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Predictive value of the aspartate aminotransferase to platelet ratio index for parenteral nutrition associated cholestasis in extremely low birth weight infants



Parenteral nutrition (PN) improves the survival of premature infants. However, prolonged PN increases the risk of PN-associated cholestasis (PNAC).


We aimed to evaluate the predictive value of aspartate aminotransferase (AST)-to-platelet ratio index (APRI) for PNAC in infants with extremely low birth weight (ELBW, birth weight < 1000 g) infants.


We retrospectively reviewed the medical records of ELBW infants from March 2010 to February 2017. Clinical data and the serial APRI, AST, alanine aminotransferase (ALT), AST-to-ALT ratio, and direct bilirubin (DB) were analyzed. PNAC was diagnosed in infants with a history of PN for at least 2 weeks and direct bilirubin concentrations > 2 mg/dL after other causes of neonatal cholestasis were excluded.


Among the 179 eligible ELBW infants, 56 (31.3%) were diagnosed with PNAC. APRI significantly differed between infants with PNAC and those without PNAC. The best APRI cut-off point was 0.410 at 2 weeks after the start of PN (area under the receiver operating characteristic curve = 0.752, p < 0.05; positive predictive value, 50.6%; negative predictive value, 84.1%).


APRI at 2 weeks after PN could be a reliable predictor of PNAC development in ELBW infants on PN.

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Parenteral nutrition (PN) is essential for improving the growth and development of premature infants before enteral feeding can be established. However, long-term PN can also increase the risk of various PN-associated hepatobiliary complications [1, 2]. PN-associated cholestasis (PNAC) is the most common clinical manifestation of PN-associated liver disease in preterm infants. The pathogenesis of PNAC is considered multifactorial. Several identified risk factors associated with PNAC are known; prematurity, small for gestational age, long duration of PN, sepsis, necrotizing enterocolitis (NEC), composition of PN solutions and a delay in enteral feeding [3, 4]. Though most cases of PNAC resolve with enteral nutrition [5], progressive hepatic failure eventually can lead to death in some patients. Therefore, early identification of groups at risk of PNAC helps with an earlier adjustment in PN to decrease the risk of progressive to severe liver dysfunction.

The diagnosis of PNAC is made by checking the increased levels of direct bilirubin (DB). It is very simple and inexpensive. However, there is a limit to predict the development of PNAC by tracking values of DB alone. In many patients, the level of DB did not increase gradually. Even, it suddenly increase up to the point to diagnose PNAC. Therefore, we sought to find a new way to predict the PNAC. Numerous studies have demonstrated that the aspartate aminotransferase (AST)-to-platelet ratio index (APRI) is a reliable marker of liver fibrosis in adult patients [6, 7]. Although studies are limited, the APRI has been investigated as a marker of hepatic fibrosis in chronic liver disease, hepatitis, and biliary atresia in the younger population [8,9,10,11]. The histopathology of PNAC has been described as a progression from bile duct proliferation to portal inflammation to bridging fibrosis to cirrhosis [12, 13]. Hence, we assumed that APRI also can be applied in PNAC of neonates. Only one study evaluated the predictive value of APRI for PNAC in premature infants, to date [14] and it enrolled a limited number of preterm infants with intestinal perforation.

This study was conducted to evaluate the predictive value of the APRI for PNAC in infants with extremely low birth weight (ELBW).



We reviewed the medical records of ELBW infants, with a birth weight of less than 1000 g, who were admitted to the NICU at Haeundae Paik Hospital, Busan, Korea between March 2010 and February 2018. The inclusion criteria were ELBW infants who received PN for at least 2 weeks and survived for more than 4 weeks. We excluded infants who had severe congenital anomalies, chromosomal abnormalities or clinically apparent congenital infections. Infants with other causes of cholestasis including hypothyroidism, gallstone were excluded and infants with congenital platelet disorder were excluded. We also excluded infants who were transferred to other hospital.


PNAC was defined as those with a direct bilirubin concentration > 2.0 mg/dL without other identifiable causes of cholestasis except for PN. We excluded the data when there was a temporary increase in DB accompanying sepsis and shortly resolved at follow up tests.

