Journal of Pediatric Gastroenterology & Nutrition:
Original Articles: Hepatology and Nutrition
Effects of Long-term Parenteral Nutrition on Serum Lipids, Plant Sterols, Cholesterol Metabolism, and Liver Histology in Pediatric Intestinal Failure
Kurvinen, Annika*; Nissinen, Markku J.†; Gylling, Helena‡; Miettinen, Tatu A.‡; Lampela, Hanna*; Koivusalo, Antti I.*; Rintala, Risto J.*; Pakarinen, Mikko P.*
*Section of Pediatric Surgery, Hospital for Children and Adolescents
†Department of Medicine, Division of Gastroenterology
‡Department of Medicine, Division of Internal Medicine, University of Helsinki, Helsinki, Finland.
Address correspondence and reprint requests to Annika Kurvinen, Section of Pediatric Surgery, Hospital for Children and Adolescents, University of Helsinki, Stenbäckinkatu 11, PO Box 281, 00029 HUS, Helsinki, Finland (e-mail: email@example.com).
Received 10 December, 2010
Accepted 20 April, 2011
This study was supported by grants from the Päivikki and Sakari Sohlberg Foundation and the Finnish Foundation of Pediatric Research.
The authors report no conflicts of interest.
Background and Objective: Plant sterols (PS) in parenteral nutrition (PN) may contribute to intestinal failure–associated liver disease. We investigated interrelations between serum PS, liver function and histology, cholesterol metabolism, and characteristics of PN.
Patients and Methods: Eleven patients with intestinal failure (mean age 6.3 years) receiving long-term PN were studied prospectively (mean 254 days) and underwent repeated measurements of serum lipids, noncholesterol sterols, including PS, and liver enzymes. PS contents of PN were analyzed. Liver biopsy was obtained in 8 patients. Twenty healthy children (mean age 5.7 years) served as controls.
Results: Median percentage of parenteral energy of total daily energy (PN%) was 48%, including 0.9 g · kg−1 · day−1 of lipids. Respective amounts of PN sitosterol, campesterol, avenasterol, and stigmasterol were 683, 71, 57, and 45 μg · kg−1 · day−1. Median serum concentrations of sitosterol (48 vs 7.5 μmol/L, P < 0.001), avenasterol (2.9 vs 1.9, P < 0.01), stigmasterol (1.9 vs 1.2, P < 0.005), but not that of campesterol (9.8 vs 12, P = 0.22), were increased among patients in relation to controls, and correlated with PN% (r = 0.81–0.88, P < 0.005), but not with PN fat. Serum cholesterol precursors were higher in patients than in controls. Serum liver enzymes remained close to normal range. Glutamyl transferase correlated with serum PS (r = 0.61–0.62, P < 0.05). Liver fibrosis in 5 patients reflected increased serum PS (r = 0.55–0.60, P = 0.16–0.12).
Conclusions: Serum PS moderately increase during olive oil–based PN, and correlate positively with PN% and glutamyl transferase. Despite well-preserved liver function, histology often revealed significant liver damage.
Children with intestinal failure (IF), regardless of the etiology, require parenteral nutrition (PN) to meet energy, fluid, and electrolyte demands (1). PN is associated with severe complications, including intestinal failure–associated liver disease (IFALD) in up to 60% of patients in the infant population, leading to fatty liver, hepatic fibrosis, cholestasis, and increased mortality rates (2–6). IFALD appears to begin with periportal inflammation and PN-associated cholestasis (PNAC), progressing from there to bile duct proliferation, fibrosis, and cirrhosis (7).
The mechanisms behind IFALD are still unknown, but the etiology is proposed to be multifactorial (4,5,8), including PS in parenteral lipid emulsions (9–11). Under physiological conditions, only 5% to 10% of dietary PS are absorbed from the small intestine, and their serum levels reflect intestinal cholesterol absorption (12). PNAC is associated consistently with increased serum concentration of PS reaching levels up to those present in phytosterolemia (9–14). Of the other serum noncholesterol sterols, cholesterol precursors (lathosterol, cholestenol, demosterol) are, particularly when expressed as proportions to cholesterol, surrogate markers of cholesterol synthesis (15,16). Cholestanol is a noncholesterol sterol metabolite of cholesterol that reflects cholesterol absorption under physiological conditions (16,17) and is a sensitive indicator of cholestasis in primary biliary cirrhosis and biliary atresia (18–21).
