A 9-Month-Old Girl With Chronic Diarrhea

Case Presentation

A previously healthy, 9-month-old girl presented with a skin rash to her pediatrician and was treated with a 10-day course of cefdinir for presumed impetigo. She developed diarrhea after 1 day of therapy and had up to 20 loose stools per day. The patient was solely on a cow's milk-based formula at the time of presentation, which was then changed to a soy formula. After antibiotics were discontinued the diarrhea persisted, prompting a change to a protein hydrolysate formula. However, the diarrhea continued and the skin rash worsened, resulting in hospitalization a few weeks later. She had no history of fever, vomiting, or hematochezia. No other symptoms were present.

The patient's past medical history was unremarkable. She was born at full term with a birth weight of 3.8 kg. She was conceived by in vitro fertilization. Her growth was normal. There were no significant medical issues, and other than cefdinir she was on no medications. She had no sick contacts or history of travel. The family history revealed that her mother had hypothyroidism, but there was no history of any gastrointestinal illnesses. The social history was noncontributory.

Upon examination at the time of hospitalization, the patient's vital signs were normal. Her weight and height were at the 50th percentile. She was alert, awake, well-developed, mildly dehydrated, and in no acute distress. Skin exam revealed a generalized erythematous rash consistent with staphylococcal scalded skin syndrome. Lung and heart examinations were normal. The abdomen was soft, nontender, nondistended, without hepatosplenomegaly, and with normoactive bowel sounds. Rectal exam was normal and negative for occult blood. Musculoskeletal and neurologic exams were unremarkable.

Laboratory evaluation was obtained, including complete blood count with differential and electrolytes, which were normal. Stool testing for ova and parasites, bacterial culture, and Clostridium difficile toxins A and B was negative. No white blood cells or eosinophils were noted in stool. Reducing substances were measured at 0.75% to 2% with a stool pH of 5. Results of the glucose breath test were normal. Oral feedings were initially held and diarrhea ceased. However, upon reintroduction of enteral feeding with an elemental amino acid-based formula, the diarrhea resumed.

Diagnostic Question

1. How would you interpret the results of the investigations at this point in work-up?

Simple steps can be taken to initially evaluate the cause of diarrhea in an infant. In this case, when oral intake was discontinued, the diarrhea ceased, indicating that it was an osmotic and not a secretory type of diarrhea. With the latter, diarrhea continues upon discontinuation of oral intake.

Evaluation of Diarrhea: Differential Diagnosis

Osmotic diarrhea is caused by the presence of unabsorbed nutrients in the gastrointestinal tract, frequently secondary to intestinal damage leading to impairment in digestion or absorption. The most common form is lactose intolerance in a setting of infection in which lactose is not being enzymatically cleaved and absorbed in the small intestine. It then reaches the colon in an intact form where the colonic bacteria ferment it causing an osmotic gradient that drives water into the lumen, leading to diarrhea.

Secretory diarrhea is characteristically due to epithelial cells secreting electrolytes and water into the lumen of the intestine. Several infectious agents, including Vibrio cholerae, enterotoxigenic Escherichia coli, and Cryptosporidium parvum, can cause secretory diarrhea through the production of a toxin that causes active transport of ions and water into the lumen. In addition to infectious causes, some hormones – such as vasoactive intestinal peptide, gastrin, serotonin, and acetylcholine – produced by neuroendocrine tumors can cause a secretory diarrhea.

Aside from discontinuation of oral intake, another method for differentiating osmotic from secretory diarrhea is by evaluation of the stool ion gap, calculated by the following formula: measured stool osmolarity - 2 (Na_[stool] + K_[stool]). Using this formula, secretory diarrhea presents with normal stool osmolarity with an ion gap of less than 50 mOsm in contrast to osmotic diarrhea, which causes increased osmolarity and a stool ion gap of greater than 100 mOsm.

The differential diagnosis for persistent diarrhea in an infant, outside of neonatal age, is relatively limited and includes viral, parasitic, or bacterial infection; celiac disease; milk protein allergy; and cystic fibrosis. Rare causes include immunodeficiency, autoimmune enteropathy, inflammatory bowel disease, glucose-galactose transporter defect, or congenital trypsinogen or disaccharidase deficiencies.

Diagnostic Question

2. What should be the next step in work-up to determine the etiology of the diarrhea?

The next step in the evaluation should consider that this was a case of an osmotic diarrhea, indicating malabsorption. Therefore, the evaluation should focus on the nutrient type that is not being efficiently absorbed, ie, protein, carbohydrate, or fat.

Diagnosis and Clinical Outcome

The patient had a persistent osmotic diarrhea with a negative work-up for infectious agents. The specific nutrient malabsorption can be determined on the basis of various tests: Positive reducing substances and acidic stool indicate carbohydrate malabsorption; fecal elastase level and 72-hour fecal fat collection for calculation of fat clearance can help evaluate for fat malabsorption; and measurement of the stool alpha-1 antitrypsin level investigates intestinal protein loss.

