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November 1, 1985, Vol 254, No. 17 >
ARTICLE | November 1, 1985

Vasculopathic Hepatotoxicity Associated With E-Ferol Syndrome in Low—Birth-Weight Infants FREE

Kevin E. Bove, MD; Niki Kosmetatos, MD; Kathryn E. Wedig, MD; Donald J. Frank, MD; Stephen Whitlatch, MD; Victor Saldivar, MD; Joel Haas, MD; Carl Bodenstein, MD; William F. Balistreri, MD
[+] Author Affiliations

Reprint requests to Division of Pediatric Gastroenterology and Nutrition, Children's Hospital Research Foundation, Elland and Bethesda avenues, Cincinnati, OH 45229 (Dr Balistreri).


JAMA. 1985;254(17):2422-2430. doi:10.1001/jama.1985.03360170062032
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References

A fatal syndrome characterized by progressive clinical deterioration with unexplained thrombocytopenia, renal dysfunction, cholestasis, and ascites developed in certain infants throughout the United States who had received E-Ferol, an intravenous vitamin E supplement. We reviewed the clinical course of all 36 infants from one (index) nursery who had received E-Ferol, which contains 25 units per milliliter of dl-α-tocopheryl acetate solubilized with 9% polysorbate 80 and 1% polysorbate 20. The syndrome was recognized in eight of the 36 infants; affected infants had a lower birth weight (<1,200 g) and had received a higher total dose of E-Ferol for longer periods than the unaffected cases. We reviewed autopsy-derived tissue from 20 infants (six from the index nursery and 14 from three other collaborating nurseries) who had received the intravenous vitamin E preparation in a reported dose of 25 to 137 units/kg/day for six to 45 days between October 1983 and March 1984. The hepatic histology in the affected cases indicated a progressive injury characterized initially by Kupffer cell exfoliation, central lobular accumulation of cellular debris, and centrally accentuated panlobular congestion. Prolonged exposure to E-Ferol was associated with progressive intralobular cholestasis, inflammation of hepatic venules, and extensive sinusoidal veno-occlusion by fibrosis. We propose that vasculocentric hepatotoxicity is the basis for the observed clinical syndrome that represents the cumulative effect of one or more of the constituents of E-Ferol.

(JAMA 1985;254:2422-2430)