The hepatobiliary system is responsible for micellar secretion of cholesterol, noncholesterol sterols, phospholipids, and bile acids into the intestine (22). PS are eliminated exclusively by biliary secretion via 2 adenosine triphosphate-binding cassette transporters, ABCG5 and ABCG8, by hepatocytes (23). In healthy humans, sitosterol has higher biliary secretion rate than campesterol, but both PS have significantly lower biliary secretion rates compared with cholesterol (22). In vitro PS, especially stigmasterol, antagonize the nuclear farnesoid X receptor regulating bile acid homeostasis in hepatocytes (24,25). Recently, several reports have demonstrated reversal of PNAC in infants with omega-3 fish oil–based lipid emulsion devoid of PS (26–28). Moreover, transition from soy-based to olive oil–based PN containing less PS decreases liver enzyme values (14,29,30) and could be beneficial in the prevention of IFALD.
To this end, we performed a prospective controlled follow-up among children with IF during repeated PN infusions with known amounts of energy and PS. In addition to serum lipids, noncholesterol sterols and squalene were measured to relate them to cholestasis and biochemical markers of liver function and to liver histology.
PATIENTS AND METHODS
Patients and Controls
We recruited 11 consecutive patients with IF (severe intestinal dysmotility, n = 6, short bowel syndrome [SBS], n = 5) stabilized on long-term PN (median 33, range 18–196 months) for the purposes of this prospective controlled study in a single tertiary referral center (Table 1). The mean patient and gestational ages were 6.3 years (1.6–16) and 37 weeks (27–40). Details of management of pediatric IF by our institution have been published previously, including early initiation and progressive advancement of enteral feeds with individually tailored nutrition based on the anatomy and function of the remaining intestine (31). Anatomical details of the remaining intestine were recorded from operative records. Percentage of age-adjusted small intestine and colon lengths were assessed according to Struijs et al (32) (Table 1). Energy requirements were assessed individually according to weight gain, height-adjusted weight, head circumference, and growth. PN was administered overnight with at least a 12-hour break between consecutive infusions. All of the patients received olive oil–based PN with routine supplementation of fat- and water-soluble vitamins and trace elements. In 1 patient, olive oil–based PN was combined with a small daily dose (0.2 g · kg−1 · day−1) of fish oil–based emulsion (Table 2). During the follow-up, 10 of the patients had at least 1 (range 1–3) episode of symptoms suggestive of intestinal bacterial overgrowth, including diarrhea, treated with oral antibiotics.
Twenty healthy Finnish day-case surgery patients (age median 5.7, range 1.1–11.8 years) without gastrointestinal disease, diabetes, or dyslipidemia and with normal liver function served as controls for serum lipids and noncholesterol sterols. The age and sex of patients were comparable with those of controls (P = 0.51 and 0.85).
During the follow-up (median 207, range 97–646 days), the PN regimen was kept virtually unchanged excluding minor assessments. Repeated measurements of serum PS, cholesterol precursors, and biochemical markers of liver function were performed 4 (2–6) times prospectively, approximately every other month (2 weeks–6 months). At the time of each measurement, the exact composition and amount of PN were recorded between the test points. Liver biopsy was obtained when clinically indicated. The degree of liver fibrosis was based upon the original pathology report (Table 1). A scale from 0 to 3 was used (0 = no fibrosis, 1 = fibrosis, 2 = portal–portal bridging fibrosis, 3 = cirrhosis). Cholestasis, steatosis, and inflammation were recorded as absent, mild, moderate, or severe, also based upon the original pathology report.
Informed consent was obtained from each patient, control, and/or their parents included in the study. The study protocol conforms to the ethical guidelines of the 1975 Declaration of Helsinki as reflected in a priori approval by the ethical committee of the Hospital for Children and Adolescents, University of Helsinki.
