|Year : 2016 | Volume
| Issue : 2 | Page : 112-114
Duodenal atresia and neonatal cholestasis in R117H cystic fibrosis
Jamie Harris, Shauna Sheppard, Bill Chiu, Ami Shah
Department of Surgery (Pediatric Surgery), Rush University Medical Center, Chicago, IL, USA
|Date of Web Publication||8-Apr-2016|
Department of Surgery (Pediatric Surgery), Rush University Medical Center, 1725 W. Harrison St. Suite 710, Chicago, IL 60612
Source of Support: None, Conflict of Interest: None
Cystic fibrosis (CF) has 20% associated rate of neonatal cholestasis. This presents in classic type CF, which initially can be confused with biliary atresia. Additionally, CF has been described with intestinal atresias but not duodenal atresia (DA). This is a case presentation highlighting a previously unreported presentation of R117H 5T CF mutation: A mutation that has recently been described and is not well-characterized. A retrospective review of single case was done. The newborn screen was sent per protocol. A 32 and 6/7 week gestation male was born with DA. Perinatal testing showed R117H mutation and 5T variant on separate chromosomes. His DA was repaired at 4 weeks of life. He had persistent jaundice, hepatobiliary iminodiacetic acid scan failed to identify the gallbladder, and raising concern for biliary atresia. At laparotomy, biliary tree was found to be normal on cholangiogram. Liver biopsy showed depleted interlobular bile ducts, with cholangiolar proliferation, consistent with CF induced cholestasis. This is an abnormal presentation for CF induced neonatal cholestasis and DA in the R117H 5T mutation that traditionally has been described as mild/atypical presentation of CF. Therefore, patients with this mutation who present with persistently elevated bilirubin should be evaluated for liver disease associated with CF.
Keywords: Cholestasis, cystic fibrosis, duodenal atresia
|How to cite this article:|
Harris J, Sheppard S, Chiu B, Shah A. Duodenal atresia and neonatal cholestasis in R117H cystic fibrosis. J Clin Neonatol 2016;5:112-4
| Introduction|| |
Cystic fibrosis (CF) is an autosomal recessive disease that results in a mutation in the CF transmembrane regulator (CFTR).  Many mutations have been identified. Currently the newborn screen uses immunoreactive trypsinogen (IRT) measurements, then CF screening if the IRT is elevated. Classic CF manifests with pulmonary symptoms, meconium ileus, recurrent pancreatitis or pancreatic insufficiency, and focal biliary cirrhosis due to obstruction of intrahepatic bile ducts.  This is a case report of a previously unreported constellation of symptoms, duodenal atresia (DA), and neonatal cholestasis in the R117H mutation of CF.
| Case Report|| |
A male was born at 32 and 6/7 weeks via cesarean section for premature labor and breach presentation. Prenatally, DA was diagnosed on ultrasound and confirmed on abdominal X-ray at birth [Figure 1]. Due to his prematurity, repair of his DA was postponed until he weighed 2.5 kg, at 4 weeks. He was on total parenteral nutrition for 38 days and progressed to full enteric feeding by 5 weeks of life. His newborn screen showed elevated IRT of 76.1. Subsequent testing demonstrated an R117H mutation and 5T variant on separate chromosomes, a mutation associated with CF. He had persistent jaundice, total bilirubin of 9.2 mg/dL, and direct bilirubin of 6 mg/dL at the time of discharge. As an outpatient, he underwent a hepatobiliary iminodiacetic acid scan that demonstrated narrowing of the biliary ducts and did not visualize a gallbladder [Figure 2].
|Figure 1: Neonatal abdominal radiograph: Demonstrates nasogastric tube in place as well as typical "double bubble" sign indicative of duodenal atresia|
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|Figure 2: Hepatobiliary iminodiacetic acid scan: No uptake within the gallbladder after 5 h, suggesting possible biliary atresia|
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He was readmitted, and his total bilirubin was 12.4 mg/dL, elevated aspartate aminotransferase of 134 U/L, and alkaline phosphate of 994 U/L. An abdominal ultrasound had nonvisualization of the gallbladder and a common bile duct at the upper limit of normal, without intrahepatic bile duct dilation. Other causes for liver dysfunction including TORCH infections, alpha-1 antitrypsin deficiency, hepatitis, history of urinary tract infection, or hypothyroidism were excluded.
Due to concern for biliary atresia, he underwent surgical exploration. The liver was soft, pink, and healthy appearing and the gallbladder was normal. Intraoperative cholangiogram demonstrated normal biliary architecture and passage of contrast into the duodenum [Figure 3]. A wedge liver biopsy demonstrated depleted interlobular bile ducts, prominent cholangiolar proliferation and severe cholestasis, with stage 2-periportal fibrosis, without uniform bridging of cirrhotic nodularity. The diagnosis of neonatal cholestasis secondary to his known CF was made. Since surgery, his bilirubin has returned to normal, and he does not require any additional medication for hyperbilirubinemia.
|Figure 3: Intraoperative cholangiogram: Done via gallbladder infundibulum that shows normal biliary tree (white arrow) with contrast draining into the duodenum, excluding the diagnosis of biliary atresia|
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| Discussion|| |
The presentation of CF can be highly variable depending on the mutation. Classic CF includes pulmonary complications as well as possible gastrointestinal complications, including hepatobiliary disease and meconium ileus. 
