003 I -3998/90/2802-0 158$02.00/0 PEDIATRIC RESEARCH Copyright O 1990 International Pediatric Research Foundation. Inc.

Carnitine Ester Excretion in Pediatric Patients Receiving Parenteral Nutrition

EBERHARD SCHMIDT-SOMMERFELD, DUNA PENN. LORAN L. BIEBER. JANOS KERNER. THOMAS M. ROSSI. AND EMANUEL LEBENTHAL D[purttnc*ntc?/'P~.dirrtric:~, Section of Gastroc~nterolo~~v,Hepatolo~p and Nlrtririon, Universitjr c?fCliica~o. Chic.cr,qo. 1llitioi.s 60637 [E.S.S.. D.P.]; Department of Biochemistrj*. Michigan State Univc~rsir~l.East Lansing. .Zli(,l~igati488-74 1L.L.B.. J.K.]: and Dc>partment r?fPediatrics, Division qf Ga.strocnrerologj~and Nutrition. Stare Univ~r.sit,rc?f'Nc\c. York at B~!ffalo,Bl!ffalo. New York 14222/T.M.R.. E.L.]

ABSTRAm. plasma concentrations and the ex- (I) and regenerating intramitochondrial coenzyme A through cretion of carnitine and individual carnitine esters were transport of acyl-groups out of the mitochondria, thereby main- determined in 25 children and adolescents with gastroin- taining conditions required for oxidative processes (2). testinal diseases receiving carnitine-free parenteral nutri- Although carnitine is synthesized de novo in mammalian tion for at least 1 mo using radiochemical and radioisotopic tissues (3). nutritional carnitine deficiency may occur under exchange HPLC methods. Children ~12-y-oldusually had certain circumstances if carnitine is not provided with the . carnitine plasma concentrations C-2 SD from the normal Infants receiving carnitine-free TPN are particularly prone to mean for age, whereas patients >12-y-old had carnitine develop carnitine deficiency, probably due to impaired carnitine plasma concentrations within the normal range. Age was (4) and low carnitine tissue stores (5). Moreover, the only variable to correlate significantly with plasma infants on TPN appear to have a decreased capacity to oxidize carnitine concentrations during parenteral nutrition. Free fatty acids that can be improved by L-carnitine supplementation carnitine (FC) excretion was closely correlated with plasma (6, 7). The question has therefore been raised whether carnitine FC concentrations and minimal at values <25 rmol/L. The should be considered an essential nutrient for the infant (8). excretion of FC and short-chain acylcarnitines was reduced It is not known at what time during human development by an order of magnitude in younger compared with older endogenous carnitine biosynthesis becomes adequate. Adults patients and controls, but the excretion of "other" acylcar- receiving TPN maintain a normal carnitine status over a longer nitines was less affected. Some of the latter were tentatively period of time than infants (9). Nonetheless. abnormally low identified using gas-liquid chromatographic and mass spec- carnitine plasma concentrations were found in 35% of an adult troscopic techniques as unsaturated and/or branched me- population on long-term home PN (10). Some of them also had dium-chain carnitine esters with a carbon chain of C8- decreased liver carnitine content. The pathogenesis of this is not C10. The results suggest that FC and short-chain acylcar- understood because, in the mature individual, endogenous car- nitine are conserved by the kidney in nutritional carnitine nitine biosynthesis should be adequate if precursors are provided deficiency but that there may be an obligatory renal excre- with TPN. However, loss of carnitine through the kidney may tion of other carnitine esters that contributes to the devel- be an important factor. opment of hypocarnitinemia in the younger age group. FC and/or AC excretion has been shown to be increased during (Pediatr Res 28: 158-165,1990) TPN in adult patients with multiple injuries (I I), with sepsis, and after surgery (12), but decreased in metabolically stable Abbreviations patients receiving long-term PN (13). Individual carnitine esters were not analyzed in the urine of these patients. PN, parenteral nutrition It has been suggested that carnitine plays a role in mitochon- TPN, total parenteral nutrition drial detoxification of excess or slowly metabolized coenzyme A- FC, free carnitine linked compounds of endogenous or exogenous origin (14). TC, total carnitine These acyl moieties are eventually excreted in the urine as AC. AC, acylcarnitine This has been well documented in inborn errors of organic acid SCAC, short-chain acylcarnitine metabolism. We hypothesized that such a mechanism may be MCAC, medium-chain acylcarnitine operational even in metabolically normal humans. The associ- PEG, polyethylene glycol ated carnitine loss may lead to decreased carnitine concentrations IBD, inflammatory bowel disease in susceptible individuals if carnitine is not provided with nutri- tion. In the following, we report the carnitine status and excretion of carnitine and carnitine esters in children and adolescents with gastrointestinal diseases requiring PN for at least 1 mo using a Carnitine (~-hydroxy-y-trimethylamino-butyricacid) plays an radioisotopic exchange HPLC method recently adapted for hu- important role in energy metabolism by facilitating the transport man urine (1 5). In addition, L-carnitine absorption was studied of FFA across the inner mitochondria1 membrane for P-oxidation in a child with a functional short bowel. Rccci\ed Junc 30. 1989: accepted March 1. 1990. Correspondcnce: Eherhard Schmidt-Sommcrfcld, M.D., Assistant Professor in PATIENTS AND METHODS Pediatrics. Dcpt. of Pediatrics. Box 107. Section of Gastroenterology. Hepatology. and Nutrition. University of Chicago. 5825 S. Maryland Avenue. Chicago. IL patienrs,T~~~~~-~~~~~ children and adolescents with gastroin- 60637. The MSU-NIH Mass Spectrometry Facility is supported in part by NIH Grant te~tinaldisease requiring PN for at least 1 mo were enrolled in DRR-00480. the study. Informed consent was obtained from the parents and/ 158