Serum cholesterol and noncholesterol sterols, including PS (sitosterol, campesterol, avenasterol, stigmasterol) and cholestanol, cholesterol precursor sterols (lathosterol, cholestenol, desmosterol), and squalene, were measured from nonsaponifiable material by gas-liquid chromatography, on a 50-m-long SE-30 nonpolar capillary column (Ultra 1 column, Hewlett-Packard, Wilmington, DE), with 5α-cholestane as internal standard (33,34). Noncholesterol sterols and squalene in serum were expressed as concentrations of or ratios to the cholesterol concentration of the same gas-liquid chromatography run, that is, 102 × mmol/mol of cholesterol (called proportions in the text), to exclude the effects of varying serum lipoprotein concentration. Parenteral and enteral PS and cholesterol intake were calculated based on parenteral and enteral emulsions analyzed for PS, squalene, and cholesterol similar to serum noncholesterol sterols as described above (Table 2).
Serum cholesterol and triglyceride (TG) levels, and that of high-density lipoprotein (HDL)-cholesterol, after precipitation of apolipoprotein-B containing lipoproteins, were determined by commercial kits (Boehringer Diagnostica, Mannheim, Germany and Wako Chemicals, Neuss, Germany). Low-density lipoprotein (LDL)-cholesterol was calculated according to Friedewald et al (35). Serum alanine aminotransferase (ALT), glutamyl transferase (GT), aspartate transaminase (AST), bilirubin, thromboplastin time, albumin, prealbumin, and vitamins A, E, and 25-hydroxy-D were determined by routine hospital methods.
Unless otherwise stated, the data are expressed as medians and ranges. Nonparametric methods were used to compare continuous variables between patients and controls (Mann-Whitney U test). Correlations were analyzed with the Spearman rank correlation test. A P value <0.05 was considered significant.
Nutrition and Growth
The percentage of parenteral energy was 48% (8–100) of total daily energy with a frequency of 7.0 (2–7) PN infusions per week. Of PN, the patients received 37 (8–72) kcal · kg−1 · day−1 and of which 69% (29–83), 29% (3–35), and 5% (0.9–14) were provided as glucose, fat, and proteins, respectively. The respective daily amounts of PN cholesterol, lipids, carbohydrates, and protein were 0.3 (0.03–0.8), 0.9 (0.1–2.2), 5.5 (0.6–13.5), and 0.6 (0.03–2.2) g · kg−1 · day−1. PN included total PS 846 (120–1938), sitosterol 683 (97–1549), campesterol 71 (10–184), avenasterol 57 (8–141), and stigmasterol 45 (5–132) μg · kg−1 · day−1 (Table 2). Nine patients also received enteral nutrient formulas, which included total PS, sitosterol, campesterol, avenasterol, stigmasterol, and cholesterol 11.0, 6.6, 3.4, 0.5, 0.5, and 1.8 mg · kg−1 · day−1, respectively. One patient received total PN and 1 received enterally 35% of total daily energy from normal food. The z score for height and relative weight of the patients was within the typical range (Table 3).
Serum Lipids, Lipoprotein, Cholesterol, and Fat-soluble Vitamins
Patients had significantly lower serum concentrations of total (enzymatic) cholesterol, 2.75 (1.70–3.95) vs 3.66 (2.30–4.60); LDL-cholesterol, 1.40 (0.47–2.50) vs 2.20 (1.10–2.60); and HDL-cholesterol, 0.80 (0.52–1.48) vs 1.27 (0.99–1.96) mmol/L compared with controls (P < 0.005 for all). The serum triglyceride concentrations were comparable between patients and controls (1.15 [0.52–2.55] vs 1.24 [0.45–5.94] mmol/L, P = 0.906). The median serum levels of vitamins A, E, and 25-hydroxy-D were within the normal range in patients (Table 3).
Serum Plant Sterols and Cholestanol
The total serum concentration of PS was increased by 2.7-fold among patients. Similarly, both serum median concentration and proportion of cholesterol of individual PS, excluding campesterol, were significantly increased among patients in relation to controls (Table 4). Because of the decreased serum cholesterol concentration among patients, the relative increase was more striking when individual PS were expressed as proportions to cholesterol (2.3- to 11-fold) instead of concentrations (1.5- to 6.4-fold). Median serum cholestanol proportion but not concentration was significantly increased among patients (Table 4). As shown in Figure 1, the percentage serum concentration of sitosterol was significantly higher and that of campesterol lower among the patients compared with controls.
