PHARMACOEPIDEMIOLOGY A N D DRUG SAFETY, VOL 3: 9 1-1 03 ( 1994)

~~ ~

ORIGINAL REPORT

Asymptomatic Abnormal Liver Function Tests in

Clinical Trials
M. D. B. STEPHENS MD. MRCGP
49 K i n g s Court, Bishop 'Y Stor ford, Hurts, CM23 2AB, UK

SUMMARY

There are many sources of asymptomatic abnormal liver function tests in clinical trials other than
hepatotoxicity. It is, therefore, important to identify these sources by looking at the patient's past
and present medical history for diseases or activities that may cause these abnormalities, study the
degree and duration of the abnormality and the ratio of the different parameters to see whether they
are consistent with the hypothesis that the drug is not hepatotoxic and that another cause is more
likely.
Diseases and activities that can cause these abnormalities are given and methods of analysis outlined.
There is no good evidence that abnormal liver function tests are predictive of hepatotoxicity.

KEY WORDS - Abnormal liver function tests, hepatotoxicity, data analysis, bilirubin, clinical trials.

INTRODUCTION (2) Serum Glutamic Oxalacetic Transaminase

Liver function test abnormalities may be present
on entry to a clinical trial or appear whilst on treat-
ment or during the post-treatment period. Appre-
ciation of the possibilities will enable those
responsible for the trial to ensure that the protocol
deals with all eventualities and that the methods
of investigation and analysis reveal the origins of
the abnormalities.
Asymptomatic abnormal liver function tests
(LFTs) occurring in clinical trials may be due to:
( 1 ) Liver disease
(2) Other systemic disease
(3) Drug hepatotoxicity
(4) Drug induced non-toxic changes
( 5 ) Inherited abnormalities
(6) Activities in normal persons
(7) Medical interventions
Liver disease and drug hepatotoxicity will not be
dealt with in this article.
The usual Screenfor liver damage in clinical trials
comprises:
(1) Total Bilirubin
(SCOT) also known as Aspartate Amino-
transfeiase (AST)
(3) Serum G1utamic 'yruvic Transaminase
(SGPT) also known as Alanine Aminotrans-
ferase (ALT)
(4) Alkaline Phosphatase (ALP) and sometimes
the
(5) Gamma-Glutamyl Transferase (GGT) also
known a s Gamma-Glutamyl Transpeptidase.
In the USA the lactic dehydrogenase (LDH) is
favoured but it is too insensitive and too non-speci-
fic for monitoring liver damage as it also occurs
in cardiac and skeletal muscle, red blood cells, lung
and spleen;' although the GGT is just as non-speci-
fic it is sensitive.
These tests are known collectively as the liver
function tests (LFTs) but do not really measure
liver function. The true liver function tests are the
serum albumen and the prothrombin time or partial
thromboplastin time; but these are not Sensitive
enough to detect early liver damage.
An excellent textbook used for this article is the
O.xjbt-d Textbook of Clinical Hepatology (OTCH).'

CCC 1053-8569/94/020091-13 Received 24 Deceniber 1993

0 1994 by John Wiley & Sons, Ltd. Accepted 12 April 1994
92 M. D. B. STEPHENS

TOTAL BILIRUBIN TRANSAMINASES

This is not the early harbinger of liver cell damage Most liver diseases cause increases in the level of
and there is no correlatiqn between its level and the transaminases and these usually indicate cell
the degree of liver disease.. Its elevation may reflect necrosis. The death of one cell in 750 is sufficient
impaired uptake, conjugation, or excretion of bilir- to cause ALT elevation.'" The degree of elevation
ubin, over-production or a leak back of conjugated is of no prognostic value and does not correlate
or unconjugated pigment from damaged cells. It with the degree of liver dysfunction.'." They do
is derived principally from the breakdown of hae- not increase with age. They catalyse the removal
moglobin. Ten to thirty per cent is derived from of an amino group from a donor amino acid and
haem precursors within the liver or bone marrow transfer it to a recipient keto acid."
or from myoglobin and other non-haemoglobin
haem proteins.' Before reaching the liver it is water-
insoluble and requires conjugation within the liver Aspartase aminotransferase ( S G O T ) ( A S T )
in order to be excreted as water-soluble conjugated This enzyme is non-specific being present in skeletal
bilirubin in the bile. It binds to plasma albumen4.' and heart muscle, ancreas, kidney, liver and red
Drugs e.g. sulphonamides, may compete with bilir- blood cells (RBC).'I4 The half-life is 17 h." There
ubin for binding sites on albumen leading to excess can be a marked elevation with 'macro AST', a
tissue deposits which may result in a lower serum very rare complexing with immunoglobulin G
level of bilirubin. Drugs may also compete for (IgG)."
uptake of bilirubin by the liver cell. The conjuga-
tion within the liver may be impaired by drugs e.g.
novobiocin.6 The bilirubin level does not alter with Alanine aminotransferase ( S G P T ) ( A L T )
age. ' This is more specific for the liver than the AST
An elevation of bilirubin may be a late sign of but may rise in disseminated cancer, muscle disease.
extensive hepatic cell damage or an early sign of acute renal disease and acute pancreatitis. ' A three-
cholestasis. Clinical jaundice is usually detected
fold rise in the ALT activity has a predictive value
when the serum bilirubin reaches 2 to 3 mg per
of 95% and the predictive value of a negative result
100 ml(34.2-5 1.3pmo1/1).' Liver enzyme induction
is 87-970/;~'~The half-life is 47 h."
can reduce the serum levels by increased metabo-
lism.
There are four congenital bilirubin disorders of Alkaline phosphatase ( A P ) and gamma glutamyl
which only one is frequent enough to cause prob- transferase ( G G T )
lems in clinical trials.
Whereas the ALT and AST are formed by the
release on cell lysis and are the main indicators
Unconjugated bilirubin of hepato-cellular damage, the AP and GGT are
( 1 ) Gilbert's disease. This is relatively common, increased by increased production although the lat-
with an incidence of 5-6%). The bilirubin usually ter is debated with the GGT. They are both indi-
varies between 20-40pmol/l(1.2-2.5 mg/dl and rar- cators of biliary cholestasis but are non-specific.
ely exceeds 80 pmolll ( 5 mg/dl). It usually presents They are also both induced by drugs which can
in the second decade so it may be noticed in a volun- raise their serum level."
teer on their first screening. It may be noticed first
during an intercurrent illness or on fasting.'
Gamma glutamyl transferase ( G G T )
( 2 ) Crigler-NajJar Syndrome. This is rare and This enzyme occurs mostly in the liver, kidney, pan-
usually presents at birth. Bilirubin levels vary creas and prostate. It may be raised in pancreatic
between 80-350 mg/l (1 368-5985 ,umol/l) disease, myocardial infarction, angina pectoris, cer-
ebral tumour, cerebrovascular accident, diabetes
mellitus, chronic obstructive airways disease, acute
Conjugated bilirubin renal failure, nephrotic syndrome, post-transplant
( 1 ) Dubin-Johnson Syndrome. Harmless. rejection, cervical cancer after radiation therapy
( 2 ) Rotor S-vndrotne. Similar to above.' and in the fortnight after severe trauma." In choles-

