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Vitamin B12 deficiency in patients after enterocystoplasty
Journal of Pediatric Urology (2015) 11, 273.e1e273.e5
Vitamin B12 deficiency in patients after enterocystoplasty Alison Keenan, Benjamin Whittam, Richard Rink, Martin Kaefer, Rosalie Misseri, Shelly King, Mark Cain Indiana University Health Riley Hospital for Children in Indianapolis, IN, USA Correspondence to: A. Keenan, Indiana University Health, Riley Hospital for Children, Division of Pediatric Urology, 705 Riley Hospital Drive, Suite 4230, Indianapolis, IN 46202, USA, Tel.: þ1 (317) 944 8896; fax: þ1 (317) 274 7481 [email protected] (A. Keenan) [email protected] (B. Whittam) [email protected] (R. Rink) [email protected] (M. Kaefer) [email protected] (R. Misseri) [email protected] (S. King) [email protected] (M. Cain) Keywords Enterocystoplasty; Neurogenic bladder; B12 Received 19 February 2015 Accepted 12 April 2015 Available online 19 June 2015
Summary Introduction Serum B12 deficiency is a known sequlae of enterocystoplasty. The complications of B12 deficiency include megaloblastic anemia, neuropsychiatric disease, and demyelinating diseases such as peripheral neuropathy. Some studies have suggested that underlying disease states may be more important than enteric absorptive capacity in predicting acquired B12 deficiency. A 38% incidence of low or low-normal serum B12 in patients who have undergone enterocystoplasty has previously been reported, and oral B12 supplementation has been demonstrated to be an effective short-term therapy; however, the long-term results remain unclear. Aims This study hypothesized that oral vitamin B12 supplementation in patients with B12 deficiency following enterocystoplasty is an effective longterm treatment. Additionally, it sought to determine if underlying disease state predicts B12 deficiency following enterocystoplasty. Design Children who underwent enterocystoplasty at the present institution prior to August 2007 were reviewed. Patients with non-ileal augment, insufficient follow-up or hematologic disorders were excluded. Patients with low or low-normal B12 levels were included. Treatment consisted of daily oral therapy of 250 mcg or monthly parenteral therapy of 1000 mcg IM. Separately, the institutional database of 898 patients who underwent enterocystoplasty was searched and patients with at least one post-
Figure
operative B12 level were highlighted. The indication for enterocystoplasty was classified as neuropathic or non-neuropathic. Results Twenty-three patients met inclusion criteria. The mean follow-up was 49 months (range 5e85) following initial abnormal B12 level. On the last follow-up, 4/23 (17%) patients had normal serum B12 levels. No patients reported sequelae of long-term B12 deficiency. In the secondary investigation, 113 patients met inclusion criteria. A total of 101 had neuropathic indications for enterocystoplasty, and 12 had non-neuropathic indications. At any time during follow-up, 48/101 (47.5%) neuropathic patients had low or low-normal B12 levels, and 4/12 (33.3%) non-neuropathic patients had low or lownormal B12 levels during follow-up (P Z 0.54) (Figure). Discussion The initial success of oral B12 deficiency treatment following enterocystoplasty does not persist over time. This contradicts previous results with short duration follow-up. Underlying disease as the indication for enterocystoplasty did not predict B12 deficiency risk. The study was limited by the small number of patients with B12 deficiency who were started on treatment, as well as by the small number of patients with non-neuropathic indications for enterocystoplasty. Conclusion The aims of the study were met. Further investigation is required to assess predictors of B12 deficiency following enterocystoplasty.
Underlying indication for enterocystoplasty does not predict B12 deficiency.
http://dx.doi.org/10.1016/j.jpurol.2015.04.026 1477-5131/ª 2015 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved.
