Abstract
Background
Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤40 IU/L is normal. This cutoff, although determined in adults, is widely used for newborns. We studied the reference ranges for ALT and AST in newborns in India.
Methods
We prospectively included babies with gestational age (GA) between 34 and 41weeks and birth weight (BW) ≥ 1500 g. We excluded the babies who either themselves or their mother had risk factors, which could cause elevation of serum levels of liver enzymes. Serum ALT and AST were measured in venous cord blood. The estimated percentile curves for ALT and AST, for BW and GA covariates, were drawn with General Additive Model for Location Scale and Shape (GAMLSS) with Box–Cox Power Exponential (BCPE).
Results
Five-hundred thirty-seven babies (Boys 53.3%; GA 34–36 wks 19.7%; appropriate for GA 74.9%; BW < 2500 g 20.5%) were included. Overall, mean [SD] serum ALT and AST were 4412 IU/L and 5218 IU/L, respectively. The serum AST was significantly higher than the ALT level, regardless of gender, BW, GA, or fetal growth categories. The percentile curve against GA remained flat for ALT, although it showed a slight rise for AST. Serum levels of ALT and AST plotted against BW were also similar and showed an increase up to 2000 g and then remained stationary after that.
Conclusion
The serum levels of ALT and AST up to 44 IU/L and 52 IU/L, respectively, can be taken as normal in newborns with BW ≥ 2000 g or GA ≥34 weeks.
Keywords: alanine aminotransferase, aspartate aminotransferase, liver enzymes, liver injury, newborns
Abbreviations: AFD, Appropriate for date; ALT, Alanine aminotransferase; AST, Aspartate aminotransferase; BCPE, Box–Cox Power Exponential; BW, Birth weight; GA, Gestational age; GAMLSS, General Additive Model for Location Scale and Shape; LFD, Large for date; SFD, Small for date; ULN, Upper limit of normal
Introduction
Liver cells, the hepatocytes, have high metabolic activity and play an important role in maintaining normal homeostasis in the human body. Hepatocytes contain several enzymes, and a few of them are measured in serum to assess the liver injury. Alanine aminotransferase (ALT), present in cytosol, and aspartate aminotransferase (AST), predominantly present inside the mitochondria, are the two most common liver enzymes, which are measured in serum.1
Regardless of its cause or nature, injury to the hepatocytes results in the release of these enzymes in serum. Hence, the serum levels of ALT and AST are the surrogate markers of liver injury.2,3. Their serum levels are used in patients with liver diseases for diagnosis, disease severity assessment, determination of optimum treatment, monitoring of treatment response, and prognosis assessment.4 Hence, the serum levels of ALT and AST are frequently measured in patients with suspected or proven liver diseases.
Liver injury is common in newborns with birth asphyxia,5 sepsis, pathological jaundice, multiorgan dysfunction syndrome, drug-induced liver injury, and metabolic liver diseases.6 An abnormal result of laboratory parameters, including serum transaminase levels, are read in the context of normal ranges. Hence, we need to know the normal ranges of ALT and AST to interpret their values accurately. The upper limit of normal (ULN) serum transaminases are 40 IU/L. This cutoff was determined in the 1950s and was based on the serum enzyme levels in blood specimens collected from the healthy adult population.7
The same cut off of 40 IU/L is used for assessing the liver injury in newborns without validation in them. It seems an oversimplification to apply the adults’ reference in newborns. This extrapolation for the newborns is partly because of the lack of literature on reference values for the newborn. We studied the normal range for ALT and AST in the cord blood of newborns of Indian origin.
Methods
This prospective, observational, single-arm study was conducted between July 2016 and June 2018 in the Department of Pediatrics, ERA’s Lucknow Medical College, Lucknow, India. We screened the singleton deliveries conducted in our institute for eligibility criteria. All the babies, who had estimated gestational age (GA) between 34 and 41 completed weeks and birth weight ≥1500 g, were considered for inclusion. The babies were excluded in the presence/suspicion of any major congenital anomaly, maternal sepsis, birth asphyxia, an inborn error of metabolism, congenital infections, hemolytic condition, hemorrhagic shock, and primary hepatobiliary diseases. We also excluded the babies born to the mothers with pregnancy-induced hypertension, jaundice during pregnancy, HBsAg or anti-HCV or HIV positive status.