In this case, stool findings indicated carbohydrate malabsorption. Glucose breath testing was performed to evaluate for the presence of glucose-galactose transporter defect; findings were negative. Further studies that can be performed to determine the specific carbohydrate that is being malabsorbed include esophagogastroduodenoscopy (EGD) with histology and additional duodenal biopsies for determination of disaccharidase levels, and rarely electron microscopy as well as other carbohydrate-specific hydrogen breath tests (lactose, sucrose, fructose, and maltose). The patient underwent EGD; findings, including histology, were normal. Dissacharidase levels were consistent with congenital deficiency of sucrase-isomaltase and maltase (Table). Cow's milk-based formula was restarted without return of symptoms. The reintroduction of a lactose-containing formula that does not contain sucrose or isomaltose was sufficient to resolve the patient's symptoms.

Table.

Disaccharidase Activity Levels (Micromole per Minute per Gram of Protein)

Disaccharidase	Activity Level	Reference Ranges
Lactase	33.4	(23 ± 8.1)
Sucrase	0.6	(45.1 ± 19.0)
Maltase	20.3	(182.3 ± 63.8)
Palatinase (isomaltase)	3.2	(15.1 ± 4.8)

*Bold type indicates abnormal values

Discussion

Congenital sucrase-isomaltase deficiency (CSID), first defined by Weijers and colleagues in 1960, is a rare autosomal recessive genetic disorder causing chronic watery diarrhea in children. The prevalence in individuals of European descent is 0.2% and up to 5% in indigenous Greenlanders. The condition occurs due to a defect in the sucrase-isomaltase enzyme complex (SI complex). The SI complex is the most abundant glycoprotein in the intestinal brush border. Six phenotypes of CSID are based on the mutation type, severity of the disease, and location of the SI complex in the cells. Sucrase hydrolyzes 1,2- and 1,4-glucosidic bonds, whereas isomaltase hydrolyzes 1,6- linkages. SI complex overlaps with maltase glucoamylase activity (MGA), which digests products of amylolysis of starches, such as maltose and maltotriose. However, only 20% of maltase activity is covered by MGA and the other 80% is covered by the SI complex. Due to MGA activity combined with the ability of colonic bacteria to break down starches, patients with CSID gradually tolerate starches much better as they get older.

Clinical features of this disorder are variable, and the appearance of symptoms is dependent on when sucrose is introduced, the load of sucrose given, and the age of the patient. Characteristic symptoms include chronic watery diarrhea, fussiness, and vomiting. CSID is rarely associated with failure to thrive unless it presents at an early age, but occasionally signs and symptoms – such as malnutrition, dehydration, and failure to thrive – are indeed present.

Diagnosis is best aided by a good nutritional history and initial recognition of the symptoms as suspect for CSID. Other studies that can help in the diagnosis of carbohydrate malabsorption include stool pH, which shows acidic stool (pH < 5.5), and positive reducing substances in stool. Although sucrose is a nonreducing sugar, maltose, which is broken down by the SI complex, can cause the stool to be positive for reducing substances. A value of > 0.25% is considered positive. The remaining tests include a positive sucrose hydrogen breath test, and finally, a determination of sucrase and isomaltase activity from biopsy specimens taken during endoscopy.

Therapy for this disorder is aimed at sucrose, isomaltose, and maltose restriction. The degree of restriction is patient-specific. During the first year of life, restriction of sucrose- and isomaltose-containing foods generally needs to be more strict, but by age 3-4 years, a liberalization of the diet can occur. Sucrose-containing foods include onions, peas, and honey as well as some foods that contain glucose polymers. Many medications also contain sucrose. Isomaltose is found in starches and in foods with amylopectin (bread and pasta). There is a sucrase supplement available in an oral form, sacrosidase, which is prepared from Saccharomyces cerevisiae (baker's yeast). This product has been used with some benefit in patients with CSID, allowing increased sucrose intake. There is no cure for this disorder, but with restriction of the diet and the use of sucrase supplements, the symptoms and side effects can be managed.

In the case of the patient presented here, the sucrose was first introduced as a component of the antibiotic cefdinir and then upon transition to other formulas that contained corn syrup solids, thus containing isomaltose and sucrose, and so the diarrhea continued. Frequently, the formulas used in suspected cases of milk/soy protein allergy are those that contain maltose and sucrose. When solid foods are introduced, care should be taken to avoid foods with sucrose or to initiate therapy with a sucrase supplement.

This case report exemplifies the importance of a thorough feeding history when evaluating diarrhea and the difficulties that can arise by making empiric formula changes in the setting of diarrhea. The approach to diagnosing diarrhea should employ a logical stepwise approach to identify atypical causes of chronic symptoms. Simple and appropriate stool evaluation can lead to more rapid diagnosis. Finally, understanding the composition of infant and pediatric formulas is essential to ensure proper decision making.