Table 5.
Effects of olive oil-based intravenous lipid emulsions on markers of liver function.
| Study | Population | Intervention and Control (n) (Lipid Dose) |
Duration | Outcomes |
|---|---|---|---|---|
| Adult studies | ||||
| Badía-Tahull et al., 2010 [33] | Gastrointestinal surgery | OO (n = 14) (0.88 g/kg/day) OO + FO {84% + 17%} (n = 13) (0.88 g/kg/day) |
5 day | No significant differences between groups in LFTs (ALT, ALP, and GGT) at Day 6 |
| García-de-Lorenzo et al., 2005 [35] | Severe burns | OO (n = 11) (1.3 g/kg/day) MCT/LCT (n = 11) (1.3 g/kg/day) |
6 day | At Day 6, of 11 MCT/LCT and 9 OO patients, more in the MCT/LCT group had abnormal LFTs: ALT 8 vs. 4, AST 6 vs. 5, ALP 7 vs. 3, GGT 9 vs. 6, and bilirubin (total or conjugated) 4 vs. 2 Markers of cholestasis * in a significantly greater proportion of MCT/LCT vs. OO group (9/11 vs. 3/9, p = 0.04, Suissa-Shuster test) Markers of cytolysis† associated with cholestasis in 3 MCT/LCT and 2 OO patients |
| Grau et al., 2007 [88] | ICU | OO or MCT/LCT (n = 303 initial TPN group) (NR) EN (n = 422) (NR) |
Not pre-specified | Multivariate analysis showed TPN is significantly associated with LD (p < 0.001) LD in 91/303 (30%) TPN patients LD in 75/233 (32%) TPN patients receiving MCT/LCT Multivariate model found no relationship between ILE used and liver dysfunction Median duration of TPN was 5 d for patients with LD vs. 0 d for those without LD (p = 0.001) Cholestasis occurred in 31/303 (10%) TPN patients |
| Jia et al., 2015 [20] | ICU | OO (n = 226) (0.8 g/kg/day) SO (n = 232) (0.8 g/kg/day) |
5–14 day | LFTs generally within normal limits ALT change from BL significantly greater in OO vs. SO group at Day 5 (p = 0.002) and EOT/Day 14 (p = 0.006) ALP and GGT changes from BL significantly greater in OO vs. SO group at Day 5 (p = 0.001 and p = 0.004, respectively), but not at EOT/Day 14. Increases in both enzymes suggest OO and SO associated with mild cholestasis No significant differences between groups for AST and total bilirubin Short-term PN with OO or SO did not appear to negatively impact liver function |
| Klek et al., 2017 [93] | Long-term PN | OO (n = 17) (0.6 g/kg/day) SO (n = 14) (0.7 g/kg/day) MCT/LCT {50% + 50%} (n = 18) (0.7 g/kg/day) SMOF (n = 16) (0.7 g/kg/day) |
12 months | No significant change from BL for ALT, AST, AP, or GGT for SO, MCT, or SMOF. Bilirubin and GGT significantly decreased from BL (p = 0.0023 and p = 0.0079) in OO group; ALT, AST, and AP remained unchanged |
| Onar et al., 2011 [38] | Abdominal surgery (oncologic) | OO (n = 10) (0.75 g/kg/day) SO (n = 10) (0.75 g/kg/day) |
7 day | ALP and GGT significantly increased from BL (p < 0.05) in both groups at Day 7 Total bilirubin significantly decreased from BL (p < 0.05) in OO group at Day 7 No significant change from BL for ALT and AST in both groups nor for total bilirubin in SO group at Day 7 No significant differences between groups for LFTs Increases in LFTs (AST, ALT, ALP, and bilirubin) occurred in 10% of patients; abnormalities resolved post PN |
| Pálová et al., 2008 [73] | Malnourished ≥10% decreased body weight | OO (n = 11) (NR) SO (n = 10) (NR) |
14 day | No significant difference between groups in number of patients with deterioration ‡ in cytosolic enzymes (1 SO [ALT] vs. 1 OO [AST]) Significantly more patients with deterioration ‡ in cholestatic enzymes in SO vs. OO group (5 vs. 1, p < 0.05): conjugated bilirubin 3 vs. 0, ALP 3 vs. 1, and GGT 6 vs. 1 |
| Piper et al., 2009 [74] | Abdominal surgery or major maxillofacial surgery | OO (n = 22) (NR) SMOF (n = 22) (NR) |