0 1994 by John Wiley & Sons, Ltd. PHARMACOEPIDEMIOLOCY AND DRUG SAFETY, VOL. 3: 9 1- I03 ( 1994)
 ASYMPTOMATIC ABNORMAL LIVER FUNCTION TESTS
tatic disease the rise usually parallels the AP; but
it is also raised in hepato-cellular disease.' It is one
of the most sensitive indicators of hepato-biliary
disease.'" It has an advantage in that it is not ele-
vated in metastatic bone disease when the AP is
raised."
Alkaline phosphatase ( A P )
This enzyme is also found in the placenta, kidney,
bone and the intestines and has iso-enzymes: (1)
placental; (2) intestinal; (3) hepatic; (4) osseous.
Elevations are common in physiological bone
growth, benign and malignant bone disease and
less commonly after infarction of the myocardium,
lung, spleen, kidney and bowel. Other causes
include pregnancy, ulcerative colitis, sepsis,
hyperthyroidism, congestive heart failure, fractures
and benign inherited elevation. If the elevation is
persistent there is usually a clinically obvious
cause." In animals the stimulus of biliary obstruc-
tion results in a rapid increase in AP in the liver.'"
The kidney AP is rarely released into the circula-
tion. Elevations < 3 x upper limit of normal
(ULN) occur in either cholestatic or hepato-cellular
injury, values > 3 x ULN are usually due to cho-
lestatic injury.'* The first sign of a drug-induced
cholestatic jaundice may be a raised AP, occurring
up to 3 weeks after dechallenge."
Lactate dehydrogenase ( L D H )
This is predominantly an intracellular enzyme and
is found in the heart muscle, skeletal muscle, liver,
kidney, brain, lung, spleen, neutrophils and eryth-
rocytes. It is a non-specific marker of cell damage
and is an insensitive index of liver functi0n.j It may
be raised in: circulatory failure with shock and
hypoxia, myocardial infarction, renal infarction,
rejection of renal transplant, malignant disease
especially liver metastases, muscle disease, pulmon-
ary embolism, infectious mononucleosis, hepatitis,
pneumonia and haematological disorders, such as
megaloblastic anaemias, acute leukaemias, lym-
phomas, thalassaemia, myelofibrosis, haemolytic
anaernia~.'.~.' There are iso-enzymes but they are
not used to any extent. Although the LDH may
be raised in liver disease such as drug-induced hepa-
titis, viral hepatitis, infectious mononucleosis, cho-
lestasis, tumours, cirrhosis and chronic active
hepatitis; it is not usually raised to the same degree
as other LFTs and has no advantage over them.'0,"
In the presence of liver disease a moderate elevation
0 1994 by John Wiley & Sons, Ltd. PHARMACOEPIDEMIOLOGYAND DRUG SAFETY, VOL.
93
suggests malignant disease and it is more sensitive
to myocardial damage and anaemias.x
CAUSES O F ABNORMAL LFTS IN
CLINICAL TRIALS
Volunteers (phase I )
Persistent abnormalities.
Laboratory workers: Volunteers who worked in
laboratories on drug research projects had more
abnormal LFTs than non-laboratory workers. The
authors postulated that the abnormalities were due
to chronic low dosage exposure to xenobiotics in
the lab~ratory.'~(See Table 1.)
Table 1
Bilirubin 18.7% versus 4.7%
Other LFTs 21%) versus 5.9%
Obesity: When 100 asymptomatic blood donors
with ALT exceeding the ULN X 1.43 were eva-
luated (Friedman Survey), one-third were given
specific diagnoses and of these in two-thirds obesity
was thought to be the cause of the abnormal ALT.25
Weight reduction of 10% normalized LFTs in over-
weight patients. The commonest abnormality was
ALT occurring in 79.5% with a mean elevation of
ULN X 2.34 +_ 1.1. The AST was elevated in 64%,
GGT in 41%, AP in 2 8 % ~ ' ~
Alcohol: In the above survey alcohol was thought
to be the cause in 45% with another 5% with specific
alcoholic liver disease i.e. 50%.
Hepatitis: The Friedman survey showed that 17O%
of the blood donors had serological evidence of
hepatitis C.'7 In a survey of phase I studies includ-
ing 328 volunteers, 11 had abnormal LFTs and all
were due to mononucleosis, five had acute infec-
tion, three had past infection and three had chronic
infection." Again in blood donors potentially infec-
tious hepatitis was detected in 8% of patients who
had an ALT c ULN X 2. In patients who had
persistently elevated aminotransferase values aver-
aging 2-3 X ULN, on liver biopsy 23/90 had alco-
holic liver disease, 17/90 had a fatty liver and 26/90
had chronic necroinflammatory disease of probable
viral origin: there were 24/90 who had miscella-
neous diseases and of these six were normal on
liver biopsy." Common viruses other than hepatitis
A, B and C which can cause abnormal LFTs are:
Epstein-Barr, cytomegalovirus, Herpes simpku,
3: 9 1-1 03 ( 1994)
94 M. D. B. STEPHENS

