Arenas Villafranca et al.

Nutrition Journal (2017) 16:66

DOI 10.1186/s12937-017-0289-7

RESEARCH Open Access

Effects of cyclic parenteral nutrition on

parenteral-associated liver dysfunction
parameters
Jose J. Arenas Villafranca1, Miriam Nieto Guindo1, Elena lvaro Sanz1,2*, Manuela Moreno Santamaria1,
Marga Garrido Siles1 and Jimena Abils1

Abstract
Introduction: One of the most common complications of parenteral nutrition (PN) is liver dysfunction (LD). Therapeutic
approaches for LD include, among others, administering cyclic parenteral nutrition (cPN), allowing some hours for
metabolic rest. The purpose of this study was to evaluate the effectiveness of cPN in treating PN-associated LD.
Materials and methods: A retrospective observational study was carried out at the Costa del Sol Hospital in Spain
between 2013 and 2014. The study involved inpatients 18 years old prescribed with cPN due to the development of
PN-associated LD. The hepatic biochemical parameters measured at baseline and after completion of cPN included
aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyltransferase (GGT), alkaline phosphatase
(ALP) and total bilirubin (TB). Quantitative values (age, biochemical parameters) were compared using matched Students
t-test; the mean change in qualitative variables (sex, indication of PN, hepatic comorbidities, presence of insulin in cPN,
infection during cPN, management of LD prior to cPN administrarion) was estimated using Mann-Whitney U
test, and bivariate correlation between quantitative variables was determined by Spearmans coefficient of correlation.
Results: Thirty-seven patients met inclusion criteria. All hepatic function parameters except ALP improved after the
administration of cPN, with statistically significant differences (p < 0.05) in AST GGT and TB.
Conclusion: cPN improves PN-associated LD by restoring abnormal AST, GGT, and BT levels to normal, and reducing
ALT levels close to normal. The results obtained suggest that the administration of cPN is effective in reverting
PN-associated LD.
Keywords: Liver dysfunction, Parenteral nutrition, Cyclic parenteral nutrition, Liver parameters

Introduction common complications of parenteral nutrition is liver

Parenteral nutrition (PN) is defined as the intravenous disfunction (LD), which is associated with a higher risk
provision of nutrients to patients in whom enteral feed- of mortality [3]; the reason is that if LD is not success-
ing is insufficient or contraindicated. It may be provided fully treated, it can progress to fibrosis and/or liver
via a central or peripheral vein and may be used as cirrhosis [4, 5].
stand-alone nutrition support or as an adjunct to enteral Although changes in hepatic function usually occur
nutrition [1]. during long-term PN (in 20 to 80% of cases), patients
Although PN is an effective method of nutrition sup- who receive PN for a short time frequently develop cho-
port, it has been associated with a range of mechanical, lestasis [6]. During the first weeks on PN, the activity of
septic, and metabolic complications [2]. One of the most hepatic enzymes increases starting with an elevation in
alkaline phosphatase (ALP) and gamma glutamyl amino-
transferase (GGT) levels in adults. ALP and GGT levels
* Correspondence: elena.as84@hotmail.com
1
Pharmacy and Nutrition Service, Costa del Sol Hospital, A7, km. 187, 29603
generally increase during the second week on PN,
Marbella (Mlaga), Spain whereas the rise in transaminase levels occurs later.
2
C/ Fernando Villaln Edf. Lorcrisur, Bloque n8, Bajo A, 29670 Marbella
(Mlaga), Spain

The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and
reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to
the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver
(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Arenas Villafranca et al. Nutrition Journal (2017) 16:66 Page 2 of 5

