Q J Med 2013; 106:541546

doi:10.1093/qjmed/hct062 Advance Access Publication 2 April 2013

The predictive value of hospital admission serum alanine

transaminase activity in patients treated for paracetamol
overdose
K. AL-HOURANI, R. MANSI, J. PETTIE, M. DOW, D.N. BATEMAN and J.W. DEAR
From the National Poisons Information Service Edinburgh, Royal Infirmary of Edinburgh,
51 Little France Crescent, Edinburgh EH16 4SA, UK

Address correspondence to Dr J.W. Dear, Consultant Clinical Pharmacologist, Royal Infirmary of Edinburgh,
51 Little France Crescent, Edinburgh EH16 4SA, UK. email: james.dear@luht.scot.nhs.uk

Downloaded from http://qjmed.oxfordjournals.org/ by guest on September 16, 2014

Received 4 January 2013 and in revised form 13 February 2013

Summary
Background: Paracetamol is a major cause of poi-
soning. Treatment decisions are predominately
based on the dose ingested and a timed blood
paracetamol concentration because most patients
present to hospital soon after overdose, before hep-
atotoxicity can be confirmed/excluded using serum
alanine transaminase (ALT). Nonetheless, ALT is
measured at hospital presentation; we investigated
its value in predicting hepatotoxicity.
Methods: From March 2011 to May 2012, patients
admitted to the Royal Infirmary of Edinburgh for
paracetamol overdose treatment were identified.
We determined the value of admission ALT (below
or above our upper limit of normal50 IU/l) at
predicting three endpoints: 1doubling of ALT;
2peak ALT >1000 IU/l; 3peak international
normalized ratio (INR) >2.
Results: From 500 patients, 410 met the entry
criteria; 264 presented within 8 h of overdose, 54
between 8 and 24 h, 53 after 24 h and 39 were stag-
gered ingestions. Admission ALT was increased in
71. For endpoint 1 (ALT doubling), the positive pre-
dictive value (PPV) of admission ALT was 19% [95%
confidence interval (CI) 1230] with a negative pre-
dictive value (NPV) of 98% (95% CI 9699); end-
point 2 (ALT >1000 IU/l: PPV 23% (95% CI 1434)
and NPV 100% (95% CI 99100) and for endpoint 3
(INR >2): PPV 14% (95% CI 725) and NPV of
100% (95% CI 99100). The NPV remained high
when only late presenters were included.
Conclusion: Admission ALT within the normal range
has a high NPV and could be used, alone or in
combination with newer biomarkers, to identify
lower risk patients at hospital presentation.

Introduction the British National Formulary, with need for treat-

Paracetamol (acetaminophen) is the most com-
monly overdosed drug in UK and a leading cause
of acute liver failure in the Western world.1 It
accounts for >40% of poisoning episodes that are
admitted to hospital: 38 000 emergency hospital
admissions in the financial year 201011 in
England alone.2 In UK, guidance on the manage-
ment of paracetamol overdose is available through
resources such as TOXBASE (www.toxbase.org) and
ment being largely determined by the dose ingested
and timed plasma paracetamol concentration.3
With the mechanism of paracetamol hepatotox-
icity extensively investigated, the current mainstay
of treatment available for paracetamol poisoning is
replenishment of cellular glutathione through the
administration of acetylcysteine (AC). Although
early treatment with AC effectively prevents hepato-
toxicity, its efficacy declines if treatment is delayed
>8 h after overdose; patients presenting late to

