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Am J Clin Nutr 89: 204-209, 2009. First published December 3, 2008; doi:10.3945/ajcn.2008.26898
 American Journal of Clinical Nutrition, doi:10.3945/ajcn.2008.26898
Vol. 89, No. 1, 204-209, January 2009
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© 2009 American Society for Clinical Nutrition

ORIGINAL RESEARCH COMMUNICATION

Pyridoxal-5'-phosphate deficiency after intestinal and multivisceral transplantation1,2,3

Laura E Matarese, Igor Dvorchik, Guilherme Costa, Geoffrey J Bond, Darlene A Koritsky, Ronaldo P Ferraris, Riva Touger-Decker, Julie K O'Sullivan-Maillet and Kareem M Abu-Elmagd

1 From the Thomas E Starzl Transplantation Institute, University of Pittsburgh Medical Center, Pittsburgh, PA (LEM, ID, GC, GJB, DAK, and KMA-E), and the University of Medicine and Dentistry of New Jersey, Newark, NJ (RPF, RT-D, and JKO-M).

2 From the dissertation of LEM, University of Medicine and Dentistry of New Jersey, 2007.

3 Reprints not available. Address correspondence to KM Abu-Elmagd, 3459 Fifth Avenue, MUH 7 South, Pittsburgh, PA 15213. E-mail: abuelmagdkm{at}upmc.edu.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: Successful intestinal transplantation is measured by the achievement of clinical nutritional autonomy (CNA). However, the ability of the graft to maintain normal micronutrient levels including vitamins has yet to be thoroughly evaluated.

Objective: After an initial clinical observation of isolated cases of pyridoxal-5'-phosphate (PLP) deficiency, this prospective study was designed to address the incidence of, risk factors for, and management of PLP deficiency in adult intestinal transplant recipients.

Design: Serum PLP and homocysteine concentrations were prospectively measured before and after transplantation at frequent intervals.

Results: PLP deficiency occurred in 10% of candidates and in 96% of recipients within a median onset of 30 d (range: 4–118 d) after transplantation. Of this group, 41% were receiving parenteral nutrition (PN), 41% were receiving enteral feeding, and the remaining 18% had already achieved CNA. The overall cumulative risk was 24% at 15 d, 59% at 30 d, 79% at 45 d, and 90% at 90 d; none of the risk factors, including homocysteine concentrations, were significant. Nonetheless, the development of PLP deficiency during PN therapy was associated with a significant (P < 0.001) delay in the achievement of CNA. Despite development of severe deficiency in most cases, none of the subjects experienced clinical manifestations of PLP deficiency because of prompt replacement therapy.

Conclusions: Serial monitoring of serum PLP concentrations is recommended for PN-dependent patients with short-bowel syndrome before and after transplantation for early detection and prompt initiation of preemptive therapy. Long-term measurement at frequent intervals is also recommended, particularly for transplant recipients, to diagnose late deficiency despite achievement of CNA and to prevent toxicity from overdose.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Intestinal transplantation has been proven to be an effective therapy for patients with irreversible intestinal failure associated with life-threatening complications of parenteral nutrition (PN) (1). With successful implantation and subsequent adaptation of the transplanted allograft, establishment of clinical nutritional autonomy (CNA) and long-term rehabilitation is achievable with early discontinuation of PN and resumption of an unrestricted oral diet (2–5). Despite such a success, it remains to be seen whether the transplanted intestine can achieve the full spectrum of nutritional autonomy, including restoration and long-term maintenance of vitamins and trace elements.

The cumulative experience and recent achievement of long-term survival have led to a very important clinical observation that triggered the discovery by the senior author (KMA-E) of micronutrient deficiencies, specifically of pyridoxal-5'-phosphate (PLP), in our intestinal transplant recipients. Nearly 5 y ago, an unexplained progressive muscle weakness and gait disturbance in an adult patient who underwent successful intestinal transplantation 2 y earlier, mandated a random full screening of serum micronutrient concentrations in addition to other specific markers for the common neuromyopathic disorders. The sole finding was an undetectable PLP concentration, and prompt initiation of intravenous replenishment and maintenance oral therapy resulted in a significant improvement in the patient's symptoms. Subsequently, most adult intestinal allograft survivors were subjected to screening for PLP and other vitamin and trace element deficiencies, particularly those with overt clinical symptoms. Replacement therapy was repeatedly successful in ameliorating a spectrum of neurologic and myopathic symptoms, including lower extremity and pelvic girdle muscle weakness with gait disturbance (6).