SCHMIDT-SOMMERFELD ET AL. Table 1. Clinical data of25 children and adolescents receivin~>I mo ofPN.* Duration Parenteral Patient Indication for of PN calories Steroid No. Primary disease PN (mo) (% total) Liver disease therapy Group I: I Intestinal neuro- Chronic diarrhea 45 100 gangliomato- sis Intestinal pseu- Hypomotility doobstruction Volvulus Obstruction 75 Gastroschisis Short bowel 100 Cirrhosis. choles- tasis Chronic diar- 100 rhea Immune defi- Chronic diarrhea 7 5 AST. ALT elevated ciency Aganglionosis Hypomotility Jejunal atresias Short bowel Chronic diar- rhea Congenital chy- 100 Cirrhosis lus ascites Necrotizing en- Obstruction terocolitis Gastroschisis Short bowel 50 Cirrhosis Gastroschisis Short bowel 100 Chronic diar- 100 AST, ALT elevated rhea Intestinal pseu- Hypomotility doobstruction

Mean

Group 2: 16 Ulcerative colitis Bowel rest + 17 Crohn's disease Obstruction + 18 Crohn's disease Obstruction + 19 Crohn's disease Growth failure - 20 Crohn's disease Growth failure + 2 1 Crohn's disease Obstruction AST, ALT elevated - 22 Ulcerative colitis Bowel rest + 23 Crohn's disease Fistulas AST. ALT elevated - 24 Crohn's disease Obstruction + 25 Crohn's disease Malnutrition AST, ALT elevated +

Mean * Patients were divided into two groups on basis of age and type of disease (see text). Aspartate (AST) and alanine (ALT) aminotransferases were elevated >3 times upper normal limit where indicated. plasma TC as the dependent variable and age, duration of PN, carnitine concentrations could be measured before the onset of and oral intake as the independent variables. PN (Fig. 2). Of the group 1 patients, two (nos. 9 and 14) had decreased and two (nos. 5 and 6) had normal carnitine plasma RESULTS concentrations at that time. All were malnourished with wt/ht < 3rd percentile and hypoalbuminemia. All six patients of group Plasma carnirine. TC, FC, and AC plasma concentrations 2 had normal carnitine plasma concentrations before the onset were lower in patients in group 1 than in those in group 2 (Table of PN. Four of them were also malnourished. In eight of 10 2). Differences in TC and FC plasma concentrations between patients, carnitine plasma concentrations dropped after 1 mo of groups 2 and 3 were much less pronounced. All children except PN. They remained relatively constant thereafter in those pa- one (no. 1 1) of group 1 had TC plasma concentrations <-2 SD tients who were followed for up to 4 mo (Fig. 2). from the normal mean for age (16). With one exception (no. 16), Carnitine excretion. Because of exceptionally low carnitine all patients in group 2 had TC and FC plasma concentrations concentrations in plasma and urine, patient no. 16. who had within 2 SD of the normal mean for age. massive blood loss from his colon requiring several transfusions Among the variables tested by multiple regression analysis, of red blood cells, was excluded from the statistical evaluation of only age was significantly correlated with TC plasma concentra- the carnitine excretion data. tions (expressed as % of the normal mean, r = 0.68, p < 0.001, Urinary excretion of TC, FC, and AC was lower and the Fig. 1). This correlation was still significant even if only patients percentage of TC excreted as AC was higher in group 1 compared in group 1 were considered (r= 0.52, p < 0.05). with group 2 patients or control children (Table 3). Carnitine In 10 children (four in group 1 and six in group 2), plasma excretion was not different between patients in groups 2 and 3. CARNlTlNE ESTER EXCRETION 161 Table 2. Plasma concentrations (pmol/L) of TC, FC, and AC in three groups yfpatients*

