GASTROENTEROLOGY 1993:104:1832-1847

SPECIAL REPORTS AND REVIEWS

Side Effects of Nonsteroidal Anti-inflammatory Drugs on the

Small and Large Intestine in Humans

INGVAR BJARNASON,* JEREMY HAYLLAR,* ANDREW J. MACPHERSON,* and ANTHONY S. RUSSELL*

*Department of Clinical Biochemistry, King’s College School of Medicme and Dentistry, Denmark Hill, London, England, and *Division of
Rheumatology and Clinical Immunology, Heritage Medical Research Centre, University of Alberta, Edmonton, Alberta, Canada

Bac&Yound: It is not widely appreciated that nonsteroi- volves the gastroduodenal mucosa.3-‘3 Accordingly,
dal anti-inflammatory drugs (NSAIDs) may cause dam- NSAIDs are associated with a range of pathology on
age distal to the duodenum. We reviewed the adverse endoscopy. Accepting that there is bias in hospital-
effects of NSAlDs on the large and small intestine, the based point prevalence studies, it would nonetheless
clinical implications and pathogenesis. Methods: A sys- appear that lo%-30% of unselected patients on
tematic search was made through Medline and Em- NSAID therapy have peptic ulceration (the variability
base to identify possible adverse effects of NSAlDs on depending on the precise definition of an ulcer) and
the large and small intestine. Results: Ingested NSAlDs
20%40% have lesions ranging from petechia and in-
may cause a nonspecific colitis (in particular, fene-
tramucosal bleeding to erosions or simply “nonspe-
mates), and many patients with collagenous colitis are
cific macroscopic gastritis.“‘0-‘6 Prolonged mucosal in-
taking NSAIDs. Large intestinal ulcers, bleeding, and
jury by NSAIDs has been regarded as a cause of
perforation are occasionally due to NSAIDs. NSAlDs
may cause relapse of classic inflammatory bowel dis- histological chronic gastritis, and more recently it has
ease and contribute to serious complications of diver- been suggested that the spectrum includes characteris-
titular disease (fistula and perforation). NSAlDs may tic antral mucosal changes termed “chemical” or
occasionally cause small intestinal perforation, ulcers, “reactive” gastritis.‘7-22 Although the prevalence of
and strictures requiring surgery. NSAIDs, however, fre- gastroduodenal lesions caused by NSAIDs may not
quently cause small intestinal inflammation, and the vary much with age, the serious complications of
associated complications of blood loss and protein NSAID-associated ulcers, namely bleeding and perfo-
loss may lead to difficult management problems. The ration, are age-related and associated with significant
pathogenesis of NSAID enteropathy is a multistage pro- mortality.‘4,23-31
cess involving specific biochemical and subcellular or- However, there are a number of clinical and experi-
ganelle damage followed by a relatively nonspecific mental observations that are inconsistent with the idea
tissue reaction. The various possible treatments of
that the side effects of NSAIDs on the gastrointestinal
NSAID-induced enteropathy (sulphasalazine, miso-
tract are selective and site specific to the gastroduo-
prostol, metronidazole) have yet to undergo rigorous
denal mucosa. These are mainly in the form of case
trials. Conclusions: The adverse effects of NSAlDs dis-
reports indicating that both the large and small in-
tal to the duodenum represent a range of pathologies
that may be asymptomatic, but some are life threat- testine may be adversely affected by NSAIDs. More
ening. recent systematic studies suggest that 60%-70% of pa-
tients on long-term NSAID therapy may have an
asymptomatic enteropathy. NSAID-induced enteropa-

N
onsteroidal anti-inflammatory drugs (NSAIDs) thy appears to be associated with low-grade blood and
are among the most widely prescribed group of protein loss, which may lead to management problems
drugs worldwide. Each year in the United States alone in these patients. The following is a review of the stud-
over 100 million NSAID prescriptions are written by ies that suggest that NSAIDs may adversely affect both
physicians and 40 billion aspirin tablets are sold over the large and small intestine.
the counter.‘a2 Although this attests to their efficacy as
analgesics, antipyretics, and anti-inflammatory agents, Abbreviations used in this paper: “CrEDTA, Chromium 51 labeled
ethylenediaminetetraacetate.
there is growing concern about their side effects, 0 1993 by the American Gastroenterological Association
which current consensus suggests most frequently in- 0016-5085/93/$3.00
June 1993 NSAID AND THE LOWER GI TRACT 1833

