies will show decreased levels of the enzyme when symptomatic treatment requires starch elimination from the diet.
Transport Defects
Glucose–Galactose Malabsorption
Glucose–galactose malabsorption is a rare disorder. Infants present in the neonatal period with hypernatremia and severe watery diarrhea, which can lead to rapid dehydration and death. Clinically, it cannot be differentiated from congenital lactase deficiency. It was first reported in 1962 in Sweden by Lindquist and Meeuwisse and is transmitted in an autosomal recessive manner.
Etiology
Glucose–galactose malabsorption derives from a defect in the intestinal glucose–galactose transport protein, SGLT1, located on the brush border membrane. SGLT1 transports glucose and galactose intracellularly coupled with Na + , using an electrical gradient to transport against the concentration gradient. The transporter has been mapped to chromosome 22q13.1, which is the site of the gene SLC5A1 . Multiple mutations have been identified in the SLC5A1 gene, but not all mutations produce glucose–galactose malabsorption; therefore, the results of mutation analysis must be used in combination with dietary changes and intestinal biopsy when trying to establish the diagnosis.
Clinical Features
The predominant sugar of breast milk is lactose, which is hydrolyzed to glucose and galactose before being absorbed. Therefore, these infants present at the start of breastfeeding or with ingestion of glucose-containing formula. This severe watery diarrhea is often confused with urine. This diarrhea can lead to rapid dehydration and electrolyte imbalance. The diarrhea is osmotic and acidotic, caused by fermentation of the nonabsorbed sugars (glucose and galactose) by the bacteria. If undiagnosed, this diarrhea can rapidly progress to death. A stool test is positive for reducing substances. An oral glucose tolerance test demonstrates a flat glucose tolerance curve with the presence of glucose in stools. The histology is normal on endoscopy and colonoscopy. Because SGLT1 is also expressed in renal tubular cells, patients may also have glucosuria. Case reports of nephrocalcinosis and urinary calculus formation in patients with glucose–galactose malabsorption have been described in the literature. Mechanisms responsible for renal stone formation, as explained earlier for congenital lactase deficiency, may also exist in glucose–galactose malabsorption. As with congenital lactase deficiency, hypercalcemia resolves after initiation of a glucose-free diet and control of diarrhea.
Diagnosis and Treatment
The diagnosis is made by the onset of diarrhea after the introduction of glucose, the presence of glucose in stools, hypoglycemia, hypernatremic dehydration, and normal intestinal morphology. The diarrhea improves on elimination of glucose, galactose, and lactose from the diet. The diagnosis can be further established by an abnormal glucose breath hydrogen test and SGLT1 sequencing, although these are not needed to confirm the diagnosis. The treatment consists of avoiding the “offending” sugars by using a fructose-containing formula. Parents should be counseled on looking at labels to be sure no glucose and galactose are added in foods and medications.
Fat Malabsorption
The absorption of lipids from the gastrointestinal tract occurs in five steps:
- 1.
Pancreatic enzyme lipolysis with lipase and colipase. Infants produce limited amounts of pancreatic lipase and only reach adult levels by 2 years of age ; therefore, infants rely on gastric lipase for fat digestion.
- 2.
Bile salt stabilization of fatty acids and monoglycerides to form micelles, which in turn stabilize cholesterols, diglycerides, and fat-soluble vitamins.
- 3.
Flow of micelles, fatty acids, and monoglycerides across luminal brush and transport of cholesterol across the brush border via ABC transporter protein. In the terminal ileum, the transport of bile salts is through the ASBT transport protein.
- 4.
Formation of the chylomicron and VLDL, which takes place in the enterocyte with triglycerides, phospholipids, and cholesterol. In the terminal ileum, the bile salts are bound with ileal bile acid-binding protein.
- 5.
Uptake of chylomicrons into the lymphatic system through pinocytosis.
When any of these steps is disrupted, it will result in fat malabsorption and, consequently, diarrhea.
Pancreatic Insufficiency
Pancreatic insufficiency results in the absence of pancreatic enzymes needed for nutrient digestion. Stool fecal elastase is highly sensitive and specific for pancreatic insufficiency. For an infant older than 2 weeks, elastase greater than 200 µg/g of feces is sufficient, and less than 100 µg/g of stool is considered a marker of pancreatic insufficiency. Fecal elastase may miss cases of mild pancreatic insufficiency. Some of the most common causes of pancreatic insufficiency include cystic fibrosis, Shwachman-Diamond syndrome, and Johanson-Blizzard syndrome.
