asymptomatic abnormal liver function tests in clinical trials

PHARMACOEPIDEMIOLOGY AND 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 Kings 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 (SCOT) also known as Aspartate Amino-

Liver function test abnormalities may be present on entry to a clinical trial or appear whilst on treatment 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.

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 as Gamma-Glutamyl Transpeptidase.

Asymptomatic abnormal liver function tests

( 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

(LFTs) occurring in clinical trials may be due to: In the USA the lactic dehydrogenase (LDH) is favoured but it is too insensitive and too non-specific 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-specific it is sensitive.

These tests are known collectively as the liver function tests (LFTs) but do not really measure

Liver disease and drug hepatotoxicity will not be dealt with in this article.

The usual Screen for liver damage in clinical trials comprises:

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).' (1) Total Bilirubin

CCC 1053-8569/94/020091-13 0 1994 by John Wiley & Sons, Ltd.

Received 24 Deceniber 1993 Accepted 12 April 1994

92 M. D. B. STEPHENS

TOTAL BILIRUBIN TRANSAMINASES

This is not the early harbinger of liver cell damage and there is no correlatiqn between its level and the degree of liver disease.. Its elevation may reflect impaired uptake, conjugation, or excretion of bilirubin, over-production or a leak back of conjugated or unconjugated pigment from damaged cells. It is derived principally from the breakdown of haemoglobin. Ten to thirty per cent is derived from haem precursors within the liver or bone marrow or from myoglobin and other non-haemoglobin haem proteins.' Before reaching the liver it is water- insoluble and requires conjugation within the liver in order to be excreted as water-soluble conjugated bilirubin in the bile. It binds to plasma albumen4.' Drugs e.g. sulphonamides, may compete with bilirubin for binding sites on albumen leading to excess tissue deposits which may result in a lower serum level of bilirubin. Drugs may also compete for uptake of bilirubin by the liver cell. The conjugation within the liver may be impaired by drugs e.g. novobiocin.6 The bilirubin level does not alter with age. '

An elevation of bilirubin may be a late sign of extensive hepatic cell damage or an early sign of cholestasis. Clinical jaundice is usually detected when the serum bilirubin reaches 2 to 3 mg per 100 ml(34.2-5 1.3pmo1/1).' Liver enzyme induction can reduce the serum levels by increased metabo- lism.

There are four congenital bilirubin disorders of which only one is frequent enough to cause prob- lems in clinical trials.

Unconjugated bilirubin ( 1 ) Gilbert's disease. This is relatively common, with an incidence of 5-6%). The bilirubin usually varies between 20-40pmol/l(1.2-2.5 mg/dl and rarely exceeds 80 pmolll ( 5 mg/dl). It usually presents in the second decade so it may be noticed in a volunteer on their first screening. It may be noticed first during an intercurrent illness or on fasting.'

( 2 ) Crigler-NajJar Syndrome. This is rare and usually presents at birth. Bilirubin levels vary between 80-350 mg/l (1 368-5985 ,umol/l)

Conjugated bilirubin ( 1 ) Dubin-Johnson Syndrome. Harmless. ( 2 ) Rotor S-vndrotne. Similar to above.'

Most liver diseases cause increases in the level of the transaminases and these usually indicate cell necrosis. The death of one cell in 750 is sufficient to cause ALT elevation.'" The degree of elevation is of no prognostic value and does not correlate with the degree of liver dysfunction.'." They do not increase with age. They catalyse the removal of an amino group from a donor amino acid and transfer it to a recipient keto acid."

Aspartase aminotransferase ( S G O T ) ( A S T ) This enzyme is non-specific being present in skeletal and heart muscle, ancreas, kidney, liver and red blood cells (RBC).'I4 The half-life is 17 h." There can be a marked elevation with 'macro AST', a very rare complexing with immunoglobulin G (IgG)."

Alanine aminotransferase (SGPT) ( A L T ) This is more specific for the liver than the AST but may rise in disseminated cancer, muscle disease. acute renal disease and acute pancreatitis. ' A three- fold rise in the ALT activity has a predictive value of 95% and the predictive value of a negative result is 87-970/;~'~ The half-life is 47 h."

Alkaline phosphatase ( A P ) and gamma glutamyl transferase (GGT) Whereas the ALT and AST are formed by the release on cell lysis and are the main indicators of hepato-cellular damage, the AP and GGT are increased by increased production although the latter is debated with the GGT. They are both indicators of biliary cholestasis but are non-specific. They are also both induced by drugs which can raise their serum level."

Gamma glutamyl transferase (GGT) This enzyme occurs mostly in the liver, kidney, pancreas and prostate. It may be raised in pancreatic disease, myocardial infarction, angina pectoris, cerebral tumour, cerebrovascular accident, diabetes mellitus, chronic obstructive airways disease, acute renal failure, nephrotic syndrome, post-transplant rejection, cervical cancer after radiation therapy and in the fortnight after severe trauma." In choles-

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ASYMPTOMATIC ABNORMAL LIVER FUNCTION TESTS 93

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 elevated 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 obstruction 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 cholestatic injury.'* The first sign of a drug-induced cholestatic jaundice may be a raised AP, occurring up to 3 weeks after dechallenge."