measles, rubella, Varicella zoster and entero viruses the ALT at 96 h (ULN x 1.5) and the LDH at
- Coxsackie A and B. All volunteers should be 1 h (ULN x 4.7).” There may be a rise in bilirubin
screened, therefore, for the human immune virus after severe exe~cise.~
(because of its association with opportunistic infec- Trauma: Stings produced an AST up to ULN X
tions), hepatitis A, B and C , and the Epstein-Barr 5.8, ALT up to ULN X 2.9 and LDH up to ULN
virus. x 3.5 within 2 h of hospital admission, as well
Diet: A sucrose-rich diet doubled the ALT in non- as acute tubular necrosis in one ~ a t i e n t . Intramus-
~’
obese volunteers, whilst in the obese this same cular injections, especially penicillin, may cause a
increase did not produce values greater than 2 X rise in the AST.l9Fractures can, of course, produce
ULN.29Two to 4 h after a fatty meal the AP (intesti- rises in AP.
nal isoenzyme) increased.’ Diet: Fasting causes an increase in bilirubin so that
Gilbert’s Syndrome: after 48 h the average increase is 240% due to dec-
reased hepatic ~learance.~
Transient changes. Other: When AP and AST were followed over 30
Chance: Using the ‘normal range’ (mean 2 stan- weeks in healthy volunteers elevations above the
dard deviations) 1 in 20 will have an ‘abnormal’ ULN were infrequent and occurred almost exclus-
result for any parameter; but since, on the whole, ively in males when the mean values were near the
one tests five LFTs the chance of a normal healthy ULN. For both parameters there were highly signi-
person having an abnormal LFT increases to 23%. ficant differences between males and females, the
This risk can be diminished if the mean plus 3 stan- latter being lower. The within-person variation is
dard deviations is used as the ‘normal range’ when small for both sexes. This suggests that separate
the figure is reduced to 1.3%. If the LFT is more ranges for the sexes should be used for volunteers
than 25% above the ULN it is very unlikely to be and that abnormal values should be compared with
due to chance.30The argument above presumes that the individual’s past results.34
the ‘normal range’ referred to excludes 2.5% at each Inveresk Clinical Research found that in five
end of the range and this may not be so, due to volunteer studies of active drug versus placebo that
the skewed distribution of LFTs and secondly it the LFTs were higher on the active drug than whilst
presumes that each parameter is independent which on placebo. The interpretation of these figures
is clearly not so for the LFTs. However the princi-
ple is highly relevant to the single abnormal LFT Table 2
which is just above the ULN.
Venepuncture: (a) Haemolysis - haemolysis of 1% Placebo Active
of the red blood corpuscles caused 220% increase AST 2/166 (1.2%) 17/265 (6.4%)
in AST, 272% increase in LDH and 55% increase ALT 6/166 (2.6%) 26/265 (13.6?40)
in ALT.’ (b) Tourniquet -a 3-min compared with AP 11166 (0.6%) 0/265 (0%)
a 1-min tourniquet increased bilirubin by 8% and BIL 0/166 (OYo) 51265 (1.840)
AST by 10%. (c) Posture - standing compared GGT 3/149 (2.2%) 5/242 (2.0%)
with supine increased ALT by 14%, AP by 11%
and AST by 5.5%.6
Alcohol: Six pints of beer drunk over 3 h did not is difficult. (See Table 2.) In one study mean values,
alter the AP, GGT, or LDH in normal healthy men at different time points, showed no statistically sig-
who usually drank moderately (6-10 pints per nificant differences between active and placebo
~ e e k ) .Increases
~’ in AST of up to 108% were seen group. The magnitude of the changes in the placebo
in non-alcoholic volunteers who drank 270 g alco- group was similar to that seen in the active group.
hol (approx. 34 drinks or 16 pints of bitter) in eight The author suggests that this may mean that there
doses over 18 h to simulate a weekend social binge, was another factor other than the active
the AST levels were < ULN X 2 and the blood A German group examined the pre-study values
alcohol levels did not exceed 80 mg: other LFTs of the liver enzymes in 397 volunteers comparing
were not analy~ed.~’ the first pre-study value with all pre-study values.
Exercise: A I-h game of handball produced a 41%) They found no tendency towards elevated enzyme
increase in AST and a 32% increase in LDH which activities in frequent study participant^.^^ The
remained over baseline for 53 h or more.I6The AST figures, however, are interesting in that the percent-