We collected basic demographic data and reviewed clinical variables including respiratory distress syndrome, patent ductus arteriosus, NEC, sepsis, transfusion history, surgery, ventilator care duration, and brochopulmonary dysplasia (BPD). NEC was defined as Bell’s criteria stage two or greater. BPD was defined as a need for oxygen at 36 weeks of postmenstrual age. Maternal data were also reviewed. Data of nutritional support were also collected including the number of days until the initiation of enteral feeding, the time points at which half (60 cc/kg/day) and full (120 cc/kg/day) enteral feeding were reached and the number of days of total PN, and types of PN solutions.

The laboratory findings were reviewed to determine levels of total bilirubin (TB), DB, and liver enzymes including AST and alanine aminotransferase (ALT). The APRI was calculated from the equation according to Wai et al. [15] as follows: (AST/upper normal limit of AST)/platelet count (109/L) *100, and upper normal limit of AST value was defined as 40 U/L. We analyzed laboratory results in each time point as 1, 2, and 3 weeks after starting PN.

Nutrition protocol

Though it was varied according to the change of guidelines of our unit and the tolerance of the individual patient, common nutritional supplementation principle was as following and this methodology was used also from a previously work [16].

Enteral nutrition protocol

The starting enteral feeding volume was 10–20 mL/kg/day divided into doses administered every 3 h and increased by 10–20 mL/kg/day according to the baby’s tolerance until full enteral feeding (120–160 mL/kg/day) was achieved. We fed the ELBW infants either human milk or premature infant formula. After the enteral feeding volume reached 100 mL/kg/day, breastmilk was fortified with a human milk fortifier.

Parenteral nutrition protocol


The infants were started at 0.5 g/kg just after birth. The dose was increased by 0.5 g/kg/day increments every day to a maximum dose of 3.0–4.0 g/kg/day according to the baby’s tolerance. From 2016, we administered 1.5 g/kg/day as starting dose of parenteral amino acid and increased rapidly by 1.0 g/kg/day to reach maximum concentration of 4.0–4.5 g/kg/day.


The infants were started at 7.0–8.0 g/kg/day just after birth. The dose was increased by 1.0–2.0 g/kg/day every day according to the baby’s tolerance to a maximum dose of 15.0–18.0 g/kg/day.


Intravenous lipid emulsion was started at 0.5 g/kg/day on day two and was increased at a dose of 0.5 g/kg/day according to tolerance to a maximum dose of 3.5 g/kg/day. Beginning in March 2010, Lipo MCT 20% (Dong guk Pharm, Seoul, Korea) was used as the primary parenteral lipid solution. Between April 2011 and January 2013, Intralipid 20% (Fresinius Kabi, Cheshire, UK) was used. Since January 2013, SMOF lipid (Fresenius Kabi, Bad Homburg, Germany) has been used in our NICU. After 2017, Omegaven (Fresinius Kabi, Cheshire, UK) was used as rescue therapy in patients with a diagnosis of PNAC. It was administered twice a week or every other day and was taken with SMOF lipid.

Statistical analyses

Data are presented as frequencies with percentages for the categorical variables and mean ± standard deviation for continuous variables. Differences in participant characteristics were compared across subgroups with a Chi-square test or Fisher’s exact test for categorical variables and independent test or Mann-Whitney’s U test for continuous variables as appropriate. To check for normal distribution, we used Shapiro-Wilk’s test. Univariate and multivariate analyses, using logistic regression, were performed in order to identify prognostic factors that were independently related to PNAC and death. In addition, the receiver operating characteristic (ROC) curve was performed to assess the sensitivity and specificity for PNAC. All statistical analyses were carried out using SPSS 24.0 and p values less than 0.05 was considered statistically significant.


Basic demographic and clinical characteristics

A total of 203 ELBW infants were admitted during the study period and 184 of these infants met the inclusion criteria. We excluded 5 infants. Four infants were transferred out to other hospital and one infant was diagnosed with an acquired cytomegalovirus infection. Finally, a total of 179 infants were enrolled in this study, and 56 (31.3%) were diagnosed with PNAC at 36.16 ± 17.67 days after birth (Fig. 1). Table 1 shows various clinical factors associated with the development of PNAC. Composition of PN solutions; use of fish-oil based lipid emulsion; and maximum concentrations and cumulative dose of macronutrient including carbohydrate, amino acids, and lipids were not associated with PNAC (data not shown).