273.e2
Introduction Enterocystoplasty is a widely accepted treatment modality for medically refractory neuropathic bladder dysfunction. The metabolic consequences of enteric bladder augmentation are well described and should be regularly monitored in all patients [1]. Serum B12 deficiency is a particularly fearsome sequlae of enterocystoplasty; this is due to the potentially irreversible neurologic changes associated with long-term deficiency. Reported complications of B12 deficiency include: megaloblastic anemia, neuropsychiatric disease, and demyelinating diseases such as peripheral neuropathy, which may not improve with appropriate replacement therapy [2]. More recently, some studies have suggested that underlying disease states may be more important that enteric absorptive capacity in predicting acquired B12 deficiency [3]. A 38% incidence of low or low-normal serum B12 has previously been reported in patients who underwent enterocystoplasty at the present institution [4]. It was subsequently demonstrated that oral B12 supplementation is an effective short-term therapy for returning serum B12 levels to normal in these patients [5]. The long-term outcomes of serum B12 deficiency, as well as the durability of oral B12 supplementation remain unclear. It was hypothesized that oral vitamin B12 supplementation in patients with serum B12 deficiency following enterocystoplasty is a long-term effective treatment with which to maintain normal B12 serum levels. Additionally, in a separate investigation designed to obtain a larger cohort, it was sought to determine if the underlying disease state was a risk factor for developing B12 deficiency in order to identify patients at higher risk of B12 deficiency following enterocystoplasty. Two separate cohorts were reviewed to assess the long-term durability of oral B12 therapy, and to assess the impact of underlying diagnosis on predicting B12 deficiency. While the two cohorts were conceived as independent investigations, the subject matter was the same. These results were reported together in an effort to maximize the strength of the B12 literature, while avoiding duplicity.
Methods A series of pediatric patients who underwent ileal bladder augmentation at the present institution prior to August 2007 were reviewed. This timeframe was chosen to ensure adequate length of follow-up with which to identify patients at risk for B12 deficiency. Serum B12 levels were measured, beginning 5 years following enterocystoplasty, as part of the institutional follow-up protocol. Patient charts were reviewed and demographics, serum B12 levels, complete blood cell count (CBC) results, type of therapy (oral or Intramuscular (IM)), compliance, and concerns for neurologic sequelae were collected. Patients with non-ileal augment segments were excluded. Patients with insufficient follow-up or confounding hematologic disorders were excluded. Patients with low or low-normal serum B12 levels were included for analysis. Treatment consisted of either daily oral therapy of 250 mcg or monthly parenteral therapy 1000 mcg IM. Treatment success was defined as having
A. Keenan et al. persistent normalization of serum B12 levels on all followup studies after initiation of therapy. In a separate and independent investigation, the institutional database of 898 patients who had undergone bladder augmentation was searched, and patients who had at least one post-operative serum B12 level reported were highlighted. Patients with non-ileal augmentation segments were excluded. This second cohort was designed to include a larger segment of patients, as the first cohort only included patients who had been initiated on oral therapy. In patients identified with at least one measured postoperative serum B12 level, the indication for enterocystoplasty was evaluated and classified as neuropathic or non-neuropathic in nature. Patients with any spinal cord dysraphism such as myelomeningocele, caudal regression syndrome, tethered spinal cord, or lipomeningocele were classified as having neuropathic disease. Patients with noncord-related illness, such as bladder exstrophy, or isolated bladder anomalies, such as bladder duplication, were categorized as having non-neuropathic indications for enterocystoplasty. All patients with underlying gastrointestinal abnormalities were excluded (e.g. cloacal exstrophy). As in all previously reported B12 studies, low B12 was classified as serum levels of 200 pg/ml, and low-normal serum levels were classified as 201e300 pg/ml. Patients were considered to have low serum B12 levels if they had at least one reported value of <200 pg/ml. Patients were considered to have low normal serum B12 levels if they had at least one reported value of 201e300 pg/ml. Patients who never had a reported serum B12 level of <300 pg/ml were considered normal [6]. Fisher’s exact and ManneWhitney U tests were used for statistical analysis.
Results Of the 30 patients identified in the previously reported review, six were excluded for insufficient follow-up, and one was excluded due to a confounding hematologic disorder. The remaining 23 patients were followed for a mean of 49 months (range 5e85 months) following the initial abnormal serum B12 level. Of these patients, 16/23 (69.6%) had documentation of initiation of B12 replacement therapy, 14 were treated with oral supplementation therapy, and two were treated with IM injection therapy. One patient was started on oral therapy but converted to IM therapy due to gastrointestinal side effects, and was included in the analysis as being started on oral therapy. Of the 14 patients started on oral therapy, six (43%) had normalization of serum B12 levels at any point during follow-up. Only 4/14 (28.6%) that were started on oral therapy had long-term treatment success (Fig. 1). One patient reported discontinuation of therapy, and the serum B12 level decreased to <200 pg/ml. One patient on IM therapy had durable normalization of B12 levels (i.e. treatment success). The patient who crossed over from oral to IM therapy had low serum B12 on the last visit, but had normal B12 levels intermittently during follow-up. It was also found that 7/23 (30.4%) patients in the cohort did not start on treatment therapy, despite documented of
Vitamin B12 deficiency in patients
273.e3
Figure 1
Individual patient outcomes.
