Efficacy of two vitamin E formulations in patients with abetalipoproteinemia and chylomicron retention disease

Abetalipoproteinemia (ABL) and chylomicron retention disease (CMRD) are extremely rare recessive forms of hypobetalipoproteinemia characterized by intestinal lipid malabsorption and severe vitamin E deficiency. Vitamin E is often supplemented in the form of fat-soluble vitamin E acetate, but fat malabsorption considerably limits correction of the deficiency. In this crossover study, we administered two different forms of vitamin E, tocofersolan (a water-soluble derivative of RRR-α-tocopherol) and α-tocopherol acetate, to three patients with ABL and four patients with CMRD. The aims of this study were to evaluate the intestinal absorption characteristics of tocofersolan versus α-tocopherol acetate by measuring the plasma concentrations of α-tocopherol over time after a single oral load and to compare efficacy by evaluating the ability of each formulation to restore vitamin E storage after 4 months of treatment. In patients with ABL, tocofersolan and α-tocopherol acetate bioavailabilities were extremely low (2.8% and 3.1%, respectively). In contrast, bioavailabilities were higher in patients with CMRD (tocofersolan, 24.7%; α-tocopherol acetate, 11.4%). Plasma concentrations of α-tocopherol at 4 months were not significantly different by formulation type in ABL or CMRD. This study provides new insights about vitamin E status in ABL and CMRD and suggests the potential of different formulations as treatment options. Abetalipoproteinemia (ABL) and chylomicron retention disease (CMRD) are extremely rare recessive forms of hypobetalipoproteinemia characterized by intestinal lipid malabsorption and severe vitamin E deficiency. Vitamin E is often supplemented in the form of fat-soluble vitamin E acetate, but fat malabsorption considerably limits correction of the deficiency. In this crossover study, we administered two different forms of vitamin E, tocofersolan (a water-soluble derivative of RRR-α-tocopherol) and α-tocopherol acetate, to three patients with ABL and four patients with CMRD. The aims of this study were to evaluate the intestinal absorption characteristics of tocofersolan versus α-tocopherol acetate by measuring the plasma concentrations of α-tocopherol over time after a single oral load and to compare efficacy by evaluating the ability of each formulation to restore vitamin E storage after 4 months of treatment. In patients with ABL, tocofersolan and α-tocopherol acetate bioavailabilities were extremely low (2.8% and 3.1%, respectively). In contrast, bioavailabilities were higher in patients with CMRD (tocofersolan, 24.7%; α-tocopherol acetate, 11.4%). Plasma concentrations of α-tocopherol at 4 months were not significantly different by formulation type in ABL or CMRD. This study provides new insights about vitamin E status in ABL and CMRD and suggests the potential of different formulations as treatment options. Hypobetalipoproteinemias (HBLs) represent a heterogeneous group of very rare diseases characterized by reduced plasma levels of LDL-cholesterol and apoB below the fifth age- and sex-specific percentile (1.Tarugi P. Averna M. Hypobetalipoproteinemia: genetics, biochemistry, and clinical spectrum.Adv. Clin. Chem. 2011; 54: 81-107Crossref PubMed Scopus (92) Google Scholar, 2.Hooper A.J. Burnett J.R. Update on primary hypobetalipoproteinemia.Curr. Atheroscler. Rep. 2014; 16: 423Crossref PubMed Scopus (39) Google Scholar, 3.Levy E. Insights from human congenital disorders of intestinal lipid metabolism.J. Lipid Res. 2015; 56: 945-962Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar). Familial HBL (MIM 107730), the most frequent monogenic form of HBL with a codominant mode of inheritance, is mainly due to loss-of-function mutations in the APOB gene leading to a defect in the secretion of β-lipoproteins. The extremely rare (less than one in one million) recessive forms of primary monogenic HBL are represented by abetalipoproteinemia (ABL; MIM 200100) and chylomicron retention disease (CMRD; MIM 246700). ABL is due to mutations in the microsomal triglyceride transfer protein large subunit gene (MTTP), which encodes the MTP protein, the apoB chaperone protein, leading to a defect in apoB lipidation and, consequently, a lack of chylomicrons and VLDL (4.Sharp D. Blinderman L. Combs K.A. Kienzle B. Ricci B. Wager-Smith K. Gil C.M. Turck C.W. Boumas M.E. Rader D.J. et al.Cloning and gene defects in microsomal triglyceride transfer protein associated with abetalipoproteinaemia.Nature. 