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542 K. Al-Hourani et al.
hospital are at an increased risk of significant liver
injury.4
It is essential to triage patients presenting with
paracetamol overdose into those in whom hepatic
damage is likely and those in whom it is unlikely.
Such hospital front door stratification would allow
new therapeutic approaches to be targeted at lower
or higher risk groups and increase the likelihood of
clinical trials being successful. At present, a timed
blood paracetamol concentration is measured to
stratify patients into two groups; those needing AC
treatment and those who do not require antidote.
However, a significant proportion of patients are
misclassified as needing treatment as they would
not get liver injury if untreated.5 Furthermore,
within the treated group further stratification could
lead to the AC dose being individualized depending
on risk of liver injury. Although it is rare for a patient
to develop toxicity if their blood paracetamol con-
centration is below the at-risk line on the treatment
nomogram, such cases do occur and have resulted
in potentially avoidable deaths and, therefore, great
concern for both clinicians and medicine regula-
tors.6 Alanine transaminase (ALT) has the potential
to aid treatment decisions at the hospital front
door. In this study, we tested the performance of
serum ALT activity at hospital admission as a
predictor of subsequent injury in a large cohort of
patients who received AC treatment.
Methods
The Edinburgh Clinical Toxicology Unit has a data-
base of all patients admitted to the toxicology
ward at the Royal Infirmary of Edinburgh (RIE), UK,
with excess paracetamol ingestion that required
treatment with intravenous AC. This does not in-
clude patients directly admitted to the Scottish
Liver Transplantation Unit, also based at RIE. This
database was the source of patient identification.
Exclusion criteria were as follows: patients who
did not complete AC treatment; patients whose
bloods were not repeated at end of AC, haemolysed
or had no INR taken. In this study, we have included
patients from March 2011 to May 2012.
The performance of hospital admission serum ALT
activity (greater than the upper limit of our hospitals
normal range, 50 IU/l) was tested as a predictor of
three endpoints. Endpoint 1 was doubling of ALT
from admission to the end of first 20.25 h course
of AC therapy. Endpoint 2 was a peak hospital stay
ALT >1000 IU/l. Endpoint 3 was a peak international
normalized ratio (INR) value >2. Patient blood re-
sults were extracted from RIE blood results system,
which stores all patient data from NHS Lothian on
an electronic database. Care was taken to maintain
patients confidentiality through removal of all pa-
tient-identifiable data and secure storage within the
National Health Service.
Positive and negative predictive values (PPV and
NPV), specificities and sensitivities with 95% confi-
dence intervals (CIs) were calculated for hospital
admission ALT. Furthermore, results were divided
according to time from ingestion to first blood sam-
pleup to 8 h, 824 h, >24 h and staggered over-
dose (ingested over 2 h or more). The statistical
package used to calculate these values was an
online resource provided by the Canadian Institute
for Health Research (www.ktclearinghouse.ca).
Results
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A total of 500 patients were admitted for AC treat-
ment in the period March 2011May 2012. In total,
90 were excluded from the study because they ful-
filled one or more of our exclusion criteria (73 pa-
tients had no end of AC treatment blood results,
eight patients had haemolysed blood results and re-
maining nine patients had no INR measurement).
Table 1 provides a summary of the patient demo-
graphics. About 264 presented to hospital within 8 h
of the overdose, 54 presented within 824 h, 53 pre-
sented 24 h after overdose and 39 were staggered
overdoses (ingested over 2 h or more) (Table 2).
On admission to hospital, serum ALT activity was
increased above the normal limit (>50 IU/l) in 71 pa-
tients. The breakdown of this by time interval from
ingestion is presented in Table 2.
Table 2 presents the PPV, NPV, sensitivity and
specificity with 95% CIs for admission ALT. For end-
point 1 (doubling of ALT from admission), there was
an overall PPV of 19.1% with the highest PPV (50%)
being in those presenting 24 h after the overdose.
In contrast, the NPV of admission ALT for endpoint
1 was 98%.
Table 1 Demographics of our cohort
Total
Number 410
Sex (M:F) 151:259
Median age (range) 37 (1390)
Number admission ALT < ULN 339
Number admission ALT > ULN 71
Number admission ALT >100 34
Number peak ALT >1000 16
Number normal INR 402
Number peak INR >2 8
ULN, upper limit of normal.
Table 2 Total number of patients at each interval following overdose and proportion who reached the endpoint

Time Total Number of Endpoint Number NPV (95% CI) PPV (95% CI) Sensitivity Specificity
interval number admission reaching (95% CI) (95% CI)
from of ALT > ULN endpoint
overdose patients n (%)