However, the most widely accepted prognostic factor for (TB) > 1.2 mg/dL; b) Hepatic necrosis: Aspartate amino-
LD is unconjugated bilirubin [4]. transferase (AST) > 40UI/L, alanine aminotransferase
While the etiology of liver dysfunction (LD) is not fully (ALT) > 42UI/L and c) Mixed pattern: ALP > 280UI/L,
understood, multiple factors are known to be involved in GGT > 50UI/L or TB > 1.2 mg/dL plus AST > 40 IU/L
the development of this disorder. Such factors can be pa- or ALT > 42UI/L [8].
tient-related (liver disease, pancreatitis, obesity, alcohol- Study variables included: a) Qualitative parameters:
ism, digestive rest, bacterial overgrowth); or nutrition- sex, diagnosis at admission, indication of PN, hepatic co-
related, (high carbohydrate intake, continuous supply of morbidities, start date of cPN, presence of insulin in
nutrients). What is certain is that LD must be treated as cPN, infection during cPN and management of liver dys-
soon as possible. Therapeutic strategies for LD include function prior to the administration of cPN (addition of
avoiding overfeeding, providing a balanced supply of taurine to the amino acid solution, reversal of the dietary
nutrients, supplying early enteral nutrition, and ad- carbohydrate/lipid ratio of PN composition, and reduc-
ministering discontinuous parenteral nutrition while tion of carbohydrate and/or lipid supply). b) Quantita-
allowing some hours for metabolic rest (cyclic paren- tives: age and biochemical parameters including AST,
teral nutrition, cPN) [4]. ALT, GGT, ALP, and TB that were measured at base-
However, only a few studies have been performed to line and at completion of cNP using validated tech-
assess the effectiveness of these strategies. The purpose niques. These parameters were monitored from the
of this study was to evaluate the effects of cPN on liver initiation of cPN until the end of the cycle, when bio-
function parameters. markers became stable. To estimate the reduction in
TB levels, only the TB values 1.2 mg/dL at the start
Materials and methods of cPN were considered.
A retrospective observational 15-month study was car- Descriptive analysis was performed using central ten-
ried out between 2013 and 2014 in the 350-bed Costa dency, dispersion, and distribution for quantitative
del Sol Hospital, Spain, which attends a population of variables, and frequency distribution for qualitative vari-
404,426 inhabitants. The study involved inpatients ables. Baseline and post-cPN hepatic values were com-
18 years who initially received continuous parenteral pared using matched Students t-test; the mean change
nutrition and were subsequently prescribed with cPN in qualitative variables was estimated using Mann-
following a decision of the team of artificial nutrition Whitney U test. Bivariate correlation between quantita-
based on the local PN management protocol. Exclusion tive variables was determined by Spearmans coefficient
criteria included: severe liver disease evidenced by of correlation. When paired samples exceeded 30 indi-
abnormal biochemical hepatic parameters, a history of viduals, parametric statistical tests were performed. A
renal failure, death during treatment or a duration of p value <0.05 was considered statistically significant.
cPN 4 days. Data were collected from clinical records. Data collection and analyses were performed using
According to the local protocol, nutrition support con- SPSS v15.
sists of a lipid emulsion comprising soy oil, MCT, olive
oil and fish oil (SMOF). Nutrition supply was individual-
ized following the guidelines of recognized scientific so- Results
cieties [1, 7]. Glucose and lipid intake never exceeded 5 Of the 557 patients who received PN during the study
and 1.5 g/kg/d, respectively. Initially, all patients received period, 56 were prescribed cPN (10%), of whom 37 met
continuous PN and, following our local protocol, a series the inclusion criteria. Demographic data are shown in
of interventions were performed prior to the administra- Table 1. All patients were considered by Costa del Sol
tion of cPN, notably: taurine was added to the amino Hospital nutritionists to have a good nutritional status.
acid solution; the dietary carbohydrate/lipid ratio in PN The mean duration of continuous parenteral nutrition
composition was reverted (in general terms, the standard until prescription of cPN was 15.2 11.2 days. Most pa-
carbohydrate/lipid ratio is 60:40 or 70:30; however, in a tients received cPN for 12 h prior to the infusion of sa-
context of LD, it is recommended that the total line solution within the following 12 h until enteral
amount of dextrose is reduced, thereby reverting the nutrition was initiated. The mean duration of cPN was
standard ratio), and the total carbohydrate and/or 12.8 12.7 days (range 3 to 42 days).
lipid supply was reduced. In all, 43.2% of patients received some treatment to
cPN was only prescribed when LD parameters became manage LD prior to cPN. The lipid and carbohydrate
abnormal. Specifically and, in accordance with previous supply was reduced in 8% of patients, and taurine was
studies, liver dysfunction (LD) was defined as: a) Chole- added to the amino acid emulsion in 38%. However, no
stasis: alkaline phosphatase (ALP) > 280UI/L, gamma- significant improvements were achieved in any hepatic
glutamyltransferase (GGT) > 50UI/L total bilirubin parameter through these interventions.
Arenas Villafranca et al. Nutrition Journal (2017) 16:66 Page 3 of 5