1993; 365: 65-69Crossref PubMed Scopus (403) Google Scholar, 5.Shoulders C.C. Brett D.J. Bayliss J.D. Narcisi T.M. Jarmuz A. Grantham T.T. Leoni P.R.D. Bhattacharya S. Pease R.J. Cullen P.M. Abetalipoproteinemia is caused by defects of the gene encoding the 97 kDa subunit of a microsomal triglyceride transfer protein.Hum. Mol. Genet. 1993; 2: 2109-2116Crossref PubMed Scopus (227) Google Scholar). CMRD is due to mutations in the SAR1B gene, which encodes the Sar1b protein involved in the control of the intracellular trafficking of chylomicrons in coat protein complex II (COPII)-coated vesicles (6.Jones B. Jones E.L. Bonney S.A. Patel H.N. Mensenkamp A.R. Eichenbaum-Voline S. Rudling M. Myrdal U. Annesi G. Naik S. et al.Mutations in a Sar1 GTPase of COPII vesicles are associated with lipid absorption disorders.Nat. Genet. 2003; 34: 29-31Crossref PubMed Scopus (295) Google Scholar). The clinical phenotype of ABL, CMRD, and homozygous or compound heterozygous familial HBL is usually severe, being characterized by intestinal lipid malabsorption, steatorrhea, fat-soluble vitamin deficiency, and “failure to thrive” in the neonatal period (7.Di Filippo M. Moulin P. Roy P. Samson-Bouma M.E. Collardeau-Frachon S. Chebel-Dumont S. Peretti N. Dumortier J. Zoulim F. Fontanges T. et al.Homozygous MTTP and APOB mutations may lead to hepatic steatosis and fibrosis despite metabolic differences in congenital hypocholesterolemia.J. Hepatol. 2014; 61: 891-902Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar). Most commonly, cases of ABL and homozygous or compound heterozygous familial HBL are complicated by retinal degeneration and ataxia beginning in the second decade of life if no treatment was initiated (3.Levy E. Insights from human congenital disorders of intestinal lipid metabolism.J. Lipid Res. 2015; 56: 945-962Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar, 8.Zamel R. Khan R. Pollex R.L. Hegele R.A. Abetalipoproteinemia: two case reports and literature review.Orphanet J. Rare Dis. 2008; 3: 19Crossref PubMed Scopus (136) Google Scholar). Oral α-tocopherol supplementation with high doses (50–200 IU/kg/day) has to be started as early as possible to prevent neurological and retinal disability and halt/abrogate progression of complications associated with this disease (9.Muller D.P. Lloyd J.K. Bird A.C. Long-term management of abetalipoproteinaemia. Possible role for vitamin E.Arch. Dis. Child. 1977; 52: 209-214Crossref PubMed Scopus (103) Google Scholar, 10.Muller D.P. Lloyd J.K. Effect of large oral doses of vitamin E on the neurological sequelae of patients with abetalipoproteinemia.Ann. N. Y. Acad. Sci. 1982; 393: 133-144Crossref PubMed Scopus (76) Google Scholar, 11.Runge P. Muller D.P. McAllister J. Calver D. Lloyd J.K. Taylor D. Oral vitamin E supplements can prevent the retinopathy of abetalipoproteinaemia.Br. J. Ophthalmol. 1986; 70: 166-173Crossref PubMed Scopus (65) Google Scholar). However, despite initiation of vitamin treatment, fundoscopic and retinal changes may appear (12.Chowers I. Banin E. Merin S. Cooper M. Granot E. Long-term assessment of combined vitamin A and E treatment for the prevention of retinal degeneration in abetalipoproteinaemia and hypobetalipoproteinaemia patients.Eye (Lond.). 2001; 15: 525-530Crossref PubMed Scopus (59) Google Scholar). Therefore, finding the most effective form and dose of tocopherol for treatment is of major interest because fat malabsorption considerably limits the correction of deficiencies with standard formulations of fat-soluble vitamins. In clinical nutrition, vitamin E is often supplemented in the form of vitamin E acetate. Tocofersolan, a water-soluble derivative of RRR-α-tocopherol, is a commercially available vitamin E supplement for lipid malabsorption syndromes, including chronic cholestasis and cystic fibrosis (13.Sokol R.J. Butler-Simon N. Conner C. Heubi J.E. Sinatra F.R. Suchy F.J. Heyman M.B. Perrault J. Rothbaum R.J. Levy J. et al.Multicenter trial of d-alpha-tocopheryl polyethylene glycol 1000 succinate for treatment of vitamin E deficiency in children with chronic cholestasis.Gastroenterology. 