As in our case, CF can present with hepatobiliary complications. Liver disease in association with CF has been quoted as high as 30%, and in a recent retrospective review at 5.7% in infants. , Leeuwen et al. found that cholestasis occurred more frequently in patients with meconium ileus as compared to those without.  Additionally, in that study, they found that all cases of cholestasis resolved, on average by 9.2 months of age.  This, however, is not always the outcome of patients with cholestasis secondary to CF. Patients who fail to resolve their liver involvement can progress to hepatic steatosis, fibrosis, or biliary cirrhosis.  Molmenti et al. found at their pediatric transplant center, liver failure due to CF accounted for 3.5% of all pediatric liver transplantation over a 16-year period.  While the exact pathogenesis remains unclear, it is known that liver disease is a result of abnormal expression of CFTR in the apical surface of the biliary epithelium. Defects in this channel are hypothesized to affect bile fluidity and viscosity.  This bile can then accumulate either intra or extraheptically. , Clearance can be done either medical or mechanical (cholagiogram) treatment as in our case. However, if disease progresses to stenosis and fibrosis of the hepatic and common bile duct, surgical correction can become necessary.  Recently, a novel mutation of CF, c. 3871 G > T, presenting with cholestasis that initially clinically resembled biliary atresia was described.  Our patient's mutation is R117H 5T; there have not been any reports of neonatal cholestasis associated with this mutation to our knowledge.
Another congenital anomaly that our patient had was DA. DA is the result of a failure of recanalization of the duodenum early during pregnancy, with an incidence of 1/10,000.  Almost half of children affected by this will also present with another congenital abnormality, including trisomy 21, cardiac abnormalities, annular pancreas, or malrotation.  DA, however, has been described only once in conjunction with CF. Akinloye et al. reported an infant with trisomy 21 and DA, repaired on day of life two, with continued failure to pass meconium after repair.  He had a meconium ileus and genetic testing for CF was positive. While atresias have been noted in CF, they are generally of the distal small bowel or colon, and only once it has been reported with DA, as in this case. 
Over 1500 mutations have been identified to cause CF.  Of these mutations, only a small number are thought to cause clinical significance. Our patient was identified as having CF gene mutation, R117H, 5T Het, trans. The 5T variant was found on two separate chromosomes. In previous literature, there have been three variants within the R177H group, 5T, 7T, and 9T, with 5T being the only group that has shown to present with symptoms of classic CF.  The 5T mutation causes aberrant splicing and reduces the number of functional CFTR mRNA.  One common presentation for this mutation is congenital bilateral absence of the vas deferens, which leads to infertility in males.  There is no literature to our knowledge describing this mutation in association with neonatal liver disease or DA.
| Conclusion|| |
This case demonstrates an abnormal presentation for CF, neonatal cholestasis as well as DA in the R117H 5T mutation that traditionally has been described as mild/atypical presentation of CF. Therefore, patients with this mutation who present with persistently elevated bilirubin should be evaluated for liver disease associated with CF.
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Conflicts of interest
There are no conflicts of interest.
| References|| |
O'Sullivan BP, Freedman SD. Cystic fibrosis. Lancet 2009;373:1891-904.
Leeuwen L, Magoffin AK, Fitzgerald DA, Cipolli M, Gaskin KJ. Cholestasis and meconium ileus in infants with cystic fibrosis and their clinical outcomes. Arch Dis Child 2014;99:443-7.
Kobelska-Dubiel N, Klincewicz B, Cichy W. Liver disease in cystic fibrosis. Prz Gastroenterol 2014;9:136-41.
Molmenti EP, Squires RH, Nagata D, Roden JS, Molmenti H, Fasola CG, et al.
Liver transplantation for cholestasis associated with cystic fibrosis in the pediatric population. Pediatr Transplant 2003;7:93-7.
Parisi GF, Di Dio G, Franzonello C, Gennaro A, Rotolo N, Lionetti E, et al.
Liver disease in cystic fibrosis: An update. Hepat Mon 2013;13:e11215.
Greenholz SK, Krishnadasan B, Marr C, Cannon R. Biliary obstruction in infants with cystic fibrosis requiring Kasai portoenterostomy. J Pediatr Surg 1997;32:175-9.
Eminoglu TF, Polat E, Gökçe S, Ezgü FS, Senel S, Apaydin S. Cystic fibrosis presenting with neonatal cholestasis simulating biliary atresia in a patient with a novel mutation. Indian J Pediatr 2013;80:502-4.
Choudhry MS, Rahman N, Boyd P, Lakhoo K. Duodenal atresia: Associated anomalies, prenatal diagnosis and outcome. Pediatr Surg Int 2009;25:727-30.
Akinloye OW, Truong W, Giacomantonio M, Mateos D, El-Naggar W. Coexistence of meconium ileus with duodenal atresia and trisomy 21 in a newborn: A case report. J Perinatol 2014;34:875-6.
Strom CM, Crossley B, Redman JB, Buller A, Quan F, Peng M, et al.
Cystic fibrosis screening: Lessons learned from the first 320,000 patients. Genet Med 2004;6:136-40.
[Figure 1], [Figure 2], [Figure 3]