low or low-normal serum B12 levels. Of these seven patients, six had persistently low serum B12 levels. One patient had spontaneous resolution of serum B12 deficiency. Of the 23 patients included in the analysis, none were diagnosed with megaloblastic anemia (an early sign of serum B12 deficiency) [7]. One patient had an elevated MCV with a low-normal B12, which persisted despite treatment and normalization of serum B12 level. No patient suffered any neurologic or hematologic sequelae of serum B12 deficiency as of the last follow-up. In the second cohort, 130 patients who had undergone enterocystoplasty with at least one postoperative serum B12 level were identified. Of them, 17 patients with underlying gut abnormalities were excluded, leaving 113 patients for analysis. A total of 101 patients had neuropathic indications for enterocystoplasty: myelomeningocele (94), sacral agenesis (two), spinal abnormalities (two), caudal regression (two) and spinal cord lipoma (one). Twelve patients had non-neuropathic indications for enterocystoplasty, including seven with bladder exstrophy, and five with isolated bladder abnormalities such as bladder duplication. The median follow-up for the non-neuropathic and
Table 1
neuropathic patients was 8 years and 9 years, respectively (P Z 0.67). Of the 12 patients with non-neuropathic indications for enterocystoplasty, four (33.3%) had low or low-normal serum B12 levels at any time and two (16.7%) had low serum B12 levels at any time. Of the 101 patients identified with neuropathic indications for enterocystoplasty, 48 (47.5%) had low or low-normal serum B12 levels at any time and 20 (19.8%) had low serum B 12 levels at any time (P Z 0.99 and P Z 0.54, respectively) (see Table 1).
Discussion In this review of a cohort of patients with known low serum B12 levels following enterocystoplasty, it was discovered that the long-term durability of oral vitamin B12 therapy is poor. This finding is contradictory to previously published results from a short trial of oral B12 supplementation [5]. In previously published series, 36 patients with low to lownormal B12 levels were initiated on daily oral B12 250 mcg, and 97% were found to have normal levels on follow-
Serum B12 levels stratified by underlying indication for enterocystoplasty.
Patient variable
Non-neuropathic bladder (n Z 12)
Neuropathic bladder (n Z 101)
P-value
Low or low normal B12 (300 pg/ml) Low B12 (200 pg/ml) Median follow-up (years, range)
4 (33.3%) 2 (16.7%) 8 (1e20)
48 (47.5%) 20 (19.8%) 9 (1e27)
0.54 0.99 0.67
273.e4 up. The notable limitation of that study was the short mean follow-up of 4 months (range 14e320 days). The current study clearly shows that the initial success of oral therapy does not persist over time. More concerning is that only 31% of the patients who were treated for B12 deficiency (parenteral or oral) had documented durable correction of serum B12 levels. Previous investigators studying B12 deficiency following enterocystoplasty have proposed parenteral supplementation as the preferred treatment due to concerns over compromised absorptive capacity in the distal ileum [4,6,8]. The distal ileum is thought to be the primary site for absorption of B12 once it has binded to intrinsic factor [9]. Surgeons have previously been concerned that resection of the terminal ileum, even with sparing of the most distal 15 cm, may lead to impaired absorption of the B12-intrinsic factor complex [10]. While the terminal ileum is indeed important for absorption of dietary B12, emerging data in the gastrointestinal and hematologic literature suggest that serum B12 levels are not entirely dependent on the terminal ileum [7]. Multiple studies have demonstrated that oral B12 supplementation is equivalent or superior to parenteral supplementation in patients with pernicious anemia and who have a deficiency of intrinsic factor [11,12]. Given the effectiveness of oral therapy in patients with intrinsic factor deficiency, current literature supports a secondary mechanism of B12 absorption as potentially being more important in total serum B12 levels than the pathway that is solely dependent on intrinsic factor. This secondary pathway is thought to be dependent on total gut health and overall health status [3]. It is suspected that the poor results with long-term oral therapy are secondary to patient discontinuation of therapy over time. Patients were initiated on oral therapy of 250 mcg B12, which is