Fig. 1
figure 1

Study flowchart

Table 1 Analysis of risk factors affecting PNAC

Laboratory test results

Figure 2 shows the trends of laboratory test results at 1, 2, and 3 weeks after PN with respect to PNAC. DB and APRI significantly differed between infants with PNAC and without PNAC at each time point and TB and AST also differed between groups at 3 weeks (Table 2). ROC curves for TB, DB, AST, ALT, AST/ALT, and APRI at 1, 2, and 3 weeks of age are presented in Fig. 3.

Fig. 2
figure 2

Change in laboratory evaluation at 1, 2, and 3 weeks after parenteral nutrition: p < 0.05, p < 0.001

Table 2 Associations with laboratory test results and development of PNAC
Fig. 3
figure 3

Receiver operating characteristic curves of the laboratory test results to predict PNAC at time of 1 week (dotted line), 2 weeks (dashed line), and 3 weeks after PN (solid line). AUC: area under the curve. *p < 0.05

Risk factors associated with PNAC

Figure 3 shows the Receiver operating characteristic (ROC) curves of the DB, APRI to predict PNAC at each time points. Various clinical factors and laboratory test results were associated with the development of PNAC. Finally, the duration of PN and hospitalization, DB and APRI at 2 weeks were determined to be independent risk factors for PNAC in the multivariate logistic regression analysis (Table 3). At 2 weeks after PN, DB > 0.70 and APRI > 0.41 are cut-off points for prediction of PNAC has a 50.0% sensitivity, 91.7% specificity, 75.7% positive predictive value (PPV), and 78.1% negative predictive value (NPV) (Table 4).

Table 3 Multiple logistic regression analysis for risk factor of PNAC
Table 4 Predictive values for PNAC of laboratory evaluation at 2 weeks after PN


PN is essential for survival in preterm infants. Especially, very low birth weight infants have to depend on support of PN for considerable time until establishment of enteral feeding [15]. Among the various clinical features of liver injury results from prolonged PN, PNAC is the most common clinical manifestation in preterm infants [17]. As increase survival of more preterm babies, incidence of PNAC also has increased. Although the precise incidence is still unknown, PNAC has become an emerging topic in neonatal intensive care units (NICUs) [18]. PNAC is an umbrella term that covers a wide spectrum from mild cholestasis or mild elevated liver enzyme to hepatic fibrosis, and cirrhosis. In some cases, the liver undergoes irreversible liver damage, end-stage liver failure, and eventually death [19, 20]. Cyclic or intermittent PN, fish-oil-based lipid emulsion use, and medications including ursodesoxycholic acid are suggested as treatments for PNAC [21, 22]. However, progressed hepatic failure results in mortality. Therefore, it is more important to stop the patient from developing irreversible terminal hepatic failure by preventing liver damage from long term PN. Hence, identification of risk groups for the development of PNAC is essential.