peaked at 24 h (ULN X 3.8) after a marathon race, ages within the ‘normal range’ (given in the litera-
 ASYMPTOMATIC ABNORMAL LIVER FUNCTION TESTS
Table 3
AST ALT GLDH
First pre-study
evaluation 92.3 92.8 94.2
All pre-study
evaluations 95.4 91.0 94.4
Percentage of values within normal range).
ture) are mostly below the expected 95%. This illus-
trates the problem of using a ‘normal range’ from
a different population. (See Table 3.)
Patients
Persistent changes (occurring during the course of
anotlier illness). The list of diseases other than liver
diseases that can cause abnormal LFTs is long and
therefore many of the indications for drug clinical
trials will be associated with liver enzyme abnorma-
lities.
Cardiovascular: (a) Myocardial infarction - ALT
although present in heart tissue it is markedly lower
than in liver disease and it does not rise after
uncomplicated myocardial infarction unless there
is a large necrotic area (upper limit ULN x 4.3)
producing a high AST (upper limit ULN X 15).’7
The GGT although low in heart tissue may be
raised in infarction and is raised in 65% of cases
with angina.” LDH level rises 2-10-fold after the
first 12 h peaking at 24-48 h.4 The AP may be
raised.”
(b) AST and LDH may be increased in acute
rheumatic carditis.‘
(c) AST may be increased after angiocardiogra-
phy and passage of a cardiac ~ a t h e t e r . ~
(d) Right ventricular failure - liver congestion
alone is usually associated with transaminases <
5 X ULN” but the AP may also be raised.”
(e) Left ventricular failure (LVF) - LVF does
not usually increase the ALT but central hepatic
necrosis due to left heart failure has been
reported’”‘” and hypotension can produce ischae-
mic hepatitis and increase the ALT > 5 x ULN
usually indicating centrilobular necrosis.”x“ There
is usually a rapid rise within 48 h which returns
to normal within 5-10
(0 Infarction of lung, spleen, kidney or bowel
can cause an elevated AP.” (Reference: the chapter
‘The liver and cardiovascular and pulmonary dis-
ease’ OTCH).
Thyroid: (a) Hyperthyroidism - out of 570
0 1994 by John Wiley &Sons, Ltd.
95
hyperthyroid patients 15% had one or more abnor-
GGT mal LFTs: AP, AST, bilirubin. ALT was not
t e ~ t e d . ~Another
’ paper put the figure as high as
72%: bilirubin - 31%, AP - 67%, AST - 24%,
92.0 ALT - 26% and LDH - 13‘%1.~‘ There is a slight
rise in GGT.“
93.8 (b) Hypothyroidism - mildly abnormal LFTs
can occur in hypothyroidism.’ The AST may be
raised in myxoedema with hypothermia.’
Pancreas: (a) Diabetes mellitus - up to 57% of
diabetics had a raised GGT.’” During a phase I
study 56% of ‘healthy’ diabetics had raised LFTs:
AP - 35%, AST - 32‘%1,LDH - 15‘%1: of these
91% were less than 30% above the ULN of the
normal non-diabetic population. The authors
recommended:
(i) Producing an acceptable range for a diabetic
population but for the moment use an entry
criterion of up to 30% above the ULN.
(ii) Increase the proportion receiving placebo
from 25% to 33% in future studies.
(iii) Using a baseline screen as well as one during
the 2 weeks prior to the
In trials 54% of diabetics were excluded for ele-
vated LFTs and so entry criteria were extended
to 30% over ULN and then only 12% were
excluded.‘‘ (Reference: the chapter ‘The effect of
endocrine disease on liver function’ OTCH).
(b) Pancreatitis - in acute pancreatitis GGT
may rise to 5 x ULN with smaller rises in chronic
di~ease.”’.~ The ALT and AST may be raised in
acute pancreatitis.’.3XThe LDH may be raised in
some cases4
(c) Carcinoma of the head of the pancreas due
to biliary obstruction.
Rheumatic diseases: In 182 patients with rheuma-
toid arthritis the GGT was raised in 47% and AP
(iso-enzyme) in 24%; but the bilirubin was normal
in all cases. Of those with a raised GGT 15% had
raised aminotransferases (ALT, AST). Similar pat-
terns are seen in ankylosing spondylitis, psoriatic
arthritis, reactive arthritis, undefined arthritis and
polymyalgia rheumatica. Statistical evaluation did
not indicate that any sin le drug or combination
of drugs was responsible.g . 4 , Serum transaminases
may be slightly raised in systemic lupus erythemato-
sus and minor elevations are common in polyarteri-
tis nodosa. AST may be raised in acute There
may be minor elevations of AP and transaminase
in giant cell arteriti~.~’
Trawnahnuscle disease: After a severe trauma the
G C T is raised,’” reaching maximum levels (up to