Lactate dehydrogenase (LDH) 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, pulmonary 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 hepatitis, viral hepatitis, infectious mononucleosis, cholestasis, 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

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 overweight 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 1 7 O % 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 infection, three had past infection and three had chronic infection." Again in blood donors potentially infectious 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 alcoholic 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 miscellaneous 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,

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measles, rubella, Varicella zoster and entero viruses - Coxsackie A and B. All volunteers should be screened, therefore, for the human immune virus (because of its association with opportunistic infec- tions), hepatitis A, B and C , and the Epstein-Barr virus. Diet: A sucrose-rich diet doubled the ALT in non- obese volunteers, whilst in the obese this same increase did not produce values greater than 2 X ULN.29 Two to 4 h after a fatty meal the AP (intestinal isoenzyme) increased.’ Gilbert’s Syndrome:

Transient changes. Chance: Using the ‘normal range’ (mean 2 stan- dard deviations) 1 in 20 will have an ‘abnormal’ result for any parameter; but since, on the whole, one tests five LFTs the chance of a normal healthy person having an abnormal LFT increases to 23%. This risk can be diminished if the mean plus 3 stan- dard deviations is used as the ‘normal range’ when the figure is reduced to 1.3%. If the LFT is more than 25% above the ULN it is very unlikely to be due to chance.30 The argument above presumes that the ‘normal range’ referred to excludes 2.5% at each end of the range and this may not be so, due to the skewed distribution of LFTs and secondly it presumes that each parameter is independent which is clearly not so for the LFTs. However the princi- ple is highly relevant to the single abnormal LFT which is just above the ULN. Venepuncture: (a) Haemolysis - haemolysis of 1% of the red blood corpuscles caused 220% increase in AST, 272% increase in LDH and 55% increase in ALT.’ (b) Tourniquet - a 3-min compared with a 1-min tourniquet increased bilirubin by 8% and AST by 10%. (c) Posture - standing compared 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 alter the AP, GGT, or LDH in normal healthy men who usually drank moderately (6-10 pints per ~ e e k ) . ~ ’ Increases in AST of up to 108% were seen in non-alcoholic volunteers who drank 270 g alcohol (approx. 34 drinks or 16 pints of bitter) in eight doses over 18 h to simulate a weekend social binge, the AST levels were < ULN X 2 and the blood alcohol levels did not exceed 80 mg: other LFTs were not analy~ed.~’ Exercise: A I-h game of handball produced a 41%) increase in AST and a 32% increase in LDH which remained over baseline for 53 h or more.I6 The AST peaked at 24 h (ULN X 3.8) after a marathon race,

the ALT at 96 h (ULN x 1.5) and the LDH at 1 h (ULN x 4.7).” There may be a rise in bilirubin after severe exe~cise.~ Trauma: Stings produced an AST up to ULN X 5.8, ALT up to ULN X 2.9 and LDH up to ULN x 3.5 within 2 h of hospital admission, as well as acute tubular necrosis in one ~at ient .~’ Intramus- cular injections, especially penicillin, may cause a rise in the AST.l9 Fractures can, of course, produce rises in AP. Diet: Fasting causes an increase in bilirubin so that after 48 h the average increase is 240% due to dec- reased hepatic ~learance.~ Other: When AP and AST were followed over 30 weeks in healthy volunteers elevations above the ULN were infrequent and occurred almost exclus- ively in males when the mean values were near the ULN. For both parameters there were highly significant differences between males and females, the latter being lower. The within-person variation is small for both sexes. This suggests that separate ranges for the sexes should be used for volunteers and that abnormal values should be compared with the individual’s past results.34

Inveresk Clinical Research found that in five volunteer studies of active drug versus placebo that the LFTs were higher on the active drug than whilst on placebo. The interpretation of these figures

Table 2

Placebo Active

AST 2/166 (1.2%) 17/265 (6.4%) ALT 6/166 (2.6%) 26/265 (13.6?40) AP 11166 (0.6%) 0/265 (0%) BIL 0/166 (OYo) 51265 (1.840) GGT 3/149 (2.2%) 5/242 (2.0%)

is difficult. (See Table 2.) In one study mean values, at different time points, showed no statistically significant differences between active and placebo group. The magnitude of the changes in the placebo group was similar to that seen in the active group. The author suggests that this may mean that there was another factor other than the active

A German group examined the pre-study values of the liver enzymes in 397 volunteers comparing the first pre-study value with all pre-study values. They found no tendency towards elevated enzyme activities in frequent study participant^.^^ The figures, however, are interesting in that the percent- ages within the ‘normal range’ (given in the litera-


Table 3

AST ALT GLDH GGT First pre-study

All pre-study evaluation 92.3 92.8 94.2 92.0

evaluations 95.4 91.0 94.4 93.8

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 abnormalities. 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 ischaemic 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 disease’ OTCH). Thyroid: (a) Hyperthyroidism - out of 570