1. Doubling of ALT 20 (4.9) 0.98 (0.960.99) 0.19 (0.120.30) 0.65 (0.430.82) 0.86 (0.820.89)
Overall 410 71 2. Peak ALT 1000 IU/l 16 (3.9) 1.00 (0.991.0) 0.23 (0.140.34) 1.0 (0.811.0) 0.86 (0.820.89)
3. INR >2 8 (1.9) 1.0 (0.991.0) 0.14 (0.070.25) 1.0 (0.681.0) 0.87 (0.840.90)
1. Doubling of ALT 7 (2.7) 0.98 (0.960.99) 0.08 (0.030.21) 0.43 (0.160.75) 0.86 (0.820.90)
08 h 264 38 2. Peak ALT 1000 IU/l 3 (1.1) 1.0 (0.981.0) 0.08 (0.030.21) 1.0 (0.441.0) 0.87 (0.820.90)
3. INR >2 3 (1.1) 1.0 (0.981.0) 0.09 (0.030.23) 1.0 (0.441.0) 0.88 (0.840.92)
1. Doubling of ALT 3 (5.6) 0.96 (0.860.99) 0.17 (0.030.56) 0.33 (0.060.79) 0.90 (0.790.96)
824 h 54 9 2. Peak ALT 1000 IU/l 0 1.0 (0.931.0) 0 0.5 (01.0) 0.84 (0.730.92)
3. INR >2 0 1.0 (0.931.0) 0 0 0.91 (0.810.96)
1. Doubling of ALT 9 (17.0) 0.97 (0.860.99) 0.50 (0.280.72) 0.89 (0.570.98) 0.82 (0.680.91)
>24 h 53 16 2. Peak ALT 1000 IU/l 10 (18.9) 1.0 (0.901.0) 0.63 (0.390.82) 1.0 (0.721.0) 0.86 (0.720.93)
3. INR >2 4 (7.5) 1.0 (0.911.0) 0.33 (0.140.61) 1.0 (0.511.0) 0.83 (0.700.91)
1. Doubling of ALT 1 (2.6) 1.0 (0.891.0) 0.13 (0.020.47) 1 (0.211.0) 0.82 (0.670.91)
Staggered 39 8 2. Peak ALT 1000 IU/l 3 (7.7) 1.0 (0.881.0) 0.38 (0.140.69) 1.0 (0.441.0) 0.85 (0.700.94)
3. INR >2 1 (2.6) 1.0 (0.891.0) 0.13 (0.020.47) 1 (0.211) 0.82 (0.670.91)
Predictive value of hospital admission serum alanine transaminase activity
543