Liver biopsy is currently the gold standard in evaluating liver fibrosis and cirrhosis. However, considering the potential risks in performing liver biopsy, numerous efforts have been made to develop reliable and non-invasive methods for assessment of hepatic fibrosis and cirrhosis. This has led to the introduction of various biological markers, including APRI. Moreover, serial serological markers can be more reliable for reflecting changes of dynamic liver fibrosis. The APRI was initially introduced to monitor and evaluate the progression of fibrosis in adult patients with chronic hepatitis C [23, 24] and it has shown high accuracy in predicting both significant fibrosis and cirrhosis in also hepatitis B [25]. Therefore, it is widely used as a predictive marker to assume the degree of hepatic fibrosis in the adult population with other liver diseases [26, 27]. Moreover, the APRI is an indicator for liver function in end stage liver disease in the younger population [8, 9, 11]. In particular, among infants and children with biliary atresia or a short gut, APRI can predict liver function, liver survival, and prognosis [7, 10]. Because of the differences in characteristics of the enrolled population and variables in the degree of liver fibrosis used as diagnostic criteria, there is a limit to the extent to which specific cut-off value of APRI can be defined. It is clear that levels of APRI are correlated with the progression of hepatic dysfunction and fibrosis in various hepatic diseases in children and adult patients. Only one study evaluated the APRI as a predictor for PNAC in premature infants to date [14]. Underwood et al. assessed 60 infants with gestational age < 34 weeks, birth weight < 2000 g and intestinal perforation due to either NEC or spontaneous intestinal perforation. They reported that APRI was significantly different between 17 infants who later developed PNAC and another 43 infants who did not. They suggested the best APRI cut-point was 0.4775 within 2 weeks after perforation. In the current study, we enrolled ELBW infants on PN regardless of bowel perforation. We checked serial AST, ALT, total bilirubin, direct bilirubin, and APRI at 1, 2, and 3 weeks after birth. Though the differences between infants with PNAC and without PNAC were more prominent with time, considering the statistical significance and values as predictors, we conclude that DB combined with APRI at 2 weeks of age was the most reliable indicator for the development of PNAC in ELBW infants. Because laboratory test results at 1 week had low statistical power and those at 3 weeks could not play a role as predictor; 14 infants were already diagnosed as having PNAC before 3 weeks of age. So, we finally analyzed 2 weeks laboratory test results and finally, the combined vales of DB and APRI has real high specificity; DB > 0.7 and APRI > 0.41 showed a sensitivity of 50.0%, specificity 91.8%, PPV 75.7%, and NPV 78.3%.

Various methods including radiologic work-ups (ultrasound, computed tomography, elastography, magnetic resonance imaging) and serological biomarkers to predict hepatic fibrosis have been proposed. With these method results are encouraging, but it is difficult to perform in preterm infants, especially clinically unstable ELBW infants within the first few weeks. However, platelet counts and basic liver function tests including TB, DB, AST, and ALT are routinely performed in ELBW infants with PN at least once a week. The APRI can be calculated from two routine laboratory tests. Therefore, additional blood sampling or invasive procedures were not needed to evaluate APRI in these neonates, making the test more accessible within the NICU.

This study has some limitations. This study was conducted retrospectively, and therefore various clinical factors including the nutritional protocol, fluconazole prophylaxis and the types of PN solution were not uniformly applied to the study populations. However, these differences allowed us to compare the effects of different clinical factors on the development of PNAC. In addition, we did not perform the live biopsy. Hence, we could not determine a correlation between the biopsy results and APRI values. We also could not determine the exact cut-point value from this single study. However, we do believe that this study suggests the possibility of APRI as an early predictor for PNAC in ELBW infants on PN. Moreover, high specificity, PPV, and NPV of APRI than DB shows the priority of APRI as early predictor.


This study showed that APRI and DB values at 2 weeks of age had a reliable predictive value for the development of PNAC in ELBW infants. More research on this topic is warranted to help determine the specific values for predicting PNAC to be applied in clinical practice.



Alanine aminotransferase


AST-to-platelet ratio index


Aspartate aminotransferase


Bronchopulmonary dysplasia


Direct bilirubin


Extremely low birth weight


Necrotizing enterocolitis


Neonatal intensive care unit


Negative predictive value


Parenteral nutrition


Parenteral nutrition-associated cholestasis


Positive predictive value


Receiver operating characteristic


Total bilirubin


  1. Chaudhari S, Kadam S. Total parenteral nutrition in neonates. Indian Pediatr. 2006;43:953–64

    PubMed  Google Scholar 

  2. Btaiche IF, Khalidi N. Parenteral nutrition-associated liver complications in children. Pharmacotherapy. 2002;22:188–211

    Article  Google Scholar 

  3. Tufano M, Nicastro E, Giliberti P, Vegnente A, Raimondi F, Iorio R. Cholestasis in neonatal intensive care unit: incidence, aetiology and management. Acta Paediatr. 2009;98:1756–61

    CAS  Article  Google Scholar 

  4. Hsieh M, Pai W, Tseng H, Yang SN, Lu CC, Chen HL. Parenteral nutrition-associated cholestasis in premature babies: risk factors and predictors. Pediatr Neonatol. 2009;50:202–7

    Article  Google Scholar 

  5. Magnalat N, Bell C, Graves A, Imseis EM. Natureal history of conjugated bilirubin trajectory in neonates following parenteral nutrition cessation. BMC Pediatr. 2014;14:298

    Article  Google Scholar 

  6. Li SM, Li GX, Fu DM, Yu W, Dang L-Q. Liver fibrosis evaluation by ARFI and APRI in chronic hepatitis C. World J of Gastroenterol. 2014;20:9528–33

    Article  Google Scholar 

  7. Suominen JS, Lampela H, Heikkilä P, Lohi J, Jalanko H, Pakarinen MP. APRi predicts native liver survival by reflecting portal fibrogenesis and hepatic neovascularization at the time of portoenterostomy in biliary atresia. J Pediatr Surg. 2015;50:1528–31

    Article  Google Scholar 

  8. Li B, Zhnag L, Zhang Z, Yan G, Zhu L, Lu W, Yu H. A noninvasive indicator for the diagnosis of early hepatitis B virus-related liver fibrosis. Eur J Gastroenterol Hepatol. 2018.

  9. McGoogan KE, Smith PB, Choi SS, Berman W, Jhaveri R. Performance of the AST-to-platelet ratio index as a noninvasive marker of fibrosis in pediatric patients with chronic viral hepatitis. J Pediatr Gastroenterol Nutr. 2010;50:344–6

    Article  Google Scholar 

  10. Grieve A, Makin E, Davenport M. Aspartate aminotransferase-to-platelet ratio index (APRi) in infants with biliary atresia: prognostic value at presentation. J Pediatr Surg. 2013;48:789–95

    Article  Google Scholar 

  11. Unlusoy Aksu A, Sari S, Yilmaz G, Eğritaş Gürkan Ö, Demirtaş Z, Dalgıç B. Aspartate aminotransferase-to-platelet ratio index in children with cholestatic liver diseases to assess liver fibrosis. Turk J Pediatr. 2015;57:492–7

    PubMed  Google Scholar 

  12. Beath SV, Kelly DA. Total parenteral nutrition-induced cholestasis: prevention and management. Clin Liver Dis. 2016;20:159–76

    Article  Google Scholar 

  13. Zambrno E, El-Hennawy M, Ehrenkranz RA, Reyes-Múgica M. Total parenteral nutrtion induced liver pathology: an autopsy series of 24 newborn cases. Pediatr Dev Pathol. 2004;7:425–32 11.

    Article  Google Scholar 

  14. Vongbhavit K, Underwood MA. Predictive value of the aspartate aminotransferase to platelet ratio index for parenteral nutrition–associated cholestasis in premature infants with intestinal perforation. J Parenter Eneteral Nutr. 2018;42:797–804

    CAS  Google Scholar 

  15. Wai CT, Greenson JK, Fontana RJ, Kalbfleisch JD, Marrero JA, Conjeevaram HS, Lok AS. A simple noninvasive index can predict both significant fibrosis and cirrhosis in patients with chronic hepatitis C. Hepatology. 2003;38:518–26

    Article  Google Scholar 

  16. Lee HH, Jung JM, Nam SH, Gina L, Chung ML. Risk factor analysis of parenterel nutrtion- associated cholestasis in extremely low birth weight infants. Acta Paediatr. 2016;105:313–9.

  17. Buchman A. Total parenteral nutrition-associated liver disease. J Parenter Enter Nutr. 2002;26:S43–8

    CAS  Article  Google Scholar 

  18. Willis TC, Carter BA, Rogers SP, Hawthorne KM, Hicks PD, Abrams SA. High rates of mortality and morbidity occur in infants with parenteral nutrition-associated cholestasis. J Parenter Enter Nutr. 2010;34:32–7

    Article  Google Scholar 

  19. Kubota A, Mochizuki N, Shiraishi J, Nakayama M, Kawahara H, Yoneda A, Tazuke Y, Goda T, Nakahata K, Sano H, Hirano S, Kitajima H. Parenteral-nutrition-associated liver disease after intestinal perforation in extremely low-birth weight infants: consequent lethal portal hypertension. Pediatr Int. 2013;55:39–43

