ABSTRACT Photooxidation of multivitamin solutions results in the generation of peroxides. Because peroxides are associated with hepatic steatosis and fibrosis as well as cholestasis, we

questioned whether multivitamins are implicated in hepatic complications of parenteral nutrition. Guinea pig pups were assigned to groups receiving intravenously either total parenteral

nutrition, photo-protected or not, or a control solution (5% dextrose + 0.45% NaCl) supplemented with either a) multivitamins; b) photo-protected multivitamins; c) multivitamins without

riboflavin; or d) peroxides (H2O2, tert-butylhydroperoxide). After 4 d, liver was sampled for histology and isoprostane-F2α levels, a marker of radical attack. Multivitamins as well as total

but not in those infused with Multi-12 pediatric multivitamins or total parenteral nutrition. Results suggest that peroxides and/or free radicals are not mediators of the induction of

steatosis observed with infusion of photo-exposed multivitamins, as there was no correspondence between histologic findings and hepatic levels of isoprostanes. It is suspected that a

component of the multivitamin solution becomes hepato-toxic after photo-exposure, as indicated by the protective effect observed when withdrawing riboflavin. Photo-oxidation of multivitamins

might be the common link between reports involving amino acids, lipids, and light exposure in the ethiology of hepatic complications of parenteral nutrition. SIMILAR CONTENT BEING VIEWED BY

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Article Open access 02 September 2020 MAIN Exposure of TPN solutions to light is linked to alterations in hepatobiliary function and histology in a perfused liver model (1) as well as _in

vivo_(2). In the presence of light, the parenteral multivitamin preparation is the site of reactions between oxygen and electron donors, resulting in the generation of peroxides. Hydrogen

peroxide (H2O2), which is regarded as a key element in the oxygen toxicity of the cell, represents over 80% of peroxides generated in multivitamins (3). Organic peroxides have also been

reported to contaminate solutions of parenteral nutrition (3–6). In parenterally fed neonates, the exposure of multivitamins to daylight is associated with an infused peroxide load and its

urinary excretion (7). Peroxides have been linked to hepatic steatosis (8) and fibrosis (9), as well as cholestasis (10). Multivitamins and peroxides induce the same oxidant response in the

lungs of guinea pig pups (11). The relative liver weight of these animals was 40% higher than controls (12), and histology revealed the presence of hepatic steatosis. We hypothesize that

multivitamins might account for part of the role of light in TPN-related liver complications. Because of the catalytic role of photo-excited riboflavin (13), protection of TPN solutions from

exposure to light results in a decreased generation of peroxides and a reduction in their rate of infusion (3). As H2O2 is a weak oxidant, it can accumulate to high concentrations owing to

its stability, or it can also be converted into reactive species (14) in the presence of transition metals (15, 16) such as Fe2+ and Cu+_via_ the Fenton/Haber-Weiss reactions. Furthermore,

the antioxidant components of the parenteral multivitamins would be expected to protect against the free radicals derived from peroxides generated in TPN solutions (12). The objective of

this study was to evaluate the role of multivitamins in TPN-related liver complications as documented by histology and to separate the effect of light exposure from that of peroxides and/or

free radicals. METHODS ANIMAL MODEL. Under ketamine/xylazine, 3-d-old guinea pig pups (Charles River, Montreal, Quebec, Canada) were fitted with a 0.4-mm polyurethane catheter (Luther