PH ARM AC:OEPIDEMIOLOGYA N D DRUG SAFETY, VOL. 3: 91-103 (1994)
96 M. D. B. STEPHENS
6 x ULN) at 1-2 weeks. The AP rises later reachin
a maximum at 3 weeks often rising to ULN X 3-5. 8
The AST ma? reach ULN x 12.5 and the ALT
ULN x 4.3.3 Muscle disease elevation is usually
< 33 i . ~In.progressive
~ ~ muscular dystrophy AST,
ALT and LDH may be AST may be
raised in dermatomyositis and pseudohypertrophic
muscular dystrophy (upper limit ULN X 6.25). A
modest rise in ALT may be seen in Duchenne dys-
trophy and active polymy~sitis.‘~ A slight rise in
GGT may be seen in dystrophia myotonica.2 In
the muscular dystrophies and dermatomyositis the
ALT does not exceed ULN x 3.38Surgical trauma
can produce increases in transamina~es~~ and
LDH.4 (Reference: the chapter ‘Musculoskeletal
disease and the liver’ OTCH).
Renal disease: The GGT may be slightly raised in
acute renal failure, the nephrotic syndrome, renal
post-transplant patients” and some cases of renal
c a r ~ i n o m aThe
. ~ ALT may be raised in acute renal
failure’ and an isolated AP in chronic renal failure.2
(Reference: the chapter ‘The liver in urogenital dis-
ease’ OTCH).
Gastrointestinal tract: (a) Ulcerative colitis and
Crohn’s disease - a review of 202 patients with
chronic ulcerative colitis showed that 55% had
abnormal LFTs, 30% were mild (AP or transami-
nase < ULN x 2) and 25%)had markedly abnor-
mal LFTs (AP or transaminases > ULN x 2) or
increased bilirubin. Asymptomatic parenchymal
liver disease was the commonest abnormality.
Those with the whole colon involved and severe
disease were more likely to have markedly abnor-
mal LFTs.’~Even in remission 3% of patients have
abnormal LFTs and the author said that the major-
ity of the patients had primary sclerosing cholangi-
tis. Fatty liver is a common finding in both
ulcerative colitis and Crohn’s disease.48
(b) AST will be raised in intestinal infarction and
after intestinal s ~ r g e r y (Reference:
.~ the chapter
‘The effect of gastrointestinal disease on the liver
and biliary tract’ OTCH).
Bacterial infection: Extrahepatic infection was
associated with elevated AP (liver iso-enzyme) in
elderly patient^.'^ Abnormal LFTs can occur in a
wide range of infectious diseases and a full list is
in ‘Liver and Biliary Disease, Pathophysiology,
Diagnosis and Man~gement’.’~ The noteworthy are
listed below:
Lobar pneumonia - raised bilirubin in 50%, ami-
notransferases in 20%, AP in 10% and LDH.
Mycoplasma pneumonia - raised transaminases
and AP not unusual.
0 1994 by John Wiley & Sons, Ltd. PHARMACOEPIDEMIOLOGY AND DRUG SAFETY, VOL.
Gonococcal bacteraemia - abnormal LFTs in
50%.
Typhoid fever - abnormal LFTs in 350/, mildly
raised aminotransferases.
Paratyphoid - abnormal aminotransferases in
80%.
Brucellosis -raised LFTs (AP, bilirubin or amino-
transferases).
Legionnaires’ disease - abnormal LFTs in 50%
of severe cases.
Tuberculosis (TB) - raised in most patients with
miliary TB.
Weil’s disease - bilirubin can be extremely high,
transferases and AP moderate.
Q fever - commonest abnormal LFT is AP, occa-
sionally marked transferases.
Malaria -abnormal LFTs in over 50%, commonly
bilirubin or transferases are raised.
Syphili~.’~
Neurological disease: Markedly elevated transami-
nases can occur after a protracted seizure in chil-
dren and was presumed to be due to hypoxia.”
Epilepsy, highly vascular tumours, cerebral
tumours and cerebrovascular accidents have been
associated with raised GGT.’6 Extensive cerebral
tissue damage associated with massive cerebral hae-
morrhages and thromboses can cause elevated
AST.38In Guillain-Barre syndrome and other neur-
ological disease there can be a slightly raised
GGT.I4
Several anti-epileptic drugs can cause raised
LFTs due to enzyme induction.
Alcoholic liver disease: It may be very important
to identify patients with alcoholic liver disease in
clinical trials, e.g. peptic ulcer trials. Alcoholic dis-
ease should be suspected if the ASTlALT ratio is
> 1 and ALT greater than 300.57 Using this formula
there would be 10% false negatives and 23% non-
alcoholics would have been incorrectly identified
as alcoholic.” In active cirrhosis of the liver if the
AST/ALT ratio > 2 it indicates alcoholic liver cirr-
hosis.” Quadratic discriminant analysis of the
usual laboratory screen was able to identify 100%
non-alcoholic disease and 100% of alcoholic liver
disease.’8
Long-term high alcohol intake may cause