II TC FC AC ACIFC Group I 15 i 2.3t R 8.8-40.4 ic 21.0 -UI Group 2 9 i 42.49 -? R 25.8-61.7 X f 43.4

Group 3 7 i 52.3 R 43.3-75.0 2 S.D. f 56.1 * Group I: PN. 12-y-old. IBD: group 3: oral nutrition. >I2-y-old. IBD. i.median: R. range: f, mean. Normal range ( 16): 1 mo- I0 y: TC. 28-84: FC. 22-66: AC. 3-32. 10-1 7 y: TC. 34-77: FC. 22-65: AC. 4-29. 0 I.I-I.I.~.I t p < 0.0001 compared with group 2. 0 1 2 3 4 5 $11 < 0.002 compared with group 2. DURATION of PN (months) 4p < 0.03 compared with group 3. Fig. 2. Plasma TC concentrations of 10 patients before and during PN. Age-matched controls (mean + 2 SD. n = 20) are given for compar- ison. El. no. 18: C. no. 22: +, no. 25: . no. 24: 0. no. 19: A. no. 6: A. no. I6:m. no. 5:*. no. 14: +. no. 9.

Table 3. Urinary excretion (pmollg creatinine) uf TC, FC, AC in three groups yfpatients and healthy controls (2.5- to 96-mo-old)*