Medical Products, Tustin, CA, U.S.A.) in the external jugular vein and exteriorized in the scapular region. The catheter was connected to a flow-through system permitting mobility of the

animals, which were housed separately in plastic boxes with wire mesh bottoms. The animals were kept in a thermo-controlled environment with a 12-h light/dark cycle, and they were fed

exclusively intravenously at 240 mL/kg/d. After 4 d, the animals were killed and the liver was divided into aliquots with samples kept in formol for histology or minced and stored at −80°C

until analysis of triglycerides and isoprostanes, an index of radical attack (17). The study was performed in accordance with the guidelines of the institutional animal committee. This

animal model was chosen because of our previous unpublished observation of hepatic steatosis in guinea pig pups. To verify whether this steatosis could be prevented by photoprotection, the

same experimental conditions had to be replicated. PROTOCOLS. To separate the effect of multivitamins and light, animals were infused with one of the following regimens containing a

multivitamin solution at a concentration similar to the one used in neonatal parenteral nutrition. Photoprotection was achieved by preparing the solutions in darkness and covering the

infusion set with opaque material and using photo-protected intravenous tubing (13) provided graciously by Baxter Canada. _MVP + light:_ 1% (vol/vol) MVP (Sabex, Boucherville, Quebec,

Canada) unprotected from ambient light, diluted in the control solution (50 g/L dextrose + 4.5 g/L NaCl + 1 unit heparin/mL); 5 mL of MVP contains the following: vitamin A, 2300 IU; vitamin

D, 400 IU; α-tocopherol, 7 IU; vitamin K, 200 μg; ascorbate, 80 mg; thiamine, 1.2 mg; riboflavin, 1.4 mg; pyridoxine, 1.0 mg; pantothenate, 5 mg; folate, 0.14 mg; cyanocobalamin, 1 μg;

nicotinamide, 17 μg; biotin, 20 μg; and the additives mannitol and polysorbates as emulsifiers. _MVP_ −_light:_ 1% (vol/vol) MVP photo-protected, diluted in the control solution. _TPN +

light:_ Two solutions unprotected from ambient light were infused in a “piggy-backed” set-up mixed close to the infusion site: a) control + 9.6 g/kg/d amino acids (Travasol, Baxter Canada,

Mississauga, Ontario, Canada) + 2% MVP at 120 mL/kg/d; b) control + 9.6 g/kg/d amino acids + 7.6 g/kg/d lipids (Intralipid 20%, Pharmacia, Peapack, NJ, U.S.A.) at 120 mL/kg/d; for a final

concentration (at 240 mL/kg/d) of 1% MVP + 4.8 g/kg/d amino acids + 3.8 g/kg/d lipids. The composition of the TPN regimen was derived from recommendations for studies in adult guinea pigs

(18). _TPN_ (−) _light:_ The same TPN preparation protected from ambient light. To evaluate whether the effects observed with MVP and TPN were related to peroxides and/or free radicals,

other groups of animals were infused with one of the following solutions: _C (control):_ 50 g/L dextrose + 4.5 g/L NaCl + 1 unit heparin/mL. _H_2_O_2: control + 200 or 500 μM H2O2 (Aldrich

Chemical, Milwaukee, WI, U.S.) (208 ± 15 and 500 ± 20 μM measured). _TBH:_ control + 50 μM TBH (Aldrich Chemical) (47 ± 1 measured). To isolate the role of riboflavin and to determine

whether the effects of multivitamins were specific to MVP, other groups of animals were infused with one of the following regimens: _C:_ same as above _MVP + light:_ as described above in

protocol 1. _MVP + light without riboflavin:_ 1% MVP prepared by Sabex without riboflavin, unprotected from ambient light and diluted in the control solution. _MVI + light:_ 1% (vol/vol) MVI

(Aventis, Strasbourg, France) unprotected from ambient light and diluted in the control solution; 5 mL solution reconstituted from powder contains the following: vitamin A, 2300 IU; vitamin

D, 400 IU; α-tocopherol, 7 IU; vitamin K, 200 μg; ascorbate, 80 mg; thiamine, 1.2 mg; riboflavin, 1.4 mg; pyridoxine, 1.0 mg; pantothenate, 5 mg; folate, 0.14 mg; cyanocobalamin, 1 μg;

nicotinamide, 17 mg; biotin, 20 μg; and the additives BHA, BHT, and mannitol, as well as polysorbates as emulsifiers. _CVI + light:_ 1% (vol/vol) Cernevit (Baxter Canada) unprotected from

ambient light and diluted in the control solution; the 5 mL solution contains vitamin A, 3500 IU; vitamin D, 220 IU; α-tocopherol, 11.2 IU; ascorbate, 125 mg; thiamine, 3.51 mg; riboflavin,

