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Original Articles: Hepatology

Difficulty Achieving Vitamin D Sufficiency With High-Dose Oral Repletion Therapy in Infants With Cholestasis

Jensen, Melissa*; Abu-El-Haija, Maisam; Bishop, Warren; Rahhal, Riad M.

Author Information
Journal of Pediatric Gastroenterology and Nutrition: August 2015 - Volume 61 - Issue 2 - p 187-189
doi: 10.1097/MPG.0000000000000751
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Abstract

What Is Known

  • Vitamin D deficiency is common in infants with cholestasis.
  • Standard vitamin D dosing used in healthy infants is not adequate in infants with cholestasis.
  • Oral high-dose repletion vitamin D therapy is effective in nutritional vitamin D deficiency and cystic fibrosis.

What Is New

  • Oral high-dose repletion vitamin D therapy may not be adequate to address vitamin D deficiency in infants with cholestasis.
  • Fat-soluble vitamin levels, including vitamin D, should be monitored closely in infants with cholestasis with consideration given to administering higher enteral doses as needed.

Vitamin D deficiency is common and remains a challenge in infants with cholestasis regardless of the underlying cause of liver disease. Vitamin D deficiency can persist with chronic cholestasis despite supplementation with 230 to 1000 IU of vitamin D per kilogram per day (1). Oral high-dose repletion (HDR) vitamin D therapy, also known as stoss therapy, is effective in treatment of nutritional vitamin D deficiency rickets in infants and young children without liver disease (2). It has also been used effectively in vitamin D–deficient children with pancreatic insufficiency related to cystic fibrosis (3). There is no literature about this approach in infants with new-onset cholestasis. In this study, we describe a case series of infants with cholestasis with vitamin D deficiency at presentation at 1 to 2 months of age, treated with HDR therapy.

METHODS

This was a retrospective chart review of infants seen by the pediatric gastroenterology service at a pediatric tertiary care center from March 2010 to March 2012. The institutional review board approved the study. Patients were identified using diagnostic billing codes (using codes for elevated liver tests or cholestasis). Inclusion criteria included the following:

  1. Diagnosis of cholestasis in infancy
  2. Documented serum 25-hydroxy-vitamin D (25(OH)-D) level
  3. Received oral HDR vitamin D therapy, defined as 300,000 IU ergocalciferol (vitamin D2)

Cholestasis was defined as an abnormal direct bilirubin value based on published guidelines (4). All of the patients were started on enteral fat-soluble vitamin supplementation that included 400 to 800 IU cholecalciferol (vitamin D3) daily and on a high medium-chain triglyceride (MCT) infant formula (Pregestimil; Mead Johnson Nutrition, Glenview, IL). All of the tests for vitamin D levels were performed in the same laboratory using Roche Modular E170 analyzers. Levels were determined by chemiluminescent microparticle immunoassay (lower detection limit 0.3 ng/mL, intra-assay CV 3.8%, interassay CV 5.9%, Roche Diagnostics, Indianapolis, IN).

Oral HDR vitamin D therapy was given as 300,000 IU ergocalciferol (vitamin D2) during either 2 or 3 days while patients were hospitalized. Compliance was documented by the nursing staff. The decision to prescribe HDR therapy was at the discretion of the treating primary pediatric gastroenterologist. Patients’ weights at the time of HDR therapy (Table 1) were used to estimate daily dietary calcium based on assumed consumption of 100 kcal · kg−1 · day−1 using published content estimates for breast milk and commercial infant formula (5).

TABLE 1
TABLE 1:
Cohort characteristics and outcome

RESULTS

A total of 32 infants were identified with cholestasis during the specified study period. Based on the criteria mentioned above, 4 cases were included in this series, and are described in detail (cohort characteristics included in Table 1). The mean and median ages at presentation were 55.3 and 59.5 days, respectively. The mean and median ages at the time of HDR were 70.3 and 68.5 days, respectively. Patients received oral HDR therapy with ergocalciferol (vitamin D2) suspension either 100,000 IU daily for 3 days (cases 1, 2, and 4) or 150,000 IU daily for 2 days (case 3) based on published literature for children without cholestasis (2,6). Patients were also given daily enteral fat-soluble vitamin supplementation containing 400 to 800 IU cholecalciferol (vitamin D3). None of the patients received parenteral vitamin D. Follow-up 25(OH)-D levels were rechecked approximately 4 weeks after HDR therapy while on maintenance therapy as specified above.

