Disorders of Digestion in the Neonate



Disorders of Digestion in the Neonate


Catherine Larson-Nath, Bhaskar Gurram and Gisela Chelimsky


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 coined many years ago by Avery to describe chronic, unexplained diarrhea in young children.1 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.2 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, typically osmotic diarrhea 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 92-1). 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 in celiac disease.3 In the absence of carbohydrate malabsorption in a patient with osmotic diarrhea, it is essential to determine whether steatorrhea is present (Table 92-2). 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 92-1.



Box 92-1   Causes of Infantile Chronic and Protracted Diarrheal Illness








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.4 These carbohydrate hydrolases convert disaccharides and oligosaccharides into simple monosaccharides that are absorbed easily through transport proteins that exist on the intestinal surface.5 These proteins include maltase-glucoamylase,4 sucrase-isomaltase (SI), and lactase-phlorhizin hydrolase.6 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 92-3) and give clues to the etiology of the diarrhea.



Patients with carbohydrate malabsorption disorders, regardless of the cause, present with severe watery diarrhea, which results from osmotic action exerted by the malabsorbed oligosaccharide4 (lactose, sucrose, or glucose) in the intestinal lumen. The malabsorbed sugars are then fermented by colonic bacteria, producing a mixture of gases (e.g., hydrogen, methane, carbon dioxide)4 and short-chain fatty acids.7 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.4 The increased volume associated with low pH will stimulate gut motility, decreasing intestinal transit time.1 In this kind of disorder, the diarrhea resolves when oral feeds are discontinued.



Disaccharidase Deficiencies


Congenital Sucrase-Isomaltase Deficiency


Congenital sucrase-isomaltase deficiency is the most common congenital disorder of carbohydrate malabsorption.8 This deficiency is most common in native Canadians, Inuits, and Greenland Eskimo populations (3% to 10%). The prevalence in North American populations is around 0.2%.9



Etiology.

Congenital sucrase-isomaltase deficiency is caused by reduced activity of the brush border enzyme sucrase-isomaltase.10 It is transmitted in an autosomal recessive form.10 However, some heterozygotes can be symptomatic.11 Several theories have been proposed for the pathogenesis of this enzyme deficiency, and there are at least seven known phenotypes.9




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 testing13 is a noninvasive test to evaluate for sucrase-isomaltase deficiency, but is not specific for a congenital deficiency and will be abnormal also if there is mucosal injury and secondary disaccharidase deficiency.14 The gold standard for diagnosis is endoscopy with biopsies analyzing the actual enzyme level.9 Treatment consists of strict lifelong avoidance of sucrose-containing fruits and beverages.14 Affected patients can try a supplemental sacrosidase (Sucraid) when ingesting sucrose-containing foods.15,16



Congenital Lactase Deficiency


Congenital lactase deficiency is a very rare autosomal recessive disorder. The babies usually present very soon after birth with watery diarrhea, vomiting, poor weight gain, lactosuria, aminoaciduria, and changes in the nervous system.17,18 Most of the cases reported are from Finland, where more than 42 cases17 have been described since the first documented diagnosis in 1959.19 More recently, mutations have been reported in a Japanese infant20 and patients from Italy and Turkey.21



Etiology.

Congenital lactase deficiency is caused by the deficiency of lactase, in the small intestine and has been linked to chromosome 2q21.17 Villous architecture of the intestinal mucosa is preserved, as seen on biopsy specimens of the small intestine.4 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 co-workers have reported it in association with other disaccharidase deficiencies such as maltase-glucoamylase.5



Clinical Features.

The symptoms appear when a 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.17 As with other disaccharidase deficiencies, the stool is acidic. The diarrhea resolves after switching to a lactose-free formula,9 which confirms the diagnosis. Apart from diarrhea, these babies are lively and have a good appetite; they exhibit poor weight gain but no vomiting.9,22 Occasionally, they can have hypercalcemia and nephrocalcinosis.22 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.22 As a result of metabolic acidosis, the urinary excretion of citrate decreases, producing hypocitruria, which associated with the hypercalcemia facilitates the development of nephrocalcinosis.23




Maltase-Glucoamylase Deficiency


Maltase-glucoamylase is a brush border hydrolase 5 that serves as an alternate pathway for starch digestion. It compensates partially for the lack of sucrase-isomaltase and vice versa.4 Congenital maltase-glucoamylase deficiency, first described in 1994, is very rare,6 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.5 Therefore, patients may have a deficiency of both enzymes.





Transport Defects


Glucose-Galactose Malabsorption


Glucose-galactose malabsorption is a rare disorder, with about 300 cases described in the literature worldwide.4 This disorder is more common in populations with a high rate of consanguinity. Infants present in the neonatal period with severe watery diarrhea, which can lead to rapid dehydration and death.4 Clinically, it cannot be differentiated from congenital lactase deficiency.23 It was first reported in 1962 in Sweden by Lindquist and Meeuwisse25 and is transmitted in an autosomal recessive manner.26



Etiology.