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hyperthyroid patients 15% had one or more abnormal LFTs: AP, AST, bilirubin. ALT was not te~ ted .~’ Another paper put the figure as high as 72%: bilirubin - 31%, AP - 67%, AST - 24%, ALT - 26% and LDH - 13‘%1.~‘ There is a slight rise in GGT.“

(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 elevated 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.’.3X The 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 patterns 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

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 GCT is raised,’” reaching maximum levels (up to

of drugs was responsible. g .4 , Serum transaminases

:OEPIDEMIOLOGY AND DRUG SAFETY, VOL. 3: 91-103 (1994)

6 x ULN) at 1-2 weeks. The AP rises later reachin a maximum at 3 weeks often rising to ULN X 3-5. 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 dystrophy 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 3.38 Surgical 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 car~inoma.~ The ALT may be raised in acute renal failure’ and an isolated AP in chronic renal failure.2 (Reference: the chapter ‘The liver in urogenital disease’ 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 transaminase < ULN x 2) and 25%) had markedly abnormal 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 abnormal LFTs.’~ Even in remission 3% of patients have abnormal LFTs and the author said that the majority 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%, aminotransferases in 20%, AP in 10% and LDH. Mycoplasma pneumonia - raised transaminases and AP not unusual.

8 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 aminotransferases). 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 transaminases can occur after a protracted seizure in children 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.38 In Guillain-Barre syndrome and other neurological 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 disease 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 cirrhosis.” 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 induction. Cancer: The ALT and LDH may be raised in disseminated cancer.’,4 A minor activity increase may be seen in AP (isolated).*’ There can be a sli ht rise in GGT in malignant diseaselradiotherapy. Haematological diseases: Biochemical signs of cho-

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lestasis, generally due to leukaemic infiltration, may be noted in acute leukaemias.m The LDH is likely to be raised when there is destruction of RBC and in myeloid l e~kaemia .~ An isolated raised AP may occur in Hodgkin's disease. (Reference: the chapter 'The effect of haematological and lymphatic disease on the liver' OTCH). Pulnionury diseuse: AST, ALT, Total bilirubin, AP, and GGT were significantly higher in chronic res- piratory insufficiency than in controls, all had POz < 60 mmHg.' The AST rises in pulmonary embolism. l4

Chronic obstructive pulmonary disease - increase in GGT in sputum."

Miscellaneous: Heat stroke - elevation of transferases (usually < 6-8 x ULN) and AP. Extramedullary haemopoiesis - AP raised in

Jejunoileal bypass - 50% have serious hepatic abnormalities. Bone marrow transplant - 83% had abnormal LFTs.~* Cervical cancer after radiotherapy - increase 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 hours and then again in 2-3 weeks. Radiation - changes are rare due to the relative radio resistance of the liver and occur mostly in the treatment of ovarian tumours. (Reference: the chapter 'Hepatic injuries due to physical agents' OTCH). Anorexia nervosa - there may be a slightly raised GGT. Porphyria cutanea tarda - there may be a slightly raised GGT.I4 (Reference: the chapter 'The effect of skin diseases on the liver' OTCH).

50'%1.

Transient changes. In addition to that mentioned under volunteers. Dief: Abnormalities of liver enzymes and bilirubin are commonly seen during total parental nutrition. There is fatty infiltration and progressive intrahe- patic cholestasis. Thirty to sixty per cent will show a rise of at least one liver test greater than 50% of baseline:4x the most frequent being the AP. initially occurring at 10-14 days, without concomi- tant changes in transaminases. The AP persists more than one month in most cases.h3 Stutus usthmuticus: Both AST and ALT may be raised in severe a~thma.~ , '

Enqwte induction: Enzyme inducers such as alcohol, phenobarbitone, phenytoin and rifampicin produce an increase in AP and GGT and a decrease in bilirubin." (See Table 4.) The marker for enzyme induction is urinary 6P-hydroxycortisol and significant increases are seen at 4 days with antipyrine, 13 days with phenobarbitone and after 2 days with rifampicin reaching maximum at 11-14 days and had not returned to baseline by 6 days.h4

Table 4

Phenytoin-treated Controls

Mean Range Mean Range epileptics

(95% C.1.) (95% C.1.)

Male ALT 25 0-63 14 0-38 AP 46 0-93 35 0-6 1 Bil 5.6 2.7-11.2 9.8 2.6-18.1

Female A LT 18 0-36 12 0-24 AP 37 6-70 29 11-47 Bil 4.6 2.5-8.5 6.9 3.5-11.3

The explanation of these differences could be the inducing effect of phen toin; but ALT has not been reported as inducible. Another study showed that the elevation of serum enzymes and serum levels of phenytoin andfor henobarbitone showed a significant correlation! There is a suggestion that rifampicin induction takes effect within a few

Benzodiazepines can increase GGT but not by enzyme induction.68 Adaptive change: In a study of two antihypertensive drugs, Guanoxan and Guanoclor, 30% and 22% had elevated transaminases before treatment and 59% and 64% of patients respectively had rises in transaminases above normal whilst on treatment. Of those patients where the outcome is known nearly all returned to normal on continued treatment (97% and 100%) respectively. (See Table 5.)