The GA of the babies was estimated with a combination of maternal recall of last menstrual period, biometric parameters on fetal ultrasound, and neonatal Ballard score within 1 h of birth.8 If the estimated GA included an incomplete week, ≤3 days were not counted, and those with 4–6 days were counted as a complete week. Fetal growth of enrolled babies was categorized as small for dates (SFD, BW < 10th centile for GA), appropriate for dates (AFD, BW between 10th and 90th centile for GA), and large for dates (LFD, BW > 90th centile for GA).9
A pediatrician attended all the deliveries. Following required resuscitation, 2–3 ml of venous blood was collected from the umbilical cord from eligible babies and transferred to the central laboratory for serum separation and enzyme estimation. All serum samples were analyzed in the central clinical laboratory of the hospital. The enzyme estimations were done with Erba Mannheim (Germany) autoanalyzer using the International Federation of Clinical Chemistry (IFCC). The normal range of measurements was 0–35 IU/L for AST and 0–45 IU/L for ALT. The performance of the assay was linear for the measurement for serum ALT and AST enzymes up to 450 IU/L. The range of measurement by assay was 0–450 IU/L.
The study was approved by institution’s ethics committee, and written informed consent was obtained from either of the parents or legal guardians of the babies before enrollment.
Statistical Analysis
Numerical data are expressed as mean with standard deviation (SD), while categorical variables are expressed as ratio and proportions. Percentile curves for ALT and AST were estimated using BW and GA as a covariate using General Additive Model for Location Scale and Shape (GAMLSS) with Box–Cox Power Exponential (BCPE) distributions in GAMLSS package. We preferred BCPE over LMS as our data has higher kurtosis in comparison to normal data.10,11 We modeled the four parameters for ALT and AST (l, r, m, and s) as a function of BW and GA by using a log link function. These functions may be interpreted as relating to location (median), scale (centile-based coefficient of variation), skewness (power transformation to symmetry), and kurtosis (degrees of freedom), respectively. We calculated the 5th, 25th, 50th, 75th, and 95th centiles curves for ALT and AST. Smooth percentile curves show the distribution of a measurement as it changes according to covariate. One of the most useful examples of smoothed percentile curves is WHO growth charts.
The optimum sample size of 400 is suggested in the literature for the calculation of all parameters in LMS and BCPE; further, we used a design effect of 1.3 and estimated the required sample size as 520.12 Categorical data and numerical data were analyzed using the Chi-square test and t-tests, respectively. For a two-tailed hypothesis, statistical significance is considered at a P-value <0.05. The data were analyzed with STATA version 16.0 and R version 3.6.3.
Results
Of the 1550 deliveries, 537 newborns (34.6%) were included in the final analysis. The reason for exclusion of 1013 babies were GA <34 weeks or >41 weeks (n = 210), BW < 1500 (n = 112), maternal sepsis (n = 134), multiple gestation (n = 51), birth asphyxia (n = 112), meconium aspiration syndrome (n = 75), maternal infection with hepatitis B virus or hepatitis C virus or HIV (n = 46), congenital infection of baby (n = 23), congenital anomaly (n = 12), or nonavailability of cord blood (n = 238). The gestational, maternal, perinatal, and neonatal data of the babies are given in Table 1. The serum ALT and AST in the overall cohort were 4412 IU/L and 5218 IU/L, respectively. The data on mean serum level of AST and ALT in various subgroups of the babies are given in Table 2. The serum levels of AST were higher than ALT regardless of gender, BW, GA, or fetal growth categories (Table 2). The serum levels of ALT or AST were not influenced by the mode of delivery, gender, GA, BW, and fetal growth categories of the baby (Table 2; all P values >0.05).
Table 1.
Details of the Mothers and Their Babies Included in Study.
| Characteristics | Number | |
|---|---|---|
| Maternal age (y) | 25.9 | (3.6) |
| Gestational age (weeks) | ||
| 34–36 | 106 | (19.7) |
| 37–41 | 431 | (81.3) |
| Birth weight of the baby | ||
| 1500–2499 | 110 | (20.5) |
| ≥2500 | 427 | (79.5) |
| Mode of delivery | ||
| Normal vaginal | 273 | (50.8) |
| Caesarean section | 264 | (49.2) |
| Gender | ||
| Boys | 286 | (53.3) |
| Girls | 251 | (46.7) |
| Fetal growth category | ||
| Small for date | 105 | (19.6) |
| Appropriate for date | 402 | (74.8) |
| Large for date | 30 | (5.6) |
| Maternal age (y) | 25.9 | 3.6 |
Categorical data are expressed as numbers (%) and numerical data are expressed as mean (standard deviation, SD).
Table 2.
Serum Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) Levels in Newborns According to Gender, Gestational Age, and Fetal Growth Category.
| Characteristics | Serum ALT (IU/L) |
Serum AST (IU/L) |
||||
|---|---|---|---|---|---|---|
| Mean (SD) | 5th–95th percentile | Mean (SD) | 5th–95th percentile | |||
| Mode of delivery | ||||||
| Vaginal | 44 | (12) | 30–69 | 53 | (18) | 32–82 |
| Caesarean section | 44 | (12) | 28–65 | 52 | (17) | 31–82 |
| Gender | ||||||
| Boys | 45 | (13) | 30–70 | 54 | (20) | 32–92 |
| Girls | 43 | (11) | 28–63 | 51 | (15) | 32–78 |
| Gestational age (weeks) | ||||||
| 34–36 | 43 | (14) | 29–62 | 51 | (16) | 32–74 |
| 37–41 | 44 | (12) | 29–69 | 53 | (18) | 32–85 |
| Birth weight | ||||||
| 1500–2499 | 44 | (13) | 29–71 | 51 | (16) | 32–78 |
| ≥2500 | 44 | (12) | 29–67 | 53 | (18) | 32–82 |
| Fetal growth category | ||||||
| Small for date | 44 | (12) | 28–68 | 53 | (17) | 31–86 |
| Appropriate for date | 44 | (12) | 30–68 | 52 | (18) | 32–82 |
| Large for date | 42 | (13) | 24–71 | 51 | (21) | 30–105 |
Data are expressed as mean (standard deviation).
The smoothened percentile curves for serum ALT (Figure 1a and c) and AST (Figure 1b and d) were plotted against GA and BW, respectively. The percentile curve for ALT against GA remained flat, and its serum levels did not change with increasing gestational age (Figure 1a). A similar percentile curve for AST against GA showed a slight but parallel rise in its serum level (Figure 1b), and its value peaked at about 40 weeks. The serum level of ALT and AST plotted against BW were also similar. They showed a relatively sharp increase up to 2000 g of BW and then remained stationary after that (Figure 1c and d).
Figure 1.
The smoothened 5th, 25th, 50th, 75th, and 95th percentile curves for serum alanine aminotransferase (a and c) and aspartate aminotransferase (b and d) plotted against gestational age and birth weight, respectively.
Of the 537 babies, 371 (69.1%) had BW ≥ 2500 g and GA ≥ 37 weeks. The mean (5th–95th percentile) serum ALT and AST levels in selected babies were 44 (30–68) IU/L and 53 (32–83) IU/L, respectively.
Discussion
This study provided data on serum levels of ALT and AST in cord blood of 537 newborns with GA ≥34 weeks and BW ≥ 1500 g. Most of the babies were AFD. We attempted to analyze the effect of GA and BW on serum levels of ALT and AST. Regardless of GA or BW, the serum level of AST was higher than ALT. The AST level showed a slight, although a consistent increase in serum level with increasing GA. When plotted against BW, the enzyme levels have reached the highest levels at around BW of 2000 g and then remained static after that. The mean serum levels of ALT and AST were at 44 IU/L and 52 IU/L, respectively for the babies with BW ≥ 2000 g and GA ≥ 34 weeks.
Serum levels of transaminase enzymes are the sensitive and specific markers of liver injury. The serum enzyme levels are affected by several common factors such as age, body weight, diet, exercise, and ethnicity.13 For the last several decades, the ULN for ALT and AST have been pegged at ≤40 IU/L, regardless of these influencing factors. It seems inappropriate to apply these reference levels for newborns because of their following inherent limitations (i) they were computed in the 1950s7 when the laboratory techniques were very crude and less sensitive as compared to the present era (ii) it was derived from the specimens collected from an adult population who were not screened for common causes of deranged LFT such as hepatitis C virus14 or fatty liver disease15,16 (iii) recently, normal serum ALT levels for adults has been revised to 30 IU/L for men, and 19 IU/L for women17 in Europe and several other countries such as China,18 Japan,19 Korea,20 including India21 (iv) separate reference ranges have been reconciled for adolescence22 and pediatric age groups23 (v) serum level of gamma-glutamyl transferase (GGT), another commonly measured liver enzyme, were found to be very different in cord blood than those in the healthy adult population.24
These facts force us to ponder upon a separate “reference range of transaminases” for newborns. The data on newborns is extremely limited at present. Only three studies have attempted to look at the serum transaminase in preterm,25 healthy full-term babies,26 or intrauterine growth-retarded babies.27
Victor et al retrospectively analyzed the serum ALT and AST of the preterm (corrected GA between 23 and 36 weeks) newborns in the United Kingdom and found that the median value of serum AST was reduced with the increasing corrected GA, but serum ALT remained unchanged. The data from this study had a few limitations, as it was a retrospective study and included babies admitted in neonatal intensive care units, and the median age at the time of blood test was 13 days. Hence, more data are needed to estimate the correct serum ALT and AST in preterm babies.25 A study from Ethiopia, which included term babies with BW > 2500 g and found a reference interval for ALT as 1.2–23.1 IU/L.26 A German study has established the neonatal reference range for cord blood ALT and AST in a large group of healthy term newborns.27 In this study, the mean (5th–95th percentile) values for ALT and AST in umbilical venous blood in babies with 37 weeks of GA were found as 4.5 (2.4–8.4) IU/L and 30.5 (22.5–41.4) IU/L, respectively. The lower reference range, as compared to our study, identified in both the previous studies26,27 may be due to the effect of ethnicity as ALT and AST levels are known to vary between the races.
The Indian data on serum ALT and AST in newborns are extremely limited. A single study of 100 full-term babies was published more than a half-century ago28 and found a mean (SD) of ALT and AST as 56 (27.2) and 100.1 (20.5) units/ml. All the studies, Indian or abroad, have found serum AST to be more than ALT. Previous Indian study28 had also found a markedly high ALT and AST as compared to the levels shown from German27 and Ethiopian data.26
This is the first study from India, which assessed the serum transaminase levels in cord blood and has revealed a few important observations. First, AST levels were higher than ALT, which is in contrast to an adult in whom AST is lower than ALT; higher serum AST was also reported by Victor et al25 and among controls in our previous work.5 Previously, serum specimens of maternal venous blood and umbilical arterial and venous samples, collected at birth and their ALT and AST levels were measured.29 The study showed that AST level was significantly higher in umbilical arterial sample as compared to corresponding venous sample; arterial AST level in newborns was higher than maternal venous level; umbilical arterial and venous ALT levels were comparable to maternal venous ALT levels. These observations suggest that the placenta could be a source of AST and contribute to neonatal serum AST level.29 Second, ALT and AST levels were more influenced by BW than the GA. Third, serum enzyme levels rise sharply and plateau after about 2000 g of BW. Fourth, the serum levels were not affected by gender. Fifth, the mean serum enzyme levels were higher in newborns than the ULN for adults.
The higher serum levels of ALT and AST in newborns, as compared to adults, could have the following explanations, a relatively shorter half-life and high turnover rate of red blood cells in newborns result in hemolysis and release of AST, a proportionately higher weight of the liver in newborns (3.5% of body weight) than adults (2.2% of body weight),30 functional leakiness of hepatocyte cell membrane because of immaturity at birth leading to a higher serum level of liver enzymes.
Our data has a few strengths and limitations as well. This is the first Indian data, which provided serum transaminase levels in cord blood of newborns. The study had a large sample size. The blood specimens for the estimation of serum enzymes were collected from cord blood, which gives the earliest possible opportunity to study the enzyme levels in newborns. However, most of the newborns in our study were AFD; a reasonable proportion was SFD, which is common in our country. This makes the results more generalizable. Our study also had a few limitations as well. First, it was a single-center study that restricted the generalizability of our data for the entire country. We need a multicentric study involving a larger sample size, which shall have representation of the babies from different ethnic and religious backgrounds. Second, a significant proportion of babies in our cohort were either SFD or preterm. The serum levels of liver enzymes are likely to be different among them as compared to term AFD babies.
In conclusion, the serum levels of ALT and AST below 44 IU/L and 52 IU/L, respectively, in newborns with BW ≥ 2000 g and GA ≥34 weeks could be considered as normal.
Ethics clearance
The study was approved by the Ethics Committee of ERA’s Lucknow Medical College, Lucknow, India.
Credit authorship contribution statement
Nanda Chhavi: Conceptualization, Data collection, Data interpretation, First draft, Writing – review & editing, Approval of the final version, Agreement to accountable; Sachi Ojha: Data collection, Formal analysis, First draft, Approval of the final version, Agreement to accountable; Ashish Awasthi: Conceptualization, Study design, Formal analysis, Data interpretation, Critical review and editing, Approval of the final version, Agreement to accountable; Shalimar: Conceptualization, Study design, Data interpretation, Critical review and editing, Approval of the final version, Agreement to accountable; Amit Goel: Conceptualization, Study design, Formal analysis, Data interpretation, Critical review and editing, Approval of the final version, Agreement to accountable.
Conflicts of interest
The authors have none to declare.
Acknowledgement
None.
Funding
None.
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