    Article  Google Scholar 

  20. Hirano K, Kubota A, Nakayama M, Kawahara H, Yoneda A, Tazuke Y, Tani G, Ishii T, Goda T, Umeda S, Hirno S, Shiraishi J, Kitajima H. Parenteral nutrition-associated liver disease in extremely low-birthweight infants with intestinal disease. Pediatr Int. 2015;57:677–8

    CAS  Article  Google Scholar 

  21. Park HW, Lee NM, Kim JH, Kim KS, Kim SN. Parenteral fish-oil containing lipid emulsions may reverse parenteral nutrition-associated cholestasis in neonates: a systematic review and meta-analysis. J Nutr. 2015;145:277–83

    Article  Google Scholar 

  22. Hsiao CC, Lin HC, Chang YJ, Yang SP, Tsao LY, Lee CH, Chen HN, Chen JY, Tsai YG. Intravenous fish oil containing lipid emulsion attenuates inflammatory cytokines and the development of bronchopulmonary dysplasia in very premature infants: a double-blind, randomized controlled trial. Clin Nutr. 2018;18:1–8

    Google Scholar 

  23. Calkins KL, Venick RS, Devaskar SU. Complications associated with parenteral nutrition in the neonate. Clin Perinatol. 2014;41:331–45

    Article  Google Scholar 

  24. Shaheen AA, Myers RP. Diagnostic accuracy of the aspartate aminotransferase-to-platelet ratio index for the prediction of hepatitis C-related fibrosis: a systematic review. Hepatology. 2007;46:912–21

    Article  Google Scholar 

  25. Jin W, Lin Z, Xin Y, Jiang X, Dong Q, Xuan S. Diagnostic accurary of the aspartate aminotransferase to platelet ration index for the prediction of hepatitis B-related fibrosis: a leading meta-analysis. BMC Gastroenterol. 2012;12:14

    CAS  Article  Google Scholar 

  26. Bang CS, Kang HY, Choi GH, Kim SB, Lee W, Song IH. The performance of serum biomarkers for predicting fibrosis in patients with chronic viral hepatitis. Korean J Gastroenterol. 2017;69:298–307

    Article  Google Scholar 

  27. Kruger FC, Daniels CR, Kidd M, Swart G, Brundyn K, van Rensburg C, Kotze M. APRI: a simple bedside marker for advanced fibrosis that can avoid liver biopsy in patients with NAFLD/NASH. S Afr Med J. 2011;101:477–80

    CAS  PubMed  Google Scholar 

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This work was supported by a grant from Research year of Inje University in 20180018.


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We declare that the important data supporting the conclusions of this article are mostly described within the article, and the database is available from the corresponding author ( on reasonable request.

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JH was involved in the concept and design of the study and acquisition of the data. JH and MC collected data, performed the statistical analysis and interpret the data. MC participated in all steps of the study design, acquisition of data, and analysis and interpretation of the data. All authors approved the final version of the manuscript and made substantial contributions to all of the following: (1) the conception and design of the study, or acquisition of data, or analysis and interpretation of data, (2) drafting the article or revising it critically for important intellectual content, (3) final approval of the version to be submitted.

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Correspondence to Mi Lim Chung.

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This study was approved by institutional review board (IRB) of Inje University Haeundae Paik Hospital. The purpose of this study is to analyze the medical records of infants who have been discharged from the hospital and because of the lack of any artificial intervention in the diagnosis and treatment of the patients, consent to participates were not applicable. And it was waived the need for consent by IRB of Inje University Haeundae Paik Hospital.

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Hwang, J.H., Chung, M.L. Predictive value of the aspartate aminotransferase to platelet ratio index for parenteral nutrition associated cholestasis in extremely low birth weight infants. BMC Pediatr 19, 126 (2019).

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  • Aspartate aminotransferase to platelet ratio index
  • Parenteral nutrition
  • Parenteral nutrition-associated cholestasis
  • Extremely low birth weight infants