the amount in most multivitamins. Therefore, when patients were started on oral therapy, a daily multivitamin (MVI) was recommended as treatment. It is suspected that over time, patients discontinued their MVI. Given that nearly all patients had initial normalization of B12 levels, it is suspected that oral therapy is successful when taken appropriately. Despite the abundant literature supporting oral therapy as an effective treatment for serum B12 deficiency (regardless of etiology), parenteral B12 therapy is being considered in this current patient population, as injection therapy requires a commitment by the prescriber and patient. Compliance may be more easily monitored in the setting of parenteral therapy. Therefore, given the poor long-term results with oral therapy, serum B12 levels are checked within 6 months of initiating oral therapy. Patients with persistent low or low-normal serum B12 levels at 6 months are initiated on parenteral therapy. In addition to considering early parenteral therapy, the serum B12 levels are being monitored at a multidisciplinary clinic, which allows for multiple providers to share the treatment responsibility of these complex patients. It is anticipated that with this new monitoring approach, long-term compliance will improve and, more importantly, B12 levels will normalize. Given that the emerging data in the medical literature are suggesting B12 deficiency as a reflection of overall health, the present study sought to explore if underlying
A. Keenan et al. diagnosis could predict B12 deficiency following enterocystoplasty. The results from this investigation of a large cohort of patients with a serum B12 levels checked following enterocystoplasty did not support diagnosis as a predictor of B12 deficiency. The small number of patients undergoing bladder augmentation for non-neuropathic indications is a considerable limitation to this analysis. Additionally, it was assumed that children with nonneuropathic bladder dysfunction (e.g. bladder exstrophy) are in better overall health than children with neuropathic bladder dysfunction (e.g. myelomeningocele) e this assumption may be inaccurate. Perhaps the most interesting finding was that no patient had any sequelae associated with serum B12 deficiency [13]. This is particularly interesting given that several patients were documented as having persistently low B12 serum levels for years. Despite this, none suffered hematologic or neurologic side effects. While this is reassuring, it is recommend that patients are screened after enterocystoplasty, given the irreversible sequelae associated with B12 deficiency. Furthermore, the findings in this study have altered the current B12 management approach following enterocystoplasty. It is recommended that serum B12 levels be checked yearly, starting at 5 years after enterocystoplasty. Currently, in the setting of low to low-normal B12 levels, it is cautiously recommended to start oral therapy, but with close follow-up (recheck within 6 months). Patients who have persistently low B12 levels, or who have recurrence of B12 deficiency after initiation of oral therapy should then be started on parenteral therapy. This investigation raises questions about serum B12 deficiency in the augmented population, and the future direction will be to check B12 levels prior to enterocystoplasty. While it has previously been demonstrated that patients begin to incur a higher risk of B12 deficiency at 5 years following enterocystoplasty, it is believed that there have been no studies that have assessed the serum B12 levels of patients pre-enterocystoplasty. As part of a recently developed pre-operative clinic, serum B12 levels are now being obtained prior to enterocystoplasty.
Conflict of interest statement We have no conflicts of interest to disclose. Ethical approval was not required for this retrospective chart review.
References [1] Gilbert SM, Hensle TW. Metabolic consequences and long-term complications of enterocystoplasty in children: a review. J Urol 2005;173(4):1080e6. [2] Lindenbaum J, et al. Neuropsychiatric disorders caused by cobalamin deficiency in the absence of anemia or macrocytosis. N Engl J Med 1988;318(26):1720e8. [3] Oberlin BS, et al. Vitamin B12 deficiency in relation to functional disabilities. Nutrients 2013;5(11):4462e75. [4] Rosenbaum DH, et al. Ileal enterocystoplasty and B12 deficiency in pediatric patients. J Urol 2008;179(4):1544e7. discussion 1547e8.
Vitamin B12 deficiency in patients [5] Vanderbrink BA, et al. Is oral vitamin B(12) therapy effective for vitamin B(12) deficiency in patients with prior ileocystoplasty? J Urol 2010;184(Suppl. 4):1781e5. [6] Metcalfe PD, Rink RC. Bladder augmentation: complications in the pediatric population. Curr Urol Rep 2007;8(2):152e6. [7] Stabler SP. Vitamin B12 deficiency. N Engl J Med 2013;368(21): 2041e2. [8] Ganesan T, et al. Vitamin B12 malabsorption following bladder reconstruction or diversion with bowel segments. ANZ J Surg 2002;72(7):479e82. [9] Stabler SP. Clinical practice. Vitamin B12 deficiency. N Engl J Med 2013;368(2):149e60. [10] Nieuwenhuijzen JA, et al. Urinary diversions after cystectomy: the association of clinical factors, complications and
273.e5 functional results of four different diversions. Eur Urol 2008; 53(4):834e42. discussion 842e4. [11] Sanz-Cuesta T, et al. Oral versus intramuscular administration of vitamin B12 for the treatment of patients with vitamin B12 deficiency: a pragmatic, randomised, multicentre, noninferiority clinical trial undertaken in the primary healthcare setting (Project OB12). BMC Public Health 2012;12:394. [12] Bahadir A, Reis PG, Erduran E. Oral vitamin B12 treatment is effective for children with nutritional vitamin B12 deficiency. J Paediatr Child Health 2014. [13] Salomon L, et al. No evidence of metabolic disorders 10 to 22 years after Camey type I ileal enterocystoplasty. J Urol 1997; 157(6):2104e6.
Vitamin B12 deficiency in patients after enterocystoplasty Alison Keenan, Benjamin Whittam, Richard Rink, Martin Kaefer, Rosalie Misseri, Shelly King, Mark Cain Indiana University Health Riley Hospital for Children in Indianapolis, IN, USA Correspondence to: A. Keenan, Indiana University Health, Riley Hospital for Children, Division of Pediatric Urology, 705 Riley Hospital Drive, Suite 4230, Indianapolis, IN 46202, USA, Tel.: þ1 (317) 944 8896; fax: þ1 (317) 274 7481 [email protected] (A. Keenan) [email protected] (B. Whittam) [email protected] (R. Rink) [email protected] (M. Kaefer) [email protected] (R. Misseri) [email protected] (S. King) [email protected] (M. Cain) Keywords Enterocystoplasty; Neurogenic bladder; B12 Received 19 February 2015 Accepted 12 April 2015 Available online 19 June 2015
Summary Introduction Serum B12 deficiency is a known sequlae of enterocystoplasty. The complications of B12 deficiency include megaloblastic anemia, neuropsychiatric disease, and demyelinating diseases such as peripheral neuropathy. Some studies have suggested that underlying disease states may be more important than enteric absorptive capacity in predicting acquired B12 deficiency. A 38% incidence of low or low-normal serum B12 in patients who have undergone enterocystoplasty has previously been reported, and oral B12 supplementation has been demonstrated to be an effective short-term therapy; however, the long-term results remain unclear. Aims This study hypothesized that oral vitamin B12 supplementation in patients with B12 deficiency following enterocystoplasty is an effective longterm treatment. Additionally, it sought to determine if underlying disease state predicts B12 deficiency following enterocystoplasty. Design Children who underwent enterocystoplasty at the present institution prior to August 2007 were reviewed. Patients with non-ileal augment, insufficient follow-up or hematologic disorders were excluded. Patients with low or low-normal B12 levels were included. Treatment consisted of daily oral therapy of 250 mcg or monthly parenteral therapy of 1000 mcg IM. Separately, the institutional database of 898 patients who underwent enterocystoplasty was searched and patients with at least one post-
Figure
operative B12 level were highlighted. The indication for enterocystoplasty was classified as neuropathic or non-neuropathic. Results Twenty-three patients met inclusion criteria. The mean follow-up was 49 months (range 5e85) following initial abnormal B12 level. On the last follow-up, 4/23 (17%) patients had normal serum B12 levels. No patients reported sequelae of long-term B12 deficiency. In the secondary investigation, 113 patients met inclusion criteria. A total of 101 had neuropathic indications for enterocystoplasty, and 12 had non-neuropathic indications. At any time during follow-up, 48/101 (47.5%) neuropathic patients had low or low-normal B12 levels, and 4/12 (33.3%) non-neuropathic patients had low or lownormal B12 levels during follow-up (P Z 0.54) (Figure). Discussion The initial success of oral B12 deficiency treatment following enterocystoplasty does not persist over time. This contradicts previous results with short duration follow-up. Underlying disease as the indication for enterocystoplasty did not predict B12 deficiency risk. The study was limited by the small number of patients with B12 deficiency who were started on treatment, as well as by the small number of patients with non-neuropathic indications for enterocystoplasty. Conclusion The aims of the study were met. Further investigation is required to assess predictors of B12 deficiency following enterocystoplasty.
Underlying indication for enterocystoplasty does not predict B12 deficiency.
http://dx.doi.org/10.1016/j.jpurol.2015.04.026 1477-5131/ª 2015 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved.
273.e2
Introduction Enterocystoplasty is a widely accepted treatment modality for medically refractory neuropathic bladder dysfunction. The metabolic consequences of enteric bladder augmentation are well described and should be regularly monitored in all patients [1]. Serum B12 deficiency is a particularly fearsome sequlae of enterocystoplasty; this is due to the potentially irreversible neurologic changes associated with long-term deficiency. Reported complications of B12 deficiency include: megaloblastic anemia, neuropsychiatric disease, and demyelinating diseases such as peripheral neuropathy, which may not improve with appropriate replacement therapy [2]. More recently, some studies have suggested that underlying disease states may be more important that enteric absorptive capacity in predicting acquired B12 deficiency [3]. A 38% incidence of low or low-normal serum B12 has previously been reported in patients who underwent enterocystoplasty at the present institution [4]. It was subsequently demonstrated that oral B12 supplementation is an effective short-term therapy for returning serum B12 levels to normal in these patients [5]. The long-term outcomes of serum B12 deficiency, as well as the durability of oral B12 supplementation remain unclear. It was hypothesized that oral vitamin B12 supplementation in patients with serum B12 deficiency following enterocystoplasty is a long-term effective treatment with which to maintain normal B12 serum levels. Additionally, in a separate investigation designed to obtain a larger cohort, it was sought to determine if the underlying disease state was a risk factor for developing B12 deficiency in order to identify patients at higher risk of B12 deficiency following enterocystoplasty. Two separate cohorts were reviewed to assess the long-term durability of oral B12 therapy, and to assess the impact of underlying diagnosis on predicting B12 deficiency. While the two cohorts were conceived as independent investigations, the subject matter was the same. These results were reported together in an effort to maximize the strength of the B12 literature, while avoiding duplicity.
Methods A series of pediatric patients who underwent ileal bladder augmentation at the present institution prior to August 2007 were reviewed. This timeframe was chosen to ensure adequate length of follow-up with which to identify patients at risk for B12 deficiency. Serum B12 levels were measured, beginning 5 years following enterocystoplasty, as part of the institutional follow-up protocol. Patient charts were reviewed and demographics, serum B12 levels, complete blood cell count (CBC) results, type of therapy (oral or Intramuscular (IM)), compliance, and concerns for neurologic sequelae were collected. Patients with non-ileal augment segments were excluded. Patients with insufficient follow-up or confounding hematologic disorders were excluded. Patients with low or low-normal serum B12 levels were included for analysis. Treatment consisted of either daily oral therapy of 250 mcg or monthly parenteral therapy 1000 mcg IM. Treatment success was defined as having
A. Keenan et al. persistent normalization of serum B12 levels on all followup studies after initiation of therapy. In a separate and independent investigation, the institutional database of 898 patients who had undergone bladder augmentation was searched, and patients who had at least one post-operative serum B12 level reported were highlighted. Patients with non-ileal augmentation segments were excluded. This second cohort was designed to include a larger segment of patients, as the first cohort only included patients who had been initiated on oral therapy. In patients identified with at least one measured postoperative serum B12 level, the indication for enterocystoplasty was evaluated and classified as neuropathic or non-neuropathic in nature. Patients with any spinal cord dysraphism such as myelomeningocele, caudal regression syndrome, tethered spinal cord, or lipomeningocele were classified as having neuropathic disease. Patients with noncord-related illness, such as bladder exstrophy, or isolated bladder anomalies, such as bladder duplication, were categorized as having non-neuropathic indications for enterocystoplasty. All patients with underlying gastrointestinal abnormalities were excluded (e.g. cloacal exstrophy). As in all previously reported B12 studies, low B12 was classified as serum levels of 200 pg/ml, and low-normal serum levels were classified as 201e300 pg/ml. Patients were considered to have low serum B12 levels if they had at least one reported value of <200 pg/ml. Patients were considered to have low normal serum B12 levels if they had at least one reported value of 201e300 pg/ml. Patients who never had a reported serum B12 level of <300 pg/ml were considered normal [6]. Fisher’s exact and ManneWhitney U tests were used for statistical analysis.
Results Of the 30 patients identified in the previously reported review, six were excluded for insufficient follow-up, and one was excluded due to a confounding hematologic disorder. The remaining 23 patients were followed for a mean of 49 months (range 5e85 months) following the initial abnormal serum B12 level. Of these patients, 16/23 (69.6%) had documentation of initiation of B12 replacement therapy, 14 were treated with oral supplementation therapy, and two were treated with IM injection therapy. One patient was started on oral therapy but converted to IM therapy due to gastrointestinal side effects, and was included in the analysis as being started on oral therapy. Of the 14 patients started on oral therapy, six (43%) had normalization of serum B12 levels at any point during follow-up. Only 4/14 (28.6%) that were started on oral therapy had long-term treatment success (Fig. 1). One patient reported discontinuation of therapy, and the serum B12 level decreased to <200 pg/ml. One patient on IM therapy had durable normalization of B12 levels (i.e. treatment success). The patient who crossed over from oral to IM therapy had low serum B12 on the last visit, but had normal B12 levels intermittently during follow-up. It was also found that 7/23 (30.4%) patients in the cohort did not start on treatment therapy, despite documented of
Vitamin B12 deficiency in patients
273.e3
Figure 1
Individual patient outcomes.
low or low-normal serum B12 levels. Of these seven patients, six had persistently low serum B12 levels. One patient had spontaneous resolution of serum B12 deficiency. Of the 23 patients included in the analysis, none were diagnosed with megaloblastic anemia (an early sign of serum B12 deficiency) [7]. One patient had an elevated MCV with a low-normal B12, which persisted despite treatment and normalization of serum B12 level. No patient suffered any neurologic or hematologic sequelae of serum B12 deficiency as of the last follow-up. In the second cohort, 130 patients who had undergone enterocystoplasty with at least one postoperative serum B12 level were identified. Of them, 17 patients with underlying gut abnormalities were excluded, leaving 113 patients for analysis. A total of 101 patients had neuropathic indications for enterocystoplasty: myelomeningocele (94), sacral agenesis (two), spinal abnormalities (two), caudal regression (two) and spinal cord lipoma (one). Twelve patients had non-neuropathic indications for enterocystoplasty, including seven with bladder exstrophy, and five with isolated bladder abnormalities such as bladder duplication. The median follow-up for the non-neuropathic and
Table 1
neuropathic patients was 8 years and 9 years, respectively (P Z 0.67). Of the 12 patients with non-neuropathic indications for enterocystoplasty, four (33.3%) had low or low-normal serum B12 levels at any time and two (16.7%) had low serum B12 levels at any time. Of the 101 patients identified with neuropathic indications for enterocystoplasty, 48 (47.5%) had low or low-normal serum B12 levels at any time and 20 (19.8%) had low serum B 12 levels at any time (P Z 0.99 and P Z 0.54, respectively) (see Table 1).
Discussion In this review of a cohort of patients with known low serum B12 levels following enterocystoplasty, it was discovered that the long-term durability of oral vitamin B12 therapy is poor. This finding is contradictory to previously published results from a short trial of oral B12 supplementation [5]. In previously published series, 36 patients with low to lownormal B12 levels were initiated on daily oral B12 250 mcg, and 97% were found to have normal levels on follow-
Serum B12 levels stratified by underlying indication for enterocystoplasty.
Patient variable
Non-neuropathic bladder (n Z 12)
Neuropathic bladder (n Z 101)
P-value
Low or low normal B12 (300 pg/ml) Low B12 (200 pg/ml) Median follow-up (years, range)
4 (33.3%) 2 (16.7%) 8 (1e20)
48 (47.5%) 20 (19.8%) 9 (1e27)
0.54 0.99 0.67
273.e4 up. The notable limitation of that study was the short mean follow-up of 4 months (range 14e320 days). The current study clearly shows that the initial success of oral therapy does not persist over time. More concerning is that only 31% of the patients who were treated for B12 deficiency (parenteral or oral) had documented durable correction of serum B12 levels. Previous investigators studying B12 deficiency following enterocystoplasty have proposed parenteral supplementation as the preferred treatment due to concerns over compromised absorptive capacity in the distal ileum [4,6,8]. The distal ileum is thought to be the primary site for absorption of B12 once it has binded to intrinsic factor [9]. Surgeons have previously been concerned that resection of the terminal ileum, even with sparing of the most distal 15 cm, may lead to impaired absorption of the B12-intrinsic factor complex [10]. While the terminal ileum is indeed important for absorption of dietary B12, emerging data in the gastrointestinal and hematologic literature suggest that serum B12 levels are not entirely dependent on the terminal ileum [7]. Multiple studies have demonstrated that oral B12 supplementation is equivalent or superior to parenteral supplementation in patients with pernicious anemia and who have a deficiency of intrinsic factor [11,12]. Given the effectiveness of oral therapy in patients with intrinsic factor deficiency, current literature supports a secondary mechanism of B12 absorption as potentially being more important in total serum B12 levels than the pathway that is solely dependent on intrinsic factor. This secondary pathway is thought to be dependent on total gut health and overall health status [3]. It is suspected that the poor results with long-term oral therapy are secondary to patient discontinuation of therapy over time. Patients were initiated on oral therapy of 250 mcg B12, which is the amount in most multivitamins. Therefore, when patients were started on oral therapy, a daily multivitamin (MVI) was recommended as treatment. It is suspected that over time, patients discontinued their MVI. Given that nearly all patients had initial normalization of B12 levels, it is suspected that oral therapy is successful when taken appropriately. Despite the abundant literature supporting oral therapy as an effective treatment for serum B12 deficiency (regardless of etiology), parenteral B12 therapy is being considered in this current patient population, as injection therapy requires a commitment by the prescriber and patient. Compliance may be more easily monitored in the setting of parenteral therapy. Therefore, given the poor long-term results with oral therapy, serum B12 levels are checked within 6 months of initiating oral therapy. Patients with persistent low or low-normal serum B12 levels at 6 months are initiated on parenteral therapy. In addition to considering early parenteral therapy, the serum B12 levels are being monitored at a multidisciplinary clinic, which allows for multiple providers to share the treatment responsibility of these complex patients. It is anticipated that with this new monitoring approach, long-term compliance will improve and, more importantly, B12 levels will normalize. Given that the emerging data in the medical literature are suggesting B12 deficiency as a reflection of overall health, the present study sought to explore if underlying
A. Keenan et al. diagnosis could predict B12 deficiency following enterocystoplasty. The results from this investigation of a large cohort of patients with a serum B12 levels checked following enterocystoplasty did not support diagnosis as a predictor of B12 deficiency. The small number of patients undergoing bladder augmentation for non-neuropathic indications is a considerable limitation to this analysis. Additionally, it was assumed that children with nonneuropathic bladder dysfunction (e.g. bladder exstrophy) are in better overall health than children with neuropathic bladder dysfunction (e.g. myelomeningocele) e this assumption may be inaccurate. Perhaps the most interesting finding was that no patient had any sequelae associated with serum B12 deficiency [13]. This is particularly interesting given that several patients were documented as having persistently low B12 serum levels for years. Despite this, none suffered hematologic or neurologic side effects. While this is reassuring, it is recommend that patients are screened after enterocystoplasty, given the irreversible sequelae associated with B12 deficiency. Furthermore, the findings in this study have altered the current B12 management approach following enterocystoplasty. It is recommended that serum B12 levels be checked yearly, starting at 5 years after enterocystoplasty. Currently, in the setting of low to low-normal B12 levels, it is cautiously recommended to start oral therapy, but with close follow-up (recheck within 6 months). Patients who have persistently low B12 levels, or who have recurrence of B12 deficiency after initiation of oral therapy should then be started on parenteral therapy. This investigation raises questions about serum B12 deficiency in the augmented population, and the future direction will be to check B12 levels prior to enterocystoplasty. While it has previously been demonstrated that patients begin to incur a higher risk of B12 deficiency at 5 years following enterocystoplasty, it is believed that there have been no studies that have assessed the serum B12 levels of patients pre-enterocystoplasty. As part of a recently developed pre-operative clinic, serum B12 levels are now being obtained prior to enterocystoplasty.
Conflict of interest statement We have no conflicts of interest to disclose. Ethical approval was not required for this retrospective chart review.
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