The Financial Burden of an Undiagnosed Congenital Diarrhea Disorder

Colleen LeBlanc, yCameron Schlegel, zJamie R. Robinson, Kelly Thomsen, zjj James R. Goldenring, and Sari Acra C ongenital diarrheal disorders (CDD) are a group of rare conditions with diverse pathophysiologies that are often associated with significant morbidity or mortality. Most are caused by monogenic disorders that lead to intestinal epithelial deficits, including transporter trafficking defects (1). The correct diagnosis of the underlying condition has often been protracted or elusive, adding to the significant economic burden of treatment. Although costly, new genetic, molecular, and histochemical techniques may offer additional avenues for the early diagnosis and correct treatment of underlying disorders. Reduction in the time before diagnosis could consequently lead to a significantly reduced economic burden (1). We managed a patient who developed severe chronic diarrhea in the first few days of life whose narrative illustrates the importance of incorporating these techniques into the diagnostic approach to congenital diarrheas. The patient was referred to the pediatric gastroenterology clinic at 7 weeks of age for vomiting and severe malnutrition. He was directly admitted to the gastroenterology service for management of failure to thrive. During this first admission, he was noted to have diarrhea. The hospitalization lasted 11 weeks because of electrolyte instability (hypokalemia, hypocalcemia), refeeding syndrome, meningitis, a central line-associated blood stream infection, and feeding intolerance. Esophagogastroduodenoscopy was nondiagnostic and showed villous blunting with patchy gastric epithelial metaplasia in the duodenum. Electron microscopy was normal. Stool studies sent for malabsorption were normal except for an elevated fecal fat. Immunology was consulted and the work-up was negative for an immunologic disorder. He underwent surgery to have a central line and gastrostomy tube placed. He was discharged home on an amino acid-based formula and total parenteral nutrition (TPN). However, his symptoms of diarrhea and the side effects of persistent diarrhea continued. Overall, this patient was admitted to the hospital 31 times before the correct diagnosis was reached with some stays requiring ICU-level care. He underwent 14 central line procedures. He required enoxaparin injections for a deep vein thrombosis. He underwent a total of 7 endoscopies. He also suffered from hypogammaglobulinemia and required intravenous immunoglobulin infusions. He was transferred at one point to another major institution for a second opinion. His course was complicated as he was initially diagnosed with autoimmune enteropathy (AE) at 15 months of age when his anti-enterocyte IgA antibody (AEA) returned positive, and his routine histologic examination showed nonspecific villous atrophy. Between 15 and 40 months of age, his AE was treated with multiple different medications including steroids, tacrolimus, abatacept, and infliximab but he never completely improved during this time period. At 42 months of age, we reviewed his histopathology again using immunohistochemical staining for brush border proteins and apical transporters to assess for their presence in enterocytes and their correct polarization. We observed significant loss of apical transporters and enzymes in enterocytes at the tips of the villi, including loss of SGLT1, CD10, DPPIV, and NHE3. This suggested that the diagnosis of autoimmune enteropathy was incorrect. Subsequently, a homozygous mutation in DGAT1 (chromosome 8, 145541756 A!G) was found on whole-exome sequencing (WES), which causes a truncation of the protein. All symptoms resolved once the correct diagnosis of DGAT1 deficiency was made and he was placed on the low-fat formula Tolerex (2–4). To better understand the costs of misdiagnosis to the health care system, we analyzed the cost of patient care in this congenital diarrhea patient. In this case, it took almost 3.5 years to make the correct diagnosis. The patient spent 586 days in our hospital. Total hospital charges at our institution before the diagnosis amounted to $4,666,010. With WES, the diagnosis was made in only a few months, and total charges for the first 1.5 years after diagnosis and diet change amounted to $138,000 (Table 1). The bulk of these charges were from slowly weaning TPN because of parental fear of stopping TPN too fast and surgery for central line removal. He has had only 1 48-hour admission for diarrhea since the mutation in DGAT1 was discovered. An earlier correct diagnosis would have prevented months in the hospital and spared the patient from exposure to multiple medications with significant side effects. The charge of WES for both the patient and the mother at the time was $4000, which although expensive, is still insignificant when compared with total charges. As CDD are diverse conditions, the work-up is not straightforward. The initial diagnosis of AE in this patient was made based on a positive AEA. However, AEA are not specific to AE, and the patient never had a significantly robust response to AE treatments (5). In addition to stool tests and endoscopy to visualize the epithelium, patients must undergo genetic sequencing and immunohistochemical staining to identify cell types present and cell structure. For novel mutations, functional studies are needed to describe the changes in the epithelium caused by the mutation (1). WES is not needed in every patient as the initial genetic test since there are now congenital diarrhea genetic panels that evaluate a large number of genes, but as this case indicates, early genetic testing is crucial to timely diagnosis. Received October 2, 2019; accepted March 1, 2020. From the Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Louisiana State University Medical Center, New Orleans, LA, the yDivision of Surgical Oncology, Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA, the zDepartment of Surgery, the §Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, the jjEpithelial Biology Center, and the Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN. Address correspondence and reprint requests to Colleen LeBlanc, Department of Pediatrics, Division of Gastroenterology, Children’s Hospital New Orleans, 200 Henry Clay Avenue, New Orleans, LA 70118 (e-mail: clebl2@lsuhsc.edu). This work was supported by the National Institute of Health (NIH) grants R01 DK48370 and RC2 DK118640 to J.R.G. and a gift from the Christine Volpe Fund and a Pilot Translational Research Award to S.A. funded by the Vanderbilt Digestive Disease Center (P30 DK058404) and the Vanderbilt Institute for Clinical and Translational Research (UL1 TR002243). C.S. was supported by T32 HD060554 and T32 DK007673. The authors report no conflicts of interest. Copyright # 2020 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition DOI: 10.1097/MPG.2735 INVITED COMMENTARIES