5 day | Mean AST significantly lower in SMOF vs. OO group at Day 2 (27 vs. 47 U/L, p < 0.02) and Day 5 (31 vs. 56 U/L, p < 0.02) Mean ALT significantly lower in SMOF vs. OO group at Day 2 (20 vs. 42 U/L, p < 0.03) and Day 5 (26 vs. 49 U/L, p < 0.03) Mean α-GST significantly lower in SMOF vs. OO group at Day 2 (5 vs. 17 µg/L, p < 0.03) and Day 5 (6 vs. 24 µg/L, p < 0.01) |
| Puiggròs et al., 2009 [71] | Abdominal surgery | OO (n = 7) (1.1–1.2 g/kg/day) SO (n = 7) (1.1–1.2 g/kg/day) MCT/LCT {50%/50%}) (n = 7) (1.1–1.2 g/kg/day) MCT/LCT {37%/63%} (n = 7) (1.1–1.2 g/kg/day) |
5 day | No significant differences between groups in changes from BL to Day 6 for LFTs (ALT, AST, ALP, GGT, and total bilirubin) A tendency (NS) to increase GGT in the SO and MCT/LCT structured groups and AST in the MCT/LCT mixture group at Day 6 was observed; however, values remained within normal limits |
| Reimund et al., 2005 [39] | Long-term PN | OO (n = 14) (31% of calories) | 3 months | No significant changes from BL in bilirubin (total and conjugated), AST, ALT, ALP, and GGT at Month 3 |
| Thomas-Gibson et al., 2004 [90] | Long-term PN | OO (n = 13) (up to 1 g/kg/day) | 6 months SO followed by 6 months OO followed by 6 months SO § | In 12 patients with >2 mo OO PN, bilirubin was within normal limits and AST was ≤15% outside normal range at BL. LFTs increased transiently in 4 patients and were persistently high in 1 severely septic patient who also had abnormal levels at baseline 1 new case of cholelithiasis was identified No biliary outflow abnormality at BL or endpoint of OO PN despite 6 patients having BL biliary disease In 11 patients with >2 mo SO PN after OO PN, no significant changes in LFTs occurred in 6 mo post OO PN |
| Vahedi et al., 2005 [91] | Long-term PN | MCT/LCT {50%/50%)}run-in, followed by OO (n = 6) (0.7 g/kg/day) SO (n = 7) (0.7 g/kg/day) |
3 months | No differences between groups in changes in LFTs from BL to Day 90 1 case of cholestasis (SO) and 1 case of cytolysis (OO) existing at BL had resolved at Day 90 Hepatic ultrasound on Day 90 detected no hepatobiliary changes compared with BL |
| Wang et al., 2013 [92] | Resectable esophageal cancer | EN + OO PN (n = 46) (~0.83 g/kg/day) EN + MCT/LCT PN (n = 48) (~0.83 g/kg/day) |
PN 7 day, EN added after Day 7 | Liver function was measured at regular intervals; results not reported |
| Pediatric studies | ||||
| Goulet et al., 1999 [51] | Long-term PN | OO (n = 9) (1.92 g/kg/day) SO (n = 9) (1.69 g/kg/day) |
Mean >30 months | No significant differences between groups in changes from BL to Day 60 in bilirubin (total and conjugated), LFTs (AST, ALT, ALP, and GGT) and biliary acids Total bilirubin increased from BL in both groups ALT increased from BL in both groups AST increased from BL in OO group and decreased in SO group ALP increased from BL in OO group and decreased in SO group GGT essentially unchanged in OO group and increased from BL in SO group Biliary acids increased from BL in OO group and essentially unchanged in SO group |
| Hartman et al., 2009 [62] | Bone marrow transplant | OO (n = 15) (1.1 g/kg/day) MCT/LCT (n = 13) (1.1 g/kg/day) |
14 day | No significant differences for LFTs between groups |
| Kurvinen et al., 2011 [75] | Long-term PN | OO (n = 11) (0.9 g/kg/day) | >3 months | ALT, AST, GGT, and bilirubin remained close to normal or within the normal range during follow-up # GGT correlated with serum PS (r = 0.61–0.62, p < 0.05). Liver biopsies showed fibrosis in 5/8 (63%) patients and cholestasis in 3/8 (38%) patients Liver fibrosis in 5 patients reflected increased serum PS (r = 0.55–0.60, p = 0.16–0.12) |
| Preterm neonate studies | ||||
| Demirel et al., 2012 [41] | <32 wk | OO (n = 20) (up to 3 g/kg/day) SO (n = 20) (up to 3 g/kg/day) |
14 day | LFTs normal and similar in both groups at 14th day of life |
