- Email: [email protected]
34 Formulations used in nutrition
M.C. Allwood and I. Hardy
34
Formulations used in nutrition
PARENTERAL NUTRITION (SED-15, 2700; SEDA-26, 377; SEDA-27, 355; SEDA-28, 383) Metal metabolism Cholestasis is a common complication of parenteral nutrition, particularly in young children. One response is to reduce or discontinue copper and manganese, to avoid accumulation, since both are normally excreted by biliary excretory pathways. If the patient depends mainly or entirely on parenteral nutrition for feeding, deficiency of these elements will ensue. Of particular concern is copper deficiency. Evidence of copper deficiency has emerged in four children, one teenager and three children under 1 year old, all of whom depended entirely on parenteral feeding for maintenance of nutritional well-being (1A ). All were monitored regularly for key markers of nutritional status. After cholestasis developed, all four had signs of copper deficiency. In the teenager, it was clearly manifest 3 months after removing copper from the feeding regimen, although his plasma copper concentrations were almost within his reference range (660 µg/l). His symptoms related principally to pancytenoia. After 6 months, when the copper concentration had fallen to 90 µg/l, copper 20 micrograms/kg every 2 weeks was re-introduced into his diet. His plasma concentrations recovered to between 570 and 920 µg/l. His bone marrow rapidly normalized, with a rise in white cell count, hematocrit, and platelet count to normal. In the three other cases, cholestasis developed at 2–6 weeks after birth, leading to severe cholestasis, when copper was reduced to 10 micrograms/kg/day in one case, or removed completely. In all cases there was Side Effects of Drugs, Annual 29 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(06)29034-2 © 2007 Elsevier B.V. All rights reserved.
copper deficiency, based on low plasma concentrations. Reintroduction of copper normalized the plasma concentrations within 1–3 months. In only one case were there effects of copper deficiency, including hypopigmentary changes in the hair and femoral and rib fractures, all of which resolved after re-introduction of copper. Although current guidelines recommend omitting copper (and manganese) from parenteral nutrition regimens in patients with obstructive jaundice (2S ), the authors recommended that copper concentrations should be checked monthly and that re-introduction of copper should be considered when concentrations suggest that there is deficiency. This can be achieved at a dosage of 20 micrograms/kg/ day in children, followed by 10 micrograms/ kg/day after concentrations have returned to normal. Liver Hepatotoxicity associated with parenteral nutrition is probably the most important metabolic complication of intravenous feeding. The literature over the past 5 years has been reviewed (3R ) for evidence about the suspected pathogenesis, commonly used diagnostic tests and procedures, and current methods for preventing and treating it. The authors concluded that, regardless of current advances in research, we are still ignorance in all these areas, with little if any new further information.
Fat emulsions Nervous system Early nutrition is a recognized component of neurosurgical intensive care treatment but it can cause raised intracranial pressure. • A 22-year-old woman with severe traumatic brain injury reproducibly developed raised intracranial pressure when Lipofundin® , a soybean oil-based emulsion for parenteral nutrition, was infused (4A ). When the intracranial pressure rose, the patient remained hemodynamically stable, and so
353
354
Chapter 34
an anaphylactic reaction was unlikely. Increased brain tissue oxygenation parallel to the rise in intracranial pressure suggested increased cerebral blood flow as a cause.
Without multimodal monitoring and data storage, the adverse effect of Lipofundin® in this patient would have been difficult to identify. It should be noted that the infusion rate of the fat emulsion was relatively rapid, and also that no other such incidences have been reported, so that the link remains speculative.
VITAMINS OF THE B GROUP (SEDA-26, 419; SEDA-27, 407; SEDA-28, 387)
Vitamin B12 (cobalamins)
(SED-15,
3668) Skin Localized drug-induced injection site reactions are rare. However, sclerodermoid injection site reactions have been reported, most commonly with vitamin K, but also pentazocine, progestin, and vitamin B12 (5A ). • A 31-year-old Caucasian woman who had been receiving monthly injections of vitamin B12 as a nutritional supplement for Crohn’s disease had no local reaction. immediately after receiving an injection in the upper arm, but after 3 years developed a “red spot” which developed into a sclerotic plaque over 1 month. There were no signs of systemic scleroderma. Because the size and extent of the lesion had been stable for several months, excision was performed under local anesthesia. The lesion healed without complications.