1993; 104: 1727-1735Abstract Full Text PDF PubMed Scopus (98) Google Scholar, 14.Papas K. Kalbfleisch J. Mohon R. of a water-soluble vitamin E formulation in Dis. Sci. 52: PubMed Scopus Google Scholar, E. B. Y. I. D. F. D. M. E. A. of oral vitamin E formulations in and children with chronic cholestasis or cystic Clin. 34: PubMed Scopus Google Scholar). on are and the of this water-soluble derivative of tocopherol in was the water-soluble tocofersolan be effective form of oral vitamin E supplement in ABL and CMRD. in plasma vitamin E is significantly reduced due to defects of chylomicron and which are for Vitamin E concentrations in and as potential of vitamin E status The of of tocopherol from of and Lipid Res. Full Text PDF PubMed Google Scholar, of vitamin E and in and patients with lipid Google Scholar, A for the of tocopherol in plasma and of the Lipid Res. Full Text PDF PubMed Google but on in are in the In this we for α-tocopherol in and in children to and we were and to of vitamin E status in CMRD C. L. J. E. A. S. Filippo M. Levy E. A. et of of in and in children to the management of chylomicron retention a rare J. Rare Dis. PubMed Scopus Google Scholar). The primary of this study was to evaluate the of tocofersolan versus acetate and to a for plasma α-tocopherol concentrations after of in and in patients with ABL and CMRD. The aims to compare the efficacy of a supplementation with tocofersolan versus α-tocopherol acetate to restore storage of vitamin E in and after 4 months treatment in a crossover clinical and to evaluate the of the two in rare patients with HBL ABL and four were in the study L. A. B. L. M. Moulin P. A. of two mutations and in a of four J. PubMed Scopus Google Scholar, M. A. Peretti N. Roy C.C. C. D. A. or chylomicron retention of mutations in the SAR1B gene on the and the of Sar1b Genet. 2008; PubMed Scopus Google Scholar). A crossover was four of the with the α-tocopherol acetate by the three were with the of tocofersolan by α-tocopherol acetate. to each was The of to a period of months α-tocopherol a to oral load of α-tocopherol acetate or tocofersolan on the by a 4 period of treatment with the of treatment by a second a with oral load and a 4 treatment with the and of study The dose for is of in the form of tocofersolan in patients from congenital chronic cholestasis or chronic However, the for the prevention of low vitamin E levels in ABL is and in CMRD R. Khan R. Pollex R.L. Hegele R.A. Abetalipoproteinemia: two case reports and literature review.Orphanet J. Rare Dis. 2008; 3: 19Crossref PubMed Scopus (136) Google Scholar, D.P. Lloyd J.K. The role of vitamin E in the treatment of the neurological of abetalipoproteinaemia and disorders of fat Dis. PubMed Scopus Google Scholar, N. A. Roy C.C. C. M. J. L. Moulin P. S. L. et for the and management of chylomicron retention disease on a of the literature and the of two J. Rare Dis. PubMed Scopus Google Scholar). to oral load of α-tocopherol acetate or tocofersolan and and for 4 the vitamin E a with were to and efficacy as as to by and measuring the or of or if and two from to were to study the of tocofersolan and α-tocopherol acetate in a crossover were for this study if no or chronic and were not vitamin or supplements for than 4 the study oral load with α-tocopherol acetate or tocofersolan in a by a for of plasma α-tocopherol concentrations were at and at time and were over vitamin E in to of α-tocopherol with The study was by the and the for and was in with the of the of patients or to and the clinical trial was at the period of vitamin E patients were for the and The of the was was at for of lipid and α-tocopherol in plasma and at and after of α-tocopherol acetate or The four time and were at the The were by a at each in a and each at for 4 from were to the after the of vitamin E of C. Peretti N. K. A. M. J. E. of the in of and in Clin. 2015; 52: PubMed Scopus Google Scholar). the of treatment, and for lipid and α-tocopherol in plasma and and were the of for lipid and for plasma were at the single dose of tocofersolan or α-tocopherol acetate and at time and and for of α-tocopherol concentrations were by a and levels of control were at the beginning of each In the in of the and after of plasma by α-tocopherol was and the was in The was by at was on at a with and with a of as by et E. C. of and in by Sci. PubMed Scopus Google Scholar). was as standard for of vitamin