Those with raised transaminases had fewer side- effects than those without. The mechanism was thought to be that the changes were an expression of metabolic effects associated with adaptive, in vitro, handling of the dru s. There was a wide variation in the time to onset. Professor Sherlock may have been referring to this when she said 'The serum transferase may rise during the first four weeks of therapy on1 to subside even though the drug is contin~ed' .~ ' Another authority may also be refer-

2

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98 M. D. 8. STEPHENS

Table 5 ~~~

Levels of transaminases (where raised) Mean ( x ULN) Range ( X ULN)

Guanoxan AST 1.96 0.15-7.5

Guanoclor AST 1.46 0.575-4.65 ALT 1.85 0.05-5

ALT 1. I4 0.14.3

n=44 n = 36 Changes in terms of ULN

N-2 x ULN 24 29 2-3 X ULN 10 5 3 4 x ULN 3 0 4-5 X ULN 3 2 5-6 x ULN 2 0 6-7 X ULN 1 0 7-8 x ULN 1 0

ring to this when saying ‘Many drugs that have not produced clinical liver disease raised the activitv of AST and ALT in the first week or two

from the ABPI Compendium. For each drug the side-effects section was examined for the presence or absence of mention ofabnormal LFTs and hepatotoxicity. (See Table 6 . )

Table 6

Hepatotoxicity Absent Present

Mentioned 102 94 196 Abnormal liver function tests

Not mentioned 61 302 363 163 396 459

Sensitivity = 62.57‘%,. Specificity = 76.26% Prevalence = 35.5‘%1. Positive predictive value = 52.04’%~ Negative predictive value = 83. I9‘%,

Of use. Indeed this finding may apply to drugs The LFTs are little more use than tossing a coin for the prediction of hepatotoxicity but the absence of abnormal LFTs on marketing is slightly better

metabolized in the liver’.6 Similar changes were described for lofepramine

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

EVALUATION AND ANALYSIS OF ABNORMAL LFTS

on continued treatment by the end o f a 12-week trial. GGT showed little change.”

Individual putierz ts DO ABNORMAL LFTS PREDICT HEPATOTOXICITY? Different patterns of abnormal LFTs are found

with hepato-cellular, cholestatic and mixed liver Using the ABPI (Association of the British Phar- injury. The highest serum transaminase in terms maceutical Industry) Data Sheet Compendium, of multiples of the ULN is divided by the AP, again 1993-94 and making the following presumptions: in terms of the multiples of the ULN. If the ratio

is 2 or less, or if the AP > 2 x ULN alone it ( I ) That the abnormal LFTs mentioned were indicates a cholestatic injury; whilst a ratio of 5 discovered at or before marketing and that the or greater, or the ALT > ULN alone it indi. hepatotoxicity was discovered after marketing cates hepato-cellular injury. A mixed liver injury is indicated if the ratio lies between 2 and 5, and or after the discovery of abnormal LFTs.

(2) That drugs were excluded if they had more the ALT > ULN with an increase in AP.7’ The than one active ingredient, if they were for local term ,hepatitis, should not be used unless there is application, if they were not normally used for biopsy evidence. I f there is no biopsy and there periods greater than 5 days and if they were is an increase in ALT or conjugated bilirubin of > 2 x ULN or a combined increase of AST, AP newer drugs marked with a V.

This does not account for the drugs removed from and total bilirubin and one of them is greater than the market. There were eight of these which had ULN X 2 then the term ‘liver injury’ should be hepatotoxicity at the time of removal: Benoxypro- used and the type of injury given as above. Other fen, Benziodarone, Ibufenac, Mebanazine, Niala- abnormalities of ALTs, ASTs and APs < 2 X ULN mide, Oxyphisatin, Phenoxypropazine and should be listed as increases in the relevant para- Temafloxacin.” The table below was compiled meter. Any other abnormalities of biochemical tests

0 1994 by John Wiley &Sons, Ltd. PHARMACOEPIDEMIOLOGY AND DRUG SAFETY, VOL. 3: 9 1-1 03 (1994)


should be recorded as such and not included in the liver section.73

The intra-individual variation is much smaller than the inter-individual variation. The Ninewells Hospital biochemical department has produced in its handbook74 a list of the individual changes in biochemical parameters which are significant at different levels. (See Table 7.)

indicating possible hepatotoxicity and need for fol- low-up evaluation. (See Table 9.)

Table 9-Criteria for possible hepatotoxicity

Phase I Aminotransferases > 2 X ULN Alkaline phosphatase > 1.25 X ULN Total bilirubin > 1.5 x ULN

Phase I1

95% 99% significance Alkaline phosphatase > 1.25 x ULN Aminotransferases > 3 x ULN

Total bilirubin > 1.5 x ULN

Table 7

Bilirubin AP ALT LDH GGT

4 6 pmol/l 26 36 U/l 16 23 U/I 46 65 U/l 10 14 U/I

Another method for intra-individual variation 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 of 1 or 2 weeks.75 (See Table 8.)

