The diagnostic approach to CDDs is a multistep process that includes the careful evaluation of the anamnesis and clinical data, results of common laboratory and instrumental procedures and molecular analysis (–). Positive familiar history of early onset chronic diarrhea, polyhydramnios and/or dilated bowel loops at ultrasound examination during pregnancy are highly suggestive of CDDs. Frequently CDDs dates to early neonatal period [2
]. However in the approach to a newborn or infant with suspected CDDs it is important to remember that also at this particular age, infections and food allergy are frequent causes of chronic diarrhea [6
], and that these conditions together with malformations of gastrointestinal tract should be considered as primary hypothesis [2
Identification of pathogenetic osmotic or secretory mechanisms leading to diarrhea.
Diagnostic diagram of congenital diarrheal disorders determined by a secretory mechanism.
Once suspected, the fundamental step in the diagnostic process of CDDs is the identification of an osmotic or secretory mechanism leading to diarrhea (). In osmotic diarrhea unabsorbed luminal substances are responsible for accumulation of fluids in intestinal lumen and diarrhea significantly improves during fasting, whereas in secretory diarrhea fluids are actively secreted in the intestinal lumen and diarrhea continues during fasting [12
]. Furthermore, the determination of stool electrolyte concentration and fecal ion gap are important to discriminate the two mechanisms responsible of CDDs ().
If ion gap is >50 fecal osmolarity derived from ingested osmotically active nutrient or non measured ion (i.e.
). In contrast a low osmotic gap (<50) is typically observed in secretory diarrhea. It is also important to measure Cl−
concentration in the stool to rule out CCD, characterized by low ion gap due to high Cl−
fecal loss (>90 mmol/L) [13
]. When an osmotic mechanism is suspected the next step of laboratory investigation includes blood gas, blood glucose, ammonium, albumin, triglycerides and cholesterol, aminoaciduria and the search of reducing substances in the stools, steatocrit and sweat test (). Finally, intestinal biopsy with hystologic examination is crucial for the diagnosis of most CDDs, more frequently for secretory forms; even if molecular analysis, when available, could limit invasive procedures ( and ).
Panel A. Diagnostic diagram of congenital diarrheal disorders determined by an osmotic mechanism. Panel B. Diagnostic diagram of congenital diarrheal disorders determined by an osmotic mechanism.
3.1. Congenital Osmotic Diarrheal Disorders
The main conditions included in this subgroup are characterized by carbohydrate malabsorption with subsequent bacteria fermentation and increased lactic acid concentration in stools [14
]. The detection of fecal reducing substances by Clinitest (normal value < 0.5%) may suggest carbohydrate malabsorption. A stool pH between 5 and 6 is indicative but, finally, unreliable screening test for the diagnosis of sugar malabsorption. Breath test and diet trials are used to address clinical suspect. Small bowel disaccharidase activity measurement on intestinal biopsy could be avoided especially when molecular analysis is available (). In the absence of carbohydrate malabsorption in a patient with osmotic diarrhea, it is essential to determine if steatorrhea is present. Although diarrhea alone may be responsible for an increase fat excretion, and generalized malabsorptive diseases may induce steatorrhea, greater rates of fat malabsorption can be explained only by one or more defects in fat digestion and absorption [2
]. Fat malabsorption can be divided into three broad categories: intraluminal maldigestion (pancreatic insufficiency), mucosal malabsorption, and post-mucosal malabsorption related to lymphatic obstruction [15
Low triglycerides and cholesterol serum levels are typically observed in children with a- or hypo-betalipoproteinemia (ALP/HLP). Biopsy is useful to confirm diagnosis of ALP/HLP. However, molecular diagnosis may be used at this point of diagnostic work up to avoid invasive procedures. Bile salts are particularly important in lipids digestion and absorption. However, in primary bile acid malabsorption (PBAM) diarrhea is generally secretory in nature (persist while fasting) and is exacerbated by the addition of dietary fats (see also ). Among osmothic CDDs, the onset of symptoms after ingestion of specific food or the presence of extraintestinal symptoms could help the diagnosis. Fructose malabsorption should be suspected when consumption of fruit juices that contain a high proportion of fructose to glucose or an excessive amount of the non-absorbable carbohydrate sorbitol are associated with diarrhea and abdominal pain [17
]. Disorders of protein digestion are unusual but should be considered when evaluating a patient with suspected CDDs. The best characterized disorder of specific protein malabsorption is the enterokinase deficiency (EKD) [18
]. Individuals with EKD present diarrhea and hypoproteinemic edema when on diet with intact proteins, while symptoms resolve on an amino acids-based diet. The presence of diarrhea associated with tubular nephropathy, hepatomegaly and abnormal glycogen accumulation, and fasting hypoglycemia suggest the presence of Fanconi-Bickel Syndrome (FBS) [19
]. The vesciculus bullous dermatitis, located on the hands, feet, perirectal and oral region, and alopecia are a consequence of Zn2+
deficiency that could be due to excessive fecal losses of Zn2+
observed in acrodermatitis enteropathica (ADE) [20
]. Severe Zn2+
deficiency can present also with anorexia, failure to thrive, immunodeficiency and neurologic features (mental lethargy and neurosensory abnormalities) associated with chronic diarrhea. A particular form of osmotic diarrhea genetically determined is the enteric anendocrinosis (or congenital malabsorptive diarrhea, CMD) [21
]. The salient pathological fact is that the mucosa of the small intestine is essentially normal, except for the absence of enteroendocrine cells and of the enteric hormones. The number of patients described so far is too small to draw reliable conclusions about the typical clinical picture of CMD. However, the diarrhea in this condition is undoubtedly of osmotic nature. While water is well tolerated, glucose-based oral rehydration solution leads to diarrhea and the patients continue to experience diarrhea while on carbohydrate-free cow’s milk or amino-acids based formulas. These infants may be optimally managed with life-long parenteral nutrition and limited enteral nutrition [21
3.2. Congenital Secretory Diarrheal Disorders
In the approach to the infant presenting with early onset secretive chronic diarrhea intestinal biopsy is generally considered useful to identify the major forms of CDDs included in this subgroup (i.e.
, enterocytes differentiation and polarization and modulation of intestinal immune response), but also in these cases molecular diagnosis may help to limit invasive approaches (). When villous atrophy is not accompanied by an inflammatory infiltrate, defect of enterocyte differentiation and polarization including microvillous inclusion disease (MVID) and congenital tufting enteropathy (CTE) are plausible [22
]. For MVID and CTE, pregnancy and delivery are uneventful, and polyhydramnios is unusual. In these conditions severe diarrhea occurs within the first weeks of life and rapidly requires total parenteral nutrition. Several cases of CTE have been reported as being associated with phenotypic abnormalities including dysmorphic facial features, choanal atresia, esophageal atresia, and keratitis. Molecular diagnosis may be an option to avoid radiological exposure [2
]. Immune dysfunction, polyendocrinopathy X-linked syndrome (IPEX) appears as a secretory diarrhea of inflammatory nature associated with dermatitis, diabetes mellitus, thyroiditis, and hematologic disorders [23
]. Most patients develop a protein-loosing enteropathy with α-1-antitrypsin loss in stools, and hypoalbuminemia [2
]. Diarrhea often starts within 3 months of life; however a later onset has occasionally been described [3