Table 1. Summary of the Adverse Effect of Ingested NSAlDs on the Large Intestine
Effect Type of damage Drug involved Reference
On “Normal” colon Colitis Fenemates (n = 12) 32-40
Ibuprofen (n = 2) 39-4 1
Naproxen (n = 1) 39
Piroxicam (n = 2) 40
Aspirin (n = 2) 42,43
Eosinophrlic colitis Naproxen (n = 1) 44
Pseudomembranous colitis Diclofenac (n = 1) 45
Collagenous colitis lndomethacin (n = 2) 46
Fenbufen (n = 1) 47
Not specified (n = 19) 48
Colonic ulcer@ Various (n = 9) 53-58
Perforation and bleeding Various (n = 56)” 60
On pre-existing disease Complicatrons of Various (n = 109) 68-76
drverticular disease
(perforation, frstulae,
bleeding)
Relapse of inflammatory Various (n = 24) 81-83
bowel disease

NOTE. n = number of cases.

aBoth patients had asthma.
bNot always possible to distinguish from colitis.
“Some cases may represent small intestinal bleeding.

NSAlDs and the Large Intestine mate-associated cases of colitis. NSAID-induced

colitis, unlike the fenemate colitis, is usually symptom-
Most of the information on the adverse effect of atic within days of starting NSAID therapy.
NSAIDs on the large intestine comes from case reports
Naproxen was implicated in eosinophilic colitis in
listed in Table 1. For practical purposes, it is conve-
one patient44 and diclofenac in pseudomembranous
nient to distinguish between the adverse effect of
colitis in another.45 Collagenous colitis has been de-
NSAIDs on the “normal” colon and where they may
scribed in patients on NSAIDs, and Tanaka et al.
exacerbate pre-existing disease.
found that 19 of their 30 patients with collagenous
colitis had been on NSAIDS.~~-~~ When put into per-
Damage to the “Normal” Colon spective, these cases are rare, and Mielants et al. found
no colonic inflammation in over 250 patients on
NSAIDs may cause colitis. A disproportionally
NSAID for rheumatoid or osteoarthritis.4”-52
high number of cases appear to occur in patients taking
fenemates (mefenamic and flufenamic acid).32-4” The There are reports of ulceration of the cecum, trans-
characteristic clinical feature is the development of verse, and sigmoid colon in patients on NSAID ther-
bloody diarrhea with profound weight loss in the apy. 53-58 Ulcer histology has shown nonspecific
course of otherwise uneventful treatment with fene- changes. However, there are formidable difficulties in
mates. Sigmoidoscopy may be normal or there may be distinguishing these ulcers from idiopathic, benign,
inflammation or ulceration resembling ulcerative coli- colonic ulcers, which are also rare and similarly found
tis. The extent of disease ranges from proctitis to pan- throughout the colon but apparently unrelated to
colitis. Most of the histological reports have been that NSAIDs.” In a large retrospective study (age- and sex-
of mild nonspecific colitis, which only rarely mimics matched controls), Langman et al. assessed the possi-
classical ulcerative colitis. On discontinuing the drug, bility that NSAIDs might be associated with large and
diarrhea ceases within days usually with full histologi- small intestinal perforation and hemorrhage.” A sys-
cal recovery. The specificity of fenemate colitis is temic case note search was done among patients over
shown by the fact that the patients tolerate other 40 years of age in whom a diagnostic code number had
NSAIDs, implying that the mechanism is not by a been given which was likely to encompass these diag-
common action of NSAIDs on cellular function or noses. NSAID ingestion was found in approximately
prostanoid metabolism. Other NSAIDs may also cause one in four patients presenting with large and small
colitis (Table 1). Of 43 consecutive new cases of co- intestinal perforation and bleeding. Moreover, pa-
ionic inflammation presenting to a specialized gastro- tients with these complications were more than twice
intestinal unit,40 there were 2 piroxicam and 2 fene- as likely to be taking NSAIDs as controls.
 1834 BJARNASON ET AL. GASTROENTEROLOGY Vol. 104, No. 6

NSAIDs given rectally are frequently associated Table 2. Summary of the Adverse Effects of NSAlDs on the
with side effects. In one study, 43 patients were treated Small Bowel

with 100-mg indomethacin suppositories. Twenty one Abnormality Clinrcal implicattons Reference
(49%) stopped treatment because of inability to retain
Perforation Requires surgery 60,85-90
the suppository, nonspecific discomfort, irritation, Massive bleedmg May require surgery 60
pain, or bleeding.6’ On average lo%-30% of patients Strictures
Broad bases May require surgery 96- 100
receiving NSAID suppositories have distressing side
Diaphragmlike May require surgery 101~105
effects.62’63 A P art from NSAID-induced proctitis,6”66 Increases intestinal May play a pathogenic role 137-151
there are 8 cases of rectal ulceration and strictures de- permeabilrty rn NSAID enteropathy
NSAID enteropathy 137, 158,
scribed following aspirin and paracetamol supposito-
163-165
ries.67 In the above cases, the histology has usually Bleedrng May contribute to iron 165. 170-173
been nonspecific and not suggestive of ulcerative coli- deficiency
tis or Crohn’s disease. Protern loss May cause 170
hypoalbuminaemra
Collectively, it would appear that NSAIDs only lleal dysfunction Asymptornatrc not clinically 137
rarely affect the normal large intestine adversely. How- relevant
ever, when they do there are significant symptoms and o-xylose Mild and not clinically 186-188
malabsorption relevant
some morbidity. The exact size of the problem still
Mrld and not clinrcally 187, 188
needs to be defined by prospective, collaborative, hos- relevant
pital, and community based studies.