4.14 mg; pyridoxine, 4.53 mg; pantothenate, 17.25 mg; folate, 414 μg; cyanocobalamin, 6 μg; nicotinamide, 46 mg; biotin, 69 μg; and the additives glycocoll, glycocholic acid, and soy bean

lecithin. HISTOLOGY. After staining with hematoxylin-eosin, hepatic histology was performed, and the severity of steatosis scored 0–4 (Fig. 1) by a pathologist (P.B.) and a hepatologist

(F.A.) unaware of the intravenous regimen received. The scores indicated the following: 0 = normal hepatic structure; 1 = presence of visible fat vacuoles in single, isolated hepatocytes; 2

= focal fatty changes of heterogeneous lobular distribution; 3 = diffuse fatty changes with rare “fat-free” zones; 4 = diffused fatty changes, without “fat-free” zones. ANALYTICAL

PROCEDURES. Peroxides were measured with the xylenol orange technique (19), as described previously. This chemical assay, which measures H2O2 as well as organic peroxides (19, 20) was

validated for TPN solutions using an enzymatic assay (21). The mean peroxide levels for three samples were MVI = 295 ± 8 μM; CVI = 358 ± 28 μM; MVP = 198 ± 14 μM; MVP photo-protected = 131 ±

10 μM; and MVP without riboflavin = 129 ± 3 μM. Isoprostane F2α was measured using a commercial enzyme immunoassay kit (Cayman Chemical, Ann Arbor, MI, U.S.A.). Liver triglyceride levels

were measured enzymatically using commercial kits (Roche Diagnostics, Laval, Quebec, Canada). STATISTICAL ANALYSIS. All results are presented as mean ± SEM. Results for steatosis were

analyzed by Mann-Whitney test for nonparametric data. Anthropometric characteristics of the animals (Table 1) and hepatic isoprostane F2α were compared by ANOVA after transformation (natural

logarithm) to ensure homoscedasticity as determined by Bartlett's chi-square. The level of significance was set at _p_ < 0.05. RESULTS There was no difference in the initial body

weight of the animals within the various protocols (Table 1). In the first protocol, photo-protection was associated with a significantly lower (_p_ < 0.05) relative liver weight

(percentage of body weight). Animals receiving photo-exposed multivitamin solutions infused as an admixture to C or to TPN presented varying degrees of hepatic steatosis. In cases of hepatic

steatosis scored 2/4, the macrovesicular fatty changes were mainly observed in lobular zones 3 and 2. In specimens evaluated as showing scores of 3 to 4/4, nodules of fat-laden hepatocytes

gathered into a circumscribed nodule. Whatever the steatosis score recorded, no inflammatory infiltration or enlargement of portal tracts were observed. Multivitamins as well as TPN were

associated with steatosis (scored 0–4), the severity of which was reduced (_p_ < 0.05) by photo-protection (Fig. 2_A_). Compared with MVP, the apparently lower score of hepatic steatosis

observed in animals receiving TPN regimens did not reach statistical significance. These histologic findings were not accompanied by corresponding changes in hepatic isoprostane levels (Fig.