Case 1

A 32-day-old full-term white female infant presented with jaundice with a direct bilirubin of 8.9 mg/dL. Workup, including hepatobiliary iminodiacetic acid scan and liver biopsy, was consistent with biliary atresia (BA). Diagnosis was confirmed by an intraoperative cholangiogram before a hepatoportoenterostomy procedure. The patient had been on breast milk with minimal supplementation of a standard infant formula. Evaluation showed an undetectable 25(OH)-D level (<4 ng/mL), which increased to 5 ng/mL with HDR.

Case 2

A 70-day-old full-term white female infant presented with jaundice and a direct bilirubin of 7.2 mg/dL. Workup was consistent with BA, confirmed by liver biopsy and intraoperative cholangiogram. The patient underwent a hepatoportoenterostomy procedure. The patient had been on standard infant formula, and was switched to a high-MCT infant formula. At presentation, 25(OH)-D level was 8 ng/mL, which increased to 10 ng/mL following HDR.

Case 3

A 60-day-old full-term white male infant presented with jaundice with a direct bilirubin of 5.0 mg/dL. Evaluation confirmed α1-antitrypsin deficiency (ZZ phenotype with a level of <30 mg/dL). The patient had been on a standard infant formula, and was switched to a high-MCT infant formula. Initial 25(OH)-D level after 1 month of fat-soluble vitamin supplementation (with 400 IU vitamin D3) was low at 5 ng/mL. A good response was noted with HDR with a rise in the 25(OH)-D level to 19 ng/mL, but this coincided with resolving cholestasis (summarized in Table 1).

Case 4

A 59-day-old full-term white male infant presented with diarrhea, vomiting, and jaundice, and was found to have a direct bilirubin of 5.5 mg/dL. Extensive evaluation suggested idiopathic neonatal cholestasis (workup negative for biliary atresia, choledochal cyst, hypothyroidism, cystic fibrosis, Alagille syndrome, progressive familial intrahepatic cholestasis, or α1-antitrypsin deficiency). Before presentation, the patient had been on standard infant formula. At presentation, the 25(OH)-D level was 5 ng/mL, which increased slightly to 6 ng/mL after HDR.

DISCUSSION

Vitamin D is vital for calcium and phosphate homeostasis, to help prevent rickets and osteomalacia. Some controversy exists as what constitutes vitamin D deficiency in infants and children. The American Academy of Pediatrics and the Pediatric Endocrine Society support a 25(OH)-D level ≥20 ng/mL as consistent with the physiological needs of infants and children (7–9). It is suggested that infants with cholestasis should have a starting cholecalciferol dose of 800 IU daily with adjustments made based on serum levels (10,11). Some support using 3 to 10 times the recommended daily intake of vitamin D in pediatric cholestatic liver disease (12). The maintenance vitamin D doses used in this cohort were low; however, the main aim of the study was to assess the efficacy of HDR in achieving sufficiency levels. There are no published guidelines about the optimal time to recheck vitamin D levels after HDR therapy. Data on patients with cystic fibrosis with vitamin D deficiency suggest that the time frame chosen is reasonable (3).

High vitamin D repletion or stoss therapy has been shown to be effective and safe for treating nutritional vitamin D deficiency rickets in infants and young children without cholestasis (2). This can include oral or intramuscular administration of vitamin D (cholecalciferol or ergocalciferol), 300,000 to 600,000 IU, as a single dose or divided doses given over days to several weeks (2,6). This approach has been used successfully in the population with cystic fibrosis using either a single-day or a 2-week course (3,13). There are no data regarding the effectiveness of oral HDR vitamin D therapy in infants with cholestasis.

In our cohort, baseline 25(OH)-D levels were in the deficient range regardless of the underlying cause for cholestasis. Each patient received oral HDR therapy with 300,000 IU ergocalciferol (vitamin D2) during 2 to 3 days. Compliance with HDR intake was verified by the nursing staff. All of the patients remained vitamin D deficient (level <20 ng/mL) at follow-up 4 weeks later, but 1 patient had a more favorable response coinciding with resolving cholestasis.

The limitations of the study include the small sample size, selection bias based on physicians’ practice patterns, low daily vitamin D maintenance dosing, and nutritional variability provided to these infants. Our findings suggest that unlike infants without liver disease and in those with pancreatic insufficiency, use of oral HDR therapy may not be adequate treatment for vitamin D deficiency in the setting of cholestasis in infants. This is likely related to the lack of intraluminal bile acids to solubilize the orally administered vitamin D. Although our cohort could have responded better to intramuscular or intravenous vitamin D, the enteral form is the only form presently available in the United States. Fat-soluble vitamin levels, including vitamin D, should be monitored closely in this population, with consideration given to administering higher enteral doses as needed.

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Keywords:

cholestasis; oral repletion; stoss; vitamin D

© 2015 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology,