Title: Hepatic function tests in babies with perinatal asphyxia: can it predict hypoxic
ischemic encephalopathy?
Abstract
Objective:
Different organ systems of the body are affected in perinatal asphyxia. Here hepatic
function was tested in full term appropriate for gestational age (AGA) newborn babies after
perinatal asphyxia and its relation with severity of hypoxic ischaemic encephalopathy (HIE)
was assessed.
Study design:
62 full term AGA asphyxiated newborns as cases and 62 apparently healthy newborns
as control group were studied. Serum glutamate pyruvate transaminase (SGPT), serum
glutamate oxaloacetate transaminase (SGOT) ,alkaline phosphatase (ALP), gamma glutamyl
transferase (GGT), total protein, albumin, total & direct bilirubin and prothrombin time were
analyzed on 3rd day of life using validated methods and compared between two groups.
Results
Liver enzymes and prothrombin time is higher in cases compared to control group.
SGPT,SGOT and P.time showed significant relation with severity of HIE. SGPT is most
significantly related.
Conclusion :
Liver function tests specially SGPT can help in diagnosis of hepatic damage in perinatal
asphyxia specially those having encephalopathy and also in retrospective diagnosis of
perinatal asphyxia in those without availability of proper birth history.
Key words: Perinatal asphyxia, Hepatic function tests, HIE (hypoxic ischemic
encephalopathy).
Introduction:
Perinatal asphyxia (PNA) is a major cause of mortality and long term morbidity among
newborn infants in developing countries like India. WHO (Organizaton, 1996) has defined
perinatal asphyxia as “failure to initiate and sustain breathing at birth”. If lung expansion
does not occur in the minutes after birth, a progressive cycle of hypoxia, hypercapnia and
acidosis evolves. During hypoxia, series of protective mechanisms collectively called as
‘diving sea reflex’ attempt to redistribute available blood flow to some vital organs like brain,
heart, and adrenals in preference to perfusion of the lungs, liver, kidneys, and intestine
(Tarcan et al., 2007). Ultimately it results in serious organ damage and multiorgan failure.
Central nervous system dysfunction associated with perinatal asphyxia is referred to as
Hypoxic ischemic encephalopathy (HIE). HIE is of foremost concern in an asphyxiated
neonate because of its potential to cause serious long-term neuromotor sequelae among
survivors. The aim of our study is to determine the degree of hepatic damage in perinatal
asphyxia and to relate the hepatic function changes with severity of HIE as determined by
Sarnat and Sarnat staging.
Materials and methods:
Study Setting : A cross sectional study has been done in the Department Of Biochemistry and
neonatal intensive care unit and nursery in the Department of Pediatric Medicine, R. G. Kar
Medical College and Hospital, Kolkata between May 2012 to August 2013.Prior ethical
permission was obtained from institutional ethical committee.A study group of 62 full term
(37weeks to 42 weeks of gestational age) newborn babies having birth weight more than or
equal to 2.5 kg(appropriate for gestational age) with perinatal asphyxia and another control
group of 62 matched healthy newborns were studied. Their hepatic function tests were done
from venous blood sample on day three of life and parameters were studied.
Inclusion Criteria was any one or more than one of the following: ( 1) Apgar score less than
or equal to 6 at 5 minutes after birth (2). History of delayed crying or not crying at all after
birth. (3) History of failure to breathe spontaneously immediately after birth. (4) History of
any resuscitation procedure needed to sustain life after birth.
Exclusion Criterias were (1) newborn babies having birth weight less than 2.5kg both preterm
and small for gestational age (2) Septicemia, (3) Suspected metabolic disease (4) Obvious
congenital anomalies (5) History of any drug intake by mother which is known to cause
hepatic function alteration.
Methods of study of different parameters:
SGPT estimation :(Mod.IFCC method) (Bergmeyer et al., 1986b). SGPT catalyses transfer
of amino group between L-alanine and alpha-ketoglutarate to form pyruvate and glutamate.
The pyruvate formed reacts with NADH in presence of lactate dehydrogenase to form NAD.
The rate of oxidation of NADH to NAD is measured as a decrease in absorbance which is
proportional to the SGPT activity in serum sample.
SGOT estimation (Mod IFCC method): (Bergmeyer et al., 1986a) SGOT catalyses the
transfer of amino group between L-aspartate and alpha keto glutarate to form oxaloacetate
and glutamate. The oxaloacetate formed reacts with NADH in presence of malate
dehydrogenase to form NAD. The rate of oxidation of NADH to NAD is measured as a
decrease in absorbance which is proportional to the SGOT activity in serum.
Alkaline phosphatase estimation: (Pnpp kinetic method) (McComb and Bowers, 1972,
1972) ALP in an alkaline pH hydrolyses para nitrophenylphosphate to form p-nitrophenol
and phosphate. The rate of formation of p- nitrophenol is measured as an increase in
absorbance which is proportional to the ALP activity in serum sample.
Gamma Glutamyl Transferase estimation:(Carboxy substrate method) (Bergmeyer et al.,
1986a) GGT catalyses the transfer of amino group between L-γ-glutamyl-3-carboxy-4
nitroanilide and glycyglycine to form L-γ-glutamylglycyglycine and 5-amino -2nitrobenzoate.Rate of its formation is measured as an increase in absorbance which is
proportional to the GGT activity in the sample.
Total protein (Biuret method ) (Gornall et al., 1949, Doumas, 1975)
Proteins in an alkaline medium bind with cupric ions present in the biuret reagent to form a
blue violet coloured complex. The intensity of colour formed is directly proportional to the
amount of protein present in the sample.
Albumin estimation (BCG method):(Doumas et al., 1971) Albumin binds with the dye
Bromocresol Green to form a green coloured complex. The intensity of colour is directly
proportional to the amount of albumin present in the sample.
Total and direct bilirubin (by Diazo method) (Pearlman and Lee, 1974, Row, 1974)
Bilirubin reacts with diazotized sulphanilic acid in acidic medium to form pink coloured
azobilirubin with absorbance directly proportional to bilirubin concentration. Direct bilirubin
being water soluble directly reacts in acidic medium. Indirect or unconjugated bilirubin is
solubilised using a surfactant and then it reacts similar to direct bilirubin.
Prothrombin time: (using tissue thromboplastin) (L, 1998, CLSI, 2008)
Coagulation process is triggered by incubation of plasma with the optimal amount of
thromboplastin and calcium. The time to formation of fibrin clot is then measured.
Method: 1 part of sodium citrate solution (0.11mol/L or 3.2%) and 9 parts of venous blood is
mixed carefully avoiding formation of foam. The specimen is centrifuged at 1500g for 15
minutes at room temperature.100 µl of supernatant is taken as sample. 200µl of reagent is
prewarmed at 37°C in automated coagulation analyzer. Sample is also incubated for 1 minute
at 37°C. Reagent is added to the sample and time of the automated coagulation analyzer is
started. After the fibrin clot is formed it showed the time which is the prothrombin time.
Instrument used were Centrifuge Machine (REMI R-8C, REMI COOLING CENTRIFUGE)
Semi auto-analyser( ERBA Chem 5), autoanalyser (ERBA–Mannheim XL-600) and
automated coagulation analyser (Sysmex CA-50 ). Calculation was done by independent‘t’
test, analysis of variance study, post hoc test (bonferroni ), logistic regression study and ROC
curve analysis with the help of spss 17 software and medcalc software.
Results:
It has been found that SGPT,SGOT,ALP, GGT and P.time is significantly raised in cases
compared to controls (p value ˂0.001) but no significant difference was found in case of
total protein, albumin, total and direct bilirubin. By analysis of variance study,it was found
that SGPT,SGOT is significantly raised with stages of HIE (p value˂0.001). P.time is also
raised but less significantly than SGPT and SGOT (p value = 0.018)(Table 2 ). The relation
of SGPT, SGPT and P.time between different stages of HIE has been more precisely detected
by bonferroni test (Table3, Table 4 & Table 5). But in logistic regression analysis, only in
SGPT, p is less than conventional 0.05 (Table 6) that is SGPT contributes significantly to the
prediction of the dependent variable (HIE). In ROC curve analysis for SGPT, the area under
the curve is 0.841 which is between 0.5 (discriminating power not better than chance) to 1.0 (
perfect discriminating power (Table7). From coordinates of the curve, it is being seen that if
we take serum SGPT value as 72.5 IU/L as cut off value between cases with no hypoxic
ischemic encephalopathy and encephalopathy , it has sensitivity of 84 % and specificity of (1.222) x100 =78 % (Table 8 ).
Discussion
In the neonatal intensive care unit one of the leading causes of neonatal morbidity and death
is perinatal asphyxia. It often results in multiple organ dysfunction including hypoxicischemic encephalopathy (HIE) and the infants with moderate and severe HIE have higher
risk of developing cerebral palsy (CP) and other long-term neurological sequel and may even
cause early death .The multiple organ dysfunction phenomenon is mechanistically related to
the ‘diving reflex’ , the reflex activated by asphyxia, consists of shunting of blood from the
skin and splanchnic area to the heart, adrenal glands and brain, to protect these vital organs
from hypoxic ischemic injury (Bocking et al., 1988, Peeters et al., 1979, Sheldon et al., 1979,
Jensen et al., 1999).
Thus, due to this, it is likely that each neonate with clinically detectable heart or brain
dysfunction resulting from intrapartum asphyxia would already have dysfunction of one or
more organs other than heart, brain or adrenal gland, particularly kidney and liver.
In our study, 62 full term appropriate for gestational age (AGA) newborn babies with
perinatal asphyxia fulfilling inclusion and exclusion
criteria were chosen as cases and
another 62 full term AGA apparently healthy matched newborns were chosen as controls.
Birth weight ± SD of the study group was 2.80±0.27 Kg and that of the reference group was
2.75± 0.28 Kg (difference not significant as p value = 0.249). Among the 62 asphyxiated
patients 18 (29.03%) babies did not develop encephalopathy, 16 babies (25.80% ) were in
HIE Stage-I, 17 babies ( 27.41% ) in HIE Stage- II and 11 babies (17.74%) in HIE Stage-III.
Mother’s mean age in case group was 24.26 ± 3.2 years and in control group was 23.26 ±
2.89years and there was no significant difference between these two groups (p value =
0.071).
In all cases and controls, liver function tests were done on day 3 of life. Beckett gj et al in a
study done in Edinburgh in 1989, showed no significant change in serum SGPT level
during initial 24 hours period after birth with perinatal asphyxia, but after 24 hours, SGPT
increased significantly (p<0.01) reaching peak median values of 2.1 times the upper limit of
reference interval by 48 hrs postpartum (Beckett et al., 1989) The plasma half life of SGPT is
~ 48 hrs. In another study done by Martín-Ancel A et al, the Apgar scores at 1 and 5 minutes
were the only perinatal factors related to the number of organs involved and the severity of
involvement; the Apgar score at 5 minutes had the stronger independent association (MartinAncel et al., 1995). Any score lower than 7 is a sign that the baby needs medical attention.
Considering these facts , study of LFT was done on 3 rd day of life in babies with 5 minute
Apgar score of 6 or less .
In our study, it has been seen that mean ± standard deviation of some liver function
parameters like SGPT, SGOT, ALP, GGT and prothrombin time are higher in cases
compared to control group (p value of
≤0.001)(Table 1). Serum total protein and albumin
level were not statistically significantly related with stages of HIE. (p=0.934 and 0.258
respectively (Table 1). The value of SGPT , SGOT and P. time also showed significant rise
with increasing severity of HIE as demonstrated by analysis of variance test and post hoc
test .( showed ‘t’ values of ˂0.001, ˂0.001 and ˂0.005 respectively) (Table 2, Table 3, Table
4 & Table 5). SGPT is most significantly related as seen by logistic regression analysis (table
6). Now we determined the value of serum SGPT which can be used as a cut off value with
highest sensitivity and specificity. SGPT value of 72.5 IU/L can be used as a cut off value
(with a sensitivity
84%
and specificity 78% to differentiate between babies without
encephalopathy and with encephalopathy following perinatal asphyxia (Table 8).
Similar results were obtained by Godambe et al .The mean SGPT levels was noted to increase
from 35.3 ± 28.8 IU/L in mild asphyxia to 65.6 ± 33.2 IU/L in severe asphyxia (Godambe et
al., 1997). Similar results were observed by other workers who noted a rise from 44 ± 61.9
IU/L in mild to 59.5 ± 108 IU/L in severe asphyxia (Saili A, 1990, Zanardo V, 1985, Beckett
et al., 1989). Karlsson et al suggested that there was a correlation existing between the
magnitude of elevation of SGPT, SGOT and the severity of the hypoxic event (Karlsson et
al., 2006). In our study also significant rise was found in case of SGPT (p value˂0.001),
SGOT (p value˂0.001) and prothrombin time (p value˂0.005) with severity of HIE (Table 2).
In our study no difference was found between cases and controls in the values of serum total
protein, albumin, serum total and direct bilirubin (Table 1). They also did not show
statistically significant change with different stages of HIE (Table 2 ). But prothrombin time
is significantly different between cases and controls (p value ˂0.001) (Table 1) and also has
significant relation with stages of HIE (p value ˂0.005) (Table 2). Similarly, in one study,
prothrombin index [PI =(mean p.time/patient’s prothrombin time) x 100%] was reduced in
all grades of asphyxia (Godambe et al., 1997) and similar observations of altered liver
dependent coagulation parameters were observed by others (Zanardo V, 1985, Bhargava et
al., 1978, Dube et al., 1986).
In the initial period of perinatal asphyxia, the blood flow to brain, heart and adrenal glands of
the newborn is preserved at the expense of reduction of perfusion to kidneys, lungs, gastrointestinal tract, liver, spleen and skeletal muscles. In case of liver asphyxia, cell death occurs
by necrosis or apoptosis. One of the earliest hepatocellular changes in hypoxia is the
formation of plasma membrane protrusions called blebs. These early changes are reversible.
Irreversible injury occurs when a plasma membrane bleb bursts, causing abrupt failure of the
plasma membrane permeability barrier. There is collapse of all electrical and ionic gradients
across the plasma membrane and release of intracellular enzymes and metabolites occur.
There is leakage of cytoplasmic enzymes from cell, but minimal release of other enzymes.
Thus necroinflammatory change in liver leads to release of SGOT and SGPT but not of
mitochondrial isoenzyme of SGOT nor to release of ALP or GGT .This might be the cause of
comparatively less increase of serum SGOT value than SGPT. In perinatal asphyxia also,
rise in transaminases indicative of liver cell dysfunction is either due to hepatocyte necrosis
or due to changes in cell permeability (Beckett GJ, 1986). The mechanism of release of
membrane bound enzyme such as GGT and ALP into the circulation is less well understood.
Serum albumin measurements are useful in assessing the chronicity and severity of liver
disease. It is the most commonly used serum protein and is produced exclusively by liver
.Hypoproteinemia is an imprecise index of the severity of liver damage due to the long life of
serum protein (AP, 1979). In our study also, serum total protein and albumin levels were not
statistically significantly related with stages of HIE. No significant difference was found in
level of serum bilirubin between cases and controls and total serum bilirubin did not show
statistically significant change with different stages of HIE. It is probably due to presence of
physiological jaundice in newborns both in cases and controls.
In our study P.time also is significantly different between cases and controls (p value ˂0.001)
and also has significant relation with stages of HIE (p value ˂0.005). The prothrombin time
(PT) measures of extrinsic pathway of coagulation. This test measures factors I (fibrinogen),
II (prothrombin), V, VII, and X. Since all these factors are made in the liver; a prolonged PT
often indicates the presence of significant liver disease.
Perinatal asphyxia remains a cause of significant morbidity and mortality in newborns despite
advances in knowledge of neonatal physiology and improvement in newborn rescucitation
procedure. According to the literature, the incidence of HIE varies between 0.1-0.4% of
births, with diagnosis being essentially clinical (Hughes and Newton, 1992). In addition to
clinical features, some markers of birth asphyxia is necessary for proper monitoring and
management. Radiological markers are helpful to some extent, but not always easily possible.
Single or combination of biochemical markers may be helpful in this respect. They may help
in knowing multiorgan involvement. Several biomarkers of birth asphyxia have been studied.
Here we have studied different liver function parameters to see if their values are altered or
not in case of perinatal asphyxia. In our study, it has been seen that value of SGPT, SGOT
and P.time showed significant rise with increasing severity of HIE (showed ‘t’ values of
˂0.001, ˂0.001 and ˂0.005 respectively). SGPT is most significantly related as seen by
logistic regression analysis. SGPT value of 72.5 IU/L can be used as a cut off value (with a
sensitivity
84%
and specificity 78%) to differentiate between babies without
encephalopathy and with encephalopathy following perinatal asphyxia.