increased GGT as a result of liver enzyme induc-
tion.
Cancer: The ALT and LDH may be raised in disse-
minated cancer.’,4A minor activity increase may
be seen in AP (isolated).*’ There can be a sli ht
rise in GGT in malignant diseaselradiotherapy.I$
Haematological diseases: Biochemical signs of cho-
3: 91-103 (1994)
 ASYMPTOMATIC ABNORMAL LIVER FUNCTION TESTS 97
lestasis, generally due to leukaemic infiltration, Enqwte induction: Enzyme inducers such as alco-
may be noted in acute leukaemias.m The LDH is hol, phenobarbitone, phenytoin and rifampicin
likely to be raised when there is destruction of RBC produce an increase in AP and GGT and a decrease
and in myeloid l e ~ k a e m i aAn
. ~ isolated raised AP in bilirubin." (See Table 4.)The marker for enzyme
may occur in Hodgkin's disease. (Reference: the induction is urinary 6P-hydroxycortisol and signifi-
chapter 'The effect of haematological and lympha- cant increases are seen at 4 days with antipyrine,
tic disease on the liver' OTCH). 13 days with phenobarbitone and after 2 days with
Pulnionury diseuse: AST, ALT, Total bilirubin, AP, rifampicin reaching maximum at 11-14 days and
and GGT were significantly higher in chronic res- had not returned to baseline by 6 days.h4
piratory insufficiency than in controls, all had POz
< 60 mmHg.' The AST rises in pulmonary embo- Table 4
lism. l4
Chronic obstructive pulmonary disease - Phenytoin-treated Controls
increase in GGT in sputum." epileptics
Miscellaneous: Mean Range Mean Range
Heat stroke - elevation of transferases (usually (95% C.1.) (95% C.1.)
< 6-8 x ULN) and AP. Male
Extramedullary haemopoiesis - AP raised in ALT 25 0-63 14 0-38
50'%1. AP 46 0-93 35 0-6 1
Jejunoileal bypass - 50% have serious hepatic Bil 5.6 2.7-11.2 9.8 2.6-18.1
abnormalities. Female
Bone marrow transplant - 83% had abnormal A LT 18 0-36 12 0-24
LFTs.~* AP 37 6-70 29 11-47
Cervical cancer after radiotherapy - increase Bil 4.6 2.5-8.5 6.9 3.5-11.3
in GGT but not LDH; this is due to the release
of GGT from the cancerous cells.62
Burns - the aminotransferases rise within a few The explanation of these differences could be the
hours and then again in 2-3 weeks. inducing effect of phen toin; but ALT has not been
Radiation - changes are rare due to the relative reported as inducible.2Another study showed that
radio resistance of the liver and occur mostly the elevation of serum enzymes and serum levels
in the treatment of ovarian tumours. of phenytoin andfor henobarbitone showed a sig-
(Reference: the chapter 'Hepatic injuries due to nificant correlation! There is a suggestion that
physical agents' OTCH). rifampicin induction takes effect within a few
Anorexia nervosa - there may be a slightly Benzodiazepines can increase GGT but
raised GGT. not by enzyme induction.68
Porphyria cutanea tarda - there may be a Adaptive change: In a study of two antihypertensive
slightly raised GGT.I4 drugs, Guanoxan and Guanoclor, 30% and 22%
(Reference: the chapter 'The effect of skin dis- had elevated transaminases before treatment and
eases on the liver' OTCH). 59% and 64% of patients respectively had rises in
transaminases above normal whilst on treatment.
Transient changes. In addition to that mentioned Of those patients where the outcome is known
under volunteers. nearly all returned to normal on continued treat-
Dief: Abnormalities of liver enzymes and bilirubin ment (97% and 100%)respectively. (See Table 5.)
are commonly seen during total parental nutrition. Those with raised transaminases had fewer side-
There is fatty infiltration and progressive intrahe- effects than those without. The mechanism was
patic cholestasis. Thirty to sixty per cent will show thought to be that the changes were an expression
a rise of at least one liver test greater than 50% of metabolic effects associated with adaptive, in
s
of baseline:4x the most frequent being the AP. vitro, handling of the dru s. There was a wide varia-
initially occurring at 10-14 days, without concomi- tion in the time to onset. Professor Sherlock may
tant changes in transaminases. The AP persists have been referring to this when she said 'The serum
more than one month in most cases.h3 transferase may rise during the first four weeks of
Stutus usthmuticus: Both AST and ALT may be therapy on1 to subside even though the drug is
raised in severe a ~ t h m a . ~ , ' contin~ed'.~' Another authority may also be refer-