While the localized scleroderma was linked directly to the vitamin injection, whether this was due to the vitamin itself or the injection vehicle was unclear.
VITAMIN D ANALOGUES (SED-15, 3669; SEDA-28, 388) Mineral balance The successful treatment of vitamin D-induced hypercalcemia with pamidronate has been reported.
M.C. Allwood and I. Hardy
• A 6-month-old girl who had accidentally been given 300 000 units of oral vitamin D for 10 days was admitted with anorexia, vomiting, polydipsia, polyuria, and constipation (6A ). The serum calcium concentration was 4.2 (reference range 2.2– 2.5) mmol/l and the serum 25-hydroxycolecalciferol concentration was 340 (reference range 10–50) µg/l. She was initially treated with hydration and furosemide (1 mg/kg every 6 hours) followed by three doses of calcitonin (2 U/kg) over 2 days. She also received prednisolone 2 mg/kg/day and oral nifedipine 1 mg/kg/day for hypertension. Despite this the serum calcium concentration remained life-threateningly high (3.9 mmol/l). Calcitonin was withdrawn and pamidronate 1 mg/kg/day was infused over 2 days. The serum calcium fell to 3.4 mmol/l on day 3 and 2.6 mmol/l on day 4. • A 3-month-old boy who had been given a total of 2 560 000 units of vitamin D over 8 days developed constipation, restlessness, anorexia, vomiting, and sweating (7A ). The serum calcium concentration was 4.1 mmol/l and the concentration of 25-hydroxycolecalciferol was 268 µg/l. He was given furosemide 2 mg/kg/day and intravenous hydration. The serum calcium remained high and he was given prednisolone 2 mg/kg/day. The serum calcium remained high and an electrocardiogram showed extra beats. Pamidronate 5 mg/l in 40 ml of isotonic saline was infused over 4 hours. The serum calcium concentration fell to 2.6 mmol/l within 36 hours and the electrocardiogram resolved. The serum calcium 21 days later was 2.9 mmol/l and the pamidronate infusion was repeated; the calcium concentration fell to 2.4 mmol/l. Further infusions of the same dose of pamidronate were given after 30 and 59 days and the calcium concentration was 2.2 mmol/l after 4 months.
Hypercalcemia due to acute vitamin D intoxication is mainly mediated by increased bone resorption, and so drugs that inhibit bone resorption may be more effective than furosemide and intravenous hydration. Calcitonin has the disadvantage of a relatively short duration of action and has been reported to lower the initial serum calcium by only up to 20% (6A ). The bisphosphonate pamidronate is often used in children to treat hypercalcemia due to malignancy and juvenile osteoporosis. The authors of these reports did not report any adverse effects of pamidronate infusion and concluded that it could be a life-saving intervention when calcium concentrations do not respond adequately to conventional management. A recent study of serum 25-hydroxycolecalciferol in 12 very premature infants fed on a specialist formula with a high vitamin D content (2700 IU/l) has shown an increased risk of hypervitaminosis (8c ). Serum 25-hydroxycolecal-
Formulations used in nutrition
355
Chapter 34
ciferol concentrations in infants fed exclusively on the premature formula (n = 40) were significantly higher than in infants fed regular formula or breast milk (n = 25) (175 versus 115 nmol/l). However, none of the infants had abnormal serum calcium or phosphorus concentrations. The authors postulated that this was probably because vitamin D-dependent active intestinal calcium resorption is limited in premature infants (9R ), but becomes relevant with intestinal maturation, which seems to be accelerated by premature delivery (10R ). Prolonged feeding of high vitamin D formula in very premature infants therefore poses the risk of hypervitaminosis. Although vitamin D requirements in premature infants are controversial, and a daily intake of 200 IU/kg has been shown to be sufficient (11c ), premature infant formulas marketed in Japan, such as the one used in this study, contain large amounts of vitamin D (2700 IU/l). The preterm formulas that are commonly used in Europe and the USA contain less vitamin D (1010–2200 IU/l) and carry a much reduced risk of hypervitaminosis. Tumorigenicity Vitamin D deficiency has been associated with an increased risk of prostate cancer due to the antiproliferative effect of 1α,25-dihydroxycolecalciferol in vitro (12E ). However, a longitudinal nested case-control study in which serum 25-hydroxycolecalciferol concentrations were measured in 622 men with prostate cancer and 1451 matched controls has shown that both high (80 nmol/l) and low (19 nmol/l) vitamin D blood concentrations carry an increased risk (13C ). The reference range (40–60 nmol/l) was associated with the lowest risk. The finding that high concentrations of vitamin D are related to an increased risk was unexpected and is difficult to explain on the basis of experimental results. The authors speculated that it might be because prostate cells regulate their own vitamin D balance by 24-hydroxylase, an enzyme that inactivates colecalciferol (vitamin D3 ). High concentrations of colecalciferol upregulate the activity of this enzyme, leading to local colecalciferol deficiency and resistance. This means that colecalciferol cannot have its antiproliferative function in prostate tissue despite high serum concentrations. Since these results suggest that even moderately high concentrations of vitamin D may have an adverse effect, care
should be taken before recommending supplementation.