E to for The of for α-tocopherol in plasma were and at and The were and at the levels of were for tocopherol as of and in plasma or by high J. Clin. PubMed Scopus Google Scholar). In were three in and in this to a of and of were at than was as The was at was by of and in and transfer in a were from the to a and standard and on The was and a The was to a and α-tocopherol was by as The was at at of α-tocopherol of for α-tocopherol in and in and patients were and the for α-tocopherol acetate and tocofersolan in the were to the after from for each time the were to the of differences in the group CMRD, or and the was to the were The differences were to be at the Plasma concentrations for α-tocopherol in and in ABL and CMRD patients were the This the of and the of available on and of for in due to and for and for and and CMRD T. P. is a in Clin. PubMed Scopus Google Scholar, N. B. A standard for and Sci. Full Text Full Text PDF PubMed Scopus Google Scholar). In to a of administered doses of α-tocopherol acetate and tocofersolan were and α-tocopherol concentrations were The of α-tocopherol was to a in but with different absorption and ABL, or The absorption and were to be different for tocofersolan and α-tocopherol acetate, of were to be of the administered and were S. L. A. R. Scholar). was by in to the the of to be and to on the as and by and standard reports the on can be in of of for each and as The in absorption characteristics α-tocopherol acetate and tocofersolan was by the of with and the as for in a with the of to the in the of of one is if the is than In to compare for α-tocopherol acetate and tocofersolan in each were of tocofersolan to be to α-tocopherol acetate. The was to evaluate the of the in with ABL two and four with CMRD one were in the ABL patients and apoB concentrations than CMRD were to hepatic were and was in patients with CMRD, as M. D. T. P. A. Peretti N. D. F. C. et disease retention a new in the gene associated with and Genet. 2008; PubMed Scopus Google Scholar). was in two of three patients with Vitamin A was the with treatment as as vitamin and vitamin and of patients with ABL and CMRD at A vitamin are as as low of high of in a new are as as low of high of In the after a single of α-tocopherol acetate and tocofersolan was and α-tocopherol acetate and tocofersolan were significantly in than in patients with ABL and CMRD In α-tocopherol acetate was than tocofersolan in In ABL the absorption of was was due to the extremely low α-tocopherol with the of the In CMRD tocofersolan to be than α-tocopherol acetate A for plasma α-tocopherol concentrations after α-tocopherol acetate or tocofersolan was A of the is in 4 and the of in the versus for and for a and the or at after a single or after by on the administered not with time or was in the of the and was for α-tocopherol acetate and tocofersolan and for α-tocopherol was on and of for the of on and, the and the on the of plasma α-tocopherol were with are large for to ABL, but be three ABL patients were in this of was to the group of α-tocopherol acetate is and of plasma α-tocopherol in ABL and CMRD patients were to the in as α-tocopherol of of plasma in a new was to the group of α-tocopherol acetate is and of plasma α-tocopherol in ABL and CMRD patients were to the in as α-tocopherol of of plasma levels of α-tocopherol plasma concentrations were for for CMRD patients and ABL patients The absorption was to be different the the the but not different patients with the α-tocopherol acetate or tocofersolan the of the administered dose plasma with a of for α-tocopherol acetate administered in was in for tocofersolan than for α-tocopherol acetate In ABL the was to be low for α-tocopherol acetate and tocofersolan In contrast, in CMRD the was than for α-tocopherol acetate with tocofersolan In the in α-tocopherol acetate was very large for tocofersolan was is not possible to and be α-tocopherol plasma be after tocofersolan In to compare absorption of tocofersolan and α-tocopherol acetate in each a was to evaluate on was to be for to the was significantly was to be for α-tocopherol acetate and tocofersolan for the three In ABL patients after the α-tocopherol plasma concentrations were low after the and after the second In the were very to the In α-tocopherol concentrations were very low with the from to with a of C. L. J. E. A. S. Filippo M. Levy E. A. et