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544 K. Al-Hourani et al.
Endpoint 2 tested the performance of admission
ALT as a predictor of ALT peaking above 1000 IU/l.
The overall PPV was 22.5%, with the PPV of those
presenting 24 h after presentation being 62.5%. The
NPV was 100% across all time intervals.
Endpoint 3 tested admission ALT against peak INR
>2. PPV remained low at 13.6%; however, NPV
was 100%. Once more, the PPV was uniformly
low across all durations, demonstrating a peak of
33.3% for those presenting >24 h after overdose.
Increasing time between overdose and starting
treatment with AC increases the risk of hepatotox-
icity. For all three endpoints, the NPV of hospital
admission ALT was high in patients presenting
late to hospital (Table 2). Out of the 53 patients
who presented >24 h after a single ingestion,
10 had a peak hospital stay ALT >1000 IU/l. In this
high-risk group, a normal ALT at presentation
still had a 100% NPV. Staggered paracetamol
overdoses are challenging to manage clinically
because the risk nomogram cannot be used.
Although the numbers of these patients were small
(n = 39), a normal ALT at presentation still had a
100% NPV.
Discussion
Paracetamol is the commonest drug taken in over-
dose in UK7,8 with an estimated hospital admission
rate of 48% of all overdoses, unfortunately leading
to 100200 deaths per year.9 In Scotland, 4050
patients per year develop significant hepatic dys-
function following paracetamol overdose
(ALT > 1000 IU/l or INR > 2) and around 20 patients
die per year as a result of overdose.10 Although the
management of early paracetamol overdose is rela-
tively straightforward, cases presenting late, follow-
ing a staggered overdose or those with additional
risk factors, present a more complex clinical picture.
Currently, UK management of paracetamol over-
dose is derived from guidelines formulated by the
National Poisons Information Service. As little as
1015 g of paracetamol taken within 24 h could be
enough to induce hepatocellular and renal tubular
necrosis. For this reason, appropriate timely treat-
ment is vital.10
Recently, the UK management of paracetamol
overdose has been changed following reviews by
the Medicines and Healthcare products Regulatory
Agency.6 A single-line treatment nomogram is used
to determine need for AC treatment based on a
timed blood paracetamol concentration. This new
nomogram may result in substantially more patients
being admitted to hospital for AC treatment.11 As
patients who present early to hospital typically
have no symptoms or signs of hepatotoxicity, there
is an urgent need to develop new circulating bio-
markers that inform treatment decisions at the hos-
pital front door. Such markers have the potential to
refine patient care in a number of important ways.
Future clinical trials of new therapeutic strategies
could be stratified using one or more biomarkers
with the objective of targeting new therapies or man-
agement pathways at lower or higher risk patients.
Qualification of new biomarkers may galvanize
the interest of pharma in developing new treatments
as patient stratification can significantly improve the
cost-effectiveness, and therefore health service use
of new drugs. If such trials were successful, more
individualized treatment would be possible at the
hospital front door, as is already the case with the
management of acute coronary syndromes (being
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routinely stratified by sensitive cardiac biomarkers
such as troponin). Currently, patients who have
taken a single paracetamol overdose, who present
late to hospital, can only have liver injury confi-
dently excluded if their standard liver function
tests are normal around 2436 h after overdose.
Biomarkers may allow earlier exclusion of injury
which would have an impact on hospital bed occu-
pancy and avoid adverse AC reactions by reducing
unnecessary treatment. Patients with a timed blood
paracetamol concentration below the at-risk line on
the treatment nomogram are usually not treated.
Sensitive biomarkers of hepatotoxicity may
increase physician confidence in discharging the
patient from hospital and could reduce the number
of patients being incorrectly classified as not
needing treatment. Serum ALT activity is the most
frequently used laboratory indicator of hepatotox-
icity.12,13 It is commonly measured on first presen-
tation to hospital, but at present, it is not used to
guide treatment decisions because most patients
present to hospital soon after drug ingestion (70%
within 4 h of overdose).2 Unfortunately, this remains
a timeframe when ALT cannot diagnose or exclude
liver injury.
Our study has demonstrated that a normal admis-
sion ALT has a high NPV for subsequent liver injury
if AC course is completed. This is consistent with a
previous study of 94 patients, all of whom had a
peak transaminase activity >1000 IU/l.14 In this
Canadian cohort of patients with significant hepato-
toxicity, transaminase activity was already increased
at hospital admission. As already stated, ALT has
important limitations as a biomarker, so our group
has recently investigated a panel of new circulating
biomarkers that have enhanced liver selectivity
(microRNA 122) or provide mechanistic information
(HMGB1 and keratin-18) in plasma from patients
following paracetamol overdose.15 In patients who
 Predictive value of hospital admission serum alanine transaminase activity
developed hepatotoxicity, these markers were sub-
stantially increased on first presentation to hospital
at a time when ALT was still in the normal range.
This demonstrated that patients who develop
paracetamol-induced hepatotoxicity have evidence
of cellular damage soon after overdose and is proof
of concept that front door biomarker development
is possible for this common poison. In the present
study, the NPV of ALT was high even in patients
presenting >8 h after overdose, although these
patient numbers were relatively small. Therefore,
this straightforward, routinely available test could
be used to identify lower risk patients. There are
two scenarios where this could be useful.
Currently, all patients are treated with the same
dose of AC. It is probable that this leads to some
patients being over-treated16 resulting in avoidable
adverse drug reactions to AC and unnecessary hos-
pital bed occupancy. Hospital admission ALT within
the normal range identifies a low-risk group and
could be used as inclusion criteria for clinical trials
of new targeted therapeutic strategies. New circulat-
ing biomarkers are in clinical development that ap-
pears more sensitive than ALT.17,18 These may make
it possible to better identify lower risk patients and
allow earlier rule in/rule out of liver cell death fol-
lowing paracetamol overdose.
Our findings suggest that admission ALT can be
used to inform the treating clinician about patient
prognosis; if the ALT activity is within the normal
range and the patient completes treatment, then
liver injury is unlikely, even in patients who present
late to hospital. In contrast, an increased ALT activ-
ity at presentation to hospital had a low PPV.
This can probably be explained through the know-
ledge that serum ALT activity is increased in
co-morbidities such as alcohol excess, biliary dis-
ease, diabetes, obesity, heart failure and myopathy.
Therefore, our findings indicate that an increased
ALT alone cannot be used to identify higher risk
patients at first presentation to hospital, whereas a
normal ALT may be useful in identifying patients
at lower risk.
Conclusion
Our study tested the predictive value of admission
serum ALT activity in paracetamol overdose. It
demonstrated that on first presentation to hospital,
normal serum ALT is a predictor of very low risk
of subsequent liver injury on completion of AC. If
confirmed in larger clinical studies, this simple test
could be used, alone or in combination with new
biomarkers, to identify low-risk patients for clinical
trials of novel therapeutic strategies.
545
Acknowledgements
J.W.D. acknowledges the contribution of the British
Heart Foundation Centre of Research Excellence
Award.
Funding
J.W.D. acknowledges the funding of NHS Research
Scotland through NHS Lothian.
Conflict of interest: None declared.
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