We can conclude that the determination of serum SGPT could offer a routine and rapid
laboratory test for establishing the presence of hepatic cellular damage following perinatal
asphyxia. They may help in modification of ongoing treatment. It will also help in
retrospective diagnosis of perinatal asphyxia mainly those leading to encephalopathy;
especially in those newborns whose birth records are not available.
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Tables
Table 1: Mean of different LFT parameters in birth asphyxia cases and controls and their
comparison
CONTROL
CASE
PARAMETER
t value
p value
(Mean±SD)
(Mean±SD)
SGPT
37.12±16.80
100.85±50.14
9.488
˂0.001
SGOT
70.69±32.65
147.90±68.79
7.983
˂0.001
134.30±60.32
239.00±113.04
6.433
˂0.001
GGT
71.53±29.60
116.45±57.0
5.505
˂0.001
Total protein
6.03±1.22
5.68±1.14
-1.606
0.111
Albumin
3.34±0.74
3.39±0.80
0.364
0.716
Total bilirubin
7.81±2.90
6.90±3.28
1.644
0.103
Direct bilirubin
1.38±0.45
1.33±0.62
0.478
0.634
13.12±1.92
15.37±2.90
5.086
˂0.001
Alkaline
Phosphatase
Prothrombin
time
Table 2: Relation of different LFT parameters with stages of HIE
(by analysis of variance study)
LFT parameters
F value
Significance(p value)
SGPT
18.596
˂0.001
SGOT
14.517
˂0.001
ALP
1.752
0.166
GGT
1.189
0.322
TP
0.453
0.716
ALB
0.371
0.774
Total bilirubin
1.884
0.142
Direct bilirubin
1.062
0.372
P.time
3.616
0.018
Comparison with other
Dependent Variable
Stages of HIE
stages
Significance
SGPT
HIE Stage 1
0.896
HIE Stage 2
˂.001
HIE Stage 3
˂.001
HIE Stage 2
0.025
HIE Stage 1 with
HIE Stage 3
˂.001
HIE Stage 2 with
HIE Stage 3
0.044
No encephalopathy with
Table 3: Multiple comparison of serum SGPT levels between different stages of HIE by
Post Hoc Test (Bonferroni)
Table 4: Multiple comparison of serum SGOT between
different stages of HIE by Post Hoc Test (Bonferroni)
Table 5: Multiple comparison of Prothrombin time levels
between different stages of HIE by Post Hoc Test
(Bonferroni)
Comparison
Dependent
Variable
with other
Stages of HIE
stages
Significance
HIE Stage 1
1
HIE Stage 2
0.02
HIE Stage 3
0.287
HIE Stage 2
0.23
HIE Stage 3
1
HIE Stage 3
1
No
encephalopathy
P. time
Comparison
Dependent
Variable
with
with other
Stages of HIE
stages
Significance
HIE Stage 1
with
HIE Stage 1
1
HIE Stage 2
No
HIE Stage 2
0.001
HIE Stage 3
˂.001
HIE Stage 2
0.004
HIE Stage 3
˂.001
with
encephalopathy
SGOT
with
HIE Stage 1
with
by Logistic regression analysis
HIE Stage 2
with
Variable
Table 6 : Coefficients and Standard Errors
HIE Stage 3
0.408
Coefficient
Std. Error
P
SGPT
0.028854
0.012839
0.0246
SGOT
0.010464
0.0086035
0.2239
P.Time
0.14155
0.13478
0.2936
Constant
(-) 4.9089
Table 7 : ROC curve analysis and Area Under the Curve
Test Result Variable(s):SGPT
Asymptotic 95% Confidence Interval
Area
0.841
Std. Error Asymptotic Sig.
0.055
0.000
Lower Bound
Upper Bound
0.733
0.949
Table 8 : Coordinates of the Curve (Test Result Variable : SGPT)
Positive if
Greater Than
Sensitivity
1 - Specificity
60
0.864
0.389
65.5
0.841
0.333
68
0.841
0.278
72.5
0.841
0.222
76
0.727
0.167
78.5
0.705
0.167
or Equal To
81
0.659
Figure:
Figure 1: Pictorial presentation of ROC curve
0.167