Further assessment of the prevalence, dynamics, and treatment of PLP deficiency after intestinal and multivisceral transplantation dictated the necessity of conducting a prospective study with repeated measures over time with the use of serum PLP concentrations before transplantation (as a baseline). In this unique, novel, prospective human study, posttransplant serial measurements of serum PLP were compared with baseline values in the milieu of achievement of full CNA. Furthermore, efforts were made to identify risk factors and establish an effective repletion algorithmic protocol.


   SUBJECTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Subjects
The population was a convenience sample of all adult consecutive patients aged ≥18 y who underwent intestinal transplantation at the University of Pittsburgh Medical Center (UPMC) between 13 October 2005 and 12 October 2006. The study was initiated after approval by the Institutional Review Board of the UPMC and of the University of Medicine and Dentistry of New Jersey (UMDNJ) Newark. All subjects provided written informed consent. All procedures followed were in accordance with the ethical standards of the UPMC and UMDNJ on human experimentation and in accordance with the Helsinki Declaration of 1975 as revised in 1983.

Over the 1-y study period, a total of 30 patients were recruited, and the transplanted allografts were isolated intestine (n = 19), combined liver intestine (n = 3), and multivisceral graft (n = 8). The multivisceral graft was either full (n = 7), which included the stomach, duodenum, pancreas, intestine, and liver, or modified with exclusion of the liver (n = 1). The pancreas was part of the allograft in all of the liver-intestine and multivisceral recipients. All patients continued to have a chimney or end ileostomy during the entire study period with defunctionalized large bowel in those who retained their colon. Of the 30 recruited patients, 1 recipient was excluded from the study after being supplemented with vitamin B-6 incidentally before any deficiency occurred. All of the remaining 29 recipients were followed for 6 mo from the time of transplantation.

Of the 29 patients, 17 were women (59%) and 12 were men (41%). The mean (±SD) age was 43.38 ± 12.95 y (range: 21–65 y). All patients had been receiving PN before transplantation, and short-bowel syndrome (59%) was the most common cause of intestinal failure. The length of the remaining native bowel was limited to the duodenum and proximal 5–10 cm of the jejunum in the isolated intestine and combined liver-intestine recipients. The underlying etiology of the intestinal failure was variable, including vascular occlusion (n = 11), Crohn disease (n = 5), pseudoobstruction (n = 3), Gardner syndrome (n = 3), trauma (n = 2), and others (n = 6).

All donors were cadaveric with a mean age of 26 ± 10.3 y (range: 14–52 y). None of the donors had been pretreated with antilymphocyte preparation or allograft irradiation. The cold ischemia time ranged from 5.2 to 11.5 h (7.5 ± 1.5 h). No attempts at lymphatic surgical reconstruction were made at the time of transplantation. Continuity of the gastrointestinal tract was established in all patients at the time of transplantation with the creation of chimney or end ileostomy. A feeding jejunostomy tube was placed in the proximal jejunal allograft for early enteral feeding.

The primary immunosuppressive regimen was tacrolimus-based for all 29 study patients. A total of 25 (86%) patients received induction therapy; 24 patients were pretreated with a single dose of Campath-1H (alemtuzumab; Genzyme, Cambridge, MA), and the remaining patients received a 5-dose perioperative course of Zenapax (daclizumab). The other 4 study patients received the conventional tacrolimus steroid regimen with no induction therapy. The Campath pretreatment protocol was a steroid-spared regimen, unless the patients developed adrenal insufficiency or allograft rejection. Full details of the immunosuppressive protocol were described elsewhere (5, 7). In addition to the immunosuppressive regimen, most patients received a short course of gut decontamination, intravenous antimicrobial prophylaxis, proton pump inhibitors, antidiarrheal agents, and antihypertensive medications when indicated. None of the patients received multivitamin supplements during the study period.