Serum cholesterol precursor sterols to cholesterol proportions, especially those of cholestenol and lathosterol, were significantly increased, up to 3-fold, among patients compared with controls. The same was true for serum concentrations of cholesterol precursor sterols, excluding desmosterol. Squalene concentration and proportion to cholesterol were significantly higher among patients than among controls (Table 5).
Among the patients, ALT, AST, GT, bilirubin, prealbumin, albumin, and thromboplastin time remained close to normal or within the normal range during follow-up (Table 3, Fig. 1).
Of the liver biopsy specimens, 63% (5/8) showed some degree of fibrosis (scale 0–3, median 2, range 0–3). Other biopsy findings included cholestasis, steatosis, reactive changes, and inflammation (Table 1).
Relation of Serum Plant Sterols to Parenteral Nutrition, Liver Function, and Cholesterol Synthesis
Of the various characteristics of PN assessed, only the percentage of parenteral energy significantly correlated with serum PS to cholesterol proportions (Table 6). Serum cholesterol precursors to cholesterol proportions were negatively and GT was positively related to serum PS proportions (Table 6). There was a positive correlation among ALT, serum bile acids, and serum total PS/PN total PS ratio (r = 0.69–0.71, P < 0.05). No significant associations were observed between serum PS to cholesterol proportions or concentrations and serum concentrations of bilirubin, ALT, or prealbumin (data not shown). Serum PS concentration or proportions to cholesterol were unrelated to absolute amount of parenteral lipids or PS or the total duration of PN (r = 0.16–0.43, P = 0.19–0.63).
Among patients with liver fibrosis (n = 5), the median sitosterol, campesterol, avenasterol, stigmasterol, total PS, and cholestanol concentrations were 2.2, 2.1, 1.4, 1.1, 1.3, and 1.5 times higher, respectively, than in patients with no liver fibrosis (n = 3). The difference, however, was statistically nonsignificant probably because of the small number of patients in both groups. The serum concentration of total and individual PS tended to correlate with the degree of liver fibrosis (r = 0.55–0.60, P = 0.16–0.12). The degree of liver fibrosis was unrelated to the biochemical markers of liver function, serum total PS/PN total PS ratio, the duration or contents of PN or the amount of lipids, PS, or energy received in PN (data not shown).
Our major findings showed that, first, during follow-up, serum PS levels significantly increased, whereas serum liver enzymes remained close to the normal range. Second, the serum concentration of cholesterol remained low, accompanied by increased cholesterol synthesis evaluated with cholesterol precursor sterols and squalene. Third, histology revealed frequent liver damage despite well-preserved biochemical liver function. In addition, serum PS related positively to GT and negatively to cholesterol precursors. Serum PS tended to reflect liver fibrosis.
It is well known that PN containing PS increases its concentration in the serum (9,11,14,36,37). In the present study, the distribution of individual PS in the serum closely paralleled that of infused lipid regimen (Fig. 2). In addition, parenteral percentage of the energy positively correlated with serum PS levels that were unrelated to the amount of PS or lipids infused. Ellegård et al (38), in their study of adult patients with short bowel syndrome receiving PN, also found high serum levels of PS but no correlation between calculated administration of PS and serum levels of PS. Because serum PS reflects the balance between input and biliary excretion, PS are expected to accumulate further after liver damage (23). High delivery of parenteral energy signifies low enteral food intake. Minute enteral feeding, however, is associated with impaired emptying of the gallbladder, decreased biliary secretion, and cholestasis (39–41). Similar to our findings, low enteral food intake has been linked to high plasma levels of PS in adults with IF (11).