VITAMIN E
(SED-15, 3677)
Death Vitamin E supplementation has been tested in many trials of prevention of cardiovascular disease and cancer. However, a few trials have reported a non-statistically significant increase in total mortality with high-dose vitamin E supplementation. The issue has been reviewed in a meta-analysis (14M ). The purpose was to look for a dose-response relation between vitamin E supplementation and total mortality, using data from randomized controlled trials. Comparing vitamin E with placebo, nine of 11 trials of high-dose vitamin E (over 400 IU/day) showed an increased risk of all-cause mortality, the pooled risk difference being 39 per 10 000 persons (95%CI = 3, 74). In low-dosage vitamin E trials there was no difference. High-dosage vitamin E may therefore be harmful and should be avoided.
Vitamin K1 (phytomenadione) (SED-15, 3681) Hematologic Safe chronic oral anticoagulation is compromised in clinical practice by many factors that cause erratic control and an increased risk of bleeding. One such factor is believed to be dietary vitamin K intake. The potential association between vitamin K intake and coagulation instability has been explored primarily in case reports and small, retrospective, uncontrolled studies. However, there has now been a prospective study of the effects of dietary vitamin K intake on coagulation in 39 out-patients taking oral coumarin derivatives who made 230 visits to one anticoagulation clinic (15C ). In a randomized crossover protocol, 12 patients with stable anticoagulation underwent 4-day in-hospital dietary interventions, 1–2 weeks apart, providing first a 500% increase and then an 80% reduction in vitamin K intake relative to baseline. There was a progressive statistically significant inverse association between vitamin K intake score and different degrees of anticoagulation. Vitamin K
356 intake was independently associated with both overcoagulation and undercoagulation. In the randomized protocol, the INR rose from 2.6 at baseline to 3.3 on day 7 in subjects on the vitamin K-depleted diet and fell from 3.1 at baseline to 2.8 on day 4 in those on the vitamin K-enriched diet. These prospective data strengthen the concept that the interaction between vitamin K and coumarins is a clinically relevant, major independent factor that interferes with anticoagulation stability. Skin Subcutaneous phytomenadione can cause adverse skin reactions, as has been illustrated in an unusual case of an erythematous papulovesicular rash (16A ). • A 21-year-old woman with Wilson’s disease was given fresh frozen plasma and subcutaneous phytomenadione 5 mg/day. On day 12 she started to complain of dryness, pruritus, and an erythematous papulovesicular rash, which was initially localized to several injection sites but eventually increased in size to 5–6 cm. Phytomenadione was withdrawn on day 15, but the rash persisted despite the use of a glucocorticoid cream. The rash finally disappeared shortly after liver transplantation and the start of immunosuppressant treatment.
While skin hypersensitivity to intramuscular phytomenadione is not uncommon, the authors thought that this case was unusual because it involved subcutaneous administration and quickly resolved after immunosuppressive drug therapy. However, it is not perhaps surprising that phytomenadione injection causes similar skin reactions irrespective of the route of injection. Recalcitrant dermatitis after intramuscular phytomenadione responded to treatment with a pulsed dye laser (17A ).