Glucose-galactose malabsorption derives from a defect in the intestinal glucose-galactose transport protein, SGLT1,4 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.4,23 The transporter has been mapped to chromosome 22q13.1, which is the site of the gene SLC5A1.27 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.

These infants present at the start of breastfeeding or ingestion of glucose-containing formula with severe watery diarrhea that often can be confused with urine. The predominant sugar of breast milk is lactose, which is hydrolyzed to glucose and galactose before being absorbed. The severe diarrhea can lead to rapid dehydration and electrolyte imbalance.26 This is an osmotic acidotic diarrhea caused by fermentation of the nonabsorbed sugar by the bacteria. 4 If undiagnosed, this diarrhea can rapidly progress to death. A stool test is positive for reducing substances.23 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.23 Case reports of nephrocalcinosis and urinary calculus formation in patients with glucose-galactose malabsorption have been described in the literature.23,26,28 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.23,28



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.4 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.4 The treatment consists of avoiding the “offending” sugars by using a fructose-containing formula.23 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;29 therefore, infants rely on gastric lipase for fat digestion.30


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 a great marker highly sensitive and specific for pancreatic insufficiency.31 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.32 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.33 It is also the most common cause of exocrine pancreatic insufficiency and lung disease in childhood.34 Although in the past, the prognosis was very poor in childhood, currently the estimated survival is 38 years.35


Cystic fibrosis affects between 1 in 1900 and 1 in 3700 live births in the white population,36 and is much less common among African Americans (1 in 17,000)36 and Asian populations (1 in 90,000).33 Despite these racial differences, CF should be considered in the differential for any child who presents with poor weight gain and chronic lung disease.37



Etiology.

Cystic fibrosis is transmitted in an autosomal recessive manner.34 In whites, about 1 in 20 individuals have the recessive form of the allele.38 In 1989, the gene responsible for CF was cloned.39 The cystic fibrosis transmembrane conductance regulator (CFTR) gene is located on chromosome 7q31.2.40 Currently, more than 1600 mutations in the CFTR gene have been described and about 1300 are thought to be pathogenic.40 The ΔF508 mutation accounts for two thirds of mutations in patients with CF.40



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.36 On abdominal x-rays, the small bowel loops may have a ground-glass appearance (Neuhauser sign) resulting from dilated loops of bowel with bubbles of gas and meconium without air-fluid levels. 37 The infants may also present with microcolon.4 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.37 The presence of meconium plug syndrome, which is a temporary obstruction of the distal colon, should also raise concerns for the possibility of CF.37


Another common presentation of CF is chronic diarrhea secondary to pancreatic fat malabsorption.9 Some CF mutations (class I-III) present earlier in life, usually within the first month with pancreatic insufficiency.41


Infants can present less commonly with extrahepatic biliary duct obstruction as a result of thick inspissated bile.37 Therefore, CF should be included in the differential diagnosis of any neonate with prolonged conjugated hyperbilirubinemia.36 Two to five percent present with symptomatic portal hypertension.42 All infants or children with pancreatic insufficiency have poor weight gain.37 Children and infants may have also respiratory symptoms.42



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.43 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.44 The diagnosis is confirmed by a sweat chloride test showing a chloride greater than 60 mEq/L,36 which is present in 99% of patients with CF.36 However, certain conditions may give falsely positive and negative values.33,36 When confirming the diagnosis of CF, the sweat test should be done in centers certified by the Cystic Fibrosis Foundation.33 Genetic testing can also be performed.45 Nevertheless, even with the most comprehensive testing, 1% to 5% of the mutation will be missed.40


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. If the pregnancy is not terminated, then the diagnosis should be confirmed by sweat testing after birth.37



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,4 and focuses on caloric intake, the replacement of fat-soluble vitamins, and the provision of supportive care.37 Any child with a fecal elastase level less than 200 µg/g should be treated with pancreatic enzyme supplementation.46 Pancreatic enzymes are generally well tolerated, but attention should be given not exceed 50,000 units of lipase per kilogram because of concerns of fibrosing colonopathy.47



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),48 Bodian and colleagues in the United Kingdom (1964),49 Burke and co-workers in Australia (1967),50 and Shwachman in the United States (1964).51 Although it is a rare cause of pancreatic insufficiency, it is the second most common cause of bone marrow failure.52 It has been reported in the North American population (1 in 50,000), Europe, Asia, and Africa.4




Clinical Features.

Patients present with failure to thrive in infancy secondary to exocrine pancreatic insufficiency and variable degrees of bone marrow failure.54 The most common hematologic abnormality is neutropenia with defective neutrophil chemotaxis, resulting in frequent bacterial infections.55 The neutropenia is cyclic, ranging from low values to normal white cell counts.52 These patients may also have anemia and thrombocytopenia.4 The bone marrow is hypocellular and is replaced with fatty infiltration.53



Diagnosis and Treatment.