Table 8-Delta limits ~ ~ ~ ~~~~~

Changes exceeded by 1% of values Decrement Increment

ALT (Uil) - 29 +28 AST (U/I) - 28 + 23 GGT (Ull) - 20 + 25 AP (U/I) -32 + 30 Bilirubin (pmol/l -10 + 12

The only two reservations about the usage of both methods is that these figures combine the intra-individual variation and the analytical variation in their particular laboratory; the latter will vary from laboratory to laboratory but the differences 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

0 1994 by John Wiley & Sons, Ltd. PHARMA(

Phase 111 and IV Minimally abnormal level (warning) Aminotransferases < 3 x ULN or 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 Total bilirubin > 2~ ULN

There is no substitute for reading the Guidelines 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- cation and Welfare, Public Health Service, Natio- nal Institute of Health, NIH Publication N079- 313. This is now out of print but can be borrowed from the British Library.

Clinical trial analysis 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 treatment 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

ZOEPIDEMIOLOGY AND DRUG SAFETY, VOL. 3: 91-103 (1994)


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 significant changes from the baseline value (percentage 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 trialist’s opinion (if ~ol lected) .~ (2) Genie Score.7x ( 3 ) Summed Ranks.75 The 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. unlikely, 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 examined for differences between sub- roups based on patient, drug and disease variables.

F

9 6

DISCUSSION

There is at first sight ambiguity between the statements which say ‘The degree of elevation of aminotransferases and the extent of liver cell necrosis evident on liver biopsy is poorly correlated. Accordingly the height of the aminotransferase elevation has little prognostic value’ . . .’ It is important to realise that significant liver disease may be present despite normal levels of the transaminases”’ 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’79 and 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 without 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, individual parameters or combinations of parameters may be useful; but to my knowledge these have


101 ASYMPTOMATIC ABNORMAL LIVER FUNCTION TESTS

not been examined. Only regulatory authorities have access to the necessary data.

REFERENCES

1. Helzberg, J. H. and Spiro, H. H. ‘Liver function tests’ test more than just the liver. JAMA 1966; 256(2): 3006-3007.

2. McIntyre, N. Benhamou, J-P., Bircher, J., Rizzetto, M. and Rodes, J. (Eds) Section 24, The liver in diseases of other systems, Oxford Textbook of Clinical Hepatology. Oxford University Press, 1991.

3. Gitnick, G. Assessment of liver function. Surgical Clinics of North America 1981; 61(1): 197-207.

4. Eastham, R. D. Biochemical Values in Clinical Medi- cine, 7th edn. Wright, 1985.

5. Statland, B. E. and Winkel, P. Effects of preanalyti- cal factors on the intraindividual variation of ana- lytes in the blood of healthy subjects: consideration of preparation of the subject and time of venipunc- ture. Critical Reviews in Clinical Sciences 1977; 8: 105-1 44.

6. Perez, V., Schaffner, F. and Popper, H. Hepaticdrug reactions, Chapter 35. In: Progress in Liver Diseases. Popper, H. and Schaffner, F. (Eds), Grune & Strat- ton, New York and London, 1972.

7. Gambert, S. R., Cauka, M. E., Duthie, E. H. and Tiegs, R. Interpretation of laboratory results in the elderly. Postgraduate Medicine 1982; 72(3): 147-152.

8. Schimmel, E. M. Diagnostic procedures in liver disease. Medical Clinics of North America 1968; 52(6): 1407- 14 16.

9. Zilva, J. F., Pannall, P. R. and Mayne, P. D. (Eds.) Clinical Chemistry in Diagnosis and Treatment, 5th edn. Lloyd-Luke (Medical Books) Ltd., 1988.

10. Moss, D. W. Diagnostic enzymology: Some princi- ples and applications. Hospital Update October 1981;

1 1. Dossing, M. and Andreason, P. B. Diagnosis of acute drug-induced liver injury. Usefulness of clinicopath- ological patterns and biochemical indices. Medical Toxicology 1986; 1: 77-82.

12. Corless, J. K. and Middleton, M. H. Normal liver function - a basis for understanding hepatic disease, Archives of Internal Medicine 1983; 143: 2291-2294.

13. Connelly, M. S., Kennedy, H. J., Dawson, C. M. Howe, G. D. and Tickner, T. R. Innocent elevation of aspartate aminotransferase. Lancet 1989; i: 847.

14. McIntryre, N. and Rosalki, S. Chapter 6.1, Bioche- mical investigations in the management of liver disease. In: Oxford Textbook of Clinical Hepatology, Oxford University Press, 199 1 .

15. Hayes, P. C. and Bouchier, 1. A. D. Liver function tests in clinical practice their uses and limitations. Clinical Chemistry and Enzyme Communication.

16. King, S. W., Statland, B. E. and Savory, J. The effect

99-1 10.