REFERENCES

1 +
 Unusual syndrome with fatalities among premature infants: Association with a new intravenous vitamin E product . MMWR 1984;; 33:198-199.
2 +
Bodenstein CJ:  Intravenous vitamin E and deaths in the intensive care unit . Pediatrics 1984;;73:733.
3 +
Lorch V, Murphy MD, Hoersten LR, et al:  Unusual syndrome among premature infants: Association with a new intravenous vitamin E product . Pediatrics 1985;;75:598-602.
4 +
FDA's Regulation of the Marketing of Unapproved New Drugs: The Case of E-Ferol Vitamin E Aqueous Solution , hearing before a subcommittee on government operations, House of Representatives, 98th Cong, 2nd sess (1984;).
5 +
Gutcher GR, Raynor WJ, Farrell PM:  An evaluation of vitamin E status in premature infants . Am J Clin Nutr 1984;;40:1078-1089.
6 +
Hittner HM, Godio LB, Rudolph AJ, et al:  Retrolental fibroplasia: Efficacy of vitamin E in a double-blind clinical study of preterm infants . N Engl J Med 1981;;305:1365-1371.
7 +
Hittner HM, Godio LB, Speer ME, et al:  Retrolental fibroplasia: Further clinical evidence and ultrastructural support for efficacy of vitamin E in the preterm infants . Pediatrics 1983;;71:423-432.
8 +
Finer NN, Schindler RF, Grant G, et al:  Effect of intramuscular vitamin E on frequency and severity of retrolental fibroplasia: A controlled trial . Lancet 1982;;1:1087-1091.
9 +
Finer NN, Schindler RF, Peters KL, et al:  Vitamin E and retrolental fibroplasia: Improved visual outcome with early vitamin E . Ophthalmology 1983;;90:428-435.
10 +
Bucher JR, Roberts RJ:  α-Tocopherol (vitamin E) content of lung, liver, and blood in the newborn rat and human infant: Influence of hyperoxia . J Pediatr 1981;;98:806-811.
11 +
Finer NN, Peters KL, Hayek Z, et al:  Vitamin E and necrotizing enterocolitis . Pediatrics 1984;;73:387-393.
12 +
Phelps DL:  Local and systemic reactions to the parenteral administration of vitamin E . Dev Pharmacol Ther 1981;;2:156-171.
13 +
Bernstein J, Chang C-H, Brough AJ, et al:  Conjugated hyperbilirubinemia in infancy associated with parenteral hyperalimentation . J Pediatr 1977;;90:361-367.
14 +
Cohen C, Olson MM:  Pediatric total parenteral nutrition: Liver histopathology . Arch Pathol Lab Med 1981;;105:152-156.
15 +
Farrell MK, Gilster S, Balistreri WF:  Serum bile acids: An early indicator of parenteral nutrition-associated liver disease . Gastroenterology 1984;;86:1074.
16 +
Zafrani ES, Pinaudeau Y, Dhumeaux D:  Drug-induced vascular lesions of the liver . Arch Intern Med 1983;;143:495-502.
17 +
Stuart KL, Bras G:  Veno-occlusive disease of the liver . Q J Med 1957;;26:291-315.
18 +
Brooks SEH, Miller CG, McKenzie K, et al:  Acute venoocclusive disease of the liver: Fine structure in Jamaican children . Arch Pathol Lab Med 1970;;89:507-520.
19 +
Fajardo LF, Colby TV:  Pathogenesis of veno-occlusive liver disease after radiation . Arch Pathol Lab Med 1980;;104:584-588.
20 +
Schulman HM, McDonald GB, Matthews D, et al:  An analysis of hepatic veno-occlusive disease following centrilobular hepatic degeneration following bone marrow transplantation . Gastroenterology 1980;;79:1178-1191.
21 +
Weitz JM, Gobel K, Loeschke K, et al:  Veno-occlusive disease of the liver in patients receiving immunosuppressive therapy . Virchows Arch Pathol Anat 1982;;395:245-256.
22 +
Ghishan FK, Greene HL, Halter S, et al:  Noncirrhotic portal hypertension in congenital cytomegalovirus infection . Hepatology 1984;; 4:684-686.
23 +
Russell RM, Boyer JL, Bagheri SA, et al:  Hepatic injury from chronic hypervitaminosis A resulting in portal hypertension and ascites . N Engl J Med 1974;;291:435-440.
24 +
Zafrani ES, Bernuau D, Feldmann G:  Peliosis-like ultrastructural changes of the hepatic sinusoids in human chronic hypervitaminosis A: Report of three cases . Hum Pathol 1984;;15:1166-1170.
25 +
Chiswick ML, Johnson M, Woodhall C, et al:  Protective effect of vitamin E (dl-alphatocopherol) against intraventricular haemorrhage in premature babies . Br Med J 1983;; 287:81-84.
26 +
Bieri JG, Corash L, Hubbard VS:  Medical uses of vitamin E . N Engl J Med 1983;;308:1063-1071.
27 +
Hittner HM, Speer ME, Rudolph AJ, et al:  Retrolental fibroplasia and vitamin E in the preterm infant: Comparison of oral versus intramuscular:oral administration . Pediatrics 1984;; 73:238.
28 +
Sobel S, Gueriguian J, Troendle G, et al:  Vitamin E in retrolental fibroplasia . N Engl J Med 1982;;306:867.
29 +
Farrell PM, Bieri JG:  Megavitamin E supplementation in man . Am J Clin Nutr 1975;; 28:1381-1386.
30 +
Newmark HL, Pool W, Bauernfeind JC, et al:  Biopharmaceutic factors in parenteral administration of vitamin E . J Pharm Sci 1975;; 64:655-657.
31 +
Colburn WA, Ehrenkranz RA:  Pharmacokinetics of a single intramuscular injection of vitamin E to premature neonates . Pediatr Pharmacol 1983;;3:7-14.
32 +
Speer ME, Blifeld C, Rudolph AJ, et al:  Intraventricular hemorrhage and vitamin E in the very low-birth-weight infant: Evidence for efficacy of early intramuscular vitamin E administration . Pediatrics 1984;;74:1107-1112.
33 +
Moore J:  Final report on the safety assessment of polysorbates 20, 21, 40, 60, 61, 65, 80, 81, and 85 . J Am Coll Toxicol 1984;;3:1-82.
34 +
 Polyoxyethylene (20) sorbitan monoesters of lauric, oleic, palmitic, and stearic acid and triester of stearic acid , in Toxicological Evaluation of Some Food Additives, Including Anticaking Agents, Antimicrobials, Antioxidants, Emulsifiers, and Thickening Agents , FAO Nutrition Meetings Report Series No. 53A. Rome, Food and Agricultural Organization, 1974;.
35 +
Nelson MF, Poulas TA, Gongwer LE, et al:  Preparations of carbon-14-labeled polyoxyethylene (20) sorbitan monolaurate and their metabolic fate in rats . J Food Sci 1966;;31:253-258.
36 +
Zaslavasky BY, Ossipov NN, Krivish VS, et al:  Action of surface-active substances in biological membranes: II. Hemolytic activity of nonionic surfactants . Biochim Biophys Acta 1978;; 507:1-7.