AC X 1001 n TC FC AC TC

Group 2 7 i 351 R 271-755 f 437

AGE (months) Fig. 1. Relationship hetween TC plasma concentrations (expressed as Controls 8 i 5 12 % of the normal mean for age) and age of 25 children and adolescents R 198-598 receiving PN for >I mo. y = 36.00 + 0.19x. r = 0.68. p < 0.001. ic 455 The patient groups are the same as in Table 2. i.median: R. range; As shown in Figure 3, there was a positive correlation (r = * 0.80. p < 0.001) between plasma FC concentrations and FC ic. mean. t p 0.001 compared with group 2. excretion (expressed as nmo1/100 mL glomerular filtrate). At FC < plasma concentrations of <25 pmol/L. FC excretion was mini- $ p < 0.002 compared with group 2. mal. The two patients with renal Fanconi syndrome had a high (j p < 0.001 compared with controls. excretion of FC despite low FC plasma concentrations. The mean fractional tubular reabsorption of FC was 99.7% in group 1, In the urine of patient no. 11, the prominent peak C-4 (reten- 96.8% in group 2, and 97.1 % in group 3 patients. The difference tion time, 20.1 min) was identified as isobutyrylcarnitine (Table between groups 1 and 2 was significant (p < 0.015), indicating 6). The MCAC in the urine of patient no. 1 I and a control child the ability to conserve FC in the former. were (partially) identified as shown in Table 6 and Figures 5 and The urinary excretion of all SCAC and other AC was lower in 6. Due to limited amounts of material, only the structure of the group I than in group 2 or controls (Tables 4 and 5). However, compound with a retention time of 36.8 min on HPLC could be the differences were more pronounced for SCAC (- 10-fold) than established as 2-methyloctanoylcarnitine. This peak was found for other AC (2- to 3-fold). The percentage of TC excreted as in the urine of 60% of the control children, in all patients in SCAC was lower and that excreted as other AC higher in group group 3, and only occasionally in patients receiving PN (groups 1 compared with group 2 or controls (Table 5). Carnitine ester 1 and 2). The peaks with retention times of 33.7 and 35.3 min excretion was not different between patients in groups 2 and 3. on HPLC were found in practically all urine samples studied. Identity of carnitine esters. Figure 4 shows HPLC chromato- No octanoylcarnitine (retention time 36.1 min) was present in grams of urinary carnitine esters of patient no. 1 1 of group 1 and any specimen. no. 18 of group 2. In the former (Fig. 4A), peaks in the area of Carnitineahsorption study. Absorption of L-carnitine was stud- MCAC were more pronounced relative to SCAC peaks (C-2 to ied in patient no. 7, who had a jejunostomy. His TC and FC C-5) than in the latter (Fig. 4B). plasma concentrations were 20.4 and 18.0 rmol/L. respectively. 162 SCHMIDT-SOMMERFELD ET AL. age was the only variable to correlate significantly with plasma TC concentrations (expressed as % of normal mean for age) in our patients receiving >1 mo of carnitine-free PN suggests that the rate of endogenous carnitine biosynthesis and/or carnitine tissue reserves are insufficient in very young patients to meet carnitine requirements during rapid growth. This is supported by the study of Helms et al. (7), in which young infants (mean age 3 mo) receiving long-term PN had even lower TC plasma concentrations (mean 9 pmol/L) than our patients in group I. On the other hand, the type of disease was strikingly different between our two patient groups. Extensive small bowel disease resulting in diarrhea and malabsorption (group 1) may have led to decreased carnitine reserves even before the onset of PN due to impaired intestinal absorption of carnitine or its precursors. This is supported by the finding of abnormally low plasma carnitine concentrations before initiation of PN in two of the four longitudinally studied patients with malabsorption. More- over, we recently found carnitine plasma concentrations to be <-1 SD from the normal mean for age in four of five children with total villous atrophy due to celiac disease (Hebel E and Schmidt-Sommerfeld E, unpublished data). Carnitine absorption Plasma FC (pmolesll) has not been studied in vivo in the human, but it has been shown Fig. 3. Relationship between FC plasma concentrations and FC ex- to be a sodium-dependent active process in biopsy specimens cretion (expressed as nmo1/100 mL glomerular filtrate). El, patients from duodenum and ileum (27). Our absorption study in a child with jejunostomy demonstrates that carnitine absorption can be receiving PN (groups I + 2): U, patients with IBD on oral food (group 3): +. two patients with renal Fanconi syndrome receiving PN (not severely impaired in a patient with a short small intestine. included in the statistical evaluation). In two children in group 1, we were able to observe carnitine plasma concentrations over a period of 3-4 mo of PN. In both Carnitine concentration was minimal (<2 pmol/L) in the initial children, levels dropped after 1 mo to subnormal values and then ostomy output. Four h after L-carnitine and D-xylose adminis- remained unchanged. This suggests that plasma carnitine con- tration, all of the administered carnitine was recovered from the centrations attain a new steady state at a decreased level during ostomy and plasma carnitine concentrations were unchanged. carnitine-free nutrition. Twelve percent of the administered D-xylose was absorbed and Most of our children and adolescents >I2 y of age with IBD the 1-h D-xylose blood level was 8 pg/dL. maintained plasma carnitine concentrations in the normal range. Moreover, plasma carnitine concentrations differed only slightly DISCUSSION from those in age-matched IBD patients not receiving PN. This indicates that, in this patient population, carnitine reserves and In the human, there is indirect evidence that low plasma synthetic capacity are probably adequate to maintain a normal carnitine concentrations reflect decreased carnitine tissue levels, carnitine status over an extended period of time on PN (mean at least in organs with a relatively high turnover rate for carnitine. 10 mo). This finding is at variance with a study that reported Premature infants receiving carnitine-free TPN have decreased that 35% of adult patients with gastrointestinal disease receiving carnitine concentrations not only in plasma (25, 26), but also in home PN had decreased carnitine plasma concentrations (10). liver, heart, and kidney (5). It has therefore been suggested that However, these patients were on PN for a longer period of time infants may have impaired endogenous carnitine biosynthesis. (mean 32 mo) and most of them, in contrast to our patients in However, it is not known at what age the capacity for carnitine group 2, had short bowel syndrome. biosynthesis is fully developed in the human. Our finding that Carnitine excretion was markedly different between our two Table 4. Urinary excretion (~rnollgcreatinine) of short-chain carnitine esters* n Acetyl-carnitine Propionyl-carnitine Isobutyryl-carnitine C5-acyl-carnitine Group I 12 x R X