Table 1 General characteristics of the study population (n = 37) the development of infection (54%), insulin supply
Age (years) 61.2 13.7 through cPN (43%), enteral stimulus (54%) and the
Gender (Man/Woman) 40.5%/59.5% reduction in hepatic parameter values.
Weight (Kg) 65.6 19.4
Discussion
BMI (kg/m2) 24.0 6.5
Some studies have been performed to assess the effect-
Indications for PN iveness of administering cPN to manage hepatic compli-
Major digestive surgery 29.7% cations but changes in hepatic parameter values have
Bowel obstruction 21.6% never been explore during cPN, and our study, also re-
Severe Acute Pancreatitis 18.9% veals that the administration of cPN (12 days on aver-
age) objectively reduced significantly abnormal AST and
Gastrointestinal Occlusion 10.8%
TB values to normal levels and ALT close to normal
Need for digestive rest 8.1%
levels. However, no changes were observed in ALP. The
High output fistula 8.1% reduction of hepatic parameters during cPN has a clear
Uncontrollable vomiting 2.7% clinical benefit in patients, as elevated transaminase
Comorbidities (No. of patients) levels caused by steatosis can progress to fibrosis or hep-
Liver angioma 1 atic cirrhosis in the long term.
Cholecystectomy 3
The administration of cPN at night was proposed by
Scribner et al. in 1970 [9]. A randomized study in adults
Cholelithiasis 3
[10] demonstrated that cPN mimicked better the physio-
Dyslipidemia 4 logic function of nutrient metabolism while the lipogen-
Alcoholism 3 esis caused by fasting was prevented, thus improving the
HBV 1 clearance of the fatty acids accumulated during continu-
None 24 (65%) ous PN. Another retrospective study in neonates asses-
HBV Hepatitis B Virus, PN Parenteral nutrition, IBD Intestinal bowel Disease
sing the prophylactic administration of cPN versus
standard PN demonstrated that cPN reduced the inci-
dence or delayed the development of hepatic abnormal-
Following cPN, an improvement in all hepatic function ities [11]. Moreover, a revision of the metabolic effects
parameters except ALP was observed, as shown in of cPN in adults and children concludes that cPN infu-
Table 2, with statistically significant differences in AST sion has a favorable riskbenefit profile in most patients
(p < 0.05), GGT (p < 0.05) and TB (p < 0.05). No correl- receiving long-term PN [12].
ation was observed between improvements in hepatic There is controversy concerning the etiology and
function parameters and any demographic variable (age, pathogenesis of LD [2]. Continuous PN may be a predis-
sex, weight and BMI), neither with cPN duration. posing factor for excess insulin levels, which cause the
In total, 35% of patients had a hepatic comorbidity accumulation of fat in the liver [2]. However, the causes
(Table 1). Improvements in hepatic parameters were not of hepatic and biliary abnormalities induced by continu-
found to be correlated with any previous comorbidity. ous PN have not been identified yet [3]. Hepatic parame-
The only exception was TB, which reduction was signifi- ters should be continuously monitored in patients
cantly greater in patients with high baseline TB levels receiving PN to prematurely detect and treat any poten-
(Table 1). No correlation was observed either between tial liver dysfunction. For this reason, our protocol
includes the weekly monitoring of hepatic parameters.
It is widely known that the most sensitive markers of
Table 2 Hepatic parameter values before and after the cholestasis are GGT and unconjugated bilirubin, al-
administration of cyclic parenteral nutrition (n = 37) though none of these parameters is specific [4]; con-
Hepatic parameter values Pre-cPN value Post-cPN value p sequently, we follow Grau et al. LD classification instead
at the start of cPN
of just waiting for an abnormal elevation of GGT and
AST (UI/L) (mean SD) 78.2 89.1 34.8 17.3 0.004 BT values.
ALT (UI/L) (mean SD) 132.5 245.4 55.0 36.2 0.058 Preventive measures are routinely implemented in our
GGT (UI/L) (mean SD) 539.5 372.9 414.2 321.5 0.040 hospital to protect the liver. Thus, patients receive indi-
Alkaline phosphatase (UI/L) 238.3 156.8 239.6 199.9 0.968 vidualized PN comprising 20% lipid emulsions, with sup-
(mean SD) plies not exceeding the intake recommended in the local
Total Bilirubin >1.2mg/dL 1.5 (1.26.2) 0.8 (0.23.1) 0.047 protocol [13]. All in all, 10% of our patients developed
(mg/dl) (n = 5) (Median (IQR)) liver dysfunction during the study period. Even so, the
cPN cyclic parenteral nutrition, IQR InterQuartile rank incidence of LD in our hospital is significant below the
Arenas Villafranca et al. Nutrition Journal (2017) 16:66 Page 4 of 5