| Deshpande et al., 2014 [64] | <30 wk | OO (n = 17) (18.45 g/kg/day) SMOF (n = 17) (18.25 g/kg/day) |
7 day | No significant difference between groups in bilirubin (total and conjugated) or LFTs (ALT and GGT) on Day 8; values within normal limits in both groups |
| Gobel et al., 2003 [87] | NICU patients, gestational age 28–36 wk | OO (n = 18) (up to 2 g/kg/day) SO (n = 15) (up to 2 g/kg/day) |
7 day | No significant differences between groups for changes from BL to Day 8 for LFTs (bilirubin [total and conjugated], AST, ALT, ALP, and GGT) AST significantly lower at Day 8 vs. BL in both groups (OO: 14.2 vs. 27.2 IU/L, p = 0.0001; SO: 13.9 vs. 25.4 IU/L, p = 0.0007) ALT lower at Day 8 vs. BL (NS) in both groups ALP significantly higher at Day 8 vs. BL in both groups (OO: 286 vs. 222 IU/L, p = 0.0039; SO: 269 vs. 207 IU/L, p = 0.0028) GGT significantly lower at Day 8 vs. BL in both groups (OO: 64.0 vs. 75.0 IU/L, p = 0.0139; SO: 63.8 vs. 83.3 IU/L, p = 0.0073) Total bilirubin lower at Day 8 vs. BL (NS) in both groups Conjugated bilirubin higher at Day 8 vs. BL in OO group (NS) and lower in SO group (NS) |
| Koksal et al., 2011 [43] | ≤34 wk | OO (n = 32) (up to 3 g/kg/day) SO (n = 32) (up to 3 g/kg/day) |
7 day | AST, ALT, and bilirubin (total and indirect) decreased from BL to Day 7 while ALP and GGT increased in both groups (NS) No significant differences between groups in LFTs |
| Savini et al., 2013 [44] | 500–1249 g | OO (n = 29) (up to 3 g/kg/day) SO (n = 30) (up to 3 g/kg/day) MCT/LCT (n = 30) (up to 3 g/kg/day) MSF (n = 27) (up to 3 g/kg/day) SMOF (n = 28) (up to 3 g/kg/day) |
21 day | No significant differences between groups in mean AST, ALT, ALP, GGT, or bilirubin (total and conjugated) at 6 weeks of age Cholestasis (conjugated bilirubin >2.0 mg/dL) in 3 (2.1%) patients (1 MCT/LCT, 1 MSF, 1 SMOF) at 6 weeks of age, when all infants were receiving minimal enteral feeding No significant correlations between phytosterol intake, conjugated bilirubin, and LFTs at 6 weeks of age |
| Wang et al., 2016 [45] | <2000 g and <37 wk | OO (n = 50) (1.45 g/kg/day) SO (n = 50) (1.41 g/kg/day) |
>14 day | Mean total bilirubin elevated at BL in both groups (OO 2.75 mg/dL, SO 38.80 mg/dL). At Day 7, mean values significantly increased in OO group (8.35 mg/dL) and significantly decreased in SO group (9.00 mg/dL) (p < 0.05). At Day 14, mean values significantly decreased from Day 7 in both groups (OO 4.13 mg/dL, SO 3.83 mg/dL) (p < 0.05) Direct bilirubin elevated at BL in both groups (OO 0.55 mg/dL, SO 0.59 mg/dL) and significantly increased at Day 7 (1.01 mg/dL, p < 0.05) and Day 14 (0.67 mg/dL) in SO group; however, increases not significant in OO group (0.75 and 0.73 mg/dL) Direct bilirubin significantly different between groups (p = 0.039) ALT not significantly different from BL at Days 7 and 14 in both groups; mean values remained within normal limits At Days 7 and 14, AST significantly decreased into normal range from high values at BL (p < 0.05) in both groups. ALP similarly elevated at BL and similarly increased significantly at Days 7 and 14 in both groups (p < 0.05) Mean GGT elevated at BL in both groups (OO 98 IU/L, SO 215 IU/L). At Days 7 and 14, mean GGT significantly increased from BL in OO group (100 and 139 IU/L) and significantly decreased in SO group (112 and 89 IU/L) (p < 0.05) No significant differences between groups for ALT, AST, ALP, GGT, and total bilirubin |
| Wang et al., 2016 [46] | <2000 g and <37 wks | OO (n = 50) (1.42 g/kg/day) MCT/LCT (n = 50) (1.30 g/kg/day) SO (n = 50) (1.39 g/kg/day) |