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Country-Specific Mortality and Growth Failure in Infancy and Yound Children and Association With Material Stature

Use interactive graphics and maps to view and sort country-specific infant and early dhildhood mortality and growth failure data and their association with maternal

1 +
 Unusual syndrome with fatalities among premature infants: Association with a new intravenous vitamin E product . MMWR 1984;; 33:198-199.
2 +
Bodenstein CJ:  Intravenous vitamin E and deaths in the intensive care unit . Pediatrics 1984;;73:733.
3 +
Lorch V, Murphy MD, Hoersten LR, et al:  Unusual syndrome among premature infants: Association with a new intravenous vitamin E product . Pediatrics 1985;;75:598-602.
4 +
FDA's Regulation of the Marketing of Unapproved New Drugs: The Case of E-Ferol Vitamin E Aqueous Solution , hearing before a subcommittee on government operations, House of Representatives, 98th Cong, 2nd sess (1984;).
5 +
Gutcher GR, Raynor WJ, Farrell PM:  An evaluation of vitamin E status in premature infants . Am J Clin Nutr 1984;;40:1078-1089.
6 +
Hittner HM, Godio LB, Rudolph AJ, et al:  Retrolental fibroplasia: Efficacy of vitamin E in a double-blind clinical study of preterm infants . N Engl J Med 1981;;305:1365-1371.
7 +
Hittner HM, Godio LB, Speer ME, et al:  Retrolental fibroplasia: Further clinical evidence and ultrastructural support for efficacy of vitamin E in the preterm infants . Pediatrics 1983;;71:423-432.
8 +
Finer NN, Schindler RF, Grant G, et al:  Effect of intramuscular vitamin E on frequency and severity of retrolental fibroplasia: A controlled trial . Lancet 1982;;1:1087-1091.
9 +
Finer NN, Schindler RF, Peters KL, et al:  Vitamin E and retrolental fibroplasia: Improved visual outcome with early vitamin E . Ophthalmology 1983;;90:428-435.
10 +
Bucher JR, Roberts RJ:  α-Tocopherol (vitamin E) content of lung, liver, and blood in the newborn rat and human infant: Influence of hyperoxia . J Pediatr 1981;;98:806-811.
11 +
Finer NN, Peters KL, Hayek Z, et al:  Vitamin E and necrotizing enterocolitis . Pediatrics 1984;;73:387-393.
12 +
Phelps DL:  Local and systemic reactions to the parenteral administration of vitamin E . Dev Pharmacol Ther 1981;;2:156-171.
13 +
Bernstein J, Chang C-H, Brough AJ, et al:  Conjugated hyperbilirubinemia in infancy associated with parenteral hyperalimentation . J Pediatr 1977;;90:361-367.
14 +
Cohen C, Olson MM:  Pediatric total parenteral nutrition: Liver histopathology . Arch Pathol Lab Med 1981;;105:152-156.
15 +
Farrell MK, Gilster S, Balistreri WF:  Serum bile acids: An early indicator of parenteral nutrition-associated liver disease . Gastroenterology 1984;;86:1074.
16 +
Zafrani ES, Pinaudeau Y, Dhumeaux D:  Drug-induced vascular lesions of the liver . Arch Intern Med 1983;;143:495-502.
17 +
Stuart KL, Bras G:  Veno-occlusive disease of the liver . Q J Med 1957;;26:291-315.
18 +
Brooks SEH, Miller CG, McKenzie K, et al:  Acute venoocclusive disease of the liver: Fine structure in Jamaican children . Arch Pathol Lab Med 1970;;89:507-520.
19 +