2_B_). Animals receiving photo-protected solutions had significantly lower isoprostane levels (_p_ < 0.01). However, compared with MVP, those animals receiving TPN exhibited

significantly higher (_p_ < 0.01) hepatic levels of this eicosanoid marker of radical attack. Figure 3, _A_ and _B_, illustrates that the oxidant load induced by peroxides generated in

light-exposed multivitamins or TPN did not account for the induction of hepatic steatosis. H2O2 infused at concentrations found in MVP or TPN (3) did not induce a score of steatosis

significantly higher than the controls (Fig. 3_A_), which exhibited a lower score (_p_ < 0.01) than animals receiving MVP exposed to light (Fig. 4). Results obtained with TBH infused at a

concentration compatible with levels of organic peroxides detected in MVI (3) were similar to C and H2O2. The results presented in Figure 3_B_ support the contention that the infused

peroxides carried an oxidant load. Indeed, the levels of hepatic isoprostanes found in animals receiving H2O2 were significantly higher than controls (Fig. 3_B_) and between 50% and 100%

higher than in animals receiving multivitamin solutions inducing a score of steatosis >2 (Fig. 2_B_). When exposed to ambient light, the different multivitamin solutions evaluated in this

study (MVP, MVI, CVI) induced a similar score of hepatic steatosis, which was significantly higher (_p_ < 0.01) than the score recorded in C or in the animals receiving MVP without

riboflavin exposed to light (Fig. 4). The latter two groups exhibited a similar low score of hepatic steatosis. Hepatic steatosis was confirmed by documenting higher (_p_ < 0.05) liver

triglyceride levels (0.81 ± 0.32 _versus_ 0.23 ± 0.07 mg/mg protein) in a subgroup of animals with overt steatosis (score 2–4: 3.1 ± 0.3, _n_ = 6) compared with those with no or little

steatosis (score 0 or 1: 0.7 ± 0.1, _n_ = 13). DISCUSSION Steatosis is a hepatic micro- or macrovesicular fat accumulation associated with metabolic diseases, diabetes, obesity (22), drugs

and toxins (23), surgical procedures, and parenteral nutrition (21), as well as nonalcoholic steato-hepatitis, in which case an oxidant stress is thought to play a pathogenic role (24).

TPN-related hepatic dysfunctions (25) have been linked to oxidant stress (26, 27) as well as genetic (28, 29), nutritional, environmental, and inflammatory factors (23). More specifically,

the following nutritional factors have been associated with steatosis and/or cholestasis: enteral starvation (30, 31), an amino acid imbalance (32, 33), photo-oxidized products of amino

acids (11, 12, 34), an excessive infusion of glucose (35) or lipids (36), a carbohydrate to nitrogen imbalance (37, 38), and the source of infused lipids (39). The results of the present

study suggest that TPN, when exposed to light, induces hepatic steatosis. The fact that this effect of light is linked to MVP points toward an oxidant stress (11, 40). The ethiology of this

steatosis might be explained by infused oxidants increasing lipogenesis, or decreasing lipid transport (2) and oxidative metabolism (41, 42). However, the results suggest that peroxides

and/or free radical are not mediators of the induction of steatosis observed with infusion of photo-exposed multivitamins, as there was no correspondence between histologic findings and

hepatic levels of isoprostanes. Starvation might account for the hepatic steatosis observed when glucose is the only source of energy provided with MVP. TPN prevented only partially the

steatosis induced by MVP. This effect of TPN could be explained by the lipid emulsion acting either as a shield protecting the multivitamins against the effect of light or as a substrate

improving the nutritional status. Since the effect of light was also observed with TPN, the later explanation is more likely. Among the nutritional factors contributing to steatosis, the

carbohydrate to nitrogen imbalance might be implicated. However, light protection reduced the risk of steatosis even in animals receiving only dextrose + MVP. In rats, diets without choline

are used to induce steatosis (43) and in humans, steatosis is corrected by giving choline (44). Choline is an important component of phosphocholine, which is involved in lipid transport.