1989; 2: 23-34.

of short bursts of exercise on activity values of enzymes in sera of healthy young men. Clin. Chim. Actu 1976; 72: 211-218.

17. Ohman, E. M., Teo, K. K., Johnson, A. H. et al. Abnormal cardiac enzyme responses after strenuous exercise: alternative diagnostic aids. British Medical Journal 1982; 285: 1523-1526.

18. Ness, M. M. and Diehl, A. M. Is liver biopsy useful in the evaluation of patients with chronically elevated liver enzymes? Annals of Internal Medicine 1989; lll(6): 473-478.

19. Davis, M. Drugs and abnormal LFTs, Adverse Drug Reactions Bulletin 1989; 139: 520-523.

20. Penn, R. and Worthington, D. J. Is serum Gamma- glutamyltransferase a misleading test? British Medi- cal Journal 1983; 286: 531-535.

21. Lieberman, D. and Phillips, D. ’Isolated’ elevation of alkaline phosphatase significance in hospital patients. Journal of Clinical Gastroenterology 1990; 12(4): 415-419.

22. Davidson, C. S., Leevy, C. M. and Chamberlayne, E. C. (Eds). Guidelines for detection of hepatotoxicity due to drugs and chemicals. U.S. Department of Health, Education and Welfare, NIH Publication No. 79-313,1979,

23. Isaacs, A. J., Macarthur, J. B. and Taylor, D. H. Jaundice in relation to chlorpromazine. British Medical Journal 1955; ii: 1 122.

24. Dickerson, J. K., Earnest, D. L. and Bressler, R. Prevalence of abnormal liver function tests in laboratory workers. Clinical Research Practices and Drug Regulatory Aflairs 1983; l(2): 151-162.

25. Friedman, L. S., Dienstag, J. L., Watkins, E. et al. Evaluation of blood donors with elevated serum alanine aminotransferase levels. Annals of Internal Medicine 1987; 107: 137-144.

26. Palmer, M. and Schaffner, F. Effect of weight reduction on hepatic abnormalities in overweight patients. Gastroenterology 1990; 99: 1408-1413.

27. Katkov, W. N., Friedman, L. S., Cody H., et al. Elevated serum alanine aminotransferase levels in blood donors: the contribution of hepatitis C virus. Annals of InternalMedicine 1991; 115: 882-884.

28. Sanders, S. W. and Tolman, K. G. Application of Epstein-Barr antibody studies in etiologic differen- tiation of aminotransferase elevation during con- trolled clinical trials. Journal ofClinica1 Research and Drug Development 1987; 2: 135-139.

29. Porikos, K. P. and Van Itallie, T. B. Diet induced changes in serum transaminase and triglyceride levels in healthy adult men. Role of sucrose and excess calories. American Journal of Medicine 1983; 624-630.

30. Schoen, I . and Brooks, S. H. Judgement based on 95% confidence limits. American Journal of Patho- logy 1970; 53: 190-195.

31. Gill, G. V., Bayles, B. H., Flear, C. T. G., Skitten, A. N. and Diggle, P. H. Acute biochemical responses



to moderate beer drinking. Briti.sli Mrcl i cd Journtrl S ( ~ t / ~ ~ t / i / i t / ~ ~ i t / / ~ JoL/,'rlt/l (!f' R h r ~ / / t l r / t o k , ~ ~ ~ 1980; 9: 8 I - 1982; 285: 1770-1773. 88.

32. Rubin, E. and Lieber, C. S. Alcoholic-induced hep- 48. Holdstock, G. Millward-Sadler, G. H. and Wright. atic injury in nonalcoholic volunteers. Ncii~ Engltrntl R. Hepatic changes in systemic disease. In: Li iw tirid

Jorrrnttl of'Midici t tc 1968; 278( 16): 869-876. Bilitrry Di.srn.se. Wright. R., Millward-Sadler. G. H.. 33. Lim. P., Tan, I. K. and Feng, P. H. Elevated serum Alberti, K. G. M. M. and Karran, S. (Eds), Bailliere.

enzymes in patients with waspibee stings and their London, 1985, pp. 1033-1076. clinical significance, C/;ll;et~ C/1;)Jlic'[/ A C T A 1976; 66: 49. Jewell. D. P. Miscellaneous disorders of the gastroin- 405409. tes tinal tract and I iver. In: O.\;fh.c/ Tc.vfhook of 'Mtdi -

34. Levin, G. E., McPherson, C. K., Fraser, P. M. and cine, 2nd edn., Vol. 1. Weatherall, D. J., Ledingham, Baron. D. N. Long-term variation in plasma activi- J. G. G. and Warrell, D. A. (Eds), Oxford University ties of aspartate transaminase and alkaline phospha- Press, 12.273-12.275. 1987. tase i n health. Clinicul Scicwcx> 1973; 44: 185-196. 50. Kataja, J. and Gordin, R. Serum gamma-glutamyl

35. Wyld, p, J. clinical pathology l,,easurel,,ents: the transpeptidase and alkaline phosphatase in severely detection significance of what is in: injured patients. Acfu Chit-. Scuntl. 1970; 136: 277- Clinicerl ~ ~ ~ ~ ' c i ~ ~ i r e r ~ i e n t in Drug E vcrlucr f ion . N immo, 281. W, S, and ~ ~ ~ k ~ ~ , G, (Eds), wolfe Publishing Ltd,, 51. Pennington. R. J. T. Biochemical aspects of muscle London, 1991, pp. 115-127. disease. In: Disorr1er.s qf' Vo1unrcir.1~ Musch~, 4th edn.