The Effect of NSAlDs on Pre-existing reported with indomethacin,” but subsequent studies

Disease show a detrimental effect of NSAIDs on disease activ-

ity. 8o Indeed, NSAIDs may cause relapse of quiescent
There are individual case reports of NShIDs inflammatory bowel disease*‘-*’ and those prone to
causing perforation of colonic diverticula.68-71 Some relapse do so within a few days of receiving NSAIDS.~’
involve Osmosin (now withdrawn from the market), Although many patients with inflammatory bowel dis-
which was a sustained release (driven by potassium ease presenting with a relapse have taken NSAIDs or
bicarbonate) preparation of indomethacin.” These paracetamol, in the preceding days of presenting to the
cases were thought to be due to the mechanical effect clinic most relapses are not caused by NSAIDS.~~
of the capsule being caught in the diverticulum. Like-
wise, NSAIDs have been implicated in other serious
NSAlDs and the Small Intestine
complications of diverticular disease, such as fistu- Table 2 summarizes the adverse effect of
las.72-76 In a controlled prospective study, Wilson et al. NSAIDs on the small intestine.
found that 31 of 92 patients admitted with complica-
tions of diverticular disease were on NSAIDs, which
Small Intestinal Perforation
was significantly greater (P < 0.001) than the control An early observation-linked indomethacin
group. 75 Furthermore, 19 of these 31 presented with treatment for patent ductus arteriosus in the preterm
perforation whereas only 8 of 61 patients not on infant to small intestinal perforation.85-s7 In adults, a
NSAIDs presented in this way (P < 0.001). A separate number of perforations were reported with Osmosin
case controlled study found that 24 of 50 (48%) pa- capsules (Merck Sharp & Dohme Ltd., Hertfordshire,
tients with severe complications of diverticular disease England) where the release of indomethacin was regu-
were on NSAIDs, which differed significantly (p < lated by potassium bicarbonate.70,88-90 It was suggested
0.01) from age and sex matched controls (18%20%).‘” that the capsules adhered to the small intestinal wall
Collectively these studies show that serious complica- where either a high concentration of potassium,
tions of diverticular disease are associated with known to cause broad based small intestinal strictures,
NSAID ingestion. A cause-effect relationship needs to or indomethacin caused the damage.9’-93 Other
be established but in the meantime it may be prudent NSAIDs may, however, occasionally cause small in-
to withhold NSAIDs from patients with diverticulitis. testinal perforation and bleeding.94,95 In their retro-
Initially, it was suggested that NSAIDs may be thera- spective review, Langman et al. found that a signifi-
peutically important in patients with ulcerative colitis cant number of patients with small intestinal
because the diseased active mucosa produces increased perforation were taking NSAIDS.~’ However, this re-
amounts of prostaglandins. 77-79 A beneficial effect was mains an uncommon complication of NSAIDs.
June 1993 NSAID AND THE LOWER GI TRACT 1835