Blood collection and biochemical analyses
Blood samples for the measurement of PLP, the active form of vitamin B-6, were collected after the subjects fasted overnight during the initial evaluation and at the time of transplantation (before surgery). Measurements were repeated for all patients at 1, 4, 8, 12, and 24 wk after transplantation. In addition, measurements were also obtained 1 wk after PN was discontinued. All recipients were also sampled at the time of achievement of CNA, defined as discontinuation of any nutritional supplements, including enteral feeding. Simultaneous measurements of urinary 4-pyridoxic acid were not performed because of the well known universal impairment of renal function in these unique recipients because of tacrolimus nephrotoxicity. With the exception of a few data points (n = 11), all of the preoperative and posttransplant samples were collected, and the assay was performed at our institution using standardized methodology (8, 9). In brief, the sample (1.0 mL) for PLP measurement was placed in an EDTA-treated tube (purple top) and wrapped in aluminum foil to protect it from light. All blood samples were analyzed by Quest Diagnostics (Lyndhurst, NJ) using a kit approved by the Food and Drug Administration (ALPCO, Windham, NH) with a radioenzymatic assay (10). PLP deficiency was defined as a serum concentration <3.3 ng/mL, and severe deficiency was defined as a concentration <2.5 ng/mL (Table 1).


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  		TABLE 1. Proposed protocol for treating pyridoxal-5'-phosphate (PLP) deficiency according to serum concentrations

 
On the basis of published data on other abdominal and thoracic organ recipients, we hypothesized that PLP deficiency would be associated with an elevation in serum homocysteine concentrations (11–16). Accordingly, serum samples were collected in a fasting state at the same study points, and homocysteine concentrations were measured in the UPMC laboratory according to Food and Drug Administration–approved methodology with a competitive immunoassay using direct chemiluminescent technology (17). The reference range was between 3.3 and 10.4 µmol/L. Serum folate and vitamin B-12 concentrations were measured as a standard of care before transplantation and infrequently after transplantation.

Nutrition interventions
Before transplantation, all patients were PN-dependent and were receiving 100% of their fluid and nutritional requirements via the parenteral route. Immediately after transplantation, all recipients continued to receive PN. Tube feeding (TF) was usually initiated within the first 2 wk after transplantation and gradually advanced as tolerated with synchronous decrease in the volume and concentration of PN. When gastric motility was recovered, most patients were allowed an oral diet while receiving PN or TF. With the achievement of the nutritional goal via the unrestricted oral diet, both TF and/or PN were discontinued and CNA was declared. The timing of discontinuation of PN, TF, and achievement of CNA was recorded for each recipient. Full details of the postoperative care and nutritional management of the intestinal transplant recipients were described elsewhere (18, 19).

Before achievement of CNA, the delivery vehicle of vitamin B-6 was PN and/or enteric formula. With PN, the patient received the standard amount of intravenous vitamin B-6 contained in the multivitamin injection (6 mg). The amount of vitamin B-6 in the used enteric formula (Replete; Nestle) was 4 mg/L. With discontinuation of PN and TF, the vitamin B-6 intake was solely delivered by the consumption of an unrestricted oral diet unless therapeutic intervention was indicated. Nonetheless, none of these patients were instructed to take any oral multivitamin supplement.

On the basis of our cumulative experience with replacement therapy and before the initiation of the reported herein prospective study, a repletion protocol was established. Full details of the adopted protocol are outlined in Table 1.

Statistical analysis
All analyses were performed by using SPSS statistical software (version 14.0; SPSS Inc, Chicago, IL). Data were prospectively collected, and a descriptive analysis of recipient demographics, cause of intestinal failure, donor characteristics, and type of transplanted allograft was made. Continuous variables were reported as means ± SDs, and categorical data were reported as proportions. The incidence, severity, and time of diagnosis of PLP deficiency were calculated for the total population and according to the degree of the nutritional autonomy achieved after transplantation. Cumulative risk was calculated by using the Kaplan-Meier method. An independent-samples t test and Fisher's exact tests were used to assess the risk of donor/recipient age, sex, cause of intestinal failure, cold ischemia time, type of allograft, and homocysteine concentration associated with the development of PLP deficiency. Pearson correlation coefficients were used to assess the strength of the hypothesized negative relation between PLP and serum homocysteine concentrations.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
During the 12-mo study period, 2 of the 29 recipients died and one graft failed to achieve CNA. The overall incidence of patient survival was 93% with a functioning graft survival of 90%. The initial discontinuation of PN was achievable in all patients within 9 to 132 d (30.8 ± 25 d) of transplantation. Enteral feeding was started at a mean of 10.3 ± 6.9 d (range: 3–35 d) and was discontinued at mean of 57 ± 36 d.