Group 2 7 x R X

Group 3 5 x R X

Controls 8 x R X -- * The groups are the same as in Table 3. 1, median; R, range; R, mean. t p < 0.001 compared with group 2. S p < 0.001 compared with controls. 3 p < 0.02 compared with group 2. 11 p < 0.003 compared with controls. CARNITINE ESTER EXCRETION 163 Table 5. Urinary e,~crerionof SCAC and other carnirine ester.7 Table 6. Identification of SCAC and MCAC separated by evpres.sc.d in prnollg creatinine and % of TC excreted* HPLC SCAC Other AC HPLC rctention n (wmol/g) (% TC) (wmollg) (% TC) time Compound Group1 12 i 3.ltS 43 11 64311 75tS Urine from (min) identified Figure R 0.2-23 0-20 30-172 54-94 Patient no. II 20.1 isobuty~lcarni- f 6.5 6 82 76 tine*t

Group 2 7 i 47.2 I2 158 43 Patient no. 11 and 33.7 8-carbonACwith 5.1 R 22.8-128 5-15 101-286 24-56 control child one double X 56.7 I I 168 4 1 bondt$

Group 3 5 i 34.4 10 160 54 Patient no. 11 35.3 ?lo-carbonAC 5B R 13-348 6.7-12.5 57-1971 46-65 with a OH- f 91 10 508 54 group and one double bondt Controls 8 i 71.6 12 178 40 ?I 0-carbon AC R 20.2-90.5 9-20 95-245 21-61 with three dou- i 58.9 13 170 4 1 ble bondst * The groups are the same as in Table 3. i.median: R. range: f, mean. t p < 0.001 compared with group 2. Control child 36.8 2-methyloctanoyl- 6.4 and R $ p < 0.001 compared with controls. carnitinetSjj jj p < 0.02 compared with group 2. * Gas-liquid chromatography of the acyl moiety. 11 p < 0.003 compared with controls. t Fast atom bombardment mass spectrometry. iPreviouslv identified in adult urine (22. 38). 5 Gas-liquid chromatography electron impact mass spectrometry of the acyl moiety.