distort the intestinal wall, the surgeon may have to feel

for the diaphragms at laparotomy, but they are more
easily detected if the intestine is inflated with air. Most
procedures to date have involved intestinal resection,
although stricturoplasty may suffice and in one case
balloon dilatation was effective.lo5 The increasing use
of small intestinal enteroscopy may facilitate the diag-
nosis. lo6 The prevalence of these lesions, however, is
very low. Allison et al. prospectively looked at the
small bowel of 713 consecutive subjects who came to
autopsy.“’ Two hundred forty-nine had taken
NSAIDs in the preceding 6 months, of which 74 had
taken the drugs regularly. Nonspecific small intestinal
ulcers were found in 22 of the subjects on NSAIDs,
which was significantly greater than that found in sub-
jects where no such history was obtained. No dia-
phragms were found in this series, but the small intes-
tine was not inflated before examination, which is
considered by some to be important for their recogni-
tion.‘03 Autolysis prevented assessment of the histolog-
ical details.
The diaphragms appear to represent a new nosologi-
Figure 1. “Diaphragm” strictures of the small intestine caused by cal entity. They have mostly been found in the mid
NSAIDs.
small intestine. One rheumatoid patient on NSAIDs
who had coexisting hypogammaglobulinemia had dia-
Small Intestinal Ulcers and Strictures phragms in the terminal ileum seen via colonoscopy,
Table 2 shows that there are a number of re- and a patient on a slow-release NSAID developed dia-
ports of NSAID associated small intestinal strictures
that may be broad based or diaphragmlike.96-‘05 In a
systematic study, Lang et al. retrospectively reviewed
all small intestinal resection specimens received at a
single hospital over 11 years (456 resections) and
found seven cases where the causal role of NSAIDs
was thought to be strong.lo3 The pathology ranged
from the previously reported nonspecific broad-based
stricture often with an ulcer to intestinal diaphragms,
which are now thought to be highly suggestive or
pathognomic of NSAIDs. These are multiple,3-70 thin
(2-4-mm), concentric diaphragmlike septa, which
may narrow the lumen down to a pinhole as shown in
Figure 1. The histology shows submucosal fibrosis
with normal overlying epithelium apart from the tip
of the diaphragm, which often contains chronic and
acute inflammatory cells. Four other cases have been
described where patients on NSAIDs developed symp-
toms of subacute small intestinal obstruction”’ and
were found to have diaphragms at surgery. The small
intestinal diaphragms are notoriously difficult to diag-
nose because no conventional diagnostic procedures
Figure 2. A small bowel enema study (enteroclysis) In a patient on
are particularly helpful, and at radiology the strictures
NSAlDs who on surgery was found to have “diaphragm” strictures.
may simply mimic exaggerated plica circularis as The strictures (between the arrows) are dtfficult to appreciate and
shown in Figure 2. Because the diaphragms do not resemble exaggerated plica clrcularis.
 1836 BJARNASON ET AL. GASTROENTEROLOGY Vol. 104, No. 6

phragms in the ascending colon.‘08,10” The diaphragms NSAlDs and intestinal permeability. Tests of in-
should not be confused with congenital duodenal dia- testinal permeability were designed to assess the func-
phragms (usually single but up to three have been tion of the intestine to act as a barrier as opposed to an
found together) although the macroscopic and micro- absorptive organ.‘33-135 This is done noninvasively,
scopic similarities are striking.110-1’2 The congenital and with a high degree of specificity, by measurement
diaphragms are distinguishable by their location in the of urinary recovery of a variety of orally administered
duodenum, and they are only rarely found in the prox- test probes.‘36 Of the main test procedures in cur-
imal jejunum. They are regarded to represent one devel- rent use-polyethylene glycol 400, di/monosaccha-
opment extreme of the atresia/stricture complex, ride urine excretion ratios, and “Cr-labeled ethylenedi-
which may have a vascular etiology.113,“4 aminetetraacetate (“Cr-EDTA)- most studies have
used 51Cr-EDTA _t monosaccharide in rheumatic pa-
NSAID-Induced Enteropathy tients as an index of intestinal permeability.137-‘41 Ini-
tially, it was shown that the 24-hour urine excretion of
The above observations suggest that NSAIDs “Cr-EDTA was normal (<3.0% of dose) in 12 patients
have an adverse reaction on both the large and small with rheumatoid arthritis untreated by NSAIDS.‘“~
intestinal mucosa. A systemic approach to elucidate Ten of 12 NSAID-treated patients had markedly
the prevalence of subclinical damage was initially increased intestinal permeability, and similar results
prompted by the possibility that the intestine might were found in NSAID-treated patients with osteoar-
play a pathogenic role in the various arthropathies. thritis.13’ The role of NSAIDs has since been con-
The possible interaction between joint disease and the firmed in patients as well as volunteers.138-148 In-
intestine form a subject of great interest.115-120 At the creased intestinal permeability occurs within 12 hours
turn of the century, the theory of “focal sepsis” was of NSAID ingestion of 2 doses of ibuprofen (400 mg
formulated and in practice led to removal of teeth, twice a day), naproxen (500 mg twice a day), or indo-
tonsils, adenoids, and appendices as possible forms of methacin (75 mg at midnight and 50 mg 1 hour before
treatment for rheumatoid arthritis and even cholecys- study) but possibly not following aspirin.‘“’ For this
tectomy and colectomy. 121,‘22This was followed un- effect to occur, subjects should not take food because
successfully by therapy with injection of dead bacte- nutrients may alter this response profoundly.‘49 After
ria.“’ In the 193Os, Svartz devised a method for the single doses, intestinal permeability reverts back to
selective delivery of an antimicrobial agent (sulfapyri- normal within 24 hours and within 4 days of taking
dine) to the colon to rid the body of the presumed NSAIDs for a week.‘43 The precise mechanism for the
pathogen. 116*123,124
Although effective as a second line permeability increase is uncertain, but a high local
disease modifying agent, it seems likely that its benefi- concentration of an active NSAID in the small intes-
cial action is due to an immunomodulatory action of tine appears to be important because pro-NSAIDs
systemically absorbed sulphapyridine rather than the (nabumetone and sulindac), whose active metabolite is
antimicrobial effect.‘25-127 There is no current agree- produced in liver following absorption, do not in-
ment regarding an infectious cause of rheumatoid ar- crease intestinal permeability in volunteers.143”44 The
thritis. stomach appears to contribute little or not at all to the
The situation in other chronic arthritides may be increased permeability induced by NSAIDS.‘~~“~~ How-
different. Klebsiella has been implicated in the etiology ever, concomitant prostaglandin ingestion (in large
of ankylosing spondilitis, and it has been suggested doses) with NSAIDs reduces the permeability changes
that the mechanism may involve molecular mimicry induced by indomethacin’50 though it loses its protec-
between the nitrogen reductase enzyme of Klebsiela and tive effect as the length and time between doses in-
a homologous 6-amino acid sequence in the HLA B27 creases.‘48,151 Curiously, a glucose-citrate formulation
molecule itself.49-52,‘28-‘31 Although this is a contro- of indomethacin may attenuate the permeability
versial issue, it is clear that Reiters syndrome may changes caused by indomethacin but not if glucose or
follow bacterial infection of the intestine.“9~132 Fur- citrate are given by themselves.149 This may partly ex-
thermore, 30%-70% of patients with ankylosing spon- plain the otherwise contradictory findings that small
dilitis and reactive arthritis have an acute or chronic intestinal permeability is not universally increased by
ileitis regardless of NSAID treatment.49-52 Because of NSAIDs when taken with food.15* There are no imme-
these confounding variables, discussion will be limited diate clinical implications of increased intestinal per-
to the possible effects of NSAIDs on patients with meability, but it may play an important pathogenic
rheumatoid and osteoarthritis. role in NSAID-induced enteropathy as discussed later.
June 1993 NSAID AND THE LOWER GI TRACT 1837