of of in and in children to the management of chylomicron retention a rare J. Rare Dis. PubMed Scopus Google Scholar). In CMRD patients at α-tocopherol concentrations were low in plasma and in but significantly higher than in ABL patients In concentrations were the and significantly higher than in ABL 4 months of of of tocopherol acetate or α-tocopherol concentrations significantly in plasma and in of the vitamin E formulation were In ABL α-tocopherol plasma concentrations from to and from to after 4 treatment with α-tocopherol acetate and The α-tocopherol concentrations were from to and from to with α-tocopherol acetate and In α-tocopherol concentrations after 4 treatment and to the in ABL In CMRD plasma α-tocopherol concentrations from to and from to after treatment by α-tocopherol acetate and in from to and from to with α-tocopherol acetate and are to the in were not due to the of patients in each In α-tocopherol concentrations after 4 treatment but were higher than in ABL patients and to the in children after 4 was no the α-tocopherol concentrations in or patients with α-tocopherol acetate or tocofersolan were in or in patients with the oral load or the 4 treatment was no in of the to In and plasma over time of after 4 treatment with tocofersolan are as in a new are as This study is the to evaluate intestinal absorption of vitamin E and to a in very rare patients with caused by ABL and CMRD. The of this study was to evaluate the absorption of tocofersolan versus α-tocopherol acetate in patients with ABL and CMRD in to vitamin E supplementation in vitamin In ABL the vitamin E was to be extremely low for α-tocopherol acetate and tocofersolan are with by et Rader D. and with by patients with Full Text PDF PubMed Scopus Google ABL patients a ability to and vitamin E. In study, plasma from ABL patients of tocopherol about of the α-tocopherol concentrations of of In contrast, in CMRD the absorption of was very low the high doses tocofersolan to be than α-tocopherol acetate. In study, the the was than for tocofersolan with α-tocopherol acetate The of with are of and administered the to absorption and and of In α-tocopherol acetate was than tocofersolan after a single oral dose for to are to by et C. J. D. M. Plasma concentrations after supplementation with and fat-soluble vitamin J. Clin. PubMed Scopus Google supplementation with tocofersolan on plasma α-tocopherol in doses of α-tocopherol acetate in a in plasma (13.Sokol R.J. Butler-Simon N. Conner C. Heubi J.E. Sinatra F.R. Suchy F.J. Heyman M.B. Perrault J. Rothbaum R.J. Levy J. et al.Multicenter trial of d-alpha-tocopheryl polyethylene glycol 1000 succinate for treatment of vitamin E deficiency in children with chronic cholestasis.Gastroenterology. 1993; 104: 1727-1735Abstract Full Text PDF PubMed Scopus (98) Google Scholar, E. B. Y. I. D. F. D. M. E. A. of oral vitamin E formulations in and children with chronic cholestasis or cystic Clin. 34: PubMed Scopus Google Scholar, R.J. of tocopherol in of vitamin patients with J. PubMed Scopus Google Scholar, P. B. J. K. J. of children with water-soluble vitamin E polyethylene glycol on vitamin E, lipid and PubMed Scopus Google intestinal absorption of tocofersolan is to of acetate severe cholestasis due to a of water-soluble a form to the in the of a are available tocofersolan in cystic fibrosis and the are due to the of the and supplementation or no supplementation with K. Kalbfleisch J. Mohon R. of a water-soluble vitamin E formulation in Dis. Sci. 52: PubMed Scopus Google Scholar, E. B. Y. I. D. F. D. M. E. A. of oral vitamin E formulations in and children with chronic cholestasis or cystic Clin. 34: PubMed Scopus Google Scholar, Vitamin associated with vitamin E J. Google Scholar). The by which tocofersolan but not intestinal of diseases is et A.C. M. of water-soluble vitamin E in the treatment of vitamin E malabsorption in J. Clin. PubMed Scopus (59) Google tocofersolan can be effective vitamin E supplement in despite severe fat malabsorption, and this case has to the tocofersolan be of interest in associated with congenital lipid malabsorption due to The was to study the of tocofersolan or α-tocopherol acetate to storage of vitamin E. a 4 treatment period with each IU/kg/day) in a crossover the concentrations of α-tocopherol were in and to the after of a single after 4 was no the α-tocopherol