rate (78%) reported by Pallars et al. [14] or the rate re- Abbreviations
ported by Aaron R. Jensen (35%) in children after 12 ALP: Alkaline phosphatase; ALT: Alanine transaminase; AST: Aspartate
aminotransferase; BMI: Body mass index; cPN: cyclic Parenteral Nutrition;
18 days on PN [11]. Such difference might be explained GGT: Gamma-glutamyltransferase; LD: Liver disfunction; PN: Parenteral
by the fact that the PN initially administered in our hos- nutrition; TB: Total bilirubin
pital includes measures for the prevention of liver dys-
Acknowledgments
function, added to the fact that patients with a previous We thank the staff of research and pharmacy services at the Costa del Sol
liver dysfunction were excluded from the study (15 pa- Hospital.
tients). According to our protocol, these therapeutic
Funding
measures must be adopted as soon as hepatic abnormal- Not applicable.
ities are detected, which contradicts a recent study that
suggests a benefit from early initiation of cPN [15]. Such Availability of data and materials
The datasets during the current study available from the corresponding
measures include avoiding overfeeding, the early admin- author on reasonable request.
istration of enteral nutrition, the administration of cPN
(812 h) [3], and the addition of taurine in PN. Taurine Disclaimers
Having reading the procedure for submissions, the authors declare there is
supplementation has been proven to improve biliary no conflict of interest.
flow by increasing the rate of biliary acid secretion
[1618] which accumulates as a result of continuous Authors contributions
JJAV and MNG equally contributed to the conception and design of the
PN [19]. research; JA contributed to the design of the research; JJAV contributed to
Although a series of interventions were performed in the acquisition and analysis of the data; EAS, MGS and MMS equally contributed
our study prior to the administration of cPN following to the acquisition, analysis, and interpretation of the data. All authors drafted the
manuscript, critically revised the manuscript, agree to be fully accountable for
our local protocol, none of these strategies was associ- ensuring the integrity and accuracy of the work, and read and approved the final
ated with a significant reduction in hepatic function manuscript.
parameter values prior to the administration of cPN.
Ethics approval and consent to participate
Therefore, cPN was the most effective strategy for the This study was approved by the Medical Ethics Committee of Costa del Sol
normalization of biochemical hepatic parameters. hospital. All of the protocols and procedures were performed according to
The identification of patients with predisposing factors the Declaration of Helsinki.
for liver dysfunction is essential [13]. However, in this Consent for publication
study, no correlation was observed between previous Not applicable.
hepatic comorbidities and biochemical changes following
Competing interests
cPN, except for TB. This might be explained by the fact The authors declare that they have no competing interests.
that increases in TB generally occur later than other
hepatic parameters [20], and the patients who had no Publishers Note
comorbidities were administered early cPN, which pre- Springer Nature remains neutral with regard to jurisdictional claims in
vented an increase in TB levels. published maps and institutional affiliations.
There are other factors that predispose patients to de- Received: 30 December 2016 Accepted: 26 September 2017
velop hepatic complications, especially in the case of
sepsis or malnutrition [8, 21]. Over 50% of our patients
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