Figure 3. (A) A normal “‘In-labeled leucocyte sclntigram showing liver, spleen, vertebra “‘In-labeled and pelvic bones. (B) A l”ln-labeled
leucocyte scintlgram from a patient with rheumatoid arthritis on NSAID therapy showing abnormal accumulation in the right iliac fossa at 20
hours.

NSAlDs and intestinal inflammation. Quantita- fossa, which represents luminal accumulation of “‘In-
tively, the NSAID-induced increases in small intes- labeled leucocytes that have traversed the mid small
tinal permeability are similar to that of patients with intestinal mucosa and are temporarily held up by the
small intestinal Crohn’s disease.‘5”-‘58 Evidence for ileocaecal brake. The reason the cells are not visualized
small intestinal inflammation in patients on NSAIDs within 4 hours is that the inflammation is of low activ-
was specifically sought by the technique of “‘In- ity and diffuse, and combined with the mobility of the
labeled neutrophils.‘“7,158 The labeled cells localize small intestine, there is insufficient indium activity for
within 4 hours to areas of active inflammation in early localization.‘58
over 90% of patients with inflammatory bowel dis- The 4-day fecal excretion of “‘In from NSAID-
ease.‘59-162 Moreover, the 4-day fecal excretion of “‘In treated patients is shown in Figure 4 and confirms the
provides an objective, sensitive index of inflammation low activity of the inflammation in comparison with
of the whole of the gastrointestinal tract giving infor- classic inflammatory bowel disease. Patients not
mation not available by other techniques.‘59-‘62 It has treated with NSAIDs have normal excretion values,
been thoroughly validated and is considered by some and 60%70% of patients on NSAIDs have increased
to be the technique of choice to assess intestinal inflam- fecal excretion of “’ In, which is the defining feature
mation and the efficacy of medical treatment in pa- of NSAID-induced enteropathy. Two similar stud-
tients with inflammatory bowel disease.‘“2 Studies in ies’63,‘64 and one with enteroscopy’“’ have since con-
over 100 patients with rheumatoid and osteoarthritis firmed these findings, but the interpretation of the re-
have not shown scintigraphic abnormalities in pa- sults from one group differed; they suggested that the
tients untreated with NSAIDS.‘~‘*‘~~ About 50% of pa- inflammation represented a primary abnormality in
tients on NSAIDs for more than 6 months have scinti- rheumatoid arthritis. ‘63 The enteroscopy study shows a
graphic abnormalities but, unlike scans of patients prevalence of damage similar to that seen with the
with inflammatory bowel disease, it is not the early leucocyte studies. The damage ranged from mucosal
scans that are abnormal but those obtained at 20 hours red spots, erosions with surrounding villus atrophy to
as shown in Figure 3. The consistent abnormality at frank ulcers.165 Although the observation and clinical
this time is accumulation of “‘In in the right iliac implications of mucosal red spots have been ques-
 1838 BJARNASON ET AL. GASTROENTEROLOGY Vol. 104, No. 6