concentrations in or with α-tocopherol acetate or tocofersolan IU/kg/day) in a is not in the vitamin E is very because of the in patients C. E. R. N. G. J. A. Peretti N. G. M. et of in on from patients with J. PubMed Scopus Google be a of the is at the intestinal in to be in the patients with ABL and CMRD C. J. D. M. Plasma concentrations after supplementation with and fat-soluble vitamin J. Clin. PubMed Scopus Google Scholar). doses of a treatment period concentrations in plasma and with tocofersolan than with α-tocopherol acetate, in CMRD tocofersolan to be in the in However, is the was be to the very of CMRD patients in this the of the study not the two in the storage of vitamin E, the of the study provides on vitamin E status in In CMRD, α-tocopherol concentrations at are higher than in ABL in plasma in and in In CMRD, vitamin E deficiency in plasma and was than in ABL after 4 months of treatment. In vitamin E concentrations in CMRD, were from the in ABL due to defects of chylomicron vitamin E concentrations to after 4 months of α-tocopherol with plasma α-tocopherol be a of to treatment, if not of the of as or vitamin E concentrations were over the study period and not by the of the two for 4 In ABL, α-tocopherol concentrations low despite treatment with higher doses for supplementation are in ABL, and The of of tocopherol from of and Lipid Res. Full Text PDF PubMed Google to be no in ABL In contrast, in CMRD, α-tocopherol concentrations were the the supplementation correction of α-tocopherol in despite low plasma and is to be to CMRD N. A. Roy C.C. C. M. J. L. Moulin P. S. L. et for the and management of chylomicron retention disease on a of the literature and the of two J. Rare Dis. PubMed Scopus Google Scholar). are with the complications are severe in patients with CMRD than in patients with ABL and, the and not in patients with CMRD A. Filippo M. Peretti N. Samson-Bouma M.E. retention disease and mutations in the SAR1B Cooper D. in Google Scholar). in the literature suggests secretion of chylomicrons be in CMRD N. A. N. A. G. A. A. J. et in abetalipoproteinemia and 2001; Full Text Full Text PDF PubMed Scopus Google Scholar, M.E. I. R. J. with of protein in intestinal and of cases of Clin. 1986; PubMed Scopus Google Scholar, C.C. Levy E. A. J. J. P. et and with intestinal B. retention Full Text PDF PubMed Scopus Google Scholar). In we protein which with Sar1b and is in the (6.Jones B. Jones E.L. Bonney S.A. Patel H.N. Mensenkamp A.R. Eichenbaum-Voline S. Rudling M. Myrdal U. Annesi G. Naik S. et al.Mutations in a Sar1 GTPase of COPII vesicles are associated with lipid absorption disorders.Nat. Genet. 2003; 34: 29-31Crossref PubMed Scopus (295) Google Scholar, A. J. D. J. M. T. E. C. et and intestinal of and in disease retention J. Rare Dis. 2011; PubMed Scopus Google the defect in Sar1b and absorption of α-tocopherol the chylomicron A. J. D. J. M. T. E. C. et and intestinal of and in disease retention J. Rare Dis. 2011; PubMed Scopus Google Scholar). In contrast, in ABL, vitamin E is the patients the concentrations of plasma α-tocopherol the concentrations in and the a for one ABL a and but a potential this the α-tocopherol a neurological the and but a by and was not with treatment. In we the and storage of vitamin E on form and in very rare α-tocopherol concentrations were not significantly different ABL and CMRD patients with one or the formulation for 4 tocofersolan be of was after a single and 4 months of treatment in as has in patients with (13.Sokol R.J. Butler-Simon N. Conner C. Heubi J.E. Sinatra F.R. Suchy F.J. Heyman M.B. Perrault J. Rothbaum R.J. Levy J. et al.Multicenter trial of d-alpha-tocopheryl polyethylene glycol 1000 succinate for treatment of vitamin E deficiency in children with chronic cholestasis.Gastroenterology. 1993; 104: 1727-1735Abstract Full Text PDF PubMed Scopus (98) Google Scholar, E. B. Y. I. D. F. D. M. E. A. of oral vitamin E formulations in and children with chronic cholestasis or cystic Clin. 34: PubMed Scopus Google Scholar, S. M. T. A. L. Effect of vitamin E on lipid in patients with Res. 2015; PubMed Scopus Google in children due to and The are to patients and for to in this the and of as and for and of abetalipoproteinemia the chylomicron retention disease of hypobetalipoproteinemia absorption standard second

Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.