>14 day | Total and direct bilirubin highest at Day 7 in all groups AST decreased from high values at BL to within normal limits in all groups at Days 7 and 14 ALT remained within normal limits in all groups ALP elevated at BL and increased at Days 7 and 14 in all groups GGT elevated at BL and decreased but remained elevated at Days 7 and 14 in all groups No significant differences in LFTs among groups at BL and Days 7 and 14 |
| Webb et al., 2008 [61] | ≥25 wk | OO (n = 39) (23.1 kcal/kg/day) SO (n = 39) (24.3 kcal/kg/day) |
5 day | LFTs were similar in both groups at BL and Day 5 No abnormalities or differences between groups in ALP, GGT, or conjugated bilirubin at BL or Day 5 Bile acids increased at Day 5 in both groups; no difference between groups |
| Systematic literature reviews and meta-analyses | ||||
| Dai et al., 2016 [83] | SLR and meta-analysis of RCTs: Neonates, infants, children, and adults | OO 8 studies SMOF 7 studies SO (control in each study) |
Various | No differences for any analyses of total bilirubin. ALP significantly higher in OO vs. SO group (infants plus children, p < 0.00001) AST and ALP significantly lower in SMOF vs. SO group (all ages combined, p = 0.004 and p = 0.02) ALT, AST, and ALP significantly lower in SMOF vs. SO group (only adults, p = 0.004, p = 0.006, and p = 0.03) GGT lower in SMOF vs. SO group (all ages combined and only adults, p = 0.07 and p = 0.08) |
| Edward et al., 2017 [66] | SLR of 17 RCTs in hospitalized pediatric patients | OO 7 studies (control in 1 study control) SMOF 8 studies SO (control 15 studies) MCT/LCT 2 studies (control in 1 study) FO 2 studies |
Various | The evidence does not point toward a particular ILE being superior in terms of effect on liver enzymes or total bilirubin. The majority of studies did not find significant differences between use of different ILEs and liver enzymes |
| Hojsak et al., 2016 [81] | SLR and meta-analysis of 23 RCTs: Preterm neonates, infants, and children | OO 2 studies SMOF 4 studies SMF 1 study MCT 1 study SO (control) |
Various | Meta-analysis showed no differences in the rate of cholestasis or bilirubin levels associated with short-term use of different ILEs in preterm infants, neonates, and children Some evidence that use of multicomponent FO-containing ILE may contribute to a decrease in total bilirubin levels in children with intestinal failure on long-term PN |
* Cholestasis defined as a value > ULN for 2 of 3 parameters (conjugated bilirubin, AP, and GGT) during treatment. † Cytolysis defined as a value > 2 × ULN for AST and/or ALT during treatment. ‡ Deterioration defined as a patient who moved to a more abnormal category after starting PN. Categories: within normal limits, elevation up to 2 × ULN, and elevation > 2 × ULN. § n = 12. # Excluded 1 patient with >20-fold increase in serum PS decreased together with ALT and bilirubin after transition from SO-based to OO-based PN after inclusion in the study. α-GST—alpha-glutathione S-transferase; ALP—alkaline phosphatase; ALT—alanine aminotransferase; AST—aspartate aminotransferase; BL—baseline; EN—enteral nutrition; EOT—end of treatment; FO—fish oil; GI—gastrointestinal; GGT—gamma-glutamyl transpeptidase; ILE—intravenous lipid emulsion; LCT—long-chain triacylglycerol; LD—liver dysfunction; LFT—liver function test; MCT—medium-chain triacylglycerol; MSF—50% MCTs/40% SO/10% FO; NEC—necrotizing enterocolitis; NICU—neonatal intensive care unit; OO—olive oil; OR—odds ratio; PN—parenteral nutrition; postop—postoperatively; PNALD—PN-associated liver disease; PS—phytosterol; RCT—randomized controlled trial; SBS—short-bowel syndrome; SLR—systematic literature review; SMOF—30% SO/30% MCT/25% OO/15% FO; SO—soybean oil; TG—triglyceride; ULN—upper limit of normal range; VLBW—very low birth weight.