Chapter 34
M.C. Allwood and I. Hardy
• A 25-year-old woman developed pruritic skin lesions on both buttocks laterally while taking several drugs, including phytomenadione. Intradermal testing showed vitamin K-induced allergic contact dermatitis. The symptoms persisted despite the use of a topical glucocorticoid and oral prednisolone 30 mg/day. Because of systemic adverse effects she was then given intralesional glucocorticoid injections and a topical glucocorticoid under an occlusive dressing. After several weeks of unsuccessful treatment she was then given two consecutive pulsed dye laser treatments (450 µsec pulse duration, 585 nm pulse width, fluence of 5 and 7 J/cm2 using a 7 mm hand piece) 3 weeks apart. The skin lesion cleared 1 week after the second laser treatment and she was followed for 7 months without recurrence.
The authors of this report acknowledged that neither the precise mechanism by which the intramuscular phytomenadione could have caused a skin reaction without any apparent systemic or neuromuscular effects, nor the exact mechanism by which the pulsed dye laser treatment improved the condition are known. Laser treatment has been successfully used for psoriatic plaques (18A , 19A ). The beneficial effect has been attributed to destruction of abnormal dermal vasculature. The authors speculated that in this case, which was not associated with abnormal dermal vasculature, the laser may have destroyed dilated vessels, thereby reducing the accumulation of inflammatory cells and cytokine release. Be cause of the high cost the authors suggested that this treatment should be reserved for lesions that are unresponsive to conventional glucocorticoid therapy.
References 1. Hurwitz M, Garcia MG, Poole RL, Kerner JA. Copper deficiency during parenteral nutrition: a report of four pediatric cases. Nutr Clin Pract 2004;19:305–8. 2. Greene HL, Hambridge KM, Schlander R, Tsang RC. Guidelines for the use of vitamins, trace elements, calcium, magnesium, and phosphorus in infants and children receiving TPN.
Report of a subcommittee on pediatric parenteral nutrition requirements from the committee on clinical practice issues of the American Society of Clinical Nutrition. Am J Clin Nutr 1988;48:1324–42. 3. Fulford A, Scolapio JS, Aranda-Michel J. Parenteral nutrition-associated hepatotoxicity. Nutr Clin Pract 2004;19:274–83.
Formulations used in nutrition
357
Chapter 34
4. Wolf S, Krammer M, Trost HA, Lumenta CB. Lipofundin® -induced intracranial pressure rise after severe traumatic brain injury—a case report. Z Neurochirurg 2004;65:81–3. 5. Ho J, Rothchild YH, Sengelmann R. Vitamin B12 -associated localized scleroderma and its treatment. Dermatol Surg 2004;30:1252–5. 6. Gurkan F, Davutoglu M, Bosnak M, Ece A, Dikici B, Bilici M, Haspolat K. Pamidronate treatment in acute vitamin D intoxication. J Endocrinol Invest 2004;27:680–2. 7. Ezgu FS, Buyan N, Gündüz M, Tümer L, Ilyas O, Hasanoglu A. Vitamin D intoxication and hypercalcaemia in an infant treated with pamidronate infusions. Eur J Pediatr 2004;163:163–5. 8. Nako Y, Tomomasa T, Morikawa A. Risk of hypervitaminosis D from prolonged feeding of high vitamin D premature infant formula. Pediatr Int 2004;46:439–43. 9. Koo WWK, Steichen JJ. Osteopenia and rickets of prematurity. In: Polin RA, Fox WW, editors. Fetal and Neonatal Physiology, vol. II. Philadelphia: WB Saunders; 1998. p. 2335–49. 10. Senterre J, Salle B. Calcium and phosphorus economy of the preterm infant and its interaction with vitamin D and its metabolites. Acta Paediatr Scand 1982;296(Suppl):85–92. 11. Backström MC, Mäki R, Kuusela A. Randomised controlled trial of vitamin D supplementation on bone density and biochemical indices in preterm infants. Arch Dis Child Fetal Neonatal Ed 1999:F161–6. 12. Ylikomi T, Laaksi I, Lou YR, Martikainen P, Miettinen S, Pennanen P, Purmonen S, Syvala H,
13.