36. Kuhlman, J.. Adelmann, H.. Loof, I . . Wargenass. Walton, J. N. (Ed.), Churchill, London, 1981. pp. M.. Weber. H. and Wingender, W. Data distribution 417447.

Hepato-biliary complications of ulcerative colitis. niticology tint/ Tliertrpwtics Abstr. 1991; 49(2): 155. Aincvicun Journcrl(?f'SLrr~Cr~' 1980; 139: I 13-1 18.

53. Kenny, R. M., Hodkinson, H. M., Prendiville. 0. diagnosis of acute myocardial infarction. Acftr F., Hayes, M. C. and Flynn, M. D. Abnormalities Midictr Sctrtit/i/itrvictr Suppl. 1972; 539 7-62. of liver function and the predictive value of liver 38. Wroblewski, F. The clinical significance of transami- function tests in infection and outcome of acutely nase activity of serum. Aiwrictin Journtrl of'Mcdic+w i l l elderly patients. AgecmdAgeing 1984; 13: 224-229.

54. Holdstock, G.. Balase-Garham, M.. Millward- 1959; 27: 91 I . 39. Cohen, J. A. and Kaplan, M. M. Left-sided heart Sadler, G, H , and Wright, R , The liver i n infection,

Chapter 39. In: Liver. tint/ Bilitrry Di,secrse, 2nd edn. failure presenting as hepatitis. G t r . s / r o ~ ~ ~ i f e r ~ ) l ~ , g ~ ,

Wright, R., Millward-Sadler, G. H., Alberti, K.G. 1978; 74: 583-587.

M. M. and Karran, S. (Eds). W. B. Saunders, Bail- 40. Nouel. 0.. Hennion, J., Bernuau, J.. Degott, C.. Rueff, B. and Benhamou, J-P. Fulminant hepatic likre-Tindall, 1985, pp. 1077-1079, failure due to transient circulatory Failure in patients 55. Ussery, x. T,, Henar, E, L., Black, D, D., Berger, with chronic heart disease. Digcwiiv Disewses ant/ s. and Whittington, p. F, Acute liver injury after

protracted seizure in children. JourntrI of' Prtlitrtric Sciencrs. 1980; 25( I ) : 49-52.

of liver enzymes in healthy volunteers, C/jliic',/ P/irrr- 52. Lupinetti, M.3 Mehigatl, D. and Cameron, J. L .

37, ~ ~ ~ i ~ ~ ~ , s. ~ ~ ~ l ~ ~ ~ i ~ ~ of SerUln enzylne ill the

41. Bynum, T. E., Bri tnel l+ J . K. and Maddrey, w. c. Ischaemic hepatitis. Dige.sti\~e D;Set/SCJS tint/ sCfC'l?CCJ.S.

Grrsfrornfrrolog?, [ lnt /Nufrj t jon 1989; 9: 421. 56, E ~ ~ ~ , L, M , and criffiths, J. seruln gamma-glutalnyl

transpeptidase: elevated levels in certain neurologi- cat diseases. Cliniccrl Clinriistrj~ I97 I ; 17(7): 642.

57. Cohen, J. A. and Kaplan, M. M. The SGOT/SGPT ratio in liver disease. Gcrstroenrerologi~ 1975; 69: 81 3.

5 8 , Ryback. R , s,, p k a r d t , M. J , , F ~ I ~ ~ & , 9. and ~ ~ ~ 1 - ings. R. R. Biochemical and hematologic correlates of alcoholism and liver disease. J A M A 1982; 248( 18):

cosis. Milittrry Merlicinp. 1978; 548-551. 59. Spech, H. J. and Liehr. H. Was leisten SCOT/ 45. Weintraub, M. and Ginsberg, G. Evaluating liver SGPT-, GGTIAP-und IgG/lgA- Quotienen differen-

enzyme abnormalities in clinical trials involving dia- tialdiagnostisch bei fortgeschrittenen Leberkrank- betic patients. Drug [ q f i m i c r t i o n Journtrl 1987; 21: heiten? Z. Gtr.sfroc.nrerologic. 1983; 21: 89-96. 29-37. 60. Rozman, C., Cervantes, F. and Bruguera, M. The

46. Averbuch, M., Pollock, D. J. and Weintraub, M. effect of haeinatologic and lymphatic disease on the Liver enzyme evaluation in clinical trials involving liver. In: Oxfbrtl Te.\-thook q f ClinicciI Hepcrtolqy. diabetic patients, Ahs. Control1c.d Clinicti1 TritrI.~ Mclntyre, N., Benhamou, J-P., Bircher, J., Rizzetto, 1987; S(3): 301. M. and Rodes, J. (Eds). Oxford University Press,

1991, pp. 1188-1 194. function in some common rheumatic disorders. 61. Barton. A. D., Power, J. L. and Lourenco. R. V.