70 - problems in assessing the importance of the individual

drug dose and delivery system in the pathogenesis of
60 - the inflammation. Elucidation of the mechanism by
which NSAIDs cause small intestinal damage is of con-
50 -
‘iii siderable theoretical importance, but the clinical im-
a
8 40- . plications are dependent on the possible associated
complications.
z!. 30 .
E .
.
Complications of NSAID-Induced
.$ 20
.-c 1 0 0 Enteropathy

Intestinal bleeding. A number of studies sug-

101 gest that NSZID-induced enteropathy is associated
5
9- with intestinal bleeding. First, there does not seem to
'Z
s a-
al
be a close relationship between upper endoscopic find-
ir 7- 10 ings and evidence of intestinal bleeding in NSAID-
$ 6- : treated patients, even when chronic blood loss has led
0
3 5- .
to an iron deficiency anemia.‘67-‘69 Second, a localiza-
i tion study was carried out in 32 patients on NSAIDs by
IF 4- 0
L ??

3- simultaneous injection of “‘In-labeled neutrophils and

d
??
2- 0
“““Tc-labeled red cells.“’ At 20 hours, 9 patients were
3 1L entirely normal and 19 patients, all of whom had iden-
1 - .
O- -t- & tical localization
“‘In
of “““Tc-labeled
accumulation
red cells, had the
in the right iliac fossa, indicating
a b C d e
that the patients had lost some blood from the inflam-
Figure 4. Fecal excretron of “lln over 4 days. (A) irritable bowel; b,
matory site. There were four discrepancies. ‘I’hird, 34
rheumatord arthritis untreated by NSAIDs; c, NSAID-treated patrents
wrth rheumatoid arthritis; d, NSAID-treated patients with osteoarthrn
tis; e, patients with rnflammatory bowel disease. Controls with the
irritable bowel syndrome excrete less than 1% of the intravenously
admrnistered dose of labeled leucocytes. Untreated patients with
rheumatoid arthritis are normal but 70% of NSAID-treated patients 0 9.7%
have small intestmal inflammation somebmes of comparable activity
as seen in inflammatory bowel disease. The horizontal lines represent 0
mean values.

tioned ‘M the evidence is rather against them being just

artifacis. lfj5
Although the permeability changes are seen within
hours, the inflammation may take longer to develop;
however, there have been no prospective or sequential
studies to see how quickly this occurs. Our own data in
a limited number of patients have shown inflamma-
tion only in 4 of 11 patients treated for <6 months.
However, once the inflammation is established, “‘In-
labeled leucocyte excretion may be increased for up to
16 months after discontinuing NSAID therapy.‘58 All 3
0
commonly used NSAIDs were observed to be asso-
I I I I I I
ciated with the inflammation, but the interpretation of 0 1 2 3 4 5 6 7
this observation is confounded by the fact that most of Faecal excretion
of 51CrRBC (ml/day)
the patients had received a number of different
Figure 5. Fecal excretron of “‘In over 4 days and the mean daily
NSAIDs in the past. This factor, together with vari-
fecal blood loss of 5’Cr-labeled red cells showrng a significant correla-
able patient compliance and concomitant second line tion (r = 0.59; P < 0.01) between mflammatory activity and blood
(disease modifying) drug treatment pose considerable loss.
June 1993 NSAID AND THE LOWER GI TRACT 1839

