Table Of ContentCurrent Topics in Pathology
Continuation of Ergebnisse der Pathologie
69
Editors
C. L. Berry E. Grundmann W. H. Kirsten
Advisory Board
H.-W. Altmann, K. Benirschke, A. Bohle, H. Cottier
M. Eder, P. Gedigk, Chr. Hedinger, S. Iijima
J. L. Van Lancker, K. Lennert, H. Meessen, B. Morson
W. Sandritter, G. Seifert, S. Sell, T. Takeuchi
H. U. Zollinger
Drug-Induced Pathology
Contributors
H.W. Altmann, H.-J. Barrach, H.V. Gartner
M. Habs, H. Jick, H.G. Laberke, H.-J. Merker
D . Neubert, E. Perucca, A. Richens
T. Riemenschneider, D. Schmahl
Editor
E. Grundmann
With 94 Figures
Springer-Verlag Berlin Heidelberg New York 1980
c.L. Berry, Professor Dr., Department of Morbid Anatomy, The London
Hospital Medical College, University of London, London Ell BB, Great Britain
E. Grundmann, Professor Dr., Pathologisches Institut der UniversiHit,
Westring 17, 0-4400 Miinster/Westf., Germany
W.H. Kirsten, Professor Dr., Department of Pathology, The University of
Chicago, 950 East 59th Street, Chicago, IL 60637, USA
ISBN -13: 978-3-642-67863-9 e-ISBN -13: 978-3-642-67861-5
DOl: 10.1007/978-3-642-67861-5
Library of Congress Cataloging in Publication Data. Main entry under title: Drug-induced patholo
gy. (Current topics in pathology; 69) Bibliography:p. I. Drugs - Toxicology. 2. Drugs - Side
effects. I. Altmann, Hans-Werner, 1916-II. Grundmann, Ekkehard. III. Series. [DNLM: 1. Drug
therapy - Adverse effects. 2. Kidney diseases - Chemically induced. WI Cu821H v. 69 / QZ42
D793]. RBI.E6 vol. 69 [RAI238]616.07s [615.9]80-24184 ISBN-13:978-3-642-67863-9(U.S.)
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2122/3130 - 543210
Contents
Epidemiological Observation on Drug-Induced Dlness.
H. Jick . . . . . . . . . . ... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . I
The Pathophysiological Basis of Drug Toxicity. With 4 Figures
E. Perucca, A. Richens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
Drug-Induced liver Reactions: A Morphological Approach. With 27 Figures
H.W. Altmann. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69
Drug-Associated Nephropathy. Part I: Glomerular Lesions. With 5 Figures
H.-V. Gartner. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 143
Drug-Associated Nephropathy. Part II: Tubulo-Interstitial Lesions. A: Acute
Interstitial Nephritis, Nephrotoxic Lesions, Analgesic Nephropathy. With
5 Figures
H.G. Laberke . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 183
Drug-Associated Nephropathy. Part II: Tubulo-Interstitial Lesions. B: Hypo
kalemic Alterations. With 4 Figures
Th. Riemenschneider. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 217
Drug-Induced Damage to the Embryo or Fetus. (Molecular and Multilateral
Approach to Prenatal Toxicology). With 43 Figures
D. Neubert, H. .J. Barrach, H. .J. Merker. . . . . . . . . . . . . . . . . . . . . . .. 241
Drug-Induced Cancer. With 6 Figures
D. Schmahl, M. Habs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 333
Subject Index. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 371
Indexed in ISR
List of Contributors
Altmann, Prof Dr. H-W. Pathologisches Institut der Universitat Wiirzburg, Luit
poldkrankenhaus, 8700 Wfuzburg, Germany
Barrach, Dr. H-J. Institut fUr Toxikologie und Embryopharmakologie, Freie
Universitat Berlin, Garystra~e 9,1000 Berlin 33, Germany
Giirtner, Dr. H -V. Pathologisches Institut der Universitat Tiibingen, Lieber
meisterstr~e 8,7400 Tiibingen, Germany
Habs, Dr. M. Institut fUr Toxikologie und Chemotherapie, Deutsches
Krebsforschungszentrum, 1m Neuenheimer Feld 280,
6900 Heidelberg, Germany
Jick, Dr. H Boston University Medical Center,400 Totten Pond Road,
Waltham, Massachusetts 02154, USA
Laberke, Dr. H G. Pathologisches Institut der Universitat Tiibingen, Lieber
meisterstra~e 8, 7400 Tiibingen, Germany
Merker, Prof Dr. H-J. Institut fUr Toxikologie und Embryopharmakologie, Freie
Universitat Berlin, Garystra~e 9,1000 Berlin 33, Germany
Neubert, Prof Dr. D. Institut fUr Toxikologie und Embryopharmakologie, Freie
Universitat Berlin, Garystra~e 9,1000 Berlin 33, Germany
Perucca, Dr. E. Institute of Neurology, Clinical Pharmacology Unit, The
National Hospital, Queen Square, London WC IN 3BG,
Great Britain
Richens, Dr. A. Institute of Neurology, Clinical Pharmacology Unit, The
National Hospital, Queen Square, London WC IN 3BG,
Great Britain
Riemenschneider, Dr. Th. Pathologisches Institut der Universitat Tiibingen, Lieber
meisterstra~e 8,7400 Tiibingen, Germany
vn
Schmiihl, Prof Dr. D. Institut ftir Toxikologie und Chemotherapie, Deutsches
Krebsforschungszentrum, hn Neuenheirner Feld 280,
6900 Heidelberg, Germany
Epidemiological Observation on Drug-Induced
D1ness
H.JICK
I. Drug Commonly Induces an Otherwise Rare Illness (Category 1, Table 1) . . 2
II. Drug Rarely Induces an Otherwise Common Illness (c:ategory 2, Table 1) . . 4
III. Drug Rarely Induces an Otherwise Rare Illness (Category 3, Table 1) . . . . . 4
IV. Drug Commonly Induces an Otherwise Common Illness (Category 4,
Table I) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
V. Both Rates in Intermediate Range (Category 5, Table 1). . . . . . . . . . . . . . 7
Case-Control Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
I. Selection of the Cases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
I . Definition of Illness . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
2. Accuracy of Diagnosis oflllness . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
3. Illness-Drug Relationship. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
4. Illness Relevance. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
5. Selection Bias . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
II. Selection of the Controls . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 10
III. Identification of the Exposure. . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. II
IV. Influence of Confounding Factors . . . . . . . . . . . . . . . . . . . . . . . . . . .. II
V. Analysis of the Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 12
VI. Interpretation of the Results. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 12
I. The Statistical Significance of the Association. . . . . . . . . . . . . . . . . .. 12
2. The Strength of the Association . . . . . . . . . . . . . . . . . . . . . . . . . . .. 12
3. Repeatability . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . .. 12
4. Biologic Plausibility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 13
5. Epidemiologic Plausibility. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 13
VII. Limitations of the Case-Control Method. . . . . . . . . . . . . . . . . . . . . . .. 13
References .......................... ~ . . . . . . . . . . . . . . . . . . .. 14
The increase in the use of drugs for both short-term and long-term treatment during
the past decades has led to a corresponding increase in concern about their potential
for inducing serious illnesses. As a result, the search for drug-induced disorders has
achieved a high priority in medical research (Allan 1976; Terselic 1976).
In many cases the identification of drug induction of illnesses is straightforward
and can be accomplished readily by informal clinical observation. Rapid discovery of a
drug-illness relation tends to occur when the induced illness is dramatic and occurs
within a very short period after a drug is taken - for example, penicillin-induced ana
phylaxis and ethacrynic-acid-induced deafness. When a drug produces such reactions
frequently, the problem is likely to be recognized during premarketing studies, and the
drug may not be approved for routine clinical use. However, when a drug produces
such an illness only rarely, the discovery of the adverse effect is more likely to occur in
the post-marketing period, after widespread clinical use.
2
Under other circumstances, drug induction of serious illness may not be recogniz
ed through informal clinical experience. Clinical observation tends to be insufficient
when the time necessary to induce the illness is long - weeks, months or years - espe
cially when the drug induces the illness only rarely or when the illness is otherwise rea
sonably common (or both). In these circumstances, the use of formal methods rather
than reliance on clinical observations is required.
Drug-induced illness may be manifested primarily by a physiologic or biochemical
abnormality or it may lead to structural changes which can be readily observed by
pathologists. Examples of the former are anaphylaxis, parkinsonism, symptomatic ele
vation of uric acid levels, and hyperkalemia leading to cardiac arrhythmia. Examples of
the latter are aplastic anemia, hepatitis, and cancer.
The major concerns of the epidemiologist are, frrstly, to discover previously unre
cognized drug-induced illness and, secondly, to provide some quantitation of risk.
The problem of discovering drug-induced illness can be defined by the magnitudes
of two risks - the added risk of illness experienced by users of a drug, and the base
line risk in the absence of the drug. Somewhat arbitrarily, each risk is taken to be
"high" if the rate of newly occurring illness exceeds one per 200 per year, "low" if less
than one per 10,000 per year and, otherwise, "intermediate". Table 1 lists various
combinations of these magnitudes of risk. For the resulting categories, the need for
formal research is determined not only by the likelihood that drug-illness relations will
be missed during the process of informal clinical observation, but also by the nature of
illnesses that in each category are particularly apt to be drug induced.
The strategy for research includes several basic approaches. The options are the
following: clinical trial - an experimental study in which patients are randomly assign
ed for the duration of the study to one of the compared treatments and are followed
forward in time, for some defmed period, to ascertain the possible development of ill
nesses; nonexperimental cohort study - a follow-up study in which the choice of drug
regimen is dictated by ordinary clinical practices rather than the interest of scientific
comparison; and case-control study - a study in which patients with an illness of in
terest are compared to a series of people without the illness for the proportions who
have and have not used any of the drugs of interest.
I. Drug Commonly Induces an Otherwise Rare Illness (Category 1, Table 1)
In this situation the rate of drug induction of a given illness is "high", and the base-line
rate is low.
Need [or Research. When a drug commonly induces an otherwise rare, serious ill
ness, the likelihood is very high that the problem will be discovered in the premarket
ing phase. In the extraordinary circumstance in which premarketing observatbn fails
to discover the adver~ effect, as in the thalidomide disaster, discovery after marketing
is likely to occur through informal clinical observation: after the necessary lag time
since the introduction oft he drug, a dramatic epidemic develops whose detection, al
though somewhat delayed, requires no formal study. An extraordinarily high propor
tion of the patients will have a positive history of exposure to the causative drug, and
this distribution leads to the rapid identification of the drug-illness relation. Because
w
Illness of particular Research approach of choice interest Drugs already Newly marketed drugs marketed "Cohort" Any rare illness Case referent Any rare illness "Cohort" Case referent 1: Clinical trial 1: Clinical trial Myocardial infarction and sudden deaths in "Cohort" 2: Case referent 2: high-risk populations "Cohort" 3: "Cohort" Particular cancers Case referent
n
o
Types of drug-illness relations able 1. a Primary mode of of illnessExample ategory Rate discovery Drug Base line induced b c Clinical observation HighThalidomide-induced Lowphocomelia Not discoverable High Low Chloramphenicol-induced 1: Clinical observatiLow Low aplastic anemia 2: Formal research High High ? Tolbutamide-induced Formal research cardiovascular mortality Interme-Interme-Estrogen-induced Formal rerearch diate diate endometrial cancer Refers to acquired illness only as> 1 /200/yr for the purposes of this paper Arbitrarily defined < as 1/1 O,OOO/yr for the purposes of this paper Arbitrarily defined
T C 2 3 4 5 a b c
4
such drug-illness connections are so readily and quickly identified when they are fully
manifested, it is unlikely that any adverse effects of this kind exist undiscovered for
drugs already on the market. Of course, if the lag time is appreciable, recognition of an
adverse effect is correspondingly delayed.
Although the needs for formal post-marketing research are minor in this category,
virtually any rare illness is a potential candidate for drug induction.
Strategy of Research. Although it is exceptional for a drug to be marketed if it
commonly induces an otherwise rare, serious illness, it is of interest to consider how
the effect, when it occurs, may be discovered. When the phocomelia epidemic of the
early 1960's became evident (Kohler et al. 1962), its cause was sought by the case-con
trol approach: a series of cases of phocomelia was contrasted to healthy babies for the
frequency of various prenatal experiences. In the case series a far greater proportion of
mothers had taken thalidomide early in pregnancy as compared to the mothers of nor
mal babies. Thus, it was inferred that the risk of phocomelia was very much higher in
the offspring of thalidomide-using mothers than in the others. In general, the potential
drug causation of an unexplained epidemic of illness is most efficiently evaluated by
the case-referent approach.
The existence of Category 1 side effects of newly marketed drugs is ruled out by
premarketing studies. In the extraordinary case in which they have oot, untoward re
actions will mme to attention rapidly upon the development of the epidemic. Conse
quently, no special follow-up effort is indicated for Category 1 drug illnesses.
II. Drug Rarely Induces an Otherwise Common Illness (Category 2, Table 1)
When an illness is rarely induced by a drug and is common in its absence, the propor
tion of cases due to the drug is very small; neither general clinical experience nor for
mal research will identify the drug-illness relation. For example, if the incidence of an
illness were one per 100 per year in the absence of drug treatment and the drug itself
induced the illness in one per 50,000 per year, the risk among the users would be in
creased only to 1.002%. Weak relations of this kind simply will have to remain undis
covered.
ill. Drug Rarely Induces an Otherwise Rare Illness (Category 3, Table 1)
There are many known examples in this category. Among the more familiar ones are
the connection between chloramphenicol and aplastic anemia (Wallerstein et al. 1969),
oral contraceptives and benign liver tumors (Contostavlos 1973), practolol and scleros
ing peritonitis (Brown et al. 1974), lincomycin and pseudomembranous colitis (Scott
et al. 1973), and diethylstilbestrol and vaginal cancer (Herbst et al. 1971).
Need for Research. Drug-illness relations in this category almost always escape
notice in the premarketing phase since a vast experience is needed before cases of the
rare illness occur. On the other hand, once experience has accrued after marketing, in
formal discovery of the problem is likely, particularly when a drug accounts for a large
proportion of the rare illness. However, even when a relation is recognized by chance,