1979; 24(2): 129-135. 42. Lancet Leader. lschaemic hepatitis. Lmicrt May 4th

1985: I01 9-1 020. 43. Ashkar, F. S., Miller, R.. Smoak. W. M. and Gilson,

A. J. Liver disease in hyperthyroidism. South Metli- ctd Journd 197 I ; 64(4): 462-465.

44. Thompson, P., Strum, D., Boehm, T. and Wartojsky, L. Abnormalities of liver function tests in thyrotoxi- 226 1-2265.

47. Akesson, A., Berglund, K. and Karlsson, M. Liver

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


Gamma glutamyl transpeptidase in chronic obstructive pulmonary disease. Proceedings of the Society for Experimental and Biological Medicine 1974; 146: 99-103.

62. Wieczorek, E. Effect of radiotherapy on gamma-glutamyl transpeptidase and lactic dehydrogenase activity in cancer of the uterine cervix. Clinica Chi- mica ACTA 1972; 37: 203-206.

63. Sheldon, G. F., Peterson, S. R. and Sanders, R. Hep- atic dysfunction during hyperalimentation. Archives of Surgery 1978; 113: 504-508.

64. Ohnhaus, E. E., Breckenridge, A. M. and Park, B. K. Urinary excretion of 6/3-hydroxycortisol and the time course measurement of enzyme induction in man. European Journal of Clinical Pharmacology 1989; 36: 3946.

65. Andreasen, P. B., Lyngbye, J. and Trolle, E. Abnor- malities in liver function tests during long-term diphenylhydantoin therapy in epileptic out-patients. Acta Medica Scandinavica 1973; 194: 261-264.

66. Ikeda, H. and Kazamatsuri, H. Elevated activity of various serum enzymes during long-term anticonvul- sant therapy. Folia Psychiatrica et Neurologica Japo- nica. 1981; 35(3): 381

67. Lal, S., Singal, S. N., Burley, D. M. and Crossley, G. Effect of rifampicin and isoniazid on liver function. British Medical Journal 1972; 1: 48.

68. Park, B. K. and Breckenridge, A. M. Clinical impli- cations of enzyme induction and enzyme inhibition. Clinical Pharmacokinetics 1981; 6: 1-24.

69. Mann, R. D., O’Neill East, M., Gooding, R. G. and Jackson, D. The significance of variation in the serum transaminases in the assessment of two new drugs. A synopsis of data from a multi-centre trial. Proceedings of the Meeting of European Society Study Drug Toxicology 1965; 6: 6 1-75.

70. Sherlock S. Hepatotoxicity caused by drug. Rational Drug Therapy 1988; 22(7): 1-7.

71. Kelly, C., Roche, S., Naguib, M., Webb, S., Roberts, M. and Pitt, B. A prospective evaluation of the hepatotoxicity of lofepramine in the elderly. Iiiternafional Clinical Psychopharmacology 1993; 8(2): 83-86.

72. Bakke, 0. M., Wardell, W. M. and Lasagna, L. Drug discontinuation in the United Kingdom and the United States, 1964 to 1983: issues of safety. Clinical Pharmacology and Therapeutics 1984; 35(5): 559- 567.

73. Danan, G., Benichou, C., Begaud, B., et al. Criteria for ascribing acute hepatitis to a drug. Gastroentero- [ogy and CZinicalBiology. 1987; 11: 581-585.

74. Burchell, B. Department of Biochemical Medicine Handbook, 4th edn. Ninewells Hospital and Medical School.

75. Leigh Thompson, W., Brunelle, R. L., Enas, G. G., Simpson, P. J. and Walker, R. L. Routine laboratory tests in clinical trials. In: Clinical Drug Trials and Tribulations. Cato, A. E. (Ed.), Drugs and the Phar- maceutical Sciences, Vol. 34, Marcel Decker, 1988.

76. Stephens, M. D. B. In: Detection of New Adverse Drug Reactions, 3rdedn. Macmillan Pub. Ltd., 1992.

77. WHO Handbook for Reporting Results on Cancer Treatment. WHO, Geneva, 1979.

78. Sogliero-Gilbert, G., Mosher, K. and Zubkoff, L. A procedure for the simplification and assessment of laboratory parameters in clinical trials. Drug Znformation Journal 1986; 20: 279-296.

79. Davis, M. and Williams, R. Hepatic disorders, Chapter 1 1. In: Textbook of Adverse Drug Reactions, 4th edn. Davies, D. M. (Ed.), Oxford Medical Press, 1991.

80. Pessayre, D. and Benhamou, J-P. Est-il possible et souhaitable de detecter l’hepatotoxicite d’un medica- ment avant sa commercialisation? Gastroenterol. Clin. Biol. 1981; 5: 560-563.


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