BILE
HYDRO- AND PROTEOLYTIC ENZYMES
blood loss, which in a normal person would amount to
NSAlDs BACTERIA
150 mL (3% of 5000 mL, circulating blood volume).
Much less is seen and the inflammation is an order of
f
magnitude greater than could be accounted by blood
loss. This is in keeping with the specificity and selectiv-
ity of neutrophil chemoattraction.
A further 32 patients were studied in a similar fash-
ion with “‘In-labeled leukocytes and 51Cr-labeled red
cells and then underwent gastroduodenoscopy.‘7’ In-
flammation was again correlated with bleeding, but
I neither of these related to the endoscopic findings
2.
- $ATP (Lanza grading) or histological appearances of biopsy
specimens taken from duodenum, antrum, or body.
/
Finally, Morris et al. examined by enteroscopy a se-
neutrobhils causing Indlsctiminant damage
wlthin tlta IIIUM)U resulting in blood and lected group of patients taking NSAIDs who had rheu-
prot&l lo%%
matoid arthritis and iron deficiency anemia, which
4.
could not be explained by gastroscopic or colono-
~ scopic findings. ‘65 In more than half of these patients,
lesions, which were thought to have the potential to
contribute significantly to intestinal blood loss, were
found in the small intestine. Collectively, these studies
establish the small intestine as a site of mild chronic
Figure 6. A schematic outline of the proposed’9o mechanism of
NSAID-Induced damage to the intestine. (I) FoIlowIng NSAID absorp- blood loss in patients on NSAID therapy. The clinical
tion there IS uncoupling of mitochondrial oxidative phosphorylation. significance of the increased blood loss (l-1 0 ml/day)
This leads to (2) reduced ATP levels, which in turn results in loss of
has to be looked at in the context of all the other fac-
control of the integrity of intercellular ]unctions with increased intes-
tinal permeability (3). Another consequence of uncoupling is (4) an tors that contribute to iron homeostasis. Thus, the ma-
efflux of calcium and hydrogen ions from mitochondria. This further jority of healthy menstruating women lose 150-300
depletes ATP stores but more importantly promotes oxygen radical mL/month (mean, 5-10 ml/day) without apparent
damage. The sick cell releases arachidonic acid, but their conversion
to prostaglandins is prevented by NSAID inhibition of cycle-oxygenase
ill effect whereas patients with gastric and colonic ma-
(5). The main consequence of this is that the rntesbnal permeabilrty lignancies, who often present with iron-deficiency ane-
changes caused by decreased ATP (3) are much more prolonged than mia, often have a mean intestinal blood loss of 1-12
otherwise would be the case. The consequence of increased intes-
mL,/day.‘74
tinal permeability (6-8) is that the mucosa is exposed to luminal ag-
gressive factors, which in the small bowel is bile, hydroeolytic and Patients with rheumatoid arthritis may have a num-
proteolytic enzymes, bacterial degradation products, and finally a bac- ber of interacting factors predisposing them to iron
terial invasion of the mucosa, which appears to be the main chemoat-
deficiency. First, food intake may be limited because of
tractant for neutrophils. On contact with the chemoattractant (9),
there is generation of reactive oxygen species, and following internal- NSAID-induced dyspepsia or cachexia from active
ization of the chemoattractant, neutrophrls release lysosomal en- disease. Some may not reduce ingested iron effectively
zymes into their immediate surroundings, leading to macroscopic dam- to the ferrous state because of relative achlorhydria
age with bleeding and protein loss.
(due to gastritis or concurrent treatment limiting or
neutralizing acid output). Finally, they may not be able
patients taking NSAIDs underwent studies to quanti- to increase iron absorption from the small intestine in
tate and correlate the inflammation (4-day fecal excre- response to iron deficiency. ‘75,176IJnder these circum-
tion of “’ In-labeled neutrophils) and blood loss (5-day stances, mild blood loss from the small intestine may
fecal excretion of “Cr-labeled red cells).‘7’,‘72 Figure 5 be an important cofactor in the development of iron
shows that the inflammatory activity correlated signifi- deficiency. The prevalence of iron deficiency in pa-
cantly (r = 0.59) with the intestinal blood loss, further tients with rheumatoid arthritis has only recently been
suggesting that the bleeding originated at the inflam- appreciated (50%) because the normal indices used to
matory site. Furthermore it shows that the fecal excre- assess iron deficiency are overshadowed by the effect
tion of “‘In-labeled leukocytes is not simply due to of “the anemia of chronic disease” on these parame-
ters,177-179
oozing or leaking because if this was the case an excre-
tion of ‘l’In-labeled neutrophils of, for example, 3% Intestinal protein loss. Approximately 10% of
(Figure 4) should be associated with an equivalent 3% patients with active rheumatoid arthritis requiring hos-
1840 BJARNASON ET AL. GASTROENTEROLOGY Vol. 104, No. 6