Fajardo LF, Colby TV:  Pathogenesis of veno-occlusive liver disease after radiation . Arch Pathol Lab Med 1980;;104:584-588.
20 +
Schulman HM, McDonald GB, Matthews D, et al:  An analysis of hepatic veno-occlusive disease following centrilobular hepatic degeneration following bone marrow transplantation . Gastroenterology 1980;;79:1178-1191.
21 +
Weitz JM, Gobel K, Loeschke K, et al:  Veno-occlusive disease of the liver in patients receiving immunosuppressive therapy . Virchows Arch Pathol Anat 1982;;395:245-256.
22 +
Ghishan FK, Greene HL, Halter S, et al:  Noncirrhotic portal hypertension in congenital cytomegalovirus infection . Hepatology 1984;; 4:684-686.
23 +
Russell RM, Boyer JL, Bagheri SA, et al:  Hepatic injury from chronic hypervitaminosis A resulting in portal hypertension and ascites . N Engl J Med 1974;;291:435-440.
24 +
Zafrani ES, Bernuau D, Feldmann G:  Peliosis-like ultrastructural changes of the hepatic sinusoids in human chronic hypervitaminosis A: Report of three cases . Hum Pathol 1984;;15:1166-1170.
25 +
Chiswick ML, Johnson M, Woodhall C, et al:  Protective effect of vitamin E (dl-alphatocopherol) against intraventricular haemorrhage in premature babies . Br Med J 1983;; 287:81-84.
26 +
Bieri JG, Corash L, Hubbard VS:  Medical uses of vitamin E . N Engl J Med 1983;;308:1063-1071.
27 +
Hittner HM, Speer ME, Rudolph AJ, et al:  Retrolental fibroplasia and vitamin E in the preterm infant: Comparison of oral versus intramuscular:oral administration . Pediatrics 1984;; 73:238.
28 +
Sobel S, Gueriguian J, Troendle G, et al:  Vitamin E in retrolental fibroplasia . N Engl J Med 1982;;306:867.
29 +
Farrell PM, Bieri JG:  Megavitamin E supplementation in man . Am J Clin Nutr 1975;; 28:1381-1386.
30 +
Newmark HL, Pool W, Bauernfeind JC, et al:  Biopharmaceutic factors in parenteral administration of vitamin E . J Pharm Sci 1975;; 64:655-657.
31 +
Colburn WA, Ehrenkranz RA:  Pharmacokinetics of a single intramuscular injection of vitamin E to premature neonates . Pediatr Pharmacol 1983;;3:7-14.
32 +
Speer ME, Blifeld C, Rudolph AJ, et al:  Intraventricular hemorrhage and vitamin E in the very low-birth-weight infant: Evidence for efficacy of early intramuscular vitamin E administration . Pediatrics 1984;;74:1107-1112.
33 +
Moore J:  Final report on the safety assessment of polysorbates 20, 21, 40, 60, 61, 65, 80, 81, and 85 . J Am Coll Toxicol 1984;;3:1-82.
34 +
 Polyoxyethylene (20) sorbitan monoesters of lauric, oleic, palmitic, and stearic acid and triester of stearic acid , in Toxicological Evaluation of Some Food Additives, Including Anticaking Agents, Antimicrobials, Antioxidants, Emulsifiers, and Thickening Agents , FAO Nutrition Meetings Report Series No. 53A. Rome, Food and Agricultural Organization, 1974;.
35 +
Nelson MF, Poulas TA, Gongwer LE, et al:  Preparations of carbon-14-labeled polyoxyethylene (20) sorbitan monolaurate and their metabolic fate in rats . J Food Sci 1966;;31:253-258.
36 +
Zaslavasky BY, Ossipov NN, Krivish VS, et al:  Action of surface-active substances in biological membranes: II. Hemolytic activity of nonionic surfactants . Biochim Biophys Acta 1978;; 507:1-7.

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