In the present study, serum PSs were inversely related to cholesterol precursors, suggesting that cholesterol homeostasis was not interfered with in the study population. In addition, the association also suggested that the higher the cholesterol synthesis, the lower the serum proportions of PS. High cholesterol synthesis is associated with increased biliary cholesterol secretion, which parallels biliary secretion of sitosterol and campesterol (22). Thus, increased cholesterol synthesis and biliary cholesterol secretion among the patients may have reduced a further increase in serum PS content by increasing their secretion in bile. The difference between serum campesterol percentages in patients compared with parenteral emulsions used was statistically significant (Fig. 2). First, this suggests that in patients with IFALD during olive oil–based PN, the ABCG5/8 transporters in hepatocytes operate relatively normally, and second, that they transport sitosterol more efficiently than campesterol, as previously reported in healthy adults (22). In accordance, we previously showed that PSs, especially sitosterol, enrich in gallstones during PN (42). In a recent study by Nikkilä et al (43), high serum levels of campesterol, sitosterol, and cholestanol in end-stage PBC were normalized after liver transplantation, suggesting that damaged liver cannot efficiently excrete PS or synthesize cholestanol. In our patients, serum PS levels reflected the content of parenteral lipid emulsions, and no relative accumulation of PS was found suggesting that liver PS excretion to bile was efficient despite frequent fibrosis in liver biopsies.
In phytosterolemia, a rare familial lipid storage disease leading to accelerated atherosclerosis, serum concentrations of sitosterol, and campesterol are extremely high, reaching values up to 1500 and 640 μmol/L in homozygotes, respectively, owing to enhanced absorption of the PS (13). In patients with heterozygous phytosterolemia who are clinically symptomless, the serum sitosterol levels are <30 μmol/L (13). In the present study, patients had a higher serum sitosterol concentration compared with controls or patients with heterozygous phytosterolemia, but clearly lower than in patients with homozygous phytosterolemia.
The patients had consistently abnormally low serum levels of total cholesterol, LDL-cholesterol, and HDL-cholesterol. At the same time, serum cholesterol precursor to cholesterol proportions, especially those of cholestenol and lathosterol, were significantly increased, up to 3-fold, among patients, reflecting increased endogenous cholesterol synthesis (14,16). This suggests that the amount of parenterally provided cholesterol alone was insufficient to compensate for the intestinal losses of cholesterol, and, therefore, cholesterol incorporated to expanding tissues in these growing children. Of note, the cholesterol content of the olive oil–based lipid regimen was several times lower than that of PS (Table 2). The magnitude of the increase in serum cholesterol precursor proportions was comparable with children with short bowel syndrome after weaning off PN (44).
During follow-up, patients received a median of 48% of total daily energy and 0.9 g · kg−1 · day−1 of lipids from olive oil–based PN. Previous studies have linked high serum PS levels to IFALD both in adults and in children (9–11,14,38), whereas excessive PN fat dose overcoming the ability of the liver to clear phospholipids and fatty acids can lead to steatosis, cholestasis, and eventually fibrosis (7). A PN lipid dose <1.0 g · kg−1 · day−1 is found to be effective in preventing biochemical signs of IFALD (1,5). During follow-up, the biochemical markers of liver function remained close to the normal range, excluding 1 patient in whom a >20-fold increase in serum PS level decreased together with ALT and bilirubin after transition from soy-based to olive oil–based PN shortly after inclusion in the present study (Fig. 1). Hallikainen et al (14) reported a similar finding in an adult patient with long-term PN caused by short bowel syndrome. Despite the fact that biochemical markers of liver function remained close to the normal range, histological liver damage was common and liver fibrosis tended to reflect serum PS. In addition, there was a positive relation between serum PS and GT and between serum total PS/PN total PS ratio and ALT and serum bile acids. A further refinement of diagnostic strategies and mechanisms behind PN-associated liver damage is needed to differentiate the significance between the total lipid dose and PS. Meanwhile, lipid preparations with low PS content, for example, by combining olive oil– and fish oil-based lipid emulsions, may be advisable. Serum PS concentration can be used to monitor and guide PN lipid dosage.
In conclusion, children with IF receiving olive oil–based PN have higher serum PS levels compared with healthy controls, but the levels are lower than those observed in phytosterolemia. The PS distribution in serum reflects their contents in the parenteral lipid emulsion. Despite the fact that liver enzyme levels remained close to the normal range and the biochemical liver function was well preserved, the biopsies showed liver damage in most of the patients. Serum PS appeared to mirror liver fibrosis.
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