pitalization have hypoalbuminemia. This has been ings. 18’Patterson et al., using a variety of tests, found a
ascribed to reduced hepatic synthesis and to increased degree of malabsorption in 16 of 22 patients (73%)
degradation or increased transcapillary loss of albu- with rheumatoid arthritis.‘88 The malabsorption was
min 180-182 insufficiently severe to cause malnutrition. Mefenamic
The possibility that small intestinal inflammation acid and sulindac, however, have been implicated in
caused by NSAIDs could be associated with intestinal severe malabsorption with subtotal villus atrophy re-
protein loss was studied in 9 patients.“’ These under- sembling celiac disease.32,33,‘89
went simultaneous study of intestinal inflammatory ac-
tivity and protein loss. The latter involves a lo-day Pathogenesis and Management of NSAID-
fecal collection following intravenous administration Induced Enteropathy
of “Cr-labeled chloride. By correlating 5’Cr activity in
stool with serum levels from the previous day a calcu- Pathogenesis. The pathogenesis of NSAID-in-
lation of mean intestinal protein loss (normal, <25 duced enteropathy is uncertain, but it has been sug-
mL serum/day) can be made. Three patients had no gested that it can be divided into two distinct stages
inflammation and no increased protein loss whereas (Figure 6). 19’The first stage would represent the spe-
the remaining 6 had NSAID-induced enteropathy and cific biochemical effect of NSAID on enterocytes re-
increased protein loss. The protein loss was usually sulting in subcellular damage, which manifests itself as
mild and of little clinical consequence, but one patient increased intestinal permeability. Increased intestinal
had a sufficiently severe loss (318 ml/day) to cause permeability is postulated to be the central mechanism
hypoalbuminemia. Like the iron deficiency, hypoalbu- in the transition between the first and the second stage
minemia may be brought about by several interacting (specific vs. nonspecific, ultrastructural vs. macro-
factors, but when established it is difficult to treat. scopic damage), which is the nonspecific tissue reac-
Although previously unrecognized or thought to be a tion caused by an interplay between luminal aggressive
consequence of amyloidosis,‘83 this small study sug- factors and mucosal defense.
gests that NSAID-induced enteropathy is a sufficient NSAIDs appear to cause specific damage to entero-
cause for intestinal protein loss. The findings need to cyte mitochondria during absorption by uncoupling
be confirmed in a larger number of patients but suggest oxidative phosphorylation. ‘90-192Electron microscopy
the possibility of an alternative therapeutic approach of rat intestine has shown pathognomic changes in
to managing severe nonrenal hypoalbuminemia in pa- mitochondrial structure within 1 hour of NSAID ad-
tients with rheumatoid arthritis. ministration. At 6 hours, before macroscopic damage
Heal dysfunction and malabsorption. Ileal is evident, there are significant biochemical changes in
function was assessed in 20 patients taking NSAIDs specific organelle markers of the mitochondria (in-
with a moderately high fecal excretion of “‘In-labeled cluding citrate synthase, succinate dehydrogenase, cy-
leukocytes. 158 A dual radioisotopic tracer technique tochrome c oxidase) and the brush border (alkaline
was designed and validated for these studies.‘84*‘85 In phosphatase). 19’ NSAID-induced uncoupling of oxi-
short, a synthetic bile acid, tauro-23-[75Se]selena-25- dative phosphorylation has been shown in vitro in
homocholic acid ([75Se]HCAT) is ingested, followed gastric tissue with reduced adenosine triphosphate pro-
by [58Co] vitamin B,, with intrinsic factor. Whole- duction.‘93-‘“5 This would render the cell energy de-
body retention measurements are made at 4, 7, and 10 pleted and cause efflux of calcium from mitochondria,
days. The 4-day data were most discriminatory for the which would in turn trigger a cascade of secondary
detection of patients with ileal Crohn’s disease. At that biochemical events that cause damage including the
time, 13 of 20 patients with NSAID-induced enteropa- generation of reactive oxygen species.‘“’ Reduced ATP
thy had evidence of bile acid malabsorption, but only levels would also result in loss of control of the inter-
the occasional patient had evidence of mild vitamin cellular junctions because their integrity is governed by
B,, malabsorption. While these studies show another an ATP-dependent process linked to the cytoskele-
intestinal abnormality in these patients, their clinical ton.196-199 The resulting increase in intestinal perme-
relevance remains uncertain. ability would be more prolonged than it would follow-
Kendall and Jackson have shown that indomethacin ing other damage because of the effect of NSAIDs
decreased xylose absorption. 186This was confirmed by inhibiting cycle-oxygenase and thereby the generation
Dyer et al., who found that 40% of their patients with of reparative prostaglandins. In this framework, the
rheumatoid arthritis had fat or xylose malabsorption, inhibitory effect on cycle-oxygenase is postulated to be
and 3 of 13 patients had abnormal jejunal biopsy find- of secondary importance. Although controversial, this
June 1993 NSAID AND THE LOWER GI TRACT 1841

sequence is in keeping with Whittles data in rats200 that the main neutrophil chemoattractant.21622” On con-
show that as macroscopic damage becomes evident the tact with such chemoattractants, there is a burst of
activities of cycle-oxygenase are or have returned to reactive radical species generation followed by inter-
normal, that there is a lack of relationship between the nalization of the chemoattractant with subsequent lyso-
degree of mucosal injury and reduced mucosal prosta- somal enