Steroid-induced pancreatitis: Does it really exist?

Steroid-induced pancreatitis: Does it really exist?

GASTROENTEROLOGY CLINICAL TRENDS AND TOPICS Steroid-Induced Really Exist? WILLIAM M. STEINBERG Division of Gastroenterology, Washington, D.C. Pa...

1MB Sizes 0 Downloads 47 Views

GASTROENTEROLOGY

CLINICAL

TRENDS

AND

TOPICS

Steroid-Induced Really Exist? WILLIAM M. STEINBERG Division of Gastroenterology, Washington, D.C.

Pancreatitis: Does It and JAMES H. LEWIS

The George Washington

The observation that corticosteroids induce or are associated with acute pancreatitis in humans has been emphasized over the past 25 yr (l-20). Two recent reviews of drug-induced pancreatitis (21,22), as well as current textbooks (23,24), cite the evidence that implicates steroids as a cause of pancreatitis. Overlooked, however, in these reviews are many case reports (25-35) and experimental data (33,3639) that suggest exactly the opposite, i.e., corticosteroids may be of benefit in the treatment of severe acute pancreatitis. In this review, we present a critical evaluation of the literature that implicates corticosteroids as a cause of pancreatitis. Our analysis casts doubt on the etiologic association between steroids and pancreatitis and, in fact, suggests that corticosteroids may indeed be useful in the treatment of acute pancreatitis.

Studies That Implicate Corticosteroids as a Cause of Pancreatitis Histopathologic

1981;81:799-808

Data in Animals

Four studies in laboratory animals (40-43) are regularly quoted as evidence in support of steroid-induced pancretitis (Table 1). Antopol et al. (40) injected massive doses (1 mg/lO g body wt) of steroids into mice-the equivalent of giving 7 g of hydrocortisone to a X)-kg adult human. He stated that “the pancreas in some of the mice showed interstitial inflammation and in a few instances, extensive necrosis of the parenchyma.” The animals had Received March 30, 1981. Accepted June 1, 1981. Address requests for reprints to: William M. Steinberg, M.D., George Washington University Medical Center, Division of Gastroenterology, 2150 Pennsylvania Avenue, N.W., Washington, D.C. 20037. The authors thank Dr. Hyman J. Zimmerman for his careful review of the manuscript, and Debra M. Katz, Nancy Marshall, and Evelyn Hughes for their excellent clerical assistance. 0 1981 by the American Gastroenterological Association 00%5085/81/100799-10$02.50

University

Medical

Center,

concomitant bacterial infections and scant data are supplied to clarify how often pancreatic lesions were seen. Lazarus and Bencosme (41), while attempting to induce diabetes, injected rabbits with moderate doses of corticosteroids and noted degranulation of p-cells and proliferation of small pancreatic ductules. No necroinflammatory changes were seen in this initial study, although a second study (42) in which cortisone was administered together with antibiotics and vitamins, did show inflammatory changes. These authors hypothesized that corticosteroids might obstruct small pancreatic ductules by leading to increased viscosity of pancreatic secretions. Stumpf et al. (43) induced pancreatic changes in 19 of 22 rabbits receiving cortisone. These changes included reduced basophilia, vacuolization of acini, peripancreatic fat necrosis, and hyperplasia of the islets of Langerhans. There was no correlation between the incidence and severity of pancreatic changes and the amount of cortisone injected. No data were given as to how extensive these lesions were, although they stated that in many cases, “the lesions were very small.” These studies do not seem to establish a convincing case for the entity of steroid-induced pancreatitis in animals for several reasons: (a) the histologic results have varied from study to study; (b) there has been no dose-relationship established between steroids and pancreatitis; (c) the data relative to the frequency and extensiveness of the pancreatic lesions have been scanty and unclear; (d) examiners were not “blinded” as to treatment groups; (e) combinations of corticosteroids with other agents (antibiotics, vitamins, etc.) confuse the results; (f) the lesions in several studies have not shown the necroinflammatory changes of pancreatitis; (g) there has been no mortality and seemingly little morbidity from the observed pancreatic changes in these animals; (h) enormous doses were used in one study (40); and (i) the steroid-induced pancreatic acinar lesions in rabbits and mice appear to be species-specific in that guinea pigs (44,45), rats, (46,47), and dogs

800

STEINBERG AND LEWIS

Table

1.

GASTROENTEROLOGY

Vol. 81. No. 4

The Effect of Steroids on Pancreatic Histology in Animals Author

Species

Steroid dose/body

wt

Histologic findings

Antopol et al (40)”

Mice

CAb 2.5 mg/20 g

Interstitial inflammation, vacuolization, parenchymal necrosis.

Lazarus and Bencosme (41)

Rabbits

CA 6-15 mg/kg x 3 days-6 wk

Proliferation of ducts and centroacinar cells. Changes in size and shape of islets. Degranulation of /&cells.

Bencosme and Lazarus (42)

Rabbits

CA 10 mg/kg x 1-6 wk plus various combinations of antibiotics and vitamins

Degranulation and glycogen infiltration of /?-cells. Ductular proliferation with inspissated secretions. Focal peripancreatic fat necrosis in rabbits treated > 36 days.

Stumpf et al (43)

Rabbits

CA 5-20 mg/kg x 21-81 days

Vascuolization of acini. Decreased basophilia of acinar cells. Dilated acinar spaces. Edematous interstitial tissue. Focal peripancreatic fat necrosis. Hyperplasia of islets.

CA plus other agents (heparin, antibiotics, Triton, protamine, methionine) 0 Reference numbers given in parentheses. b CA = cortisone acetate.

(48) do not sustain histologic damage in pancreatic exocrine tissue when steroids are given. In addition, we have administered cortisone in the range of 5-30 mg/kg body wt to mice, and were unable to induce any pancreatic acinar changes (Steinberg WM, Lewis JH; unpublished data). Case Reports In reviewing the clinical reports in humans, we have been able to find 36 cases in 19 reports in the English language literature (l-19) that implicate steroids as the cause of acute pancreatitis (Table 2). Two-thirds of these cases were in children <17 yr old, two-thirds were male, and 80% died of acute pancreatitis. For the purpose of our critical evaluation, a diagnosis of steroid-induced pancreatitis was considered likely only if other known etiologic associations with acute pancreatitis were absent (i.e., gallstones, postoperative state, history of familial pancreatitis, hypercalcemia, hypertriglyceridemia, etc.), and the patient was receiving no other drugs. Furthermore, if a postmortem examination was performed on a patient who died of acute pancreatitis, we looked for a description of a patent common bile duct, the absence of gallstones, and no evidence of stenosis of the pancreatic duct: each of which has been implicated as a mechanical cause of acute pancreatitis. None of the 36 individuals fulfilled all of these criteria for “likely” steroid-induced pancreatitis. Eighteen of the 36 patients were on other medications in addition to steroids. Thirteen of these

18 received one or more drugs (Table 2) strongly implicated in their own right as a cause of pancreatitis (22). These included azathioprine and 6-mercaptopurine (49-53), thiazide diuretics (54-56), oral contraceptives (57,58), tetracyclines (59,60), and ethpatients had acrynic acid (61). Seven additional underlying disease processes that have also been associated with acute pancreatitis (23): 2 of them were hypercalcemic and a third had parathyroid hyperplasia (with possible hypercalcemia); 1 patient developed pancreatitis postoperatively; 2 patients had cholelithiasis; and 1 had hypertriglyceridemia. In the remaining patients incomplete information was supplied concerning serum calcium or triglyceride levels, or postmortem findings detailing the patency of the biliary tree or pancreatic ducts. Of 28 autopsies performed, in only 2 cases were the descriptions of the pancreaticobiliary trees adequate to exclude mechanical obstruction. In neither of these 2 cases, however, was information available as to antemortern triglyceride or calcium levels. Thus, other potential causes of acute pancreatitis in these patients could not be excluded. In short, none of the reports implicating steroids as a cause of acute pancreatitis has excluded other possible causes convincingly enough to assign the etiologic responsibility to the steroids alone. Furthermore, the clinical reports delineating the relationship between corticosteroids and acute pancreatitis (1-19) do not allow us to define a particular type of drug-induced pancreatic injury pattern in this setting. There has been no demonstrable corre-

October

STEROID-INDUCED

1981

lation between the dose of steroids, duration of treatment (hours to years), or the type of steroid administered (cortisone, hydrocortisone, prednisone, prednisolone, ACTH*) and ensuing pancreatic damage (Table 2). Eight patients (2,4,8,11,14,17) were found to have pancreatitis after the recent onset (within 1 mo) of steroids; in 2 of these 8 patients (2,14) steroid therapy had been started only hours before their deaths. Four patients (3,8,16,17) developed acute pancreatitis within 1 mo of discontinuing steroids, and 4 others (1,8,17) developed acute pancreatitis after a recent tapering of their steroid dose. Four were said to have developed acute pancreatitis after a recent increase in steroids (3,8,17) and 8 had been on a long-term maintenance dose of steroids (2,5,10,12,15,17,18). In 8 cases (6,7,9,19) there was insufficient information to determine the relationship between the dose and duration of steroids and pancreatitis. In addition, there has been no evidence presented that steroid-induced pancreatitis occurs in the setting of a hypersensitivity reaction in that there have been no reports of acute pancreatitis accompanied by eosinophilia, arthralgias, or skin rash. Finally there have been no reports of patients thought to have steroid-induced pancreatitis who were rechallenged with steroids to confirm these drugs as the etiologic agents. Autopsy

Duta

Two autopsy studies are frequently quoted as giving evidence that steroids cause pancreatitis in Oppenheimer and Boitnott (19)comhumans (19,20). pared 52 children who died of renal disease or leukemia in the presteroid era with a similar number who died after 1955 and who had received steroids as part of their management. The steroid-treated group had a higher incidence of pancreatic disease than did the “historic” control group (40% vs. 15%). However, no information is given concerning other drugs or clinical conditions that may have predisposed these children to pancreatitis. It hardly seems fair to single out corticosteroids as the cause of pancreatic damage when treatment undoubtedly differed in many other respects between the presteroid and steroid eras. The study of Carone and Liebow (20) compared the postmortem pancreatic findings in 54 patients with leukemia, collagen vascular disease, or other disorders who had not received steroids, with a similar age-matched group who had received steroids. Although not specifically stated, it may be deduced that the nonsteroid-treated group were historic controls from the presteroid era rather than -.-__ ?? ACTH paper.

is included

as a corticosteroid

for the purpose

of this

PANCREATITIS

801

concurrent ones. Sixteen of 54 patients in the steroid group had histologic evidence of pancreatitis (one had clinical pancreatitis), while only 2 of the 54 controls had similar pancreatic findings. This report also contained little or no information concerning other drugs or conditions known to predispose to pancreatitis.

Secretory

Data

There have been several pathogenetic mechanisms proposed to explain why corticosteroids might cause pancreatitis. Bencosme and Lazarus (42) postulated that steroids induce pancreatitis through the production of viscous proteinaceous secretions that obstruct pancreatic ductules and cause localized inflammation. However, species other than the rat (46,47), rabbit-including the guinea pig (44,45), and dog (48)-show none of these pathological findings. Furthermore, numerous studies in both dogs (48,62-64) and humans (65,66) fail to reveal any consistent pancreatic secretory abnormalities produced by steroids (Table 3). In humans, Dreiling et al. (66) showed that an i.v. bolus injection of ACTH, hydrocortisone, or prednisolone decreased pancreatic volume as well as bicarbonate and amylase output. These results are countered by the studies of Pfeffer and Hinton (65) and Gullo et al. (67,68), showing no effect of ACTH or hydrocortisone on volume, bicarbonate, or lipase output. In dogs, the variability has been as great as in humans. Nelp et al. (48) showed that chronic administration of cortisone to dogs increased volume output, but had little effect on bicarbonate secretion. Viscosity of pancreatic juice was increased in three of 12 determinations when the animals were given cortisone. Tiscornia et al. (62) showed little change in pancreatic volume or bicarbonate output in 7 dogs treated with cortisone or ACTH, although amylase concentrations decreased. More recently, Kimura et al. (64) perfused an isolated canine pancreas model with massive doses of methylprednisolone. No evidence of gross morphologic or biochemical changes was seen. Steroids did not change pancreatic volume output or concentrations of trypsin or bicarbonate, but the viscosity of the secretions increased. A number of investigators have postulated that steroids cause an increase in total lipids, which in turn may induce acute pancreatitis (8,43,69,70). Of all the cases we reviewed in which corticosteroids were implicated as a cause of acute pancreatitis, only 1 patient (18)had hypertriglyceridemia documented. This patient, however, had chronic renal disease, a condition that can also cause hyperlipidemia. In summary, the lack of convincing clinical and

STEINBERG AND LEWIS

802

Table 2.

Steroid-Induced

GASTROENTEROLOGY

Pancreatitis

Age

Vol. 81,No. 4

in Humans Underlying disease(s)

Dose and duration of steroids

Other predisposing causes of AP

(yr)

Sex

Dx

Zion et al. (1)

47

F

PM

Scleroderma,

Baar and Wolff (2)

11

F

PM

Asthma

CA x 5 mo then D/C x 5 wk CA 25 mg single dose 5% h before death

2?4

M

PM

Polymyositis

pred 15 mg/day XlOmo

5

M

PM

Still’s disease, smallpox

ACTH 40 mg/day x4mo

Bourne and Dawson (4)

65

M

clin

Nephritis

prednis lo-40 mg/day xlmo

Dabrowski et al. (5)

73

F

PM

Aplastic anemia

pred 30 mg/day x 4 mo, ACTH 100 mg

Sash (6)

71

F

PM

Rheumatoid

pred lo-15 mg X 6 mo

Meltzer et al. (7)

56

F

PM

Multiple myeloma

pred 50-80 mg/day X8mo

Nelp(8)

42

M

lap

Systemic lupus

ACTH 20 LJ, pred 20 mg/day x 2 mo

63

M

lap

Multiple myeloma

pred 20-40 mg/day X 1 yr

60

M

PM

Multiple myeloma

pred 30 mg/day X 1 mo Hypercalcemia

21

M

PM

Rheumatic heart disease

pred 40-60 mg/day x2mo

16

F

PM

Hemolytic anemia

ACTH intermittently x 3 yr; pred 30 mg/day x 2 wk

50

M

PM

Asthma

ACTH 80 U; pred 20 mg xlmo

4

F

PM

Nephrosis

ACTH 100 mg X 1 mo

3b

M

PM

Cirrhosis

6b

M

PM

Cirrhosis

35

M

PM

Chronic pyelonephritis, renal transplant

pred O-200 mg x 11 mo

Azathioprine

27

M

PM

Renal transplant, chronic glomerulonephritis

pred O-200 mg x 9 mo

Azathioprine

13

M

clin

Nephrosis

prednis 50 mg/day x 10 days

INH, PAS

9

M

clin

Leukemia

pred 2-3 mg/kg . day-’ X 6 mo

Author“

MarczynskaRobowska (3)

Frey and Redo (9)

Tilney et al. (10)

Chandra et al. (11)

Akhtar et al. (12)

uremia

arthritis

Other drugs

CA 50-300 mg/day X6mo Hyperparathyroidism

Chlortetracycline Aminophylline Epinephrine Digoxin Penicillin Mersalyl Tetracycline

Reserpine Katonium Chlorothiazide Gallstones

B Vitamins

Insulin Hypercalcemia

Urethane Penicillin Antibiotics

Gallstones

Postoperative Penicillin Tetracycline Chloramphenicol

6-Mercaptopurine Aminopterine

October

STEROID-INDUCED

1981

PANCREATITIS

803

Table 2. (Continued) (yr)

Heuser

and (14)

et al (15)

Dx

F

clin

Idiopathic thrombocytopenic purpura

pred 40-200 mg/day x 15 days

10

F

PM

Asthma

pred 75 mg/day x 2 days

12

F

PM

Asthma

HC 3 mg/kg single dose 17 h before death

6

M

PM

Nephrosis,

Schrier and Bulger (13)

Richards Patrick

Sex

chicken

Pox

Cortese

and Glenn

Kobayashi

et al. (16)

Oppenheimer and Boitnott (19)

Other predisposing causes of AP -_____

M

PM

Systemic

lupus

pred 15 mg intermittently X 1 yr

12

M

PM

Systemic

lupus

pred 90-150

Other

drugs

S-Mercaptopurine Orthonovum

6-Mercaptopurine Hydrochlorothiazide Spironolactone

pred 15 mg/day XJ3mo

27

(16) Riemenschneider et al. (17)

Dose and duration of steroids

Underlying disease(s)

Age Author”

mg q.o.d.

Metaraminol Ampicillin Chloramphenicol Atropine

X5mo

14

F

PM

Systemic

lupus

pred 25-80 mg/day X6mo

Azathioprine Reserpine Chlorothiazide

11

M

clin

Systemic

lupus

pred 60-120 xlmo

Reserpine a-Methyldopa Ethacrynic acid

9

M

clin

Systemic

lupus

16

M

PM

Rheumatic heart disease, bacterial endocarditis

pred 60 mg/day x6wk pred 100 mg/day x 6 days

8

M

PM

Lymphoma, acute renal failure, histoplasmosis

pred 20-40 mg/day X5mo

9

M

PM

Nephrosis

betameth X 1 yr

zh

PM

Congenital kidneys

3"

PM

lib

PM

cystic

mg/day

1.5-5 mg/day

? steroid

x 1 mo

Nephrosis

? steroid

x 1 yr

Chronic glomerulonephritis

? steroid

x 10 mo

Azathioprine Penicillin Chloramphenicol Digoxin Meralluride 6-Mercaptopurine Nitrogen mustard Uricosuric therapy Hypertriglyceridemia

Abbreviations: Dx = means of diagnosing pancreatitis; F = female; M = male; PM = postmortem lap = laparotomy; clin = clinical diagnosis; pred = prednisone; HC = hydrocortisone; betameth ’ Detailed case report tate: prednis = prednisolone. a Reference numbers given in parentheses.

laboratory reports, the difficulty in attributing a known type of drug-induced tissue-injury pattern to corticosteroids, and the absence of any consistent secretory abnormalities or other pathogenetic mechanisms lead us to seriously question the existence of steroid-induced pancreatitis as a clinically significant entity.

Cyclophosphamide Insulin

examination; AP = acute pancreatitis; = betamethasone; CA = cortisone acenot given.

Studies That Suggest Corticosteroids Useful in the Treatment of Acute Pancreatitis

Are

It would seem reasonable that the known antiinflammatory, vascular supportive, and antiallergic properties of corticosteroids (70,7l) might

3.

and Hinton

et al. (66)

et al. (64)

(63)

et al. (62)

(65)

a Reference

numbers

given

acetate;

is)

isolated uancreas

Dog

(3) (2) (1) (1)

Dog

(7)

Dog

(5)

Human

(7)

Human

(59)

Human

(2)

Dog

(47)

Human

(n)

Secretory

b Concentration.

Ins = insulin;

i.v. bolus i.v. bolus

i.v. bolus 53-120 days chronic chronic

70-90 days i.v. bolus i.v. bolus i.v. bolus

i.v. bolus

i.v. bolus

i.v. bolus i.v. bolus i.v. bolus

6wk 6wk

i.v. bolus iv. bolus

Duration

HC = hydrocortisone;

MP 200 mg MP 400 mg

S S

CCK = cholecystokinin;

HC CA ACTH ACTH

CA HC ACTH HC

HC

S S+CCK S+CCK Food + CCK

S S S S+CCK

S+CCK

ACTH

ACTH HC P

S

S+CCK

CA CA

ACTH HC

Steroid

Function

Meat S+CCK

S + Ins

Stimulus

on Pancreatic

in parentheses.

Abbreviations: CA = cortisone decrease; NC = no change.

Kimura

Sircus

Tiscornia

Gullo et al. (68)

Gullo et al. (67)

Dreiling

Nelp et al. (48)

Pfeffer

Species

The Effect of Steroids

Investigators”

Table

S = secretin;

D/I

NC

I I I D

NC NC NC

NC

NC

NC

D

I I

NC

Volume

P =

I I

NC

D

NC NC

Proteinb

I I I NC

D

D

D NC

D

Amylaseb

NC NC

NC I I

Trypsinb

I

NC NCorI

Viscosity

prednisolone; Mp = methylprednisolone; I = increase; D =

NC NC

I D D D

NCorI NC NC NC

NC

NC

D

I NC

NC

HC03b

October

STEROID-INDUCED

1961

Table 4. The Effect of Steroid Treatment

Animal

Investigators” Anderson Stewart Cotlar

et al. (33) et al. (36)

et al. (37)

Anderson Schiller

et al. (38) et al. (39)

a Reference

numbers

prove beneficial creatitis. Indeed, dence suggesting disorder.

given

on

Experimentally-Induced

Method

of inducing

pancreatic

Trypsin

+ blood

Dog

Trypsin

+ bile salts into PD

Dog

Staphylococcal

Dog

Trypsin

+ blood

Dog

Trypsin

into PD

in parentheses.

b PD = pancreatic

duct.

in the treatment of acute panthere is a substantial body of evithat steroids are beneficial in this

Experimental

Pancreatitis in Animals

Dog

Data

Five in vivo studies (Table 4) have found steroids to be effective in reducing the mortality of experimentally induced pancreatitis in dogs (33,36-39). In each case a mixture of trypsin, blood, bile salts, or other toxins injected into the pancreatic duct was fatal in more than two-thirds of cases. Although no animal model mimics the human condition exactly, steroid treatment reduced the mortality in these models by one-half to two-thirds.

Case Reports We have been able to find 48 instances in 11 reports (25-35) in which steroids or ACTH has been used as a treatment for acute pancreatitis. Table 5 summarizes the clinical details of these patients. Detailed case reports were available for 24 of these 48 patients, all of whom survived their bouts of pancreatitis. Corticosteroids were thought to be “lifesaving” in 11 of 24 instances. Eighteen of the 48 cases had acute hemorrhagic pancreatitis and 4 of these 18 died (22%). This mortality would appear to compare favorably with a mortality of over 50% in other published series (72,73), although we are aware of the problems that exist when comparing a consecutive series with a collection of individual case reports. Furthermore, it is possible that in some instances authors reported only those cases having a beneficial reponse to steroid therapy. The number of patients not having a favorable outcome when steroid therapy was given is not known.

into ligated

into ligated

% Mortality __group

Control

injury

into PDb

toxin

PD

PD

40 was given

with

Steroid

group

90

40

94

52

67

27

82

38

100 c Dextran

605

PANCREATITIS

33c

steroids.

In addition to the cases above, there are two reports (51,74) that suggest that corticosteroids may protect patients from the pancreatitis induced by azathioprine or 6-mercaptopurine. The possibility that steroids may inhibit the development of pancreatitis under these circumstances deserves further study.

Summary and Conclusions The evidence used to incriminate steroids as a cause of acute pancreatitis can be challenged as inconclusive on several fronts: First, none of the case reports or autopsy studies that single out corticosteroids as the etiologic agent has completely excluded other potential causes of pancreatitis. Second, no consistent pancreatic secretory or histopathologic changes appear to be induced by corticosteroids in humans or in animals that would explain the pathogenesis of acute pancreatitis. Third, there does not appear to be any consistent relationship between the dose of steroids given or the duration of treatment and the onset of pancreatitis. In contrast, a substantial body of reports has been overlooked in the recent literature that suggests corticosteroids may be helpful in both the treatment and prevention of acute pancreatitis. We are aware that these seemingly beneficial effects of corticosteroids are uncontrolled anecdotal observations that are in many respects as inconclusive as the reports that incriminate corticosteroids as a cause of acute pancreatitis. The case for the use of steroids in the treatment of acute pancreatitis can only be proved by the use of these agents in a randomized, doubleblind, controlled fashion. Indeed, as there is a lack of medical agents of proven efficacy for the treatment of severe acute pancreatitis (75), a controlled study of steroid therapy in this illness seems warranted.

806

STEINBERG AND LEWIS

Table

5.

GASTROENTEROLOGY

The Effect of Steroid Treatment

Authors” Stephenson

et al. (25)

No. of patients 1

Eskwith et al. (26)

on Acute Pancreatitis

Vol. 81, No. 4

in Humans Predisposing etiology

Age (yr)

Sex

Illness

Diagnosis

25

F

AHP

lap

NPF

CA, antibiotics

Alive

40

M

AHP

clin

NPF

CA, antibiotics

Alive

Rx

Outcome

Solem et al. (27)

1

83

F

AP

clin

Gallstones

ACTH, antibiotics

Alive

Rogers et al. (28)

6

45 36

M F

AEP AHP

lap lap

NPF Gallstones

pred, HCN. antibiotics pred, HCN, antibiotics

Alive Alive

47

M

AHP

lap

Postoperative

pred, HCN, antibiotics

Alive

56

M

AP

clin

NPF

pred

Alive

73

M

AP

clin

NPF

pred, antibiotics

Alive

55

F

AP

clin

NPF

pred, antibiotics

Alive

and Cohen

17

M

AP

clin

Mumps

CA, antibiotics

Alive

Brockis and Jones (30)

64

F

AHP

clin

NPF

CA, antibiotics

Alive

74

F

AHP

clin

Gallstones

CA. antibiotics

Alive

47

F

AP

lap

Gallstones

CA, anticholinergics

Alive

62

F

ANP

lap

Gallstones

CA, antibiotics

Alive

46

M

ANP

lap

Postoperative

CA, antibiotics,

73

F

AEP

lap

Gallstones

CA, anticholinergics

Alive

49

M

AHP

lap

NPF

HCN, anticholinergics, antibiotics

Alive

45 75

F F

AEP AEP

lap lap

Gallstones Gallstones

HCN CA

Alive Alive

54

F

AHP

lap

NPF

ACTH, CA

Alive

Bloodworth (29)

Kaplan (31)

levophed

Alive

Ericson (32)

1

22

F

AHP

lap

Gallstones

ACTH, antibiotics

Alive

Anderson

2

47

F

AHP

lap

Postoperative

HCN, antibiotics

Alive

Ericson (34)

1

59

M

AHP

lap

Postoperative

ACTH. antibiotics

Alive

Kaplan (35)

gb

AHP

NPF 4 Postoperative 3 Gallstones 1 ETOH 1

4/9 Alive

6b

AEP

NPF 5 Gallstones

6/6 Alive

et al. (33)

Ericson (32) Ericson

(34)

lib 6b

12-83

1

AP

clin

Gallstones 9

ACTH, antibiotics

ll/ll

AP

clin

Postoperative

ACTH

6/6 Alive

Abbreviations: AEP = acute edematous pancreatitis, AHP = acute hemorrhagic pancreatitis, = acute pancreatitis unspecified, clin = clinical, CA = cortisone acetate, HCN = hydrocortisone, factor, pred = prednisone, F = female, M = male, ETOH = alcohol. 0 Reference numbers given in parentheses. b Detailed case reports not given.

References 1. Zion, MM, Goldberg B, Suzman MM. Corticotrophin and cortisone in the treatment of scleroderma. Q J Med 1955;24:215-7.

Alive

ANP = acute necrotizing pancreatitis, AP lap = laparotomy, NPF = no predisposing

2. Baar HS, Wolff OH. Pancreatic necrosis in cortisone-treated children. Lancet 1957;1:812-5. 3. Marczynska-Robowska M. Pancreatic necrosis in a case of Still’s disease. Lancet 1957;1:815-6. 4. Bourne MS, Dawson H. Acute pancreatitis complicating pred-

October

1981

nisolone therapy. Lancet 1958;11:1209-10. 5. Dabrowski S, Lozinski J, Mielnik W. Acute hemorrhagic necrosis of the pancreas during corticosteroid treatment (lett). Lancet 1959;I1:1148-9. 6. Sash, L. Relationship of cortisone therapy to pancreatic necrosis. Br Med J 1959;2:867-8. 7. Meltzer LE, Palmon FP, Paik YK, Custer RP. Acute pancreatitis secondary to hypercalcemia of multiple myeloma. Ann Intern Med 1962;57:1008-12. 8. Nelp WB. Acute pancreatitis associated with steroid therapy. Arch Intern Med 1981;108:702-10. 9. Frey C, Redo SF. Inflammatory lesions of the pancreas in infancy and childhood. Pediatrics 1983;32:93-102. 10. Tilney NL, Collins JJ, Wilson, RE. Hemorrhagic pancreatitis: a fatal complication of renal transplantation. N Engl J Med 1968;274:1051-7. Il. Chandra RK, Rao MN, Kapoon P. Pancreatitis in a child on intensive prednisolone therapy: report of a case. J Indian Pediat sot 1963;2:93. 12. Akhtar M, Bhakoo DN, Chandra RK. Pancreatitis in a child with leukemia on intensive steroid therapy: Report of a case. Indian J Pediat 1964;31:327. 13. Schrier RW, Bulger RJ. Steroid-induced pancreatitis. JAMA 1965;194;564-5. 14. Richards W, Patrick JR. Death from asthma in children. Am J Dis Child 1965;110:4-21. 15. Heuser E, Lieberman E, Donnel G, et al. Subcutaneous fat necrosis with acute hemorrhagic pancreatitis: a case in a child with steroid resistant nephrosis treated with 6-mercaptopurine. Calif Med 1967;106:58-63. 16. Cortese AF, Glenn F. Hypocalcemia and tetany with steroidinduced acute pancreatitis. Arch Surg 1988;96:119-22. 17. Reimenschneider TA, Wilson JF, Vernier RL. Glucocorticoidinduced pancreatitis in children. Pediatrics 1968;41:428-37. 18. Kobayashi A, Utsunamiya T, Horino M, et al. Nephrosis, steroids, pancreatitis and diabetic ketoacidosis. Am J Dis Child 1973;125:726-9. 19. Oppenheimer EH, Boitnott JK. Pancreatitis in children following adrenal corticosteroid therapy. Bull John Hopkins Hosp 1960;107:297-306. 20. Carom AF, Liebow AA. Acute pancreatic lesions in patients with ACTH and adrenal corticoids. N Engl J Med 1957; 257:690-7. 21. Nakashima Y, Howard JM. Drug-induced pancreatitis. Surg Gynecol Obstet 1977;145:105-9. 22. Mallory A, Kern F. Drug-induced pancreatitis: a critical review. Gastroenterology 1980;78:613-20. 23. Bandborg LL, Acute pancreatitis. In: Sleisenger M, Fordtran J, eds. Gastrointestinal disease. Philadelphia: WB Saunders, 1978:1409-39. 24. Schmidt H, Creutzfeldt W. Etiology and pathogenesis of pancreatitis. In: Bockus HL, ed. Gastroenterology. Vol. III. Philadelphia: WB Saunders, 1976:1005-19. 25. Stephenson HE, Pfeffer RB, Saypol GM. Acute hemorrhagic pancreatitis: report of a case with cortisone treatment. Arch Surg 1952;65:307-8. 26. Eskwith IS, Cacace VA, Sollosy A. Acute hemorrhagic pancreatitis: treatment with cortisone. N Engl J Med 1955; 252:494-s. 27. Solem JH, Knutrud 0, Andresen KR. Treatment of acute pancreatitis with cortico-depot. Acta Chir Stand 1955;109:415-20. 26. Rogers NC, Wilson AO, Meynell MJ, et al. Treatment of acute hemorrhagic pancreatitis with cortisone. Lancet 1956;11:651-2. 29. Bloodworth AF, Cohen S. Cortisone in treatment of acute pancreatitis associated with mumps epidemic parotitis. US Armed Forces Med 1 1956;7:285-7.

STEROID-INDUCED

PANCREATITIS

807

30. Brockis JG, Jones ET. Treatment of acute hemorrhagic pancreatitis with cortisone. Br Med J 1956;2:1524-5. 31. Kaplan MH. Acute and chronic relapsing pancreatitis: the clinical implications of their acceptance as diseases of adaptation Am J Gastroenterol 1956;25:234-52. 32. Ericson, SM. ACTH in the treatment of acute pancreatitts. Gastroenterologia 1957;87:380-3. 33. Anderson MC, Mehn WH, Method HL. Treatment of acute hemorrhagic pancreatitis with adrenocorticosteroids. Arch Surg 1959;78:146-53. 34. Ericson SM. ACTH in the treatment of acute post-operative pancreatitis. Gastroenterologia 1960;93:129-33. 35. Kaplan MH, Cotlar AM, Stagg SJ. Acute pancreatitis. Six year survey with evaluation of steroid therapy. Am J Surg 1964;108:24-30. 36. Stewart WR, Elliott DW, Zollinger RM. Cortisone in the treatment of experimental acute pancreatitis. Surg Forum 1959;9:537-41. 37. Cotlar AM, Hudson TL, Kaplan MH, et al. Experimental hemorrhagic pancreatitis produced by staphylococcal toxin. Surgery 1960;47:587-93. 38. Anderson MC, Booher DL, Lim RB. Treatment of acute pancreatitis with adrenocorticosteroids. Surgery 1964;55:551-8. 39. Schiller WR, Duprez A, Iams WB, et al. Experimental pancreatitis. Treatment by colloid replacement and adrenocorticosteroid therapy combined with thoracic duct drainage. Arch Surg 1969;98:698-702. 40. Antopol W, Glaubach S, Quittner H. Experimental observations with massive doses of cortisone. Rheumatism 1951; 7:177-86. 41. Lazarus SS, Bencosme SA. Alterations of pancreas during cortisone diabetes in rabbits. Proc Sot Exp Biol Med 1955;89:114-8. 42. Bencosme SA, Lazarus SS. The pancreas of cortisone-treated rabbits. Arch Path01 1956;62:285-95. 43. Stumpf HH, Wilens SL, Somoza C. Pancreatic lesions and peripancreatic fat necrosis in cortisone-treated rabbits. Lab Invest 1956;5:224-35. 44. Hausberger F, Ramsay AJ. Steroid diabetes in guinea pigs. Endocrinology 1953;53:423-5. 45. Abelove WA, Paschkis KE. Comparison of the diabetogenic action of cortisone and growth hormone in different species. Endocrinology 1954;55:637-54. 46. Franckson JB, Gepts W, Bastenie PA, et al. Observations sur le diabete steroide experimental du rat. Acta Endocrinol 1953;14:153-69. 47. Short DW. The effect of drugs upon experimental pancreatitis in the rat. Br J Surg 1960/61;48:446-54. 48. Nelp WB, Banuell JG, Hendrix TR. Pancreatic function and the viscosity of pancreatic juice before and during cortisone administration. Bull John Hopkins Hosp 1961;109:292-301. 49. Nogueira JR, Freedman MA. Acute pancreatitis as a complication of Imuran therapy in regional enteritis. Gastroenterology 1972;62:1040-1. 50. Kawanishi H, Rudolph E, Bull FE. Azathioprine-induced acute pancreatitis. N Engl J Med 1973;289:357. 51. Huizenga KA, Shorter RG, Phillips SF. Pancreatitis: a specific complication of azathioprine treatment of Crohn’s disease (abstr). Gastroenterology 1976;70:895. 52. Paloyan D, Levin B, Simonowitz D. Azathioprine-associated acute pancreatitis. Am J Dig Dis 1977;22:839-40. 53. Singleton JW, Law DH, Kelley ML, et al. National Cooperative Crohn’s Disease Study: adverse reactions to study drugs. Gastroenterology 1979;77:870-82. 54. Cornish AL, McClellan JT, Johnston DH. Effects of chlorthiazide on the pancreas. N Engl J Med 1961;265:673-5. 55. Bourke JB, McIllmurray MB, Mead GM, et al, Drug-associated

808

STEINBERG AND LEWIS

primary acute pancreatitis. Lancet 1978;1:706-8. 56. Bourke JB, Langman MJS. Thiazides, diuretics, cholecystitis and pancreatitis (lett). N Engl J Med 1980;304:233-4. 57. Davidoff F, Tishler S., Rosoff C. Marked hyperlipemia and pancreatitis associated with oral contraceptive therapy. N Engl J Med 197X289:552-5. 58. Foster ME, Powell DEB. Pancreatitis, multiple infarcts and oral contraception. Postgrad Med J 197$51:667-g. 59. Whaley PJ, Adams RH, Combes B. Tetracycline toxicity in pregnancy: liver and pancreatic dysfunction. JAMA 1964;189:103-8. 60. Kunelis CT, Peters JL, Edmondson HA. Fatty liver of pregnancy and its relationship to tetracycline therapy. Am J Med 1965;38:359-77. 61. Schmidt P, Friedman IS. Adverse effects of ethacrynic acid. NY State J Med 1967;67:1438-42. 62. Tiscornia OM, Hansky J, Janowitz HD, et al. The adrenal cortex and external pancreatic secretion in the dog. J Mt Sinai Hosp 1965;32:551-61. 63. Sircus W. The effect of corticotrophin and corticosteroids on external secretion of the pancreas of dogs. Gut 1961;2:338-45. 64. Kimura T, Zuidema GD, Cameron JL. Steroid administration and acute pancreatitis: studies with an isolated perfused canine pancreas. Surgery 1979;85:520-4. 65. Pfeffer RB, Hinton JW. Some relationship between adrenal medullary and cortical substances and exocrine function of the pancreas in man. Gastroenterology 1956;31:746-57.

GASTROENTEROLOGY

Vol. 81, No. 4

66. Dreiling D, Janowitz HD, Rolbin H. Effect of ACTH and adrenocortical steroids on external pancreatic secretion in man. N Engl J Med 1958;258:603-5. 67. Gullo K, Costa PL, Fontana G, et al. Effect of adrenocorticotropic hormone on pure exocrine pancreatic secretion in man. Gastroenterology 1977;73:762-4. 68. Gullo K, Costa PL, Tessari R et al. Cortisone and pancreatic secretion. Stand J Gastroenterol 1980;15:45-7. 69. Cameron JL, Capuzzi DM, Zuidema GD, et al. Acute pancreatitis with hyperlipemia: the incidence of lipid abnormalities in acute pancreatitis. Ann Surg 1973;177:483-9. 70. Melby JC. Systemic corticosteroid therapy: pharmacology and endocrinologic considerations. Ann Intern Med 1974;81:50512. 71. Fauci AS, Dale DC, Balow JE. Glucocorticoid therapy; mechanisms of action and clinical considerations. Ann Intern Med 1976;84:304-15. 72. Jordan GL, Spjut HJ. Hemorrhagic pancreatitis. Arch Surg 1972;104:489-93. 73. Nugent W, Atendido WA, Gibb SP. Comprehensive treatment of acute hemorrhagic pancreatitis. Am J Gastroenterol 1967;47:511-7. 74. Sleisenger M. How should we treat Crohn’s disease? (editorial) N Engl J Med 1980;302:1024-6. 75. Regan PT. Medical treatment of acute pancreatitis. Mayo Clin Proc 1979;54:432-4.