Cystic Fibrosis
Cystic fibrosis (CF) is one of the most common fatal genetic disorders. It is also the most common cause of exocrine pancreatic insufficiency and lung disease in childhood. Although in the past, the prognosis was very poor in childhood, currently the estimated survival is 43 years.
Cystic fibrosis affects between 1 in 1900 and 1 in 3700 live births in the white population and is much less common among African Americans (1 in 17,000) and Asian populations (1 in 90,000). Despite these racial differences, CF should be considered in the differential for any child who presents with poor weight gain and chronic lung disease.
Etiology
Cystic fibrosis is transmitted in an autosomal recessive manner. In whites, about 1 in 20 individuals have the recessive form of the allele. In 1989, the gene responsible for CF was cloned. The cystic fibrosis transmembrane conductance regulator ( CFTR ) gene is located on chromosome 7q31.2. Currently, more than 1600 mutations in the CFTR gene have been described and about 1300 are thought to be pathogenic. The ΔF508 mutation accounts for two-thirds of mutations in patients with CF.
Clinical Features
This disorder can present very early in life with meconium ileus, which is an obstruction of the ileum as a result of thick meconium plugs. On abdominal x-rays, the small bowel loops may have a ground-glass appearance resulting from dilated loops of bowel with bubbles of gas and meconium without air-fluid levels. The infants may also present with microcolon. About half of the infants presenting with meconium ileus develop complications, including peritonitis, volvulus, atresia, and necrosis, which may show up as calcifications on abdominal x-ray. The presence of meconium plug syndrome, which is a temporary obstruction of the distal colon, should also raise concerns for the possibility of CF.
Another common presentation of CF is chronic diarrhea secondary to pancreatic fat malabsorption. Some CF mutations (class I-III) present earlier in life, usually within the first month with pancreatic insufficiency.
Infants can present less commonly with extrahepatic biliary duct obstruction as a result of thick inspissated bile. Therefore CF should be included in the differential diagnosis of any neonate with prolonged conjugated hyperbilirubinemia. If not supplemented with pancreatic enzymes, infants and children with pancreatic insufficiency have poor weight gain and worse pulmonary outcomes.
Diagnosis and Treatment
Since 2010, every state in the United States plus the District of Columbia includes screening for CF as part of the newborn screen. The screening program is less accurate in children with less common alleles; therefore, a normal newborn screen does not rule out the presence of CF. The diagnosis is confirmed by a sweat chloride test showing a chloride greater than 60 mEq/L, which is present in 99% of patients with CF. However, certain conditions may give falsely positive and negative values. When confirming the diagnosis of CF, the sweat test should be done in centers certified by the Cystic Fibrosis Foundation. Genetic testing can also be performed. Nevertheless, even with the most comprehensive testing, 1%-5% of the mutation will be missed.
The prenatal diagnosis of CF can be done based on the carrier status of the parents by mutational analysis of fetal cells obtained by chorionic villus sampling or amniocentesis. The diagnosis should be confirmed by sweat testing after birth.
Management
The management of infants and children with CF is a multidisciplinary team effort that includes a gastroenterologist, a pulmonologist, a nutritionist, and a social worker, and it focuses on caloric intake, the replacement of fat-soluble vitamins, meticulous pulmonary toilet and chest physiotherapy, pancreatic enzyme replacement, and the provision of supportive care. Any infant with a fecal elastase level less than 200 µg/g or with a mutation associated with pancreatic insufficiency should be treated with pancreatic enzyme supplementation.
Shwachman-Diamond Syndrome
The Shwachman-Diamond syndrome complex includes exocrine pancreatic insufficiency, bone marrow failure, and skeletal changes. It was described by many groups, including Nezelof and Watchi (1961), Bodian and colleagues in the United Kingdom (1964), Burke and coworkers in Australia (1967), and Shwachman in the United States (1964). Although it is a rare cause of pancreatic insufficiency, it is the second most common cause of bone marrow failure. It has been reported in the North American population (1 in 50,000), Europe, Asia, and Africa.
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