0 1994 by John Wiley & Sons, Ltd. PHARMACOEPIDEMIOLOGY A N D DRUG SAFETY, VOL. 3: 91-103 (1994)
98 M. D. 8.STEPHENS

Table 5 from the ABPI Compendium. For each drug the

side-effects section was examined for the presence
~~~

Levels of transaminases (where raised)

Mean ( x U L N ) Range ( X ULN) or absence of mention ofabnormal LFTs and hepa-
totoxicity. (See Table 6 . )
Guanoxan AST 1.96 0.15-7.5
ALT 1.85 0.05-5
Guanoclor AST 1.46 0.575-4.65 Table 6
ALT 1. I4 0.14.3
Hepatotoxicity
Changes in terms of ULN Absent Present
n=44 n = 36
N-2 x ULN 24 29
2-3 X ULN 10 5
Mentioned 102 94 196
3 4 x ULN 3 0 Abnormal liver
4-5 X ULN 3 2 function tests
5-6 x ULN 2 0 Not mentioned 61 302 363
6-7 X ULN 1 0 163 396 459
7-8 x ULN 1 0
Sensitivity = 62.57‘%,.
Specificity = 76.26%
Prevalence = 35.5‘%1.
ring to this when saying ‘Many drugs that have Positive predictive value = 52.04’%~
not produced clinical liver disease raised the Negative predictive value = 83. I9‘%,
activitv of AST and ALT in the first week or two
Of use. Indeed this finding may apply to drugs
The LFTs are little more use than tossing a coin
metabolized in the liver’.6
for the prediction of hepatotoxicity but the absence
Similar changes were described for lofepramine
of abnormal LFTs on marketing is slightly better
where three Out Of 43 had raised at week for predicting the absence of hepatotoxicity.
becoming normal by week 3.20 had raised AP (the
maximug was ULN x I S ) 17 returning to normal
on continued treatment by the end o f a 12-week EVALUATION AND ANALYSIS OF
trial. GGT showed little change.”
ABNORMAL LFTS

DO ABNORMAL LFTS PREDICT
HEPATOTOXICITY?
Using the ABPI (Association of the British Phar-
maceutical Industry) Data Sheet Compendium,
1993-94 and making the following presumptions:
( I ) That the abnormal LFTs mentioned were
discovered at or before marketing and that the
hepatotoxicity was discovered after marketing
or after the discovery of abnormal LFTs.
(2) That drugs were excluded if they had more
than one active ingredient, if they were for local
application, if they were not normally used for
periods greater than 5 days and if they were
newer drugs marked with a V.
This does not account for the drugs removed from
the market. There were eight of these which had
hepatotoxicity at the time of removal: Benoxypro-
fen, Benziodarone, Ibufenac, Mebanazine, Niala-
mide, Oxyphisatin, Phenoxypropazine and
Temafloxacin.” The table below was compiled
Individual putierz ts
Different patterns of abnormal LFTs are found
with hepato-cellular, cholestatic and mixed liver
injury. The highest serum transaminase in terms
of multiples of the ULN is divided by the AP, again
in terms of the multiples of the ULN. If the ratio
is 2 or less, or if the AP > 2 x ULN alone it
indicates a cholestatic injury; whilst a ratio of 5
or greater, or the ALT > ULN alone it indi.
cates hepato-cellular injury. A mixed liver injury
is indicated if the ratio lies between 2 and 5, and
the ALT > ULN with an increase in AP.7’ The
term ,hepatitis,should not be used unless there is
biopsy evidence. I f there is no biopsy and there
is an increase in ALT or conjugated bilirubin of
> 2 x ULN or a combined increase of AST, AP
and total bilirubin and one of them is greater than
ULN X 2 then the term ‘liver injury’ should be
used and the type of injury given as above. Other
abnormalities of ALTs, ASTs and APs < 2 X ULN
should be listed as increases in the relevant para-
meter. Any other abnormalities of biochemical tests

0 1994 by John Wiley &Sons, Ltd. PHARMACOEPIDEMIOLOGYA N D DRUG SAFETY, VOL. 3: 9 1-1 03 (1994)
 ASYMPTOMATIC ABNORMAL LIVER FUNCTION TESTS 99
should be recorded as such and not included in indicating possible hepatotoxicity and need for fol-
the liver section.73 low-up evaluation. (See Table 9.)
The intra-individual variation is much smaller
than the inter-individual variation. The Ninewells
Hospital biochemical department has produced in Table 9-Criteria for possible hepatotoxicity
its handbook74a list of the individual changes in Phase I
biochemical parameters which are significant at dif- Aminotransferases > 2 X ULN
ferent levels. (See Table 7.) Alkaline phosphatase > 1.25 X ULN
Total bilirubin > 1.5 x ULN
Phase I1
Table 7 Aminotransferases > 3 x ULN
95% 99% significance Alkaline phosphatase > 1.25 x ULN
Total bilirubin > 1.5 x ULN
Bilirubin 4 6 pmol/l
Phase 111 and IV
AP 26 36 U/l
Minimally abnormal level (warning)
ALT 16 23 U/I
LDH 46 65 U/l
Aminotransferases < 3 x ULN or
GGT 10 14 U/I Alkaline phosphatase < 1.5 x ULN or
Total bilirubin < 2 x ULN
Markedly abnormal level (take immediate action)
Aminotransferases > 3 x ULN or
Alkaline phosphatase > 1.5 x ULN or
Another method for intra-individual variation Total bilirubin > 2~ ULN
is the Delta Limits which are the values that just
exclude 1% of the largest decrements and the values
that just excluded 1% of the largest increments
taken from a reference population at an interval
There is no substitute for reading the Guidelines
of 1 or 2 weeks.75(See Table 8.)
for Detection of Hepatotoxicity due to Drugs and
Chemicals2’ Davidson, C. S., Carroll, M. L. and
Chamberlain, E. C. (Eds), US Dept of Health, Edu-
Table 8-Delta limits cation and Welfare, Public Health Service, Natio-
~ ~ ~ ~~~~~

Changes exceeded by 1% of values nal Institute of Health, NIH Publication N079-

Decrement Increment
ALT (Uil) -29
AST (U/I) -28
GGT (Ull) -20
AP (U/I) -32
Bilirubin (pmol/l -10
The only two reservations about the usage of
both methods is that these figures combine the
intra-individual variation and the analytical varia-
tion in their particular laboratory; the latter will
vary from laboratory to laboratory but the differ-
ences should not be great. The second reservation
is that these figures are based on changes seen in
patients from a single hospital and patients from
a central clinical trial database respectively whereas
ideally the intra-individual changes should be cal-
culated from a group of patients with the disease
similar to that expected in the clinical trial. The