Diagnosis of Shwachman-Diamond syndrome requires fulfillment of two criteria. The first criterion is demonstration of a hematologic cytopenia, which includes any of the three cell lines. The neutropenia is usually cyclic; therefore, neutrophils of less than 1.5 × 109/L must be demonstrated on two separate occasions over at least a 3-month period. The second criterion is documentation of exocrine pancreatic insufficiency.56 Other findings support the diagnosis of Shwachman-Diamond syndrome, such as persistent elevation of hemoglobin F, persistent macrocytosis, abnormal 72-hour fecal fat, reduced levels of at least two fat-soluble vitamins, evidence of pancreatic lipomatosis, bone abnormalities, behavioral problems, or the presence of other family members with Shwachman-Diamond syndrome. Genetic testing is available, but up to 10% of patients are negative for mutations in the SBDS gene.57


The management of children with Shwachman-Diamond syndrome includes pancreatic enzyme replacement and supportive care. When the cytopenia is severe, these patients may require G-CSF therapy and blood and platelet transfusion.57 Children should be monitored by measuring CBC, levels of fat-soluble vitamins, growth, bone density, and neuropsychological functioning.57



Johanson-Blizzard Syndrome


Johanson-Blizzard syndrome (JBS) is a very rare autosomal recessive disorder that was first described in 1971 by Johanson and Blizzard,19 and there are still fewer than 100 patients reported worldwide.58




Clinical Features.

Affected infants have characteristic phenotypic features, including aplastic alae nasi (which gives the appearance of a beaklike nose with large nostrils),60 extension of the hairline to the forehead with upswept frontal hair,61 low-set ears, large anterior fontanelle, micrognathia, thin lips, microcephaly,62 aplasia cutis (patchy distribution of hair with areas of alopecia), dental anomalies, poor growth, pancreatic exocrine aplasia, and anorectal anomalies (mainly imperforate anus).60,63 Other findings include mental retardation, deafness, genitourinary abnormalities, hypothyroidism, cardiac malformations,60 cholestatic liver disease,64 growth hormone deficiency,63 and transfusion-dependent anemia.65



Diagnosis.

Patients present with exocrine pancreatic insufficiency with poor weight gain, failure to thrive, hypoalbuminemia, edema, and anemia.60 Sometimes, prenatal ultrasound can show a beaklike nose and dilation of the sigmoid colon as a result of an imperforate anus.60 These infants have normal karyotype60 and normal sweat chloride.



Miscellaneous Causes of Pancreatic Insufficiency


Many other syndromes and diagnoses can be associated with pancreatic insufficiency. Donlan syndrome is similar to JBS, but with normal alae nasi and cleft palate.61 Pearson syndrome is characterized by pancreatic insufficiency, sideroblastic anemia,61 variable neutropenia, thrombocytopenia, and vacuolization of bone marrow precursors.4 Jeune syndrome is a rare autosomal recessive disorder of pancreatic insufficiency and asphyxiating thoracic dystrophy.4 Isolated deficiencies of amylase, lipase, colipase, and trypsinogen have also been described. Familial pancreatitis with mutations in the trypsinogen gene can cause chronic pancreatitis, pancreatic insufficiency, and chronic diarrhea.



Defective Handling of Bile Acids


Chronic diarrhea can also stem from alterations in bile acid metabolism and enterohepatic circulation. These disorders should be considered when the more common causes of chronic diarrhea have been ruled out. Bile acid diarrhea happens when there is disease or resection of the terminal ileum as well as congenital conditions affecting the terminal ileum, which disrupt the enterohepatic circulation.67 The enterohepatic circulation of bile is the primary mechanism by which the body reabsorbs 98% of the bile that then is reused as bile salts.66 When the bile is not reabsorbed, it reaches the colonic mucosa with subsequent secretion of fluid and electrolytes, leading to diarrhea, steatorrhea, and decreased blood cholesterol levels.67



Primary Bile Acid Malabsorption



Etiology.

Primary bile acid malabsorption is linked to a missense mutation in the sodium–bile acid cotransporter gene, SCL10A2.67,68 The pathophysiology is not clear, but may be related to a reduced secretion of the hormone fibroblast growth factor 19, which prevents bile acid secretion through a negative feedback mechanism. When this factor is decreased, then the excessive bile acid leads to diarrheal fat malabsorption and secretion of fluids from the colonocytes secondary to bile acid stimulation.69,70




Diagnosis and Treatment.

The measurement of bile acids in stool is done mainly for research.69 Clinically, it can be done by ingesting a capsule with a gamma emitter selenium 75-homocholic acid taurine (SeHCAT), which is a selenium-labeled bile acid. The results are expressed as a percent retention, with retention of less than 10% after 7 days having a sensitivity of up to 100% and specificity of up to 94% for primary bile acid malabsorption.69,70 The treatment of primary bile acid malabsorption is the use of bile acid resins such as cholestyramine, which prevents the secretory action of bile acids.69,70

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Jun 6, 2017 | Posted by in PEDIATRICS | Comments Off on Disorders of Digestion in the Neonate

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