14.
15.
16. 17. 18. 19.
Vienonen A, Tuohimaa P. Antiproliferative action of vitamin D. Vitam Horm 2002;64:357– 406. Tuohimaa P, Tenkanen L, Ahonen M, Lumme S, Jellum E, Hallmans G, Stattin P, Harvei S, Hakulinen T, Luostarinen T, Dillner J, Lehtinen M, Hakama M. Both high and low levels of blood vitamin D are associated with a higher prostate cancer risk: a longitudinal, nested casecontrol study in the Nordic countries. Int J Cancer 2004;108:104–8. Miller ER, Pastor-Barriuso R, Dalal D, Riemersma RA, Appel LJ, Guallar E. Metaanalysis: high-dosage vitamin E supplementation may increase all-cause mortality. Ann Intern Med 2005;142:37–46. Franco V, Polanczyk CA, Clausell N, Rohde LE. Role of dietary vitamin K intake in chronic oral anticoagulation: prospective evidence from observational and randomized protocols. Am J Med 2004;116:651–6. Bui L, Huynh T, Lam V. Skin reaction to subcutaneous phytonadione injections. Am J HealthSystem Pharm 2004;61:407. Jung J, Cho SB, Chung KY. Recalcitrant adverse reaction to vitamin K: response to pulsed dye laser. Dermatol Surg 2004;30:931–3. Apfelberg D. Psoriasis response to the pulsed dye laser. Plast Reconstr Surg 1998;101:559–60. Ros A, Garden JM, Bakus AD, Hedblad MA. Psoriasis response to the pulsed dye laser. Lasers Surg Med 1996;19:331.
34
Formulations used in nutrition
PARENTERAL NUTRITION (SED-15, 2700; SEDA-26, 377; SEDA-27, 355; SEDA-28, 383) Metal metabolism Cholestasis is a common complication of parenteral nutrition, particularly in young children. One response is to reduce or discontinue copper and manganese, to avoid accumulation, since both are normally excreted by biliary excretory pathways. If the patient depends mainly or entirely on parenteral nutrition for feeding, deficiency of these elements will ensue. Of particular concern is copper deficiency. Evidence of copper deficiency has emerged in four children, one teenager and three children under 1 year old, all of whom depended entirely on parenteral feeding for maintenance of nutritional well-being (1A ). All were monitored regularly for key markers of nutritional status. After cholestasis developed, all four had signs of copper deficiency. In the teenager, it was clearly manifest 3 months after removing copper from the feeding regimen, although his plasma copper concentrations were almost within his reference range (660 µg/l). His symptoms related principally to pancytenoia. After 6 months, when the copper concentration had fallen to 90 µg/l, copper 20 micrograms/kg every 2 weeks was re-introduced into his diet. His plasma concentrations recovered to between 570 and 920 µg/l. His bone marrow rapidly normalized, with a rise in white cell count, hematocrit, and platelet count to normal. In the three other cases, cholestasis developed at 2–6 weeks after birth, leading to severe cholestasis, when copper was reduced to 10 micrograms/kg/day in one case, or removed completely. In all cases there was Side Effects of Drugs, Annual 29 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(06)29034-2 © 2007 Elsevier B.V. All rights reserved.
copper deficiency, based on low plasma concentrations. Reintroduction of copper normalized the plasma concentrations within 1–3 months. In only one case were there effects of copper deficiency, including hypopigmentary changes in the hair and femoral and rib fractures, all of which resolved after re-introduction of copper. Although current guidelines recommend omitting copper (and manganese) from parenteral nutrition regimens in patients with obstructive jaundice (2S ), the authors recommended that copper concentrations should be checked monthly and that re-introduction of copper should be considered when concentrations suggest that there is deficiency. This can be achieved at a dosage of 20 micrograms/kg/ day in children, followed by 10 micrograms/ kg/day after concentrations have returned to normal. Liver Hepatotoxicity associated with parenteral nutrition is probably the most important metabolic complication of intravenous feeding. The literature over the past 5 years has been reviewed (3R ) for evidence about the suspected pathogenesis, commonly used diagnostic tests and procedures, and current methods for preventing and treating it. The authors concluded that, regardless of current advances in research, we are still ignorance in all these areas, with little if any new further information.