Fogarty Report has given guidance on thresholds
313. This is now out of print but can be borrowed
from the British Library.
+28
+23
+25
+30 Clinical trial analysis
+ 12
Individual parameters.
Changes in central tendency over time: It is probably
best to use the geometric mean or median since
the distributions are skewed. Compare differences
between before and after treatment for the two
treatments. This is best illustrated by a box and
whisker plot. This should pick up Type A ADR.
i.e. changes due to enzyme induction or adaptive
changes.
Shijit tables: Usually illustrated by a noughts and
crosses figure, the abscissa, ‘Y’axis, has three levels
low, normal range and high for the baseline results
and the ordinate, ‘X’ axis, the same for after treat-
ment results. There are more sophisticated types
of shift tables76 and it would be possible to use
the five WHO cancer study g r a d i n g ~ .This
~ ~ is a

0 1994 by John Wiley & Sons, Ltd. PHARMA(ZOEPIDEMIOLOGYAND DRUG SAFETY, VOL.3: 91-103 (1994)
100 M. D. B.
fairly crude method; but useful for a preliminary
scan and for comparisons between two groups.
ClinicaIly significant thresfiolds: Compare numbers
going beyond the threshold values for the different
treatments.
(a) Absolute thresholds - either use the
Fogarty Report levels or it can be done as
shown by Mann et al. already referred to
above i.e. number of patients above the ULN
but below ULN x 2, above ULN X 2 but
below ULN x 3 etc. In some studies where
there are expected to be large changes there
may be a need for more than three levels
e.g. cancer where the five WHO gradings can
be used as threshold^.^' The use of a single
threshold value is rather crude like the simple
shift table.
(b) Relative thresholds - here we need signifi-
cant changes from the baseline value (per-
centage change) and these are very useful
when there are many abnormal values prior
to a study and for the accurate measurement
of change. (i) Use the Ninewells Hospital
figures (99% level) or use various percentage
band changes from baseline e.g. 10%1,20%
etc., (Table 7) or (ii) Use the Delta Limits.75
These should pick up the Type B ADR.
Individual patient assessment: Those going beyond
threshold levels require assessment of any clinical
details as well as the complete laboratory profile.
Liver group parameters. These look at the whole
group of liver function tests to ether: (1) Clinical
F
trialist’s opinion (if ~ollected).~(2) Genie Score.7x
( 3 ) Summed Ranks.75The latter two do not add
much as an assessment of quality but they quantify
the individual changes and combine them into a
single figure and are, therefore, useful in group
comparisons. The clinical trialist’s opinion of the
whole group of LFTs should be given as the prob-
ability that they are caused by the drug. i.e. unlik-
ely, possible, probable and almost certain. If the
assessments are made by a general physician then
they should be considered as essential.
The choice of methods for any individual trial
will depend on the underlying disease, the size of
the study, the degree of change expected over the
course of the study and the duration of the study.
Any clinically significant changes must be exa-
mined for differences between sub- roups based on
patient, drug and disease variables.9 6
0 1994 by John Wiley & Sons, Ltd. PHARMACOEPIDEMIOLOGYA N D DRUG SAFETY, VOL.
STEPHENS
DISCUSSION
There is at first sight ambiguity between the state-
ments which say ‘The degree of elevation of amino-
transferases and the extent of liver cell necrosis
evident on liver biopsy is poorly correlated.
Accordingly the height of the aminotransferase ele-
vation has little prognostic value’ . . .’ It is import-
ant to realise that significant liver disease may be
present despite normal levels of the transami-
nases”’ or ‘Although elevated serum levels of these
enzymes (AST, ALT) indicate the presence of liver
injury, the degree of elevation is of no prognostic
value and does not correlate with the degree of
liver dysfunction’.’ and ‘Like several other investi-
gators, we found no correlation between the degree
of liver enz me elevation and the degree of histolo-
gic injury”‘with other statements, such as, ‘Minor
abnormalities (AST I 2 X ULN) are often self-
limiting and of little significance while elevations
greater than this should be taken seriously’79and
again ‘With regular monitoring it is reasonable to
continue for up to 6 weeks in an asymptomatic
patient who has minor (up to two-fold) elevations
in transaminase because such abnormalities are
often self-limiting’.’’ The Fogarty threshold values
themselves suggest that there is some correlation
between the degree of elevation and the liver
damage. The large number of drugs which had
abnormal LFTs mentioned in their data sheet with-
out causing hepatotoxicity suggests an adaptive
change. If the majority of these were less than 2
x ULN then it would explain the ambiguity. The
figures given by Mann and his colleagues6’support
this, in that 8.5% were less than 3 X ULN and 66%
less than 2 x ULN. It is a pity that papers similar
to the Mann paper have not been written about
other drugs.
The very wide range of diseases that can cause
raised LFTs emphasizes the need to request the
clinical trialist’s opinion on the laboratory form.
Many of the diseases will fall outside the trialist’s
speciality and in these cases it is frequently wise
to ask them to obtain an opinion from a relevant
specialist.
The lack of predictability of hepatotoxicity has
been summed up ‘Les anomaIies des tests fins de
detection ne permettent pas de prevoir le risque
hepatotoxique’.xO
Although abnormal LFTs have little part to play
in the prediction of hepatotoxicity as a group, indi-
vidual parameters or combinations of parameters
may be useful; but to my knowledge these have
3: 91-103 (1994)
 ASYMPTOMATIC ABNORMAL LIVER FUNCTION TESTS
not been examined. Only regulatory authorities
have access to the necessary data.
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