Therefore, the 99 mg% phosphocholine provided to the guinea pigs by the lipid emulsion might account for this observation. Various sources of multivitamins (MVP, MVI, and CVI) were found to

induce the same score of steatosis despite differences in vitamin concentrations, in additives (polysorbates, BHT, BHA, mannitol), in means of conservation (powder _versus_ liquid form) or

in levels of H2O2. This is further evidence that infused H2O2 is not implicated in this common hepatic complication of TPN. Although TBH was not found to be associated with steatosis, this

does not preclude a possible role for further organic peroxides generated by photo-oxidation. It is suspected that a component of the multivitamin solution becomes hepato-toxic after light

exposure as indicated by the protective effect observed when withdrawing riboflavin. Apart from the generation of peroxides, photo-excited riboflavin also produces strongly oxidizing

triplets. A direct effect of activated riboflavin on the induction of steatosis cannot be excluded. Photo-oxidation of multivitamins might be the common link between reports involving amino

acids (34), lipids (39), and light exposure (1, 2) in the ethiology of hepatic complications of parenteral nutrition. Multivitamins and H2O2 induced similar responses on markers of oxidation

measured in the lungs (11, 40), whereas in the liver they induced separate effects on hepatic isoprostane levels as well as on steatosis. After their infusion, multivitamins and peroxides

will transit through the lungs before reaching the liver. This could explain in part why the responses elicited in these tissues are different. However, this discrepancy does not result from

peroxides being consumed before reaching the liver, as they did cause a marked increase in hepatic isoprostane levels. It is questionable whether our observations made in a 4-d infusion

model can be extrapolated to subjects receiving complete TPN for a longer time, or to patients with low antiperoxide defenses such as premature infants (22). The development of hepatic

steatosis observed in the present study could be related specifically to the animal model. Guinea pig tissues other than the brain do not use much glucose, and they do not respond to insulin

by increasing glucose uptake. It is therefore important to recognize that interspecies differences make extrapolations to the clinical situation hazardous (21). In summary, multivitamins

exposed to light induce hepatic steatosis. This complication of TPN is not related to the level of hydrogen peroxide or to a radical attack. A photosensitive component of the multivitamin

solution is suspected. In spite of its peroxide load, MVP carries antioxidant properties (12) as documented by the 3-fold lower hepatic isoprostane levels observed with photo-protected MVP

(Fig. 2_B_) compared with C (Fig. 3_B_). Because free radicals are produced in response to various sources of oxidant stress, improving free radical scavenging properties of MVP by

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with intravenous choline supplementation. _Hepatology_ 22: 1399–1403 CAS  PubMed  Google Scholar  Download references AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Department of Pediatrics,

Perinatal Service and Research Center, Hôpital Ste-Justine, University of Montreal, Montreal, Quebec, Canada Philippe Chessex, Jean-Claude Lavoie, Thérèse Rouleau, Pierre Brochu, Patrick

St-Louis, Emile Lévy & Fernando Alvarez Authors * Philippe Chessex View author publications You can also search for this author inPubMed Google Scholar * Jean-Claude Lavoie View author

publications You can also search for this author inPubMed Google Scholar * Thérèse Rouleau View author publications You can also search for this author inPubMed Google Scholar * Pierre

Brochu View author publications You can also search for this author inPubMed Google Scholar * Patrick St-Louis View author publications You can also search for this author inPubMed Google

Scholar * Emile Lévy View author publications You can also search for this author inPubMed Google Scholar * Fernando Alvarez View author publications You can also search for this author

inPubMed Google Scholar CORRESPONDING AUTHOR Correspondence to Jean-Claude Lavoie. ADDITIONAL INFORMATION Supported in part by a grant from Sabex (Boucherville, Québec, Canada) and by

institutional funding from the Research Centre of Hospital Sainte-Justine. RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Chessex, P., Lavoie, JC.,

Rouleau, T. _et al._ Photooxidation of Parenteral Multivitamins Induces Hepatic Steatosis in a Neonatal Guinea Pig Model of Intravenous Nutrition. _Pediatr Res_ 52, 958–963 (2002).

https://doi.org/10.1203/00006450-200212000-00023 Download citation * Received: 03 July 2001 * Accepted: 17 July 2002 * Issue Date: 01 December 2002 * DOI:

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