Fat emulsions Nervous system Early nutrition is a recognized component of neurosurgical intensive care treatment but it can cause raised intracranial pressure. • A 22-year-old woman with severe traumatic brain injury reproducibly developed raised intracranial pressure when Lipofundin® , a soybean oil-based emulsion for parenteral nutrition, was infused (4A ). When the intracranial pressure rose, the patient remained hemodynamically stable, and so
353
354
Chapter 34
an anaphylactic reaction was unlikely. Increased brain tissue oxygenation parallel to the rise in intracranial pressure suggested increased cerebral blood flow as a cause.
Without multimodal monitoring and data storage, the adverse effect of Lipofundin® in this patient would have been difficult to identify. It should be noted that the infusion rate of the fat emulsion was relatively rapid, and also that no other such incidences have been reported, so that the link remains speculative.
VITAMINS OF THE B GROUP (SEDA-26, 419; SEDA-27, 407; SEDA-28, 387)
Vitamin B12 (cobalamins)
(SED-15,
3668) Skin Localized drug-induced injection site reactions are rare. However, sclerodermoid injection site reactions have been reported, most commonly with vitamin K, but also pentazocine, progestin, and vitamin B12 (5A ). • A 31-year-old Caucasian woman who had been receiving monthly injections of vitamin B12 as a nutritional supplement for Crohn’s disease had no local reaction. immediately after receiving an injection in the upper arm, but after 3 years developed a “red spot” which developed into a sclerotic plaque over 1 month. There were no signs of systemic scleroderma. Because the size and extent of the lesion had been stable for several months, excision was performed under local anesthesia. The lesion healed without complications.
While the localized scleroderma was linked directly to the vitamin injection, whether this was due to the vitamin itself or the injection vehicle was unclear.
VITAMIN D ANALOGUES (SED-15, 3669; SEDA-28, 388) Mineral balance The successful treatment of vitamin D-induced hypercalcemia with pamidronate has been reported.
M.C. Allwood and I. Hardy
• A 6-month-old girl who had accidentally been given 300 000 units of oral vitamin D for 10 days was admitted with anorexia, vomiting, polydipsia, polyuria, and constipation (6A ). The serum calcium concentration was 4.2 (reference range 2.2– 2.5) mmol/l and the serum 25-hydroxycolecalciferol concentration was 340 (reference range 10–50) µg/l. She was initially treated with hydration and furosemide (1 mg/kg every 6 hours) followed by three doses of calcitonin (2 U/kg) over 2 days. She also received prednisolone 2 mg/kg/day and oral nifedipine 1 mg/kg/day for hypertension. Despite this the serum calcium concentration remained life-threateningly high (3.9 mmol/l). Calcitonin was withdrawn and pamidronate 1 mg/kg/day was infused over 2 days. The serum calcium fell to 3.4 mmol/l on day 3 and 2.6 mmol/l on day 4. • A 3-month-old boy who had been given a total of 2 560 000 units of vitamin D over 8 days developed constipation, restlessness, anorexia, vomiting, and sweating (7A ). The serum calcium concentration was 4.1 mmol/l and the concentration of 25-hydroxycolecalciferol was 268 µg/l. He was given furosemide 2 mg/kg/day and intravenous hydration. The serum calcium remained high and he was given prednisolone 2 mg/kg/day. The serum calcium remained high and an electrocardiogram showed extra beats. Pamidronate 5 mg/l in 40 ml of isotonic saline was infused over 4 hours. The serum calcium concentration fell to 2.6 mmol/l within 36 hours and the electrocardiogram resolved. The serum calcium 21 days later was 2.9 mmol/l and the pamidronate infusion was repeated; the calcium concentration fell to 2.4 mmol/l. Further infusions of the same dose of pamidronate were given after 30 and 59 days and the calcium concentration was 2.2 mmol/l after 4 months.
Hypercalcemia due to acute vitamin D intoxication is mainly mediated by increased bone resorption, and so drugs that inhibit bone resorption may be more effective than furosemide and intravenous hydration. Calcitonin has the disadvantage of a relatively short duration of action and has been reported to lower the initial serum calcium by only up to 20% (6A ). The bisphosphonate pamidronate is often used in children to treat hypercalcemia due to malignancy and juvenile osteoporosis. The authors of these reports did not report any adverse effects of pamidronate infusion and concluded that it could be a life-saving intervention when calcium concentrations do not respond adequately to conventional management. A recent study of serum 25-hydroxycolecalciferol in 12 very premature infants fed on a specialist formula with a high vitamin D content (2700 IU/l) has shown an increased risk of hypervitaminosis (8c ). Serum 25-hydroxycolecal-
Formulations used in nutrition
355
Chapter 34
ciferol concentrations in infants fed exclusively on the premature formula (n = 40) were significantly higher than in infants fed regular formula or breast milk (n = 25) (175 versus 115 nmol/l). However, none of the infants had abnormal serum calcium or phosphorus concentrations. The authors postulated that this was probably because vitamin D-dependent active intestinal calcium resorption is limited in premature infants (9R ), but becomes relevant with intestinal maturation, which seems to be accelerated by premature delivery (10R ). Prolonged feeding of high vitamin D formula in very premature infants therefore poses the risk of hypervitaminosis. Although vitamin D requirements in premature infants are controversial, and a daily intake of 200 IU/kg has been shown to be sufficient (11c ), premature infant formulas marketed in Japan, such as the one used in this study, contain large amounts of vitamin D (2700 IU/l). The preterm formulas that are commonly used in Europe and the USA contain less vitamin D (1010–2200 IU/l) and carry a much reduced risk of hypervitaminosis. Tumorigenicity Vitamin D deficiency has been associated with an increased risk of prostate cancer due to the antiproliferative effect of 1α,25-dihydroxycolecalciferol in vitro (12E ). However, a longitudinal nested case-control study in which serum 25-hydroxycolecalciferol concentrations were measured in 622 men with prostate cancer and 1451 matched controls has shown that both high (80 nmol/l) and low (19 nmol/l) vitamin D blood concentrations carry an increased risk (13C ). The reference range (40–60 nmol/l) was associated with the lowest risk. The finding that high concentrations of vitamin D are related to an increased risk was unexpected and is difficult to explain on the basis of experimental results. The authors speculated that it might be because prostate cells regulate their own vitamin D balance by 24-hydroxylase, an enzyme that inactivates colecalciferol (vitamin D3 ). High concentrations of colecalciferol upregulate the activity of this enzyme, leading to local colecalciferol deficiency and resistance. This means that colecalciferol cannot have its antiproliferative function in prostate tissue despite high serum concentrations. Since these results suggest that even moderately high concentrations of vitamin D may have an adverse effect, care
should be taken before recommending supplementation.
VITAMIN E
(SED-15, 3677)
Death Vitamin E supplementation has been tested in many trials of prevention of cardiovascular disease and cancer. However, a few trials have reported a non-statistically significant increase in total mortality with high-dose vitamin E supplementation. The issue has been reviewed in a meta-analysis (14M ). The purpose was to look for a dose-response relation between vitamin E supplementation and total mortality, using data from randomized controlled trials. Comparing vitamin E with placebo, nine of 11 trials of high-dose vitamin E (over 400 IU/day) showed an increased risk of all-cause mortality, the pooled risk difference being 39 per 10 000 persons (95%CI = 3, 74). In low-dosage vitamin E trials there was no difference. High-dosage vitamin E may therefore be harmful and should be avoided.