B

c-2

C-4 I

C-3 WC C-S i

I I - I&, Fig. 5. Fast atom bombardment mass spectra of two peaks in Figure "7 52: m 0 m 0 w m m 4A with retention times of 33.7 (A) and 35.3 (R) min. A: Protonated Retrntxon tine (nln ) mol wt = 286 (Na-adduct mol wt = 308) best fit an 8-carbon AC with Fig. 4. Chromatograms of urinary carnitine esters of: A) a 9-mo-old one double bond. B: Protonated mol wt = 330 (Na-adduct mol wt = infant (no. I I) with small bowel obstruction after extensive gut resection 352) best fit a 10-carbon AC with an OH-group and one double bond: for necrotizing enterocolitis who received TPN for 1 mo, and B) a 22-y- protonated mol wt = 310 best fits a 10-carbon AC with three double old patient (no. 18) with small bowel obstruction due to Crohn's disease bonds (see Table 6). Peaks at 207.277.299. 369. and 39 1 are due to the who received TPN for I mo. Carnitine excretion (in pmollg creatinine) glycerol matrix used. in .J: FC = 20.0: acetylcarnitine (C-2) = 3.0: isobutyrylcarnitine (C-4) = 4.8. In B: FC = 112: C-2 = 28.2: propionylcarnitine (C-3) = 6.6: C-4 = groups of patients receiving PN, but not different between groups 9.0: 5-carbon AC (C-5) = 3.4. The amount of MCAC was not calculated 2 and 3 (IBD with and without PN). This suggests that carnitine because their complete exchange with the labeled FC pool could not be excretion is not influenced by the type of nutrition or carnitine established. intake, but primarily by plasma carnitine concentrations. The 164 SCHMIDT-SOMMERFELD ET .-1L they received suggests that an endogenous origin is likely. This is supported by our recent finding of complex medium-chain carnitine esters in the urine of newborn infants collected before the onset of feedings (Schmidt-Sommerfeld E, unpublished data). It is also not known in which organs and cell organelles they are formed and whether they are transported through the blood stream. Nor is it known which carnitine acyltransferases are involved in their formation. Some of them may be secreted directly into urine by the kidney. Hokland and Bremer (30) found unidentified carnitine metabolites in rat urine after per- fusion of the kidney with labeled carnitine. Judging from their Rr values on thin-layer chromatography, these metabolites could have been medium-chain carnitine esters. It has been suggested that, in renal Fanconi syndrome (32, 33), organic acidurias (34), and primary disturbances of carnitine transport (35), carnitine deficiency results from carnitine loss in the urine. Apart from our two patients with renal Fanconi syndrome, this was not apparent in our hypocarnitinemic pa- tients in group l. Their kidneys were able to conserve FC and SCAC. However, they lost appreciable amounts of carnitine in the form of MCAC and other yet to be identified carnitine esters with the urine. On the basis of these findings, one could speculate that carni- tine has a role in the removal of presumably slowly metabolized acyl moieties from the body. Such a role has been suggested before for the elimination of fatty acid-like drugs such as valproic and pivaloic acids, which are excreted as their respective carnitine esters (36, 37). This normal metabolic pathway proceeds despite hypocarnitinemia and contributes to a state of carnitine defi- Fig. 6. Identification of MCAC from the urine of a 5-y-old control ciency in young children who receive carnitine-free nutrition child. Retention time on HPLC: 36.8 min. :l. Fast atom bombardment and in whom rates of endogenous carnitine biosynthesis may be mass spectral analysis. Protonated mol wt = 302 (Na-adduct mol wt = inadequate. It remains to be established whether carnitine sup- 324) best fit a 9-carbon saturated AC (see Table 6). B. Gas-liquid plementation of PN is warranted in this situation. chromatographic electron impact mass spectral analysis of the acyl moiety after hydrolysis: base peak 74 and fragment 87 indicate a methyl branch in position 2. Acknowledgment. The authors thank the MSU-NIH Mass , Spectrometry Facility under the direction of Dr. J. T. Watson. ~ apparent renal threshold for FC was -25 pmol/L in our patient Department of Biochemistry, Michigan State University for their 1 population. This value is lower than the extrapolated value (46 assistance. I pmol/L) reported by Engel ef al. (28) in normal adults receiving i.v. L-carnitine. Because all our children with low FC blood concentrations and low urinary FC excretion received PN and REFERENCES were in the younger age group, we cannot comment as to whether I. Fritz IB 1959 Action of carnitine on long chain fatty acid oxidation by liver. the apparent renal threshold for FC is influenced by PN or age. Am J Physiol 197297 Although the kidney was capable of conserving FC when plasma 2. Bieher LL, Emaus R. Valkner K. Farrell S 1982 Possible function of short- chain and medium chain carnitine acyltransferases. Fed Proc 41:28.'8 i levels were decreased, FC was always detected in the urine. This 3. Englard S 1979 of y-butyroheta~neto carnitine in human and may reflect secretion of FC by the kidney (29). monkey tissues. FEBS Lett 102:297-300 Quantitation of individual urinary carnitine esters revealed 4. Olson AL. Rebouche CJ I987 y-butyrobetaine hydroxylase activity is not rate that the excretion of short (branched)-chain AC was also sharply limiting for carnitine biosynthesis in the human infant. J Nutr 117: 1024- 1031 reduced in our patients in group 1, suggesting that they are 5. Penn D. Ludwigs B. Schmidt-Sommerfcld E. Pascu F 1982 Effect of nutrition reabsorbed by the kidney tubule to a similar extent as FC. This on tissue carnitine concentrations in infants of different gestational ages. is in agreement with studies by Hokland and Bremer (30) using Biol Neonate 47: 130- 135 the perfused rat kidney. However, the excretion of other carnitine 6. Schmidt-Sommerfeld E. Penn D. Wolf H 1983 Carnitine deficiency in pre- mature infants receiving total parenteral nutrition. Effect of I.-carnitine metabolites including MCAC was reduced to a much lesser extent supplementation. J Pediatr 102(6):931-935 in group I patients and was appreciable in all patient groups and 7. Helms RA. Whitington PF. Mauer EC. Catarau EM, Christensen ML. Borum controls. These AC made up a significantly higher percentage of PR 1986 Enhanced lipid utilization in infants receiving oral I.-carnitine TC excreted by patients in group 1 compared with group 2 or during long term parentcral nutrition. J Pediatr 109:984-988 8. Borum PR 1985 Role of carnitine during development. Can J Physiol Phar- age-matched controls. macol63:57 1-576 We were able to identify tentatively some of these compounds 9. Hahn P. Allardyee DB. Frohlich J 1982 Plasma carnitine levels during total as unsaturated and/or branched medium-chain carnitine esters parenteral nutrition of adult surgical patients. 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