At the initial evaluation, all patients were PN-dependent and had a mean serum PLP concentration of 13.4 ± 14.7 (range: 2.40–74.5 ng/mL). Three patients had subnormal values that were corrected by augmented intravenous replacement while they awaited transplantation. Immediately before transplantation, only one patient had subnormal serum PLP concentrations, which ranged from 2.7 to 65 ng/mL (14.6 ± 13.5 ng/mL). During the 6-mo study period, a total of 27 (96%) of the 28 patients with normal pretransplant values experienced an initial subnormal serum concentration at different time points from the date of transplantation with a median onset of 30 d (range: 4–118 d) (Figure 1). Of these patients, 24 (89%) had a severe deficiency (<2.5 ng/mL). At the time of the diagnosis of deficiency, 11 of the 27 patients (41%) were receiving PN, 11 (41%) were receiving enteral nutrition, and the remaining 5 (18%) had achieved full CNA (Figure 2). Of the 11 recipients who experienced subnormal PLP concentrations during PN therapy, the deficiencies were severe in 9 (82%) and the diagnosis was made within the first 31 d after transplantation in 8 (89%), with a median onset of 7 d (range: 4–59 d) (Figure 1).


Figure 1
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  		FIGURE 1. Distribution of the onset of pyridoxal-5'-phosphate deficiency (n = 27) diagnosed during the study period. Most deficiencies were clustered within the first 40 d after transplantation.

 

Figure 2
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  		FIGURE 2. Feeding route at the time of posttransplant pyridoxal-5'-phosphate (PLP) deficiency. The 27 PLP-deficient patients clustered according to time of diagnosis from transplantation with a special reference to the need for nutritional support and achievement of clinical nutritional autonomy (CNA). Note the development of PLP deficiency in 11 (41%) patients in whom parenteral nutrition was discontinued and were receiving tube feeding only. Interestingly, only 5 (18%) recipients developed PLP deficiency after achievement of CNA.

 
After the discontinuation of PN, PLP deficiency was diagnosed for the first time in a total of 16 (59%) recipients, 11 of whom were receiving full or partial enteral feeding and the rest of whom were consuming an unrestricted oral diet without any nutritional support. The diagnosis was made between 1 and 103 d (median: 8 d) from the time that PN was discontinued; serum PLP concentrations had been normal during PN therapy. The deficiency occurring after achievement of full CNA was diagnosed between 1 and 91 d (median: 8 d) after enteral feeding was discontinued. Most of the patients had severe deficiency (mean: 2.42 ± 0.08 ng/mL; range: 2.4–2.7 ng/mL).

With a mean follow-up of 182 d, the cumulative risk of PLP deficiency was 24% at 15 d, 59% at 30 d, 79% at 45 d, 90% at 90 d, and 93% at 180 d (Figure 3). The statistical analyses failed to show any significant risk factors associated with the development of PLP deficiency, including donor and recipient age, sex, cause of intestinal failure, type of allograft, and cold ischemia time. There was also no significant impact of these factors on the development of PLP deficiency during or after discontinuation of nutritional support. However, the development of PLP deficiency during PN therapy was associated with a significant (P < 0.001) delay in the achievement of CNA. Acute rejection was diagnosed before or at the time of PLP deficiency in 6 (22%) patients.


Figure 3
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  		FIGURE 3. Cumulative risk of pyridoxal-5'-phosphate deficiency among the intestinal and multivisceral transplant patients calculated by the Kaplan-Meier method.

 
Serum homocysteine concentrations were within the reference range for most patients before transplantation (11.23 ± 5.72 µmol/L). Posttransplant concentrations were slightly lower 1 wk after transplantation; the mean concentration was 8.59 ± 3.53 µmol/L. Restoration of the serum concentration was observed during the 6-mo follow-up period with a concentration of 9.69 ± 4.69 µmol/L at 1 mo, 11.23 ± 5.93 µmol/L at 2 mo, 13.22 ± 6.47 µmol/L at 3 mo, and 13.10 ± 5.47 µmol/L at 6 mo. The relatively low baseline homocysteine concentrations and the early posttransplant dynamic changes observed may have reflected the status of folate body stores before transplantation, ie, a state of high metabolic demand after the transplant procedure. Unfortunately, the study did not systematically measure serum folate concentrations in these complex patients. Nonetheless, homocysteine concentrations did not change significantly in any of the patients, and no significant negative correlation was observed between serum PLP and homocysteine concentrations in the absence of replacement therapy (Figure 4).


Figure 4
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  		FIGURE 4. Correlation between serum homocysteine and pyridoxal-5'-phosphate (PLP) concentrations tested by Pearson correlation coefficient analysis. Serum homocysteine concentrations varied (x axis), and serum PLP concentrations were detectable in only 3 of the 27 patients, as shown in the scatter plot (y axis). Homocysteine concentrations were measured at the time of PLP deficiency. Note the lack of a negative linear correlation between the 2 tested variables (r = 0.202), with only one point falling on the straight line.

 
None of the patients experienced any clinical evidence of PLP deficiency. This observation reflects the prompt diagnosis of a deficiency and prompt therapeutic intervention. Serum PLP concentrations normalized in all patients with a single dose of intravenous therapy followed by a maintenance oral dose of 50 mg/d within 1 mo after initiation of therapy. However, 21 (78%) patients experienced a concentration above the reference range that required reduction or temporary discontinuation of therapy. None of these patients developed overdose toxicity.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Intestinal and multivisceral transplantation has recently evolved to be an effective alternative therapy for PN-dependent patients. It has been assumed that the achieved nutritional autonomy after successful transplantation with discontinuation of PN is associated with restoration and long-term maintenance of the micronutrient status, including vitamins. However, it has been our initial clinical observation that some intestinal transplant recipients experience low serum zinc, vitamin E, and folate concentrations particularly during the early postoperative period (20, 21). The poor early assimilation of vitamin E has also been documented by other centers (22). Other potential deficiencies may include fatty acids and other micronutrients, including trace elements, particularly in patients with occult graft dysfunction during the evolution of chronic rejection (KM Abu-Elmagd, unpublished observations).

The clinical observation by the senior author (KMA-E) of unexplained neuropathy or myopathy in a few of our long-term survivors triggered the search for the underlying cause, including possible unfamiliar micronutrient deficiencies. The documented undetectable PLP concentration in most of these morbid patients, who responded promptly to replacement therapy, revealed the true existence of PLP deficiency in the intestinal and multivisceral transplant patients with significant clinical morbidity. Accordingly, the current prospective study was designed to address the prevalence, severity, and possible underlying causes of PLP deficiency with establishment of management guidelines, including effective preemptive replacement therapy.

Unexpectedly, an overall incidence of PLP deficiency of 10% was observed before transplantation, despite PN therapy (with micronutrients) according to standard therapeutic guidelines. A similar observation was reported during the parenteral multivitamin shortage in 1997, and low vitamin B-6 concentrations were observed in the home PN patients (23). After transplantation, PLP deficiency was documented with an overall incidence of 96% and a severe deficiency index of 89%. Nearly half of all PLP deficiencies occur despite continuation of PN therapy, mostly during the early postoperative period after transplantation. Furthermore, during the first 6 wk after surgery, some patients developed new PLP deficiencies after discontinuation of PN therapy, which resulted in a total cumulative risk of 86% (Figures 2 and 3).

A possible explanation for this observation was the high metabolic demand triggered by a relatively high surgical catabolic phase compounded by the use of lympholytic agents, including Campath, steroids, and other immunosuppressive and nonimmunosuppressive drugs. A change in pyridoxine metabolism may also have been responsible for the lack of correlation between serum concentrations and intake. Equally important was the documented massive regenerative activity of the allograft enterocytes in response to unavoidable ischemia reperfusion injury that is commonly associated with visceral transplantation (24). In addition, the very active process of the initial donor-recipient immune interaction with persistence of the clonal-deletion-exhaustion mechanism essential for graft acceptance and tolerance could also contribute to a relatively high metabolic demand with utilization of vitamin B-6 as a cofactor (7, 19). All of the above mechanisms in the milieu of reduced lean body mass, observed in most of these patients, with inadequate vitamin B-6 muscle storage collectively precipitated a rapid decrease in serum PLP concentrations soon after transplantation (25).

Despite the discontinuation of PN therapy according to a standard clinical management protocol, the new onset PLP deficiency occurred with or without administration of enteral feeding. The PLP deficiency may reflect global or selective defects in intestinal allograft functions, excessive urinary excretion, or altered vitamin B-6 metabolism. Some of the structural and functional defects inherent to intestinal transplantation include lymphatic disruption, visceral denervation, and graft dysmotility with the development of refractory bacterial overgrowth that requires intermittent probiotic and gut decontamination therapy (26–29). Diarrhea with a rapid transit time is also commonly experienced by recipients who lost part or all of their colon before transplantation. The colonic factor should also be addressed in light of the absence of vitamin B-6 bacterial flora synthesis in patients with a resected or defunctionalized large bowel, as shown in the present study.

It is also conceivable that the different proposed mechanisms of vitamin B-6 absorption in the gut could be altered or compromised (30–32). In addition to allograft dysfunction, competitive inhibition of the active absorptive mechanisms of vitamin B-6 by drugs or other intraluminal molecules could also contribute to PLP deficiency. Other factors, including the different intravenous and oral medications commonly required after transplantation, may precipitate PLP deficiency by altering the synthetic pathways and/or by depleting the body reserves (31–33).

It is obvious from this study that the risk of PLP deficiency is significantly higher after intestinal and multivisceral transplantation compared with the solid abdominal and thoracic organs (11, 12, 14, 34). This may be partially explained by the complex nature of the visceral transplant procedures and the higher metabolic demands during the protracted postoperative course because of immunologic and nonimmunologic factors, including the massive transplantation of donor tissue. Furthermore, the transplanted allograft is the site of the nutrient absorption, and most of the intestinal recipients have already lost most, if not all, of their native colon (1).

With a cumulative risk approaching {approx}100% by 6 mo after transplantation, the statistical analyses failed to show any significant risk factors associated with the development of PLP deficiency, including cause of intestinal failure, recipient characteristics, serum homocysteine concentrations, and donor factors (with a special reference to the liver-containing allografts) (1, 8, 11–13, 35, 36). However, the development of PLP deficiency during PN therapy was associated with a significant (P < 0.001) protraction in the achievement of full CNA. Such a statistical observation may underscore the theory of high metabolic demand because of significant injury to the intestinal allograft at the time of transplantation that prolonged its full recovery and the restoration of nutritional autonomy.

Because of the use of a protocol including biochemical diagnosis and preemptive therapy, none of the study patients experienced clinical symptoms related to PLP deficiency. Furthermore, serial measurement of serum PLP concentrations during replacement therapy was able to detect undesirably high levels in a few nonsymptomatic patients that guided adjustment and/or temporary discontinuation of oral replacement therapy before the development of B-6 toxicity. Nonetheless, most of the patients required oral maintenance replacement with 25–50 mg daily or every other day. Interestingly, maintenance therapy was inadvertently discontinued in 2 patients a few months after completion of the study, both of whom became symptomatic and had undetectable concentrations at the time of diagnosis. At different stages after transplantation, factors influencing vitamin B-6 absorption and metabolism are highly variable and often require management. Overall, the proposed management plan was practical and effective at preventing the development of clinically overt PLP deficiency or toxicity syndrome.

Two of the significant limitations of the current study were the relatively small sample size and the inclusion of adult patients only. Accordingly, further validation of the prevalence, risk factors, and proposed management algorithm reported herein may call for a multicenter study because of the orphan nature of the intestinal failure patients. A third important limitation was the lack of measurement of several micronutrients, which may have uncovered other relevant new deficiencies. Such discoveries may highlight some important common metabolic pathways that explain the pathogenesis of vitamin B-6 and other micronutrient deficiencies in light of the potentially inherited and acquired abnormalities associated with intestinal and multivisceral transplantation.

PLP deficiency occurred during PN therapy in patients with intestinal failure and was common after intestinal and multivisceral transplantation. Most of the deficiencies were diagnosed during the early postoperative period, despite continuation of PN therapy, and continued to develop despite clinical achievement of full CNA. Accordingly, serial monitoring of serum PLP concentrations is recommended so that early signs of deficiency can be detected and preemptive therapy started promptly when necessary. Long-term PLP measurements at frequent intervals are recommended to avoid late deficiency or overtoxicity.


   ACKNOWLEDGMENTS
 
The authors' responsibilities were as follows—LEM: conceived and designed the study, provided direct nutritional patient care, collected and analyzed the data, and wrote the initial manuscript draft; ID: supervised the project and the statistical analysis and finalized the manuscript; GC and GJB: performed the surgeries, provided direct patient care, and reviewed the manuscript; DAK: assisted with the Institutional Review Board approvals and reviewed the manuscript; RPF, JKO-M, and RT-D: supervised the project, provided scientific guidance, and finalized and revised the manuscript; and KMA-E: performed the surgeries, provided direct patient care, supervised the project, and finalized the manuscript including different scientific, intellectual, and hypothetical explanations and statements. None of the authors had a personal or financial conflict of interest.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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Received for publication August 28, 2008. Accepted for publication October 20, 2008.





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