Vitamin K1 (phytomenadione) (SED-15, 3681) Hematologic Safe chronic oral anticoagulation is compromised in clinical practice by many factors that cause erratic control and an increased risk of bleeding. One such factor is believed to be dietary vitamin K intake. The potential association between vitamin K intake and coagulation instability has been explored primarily in case reports and small, retrospective, uncontrolled studies. However, there has now been a prospective study of the effects of dietary vitamin K intake on coagulation in 39 out-patients taking oral coumarin derivatives who made 230 visits to one anticoagulation clinic (15C ). In a randomized crossover protocol, 12 patients with stable anticoagulation underwent 4-day in-hospital dietary interventions, 1–2 weeks apart, providing first a 500% increase and then an 80% reduction in vitamin K intake relative to baseline. There was a progressive statistically significant inverse association between vitamin K intake score and different degrees of anticoagulation. Vitamin K
356 intake was independently associated with both overcoagulation and undercoagulation. In the randomized protocol, the INR rose from 2.6 at baseline to 3.3 on day 7 in subjects on the vitamin K-depleted diet and fell from 3.1 at baseline to 2.8 on day 4 in those on the vitamin K-enriched diet. These prospective data strengthen the concept that the interaction between vitamin K and coumarins is a clinically relevant, major independent factor that interferes with anticoagulation stability. Skin Subcutaneous phytomenadione can cause adverse skin reactions, as has been illustrated in an unusual case of an erythematous papulovesicular rash (16A ). • A 21-year-old woman with Wilson’s disease was given fresh frozen plasma and subcutaneous phytomenadione 5 mg/day. On day 12 she started to complain of dryness, pruritus, and an erythematous papulovesicular rash, which was initially localized to several injection sites but eventually increased in size to 5–6 cm. Phytomenadione was withdrawn on day 15, but the rash persisted despite the use of a glucocorticoid cream. The rash finally disappeared shortly after liver transplantation and the start of immunosuppressant treatment.
While skin hypersensitivity to intramuscular phytomenadione is not uncommon, the authors thought that this case was unusual because it involved subcutaneous administration and quickly resolved after immunosuppressive drug therapy. However, it is not perhaps surprising that phytomenadione injection causes similar skin reactions irrespective of the route of injection. Recalcitrant dermatitis after intramuscular phytomenadione responded to treatment with a pulsed dye laser (17A ).
Chapter 34
M.C. Allwood and I. Hardy
• A 25-year-old woman developed pruritic skin lesions on both buttocks laterally while taking several drugs, including phytomenadione. Intradermal testing showed vitamin K-induced allergic contact dermatitis. The symptoms persisted despite the use of a topical glucocorticoid and oral prednisolone 30 mg/day. Because of systemic adverse effects she was then given intralesional glucocorticoid injections and a topical glucocorticoid under an occlusive dressing. After several weeks of unsuccessful treatment she was then given two consecutive pulsed dye laser treatments (450 µsec pulse duration, 585 nm pulse width, fluence of 5 and 7 J/cm2 using a 7 mm hand piece) 3 weeks apart. The skin lesion cleared 1 week after the second laser treatment and she was followed for 7 months without recurrence.
The authors of this report acknowledged that neither the precise mechanism by which the intramuscular phytomenadione could have caused a skin reaction without any apparent systemic or neuromuscular effects, nor the exact mechanism by which the pulsed dye laser treatment improved the condition are known. Laser treatment has been successfully used for psoriatic plaques (18A , 19A ). The beneficial effect has been attributed to destruction of abnormal dermal vasculature. The authors speculated that in this case, which was not associated with abnormal dermal vasculature, the laser may have destroyed dilated vessels, thereby reducing the accumulation of inflammatory cells and cytokine release. Be cause of the high cost the authors suggested that this treatment should be reserved for lesions that are unresponsive to conventional glucocorticoid therapy.
References 1. Hurwitz M, Garcia MG, Poole RL, Kerner JA. Copper deficiency during parenteral nutrition: a report of four pediatric cases. Nutr Clin Pract 2004;19:305–8. 2. Greene HL, Hambridge KM, Schlander R, Tsang RC. Guidelines for the use of vitamins, trace elements, calcium, magnesium, and phosphorus in infants and children receiving TPN.
Report of a subcommittee on pediatric parenteral nutrition requirements from the committee on clinical practice issues of the American Society of Clinical Nutrition. Am J Clin Nutr 1988;48:1324–42. 3. Fulford A, Scolapio JS, Aranda-Michel J. Parenteral nutrition-associated hepatotoxicity. Nutr Clin Pract 2004;19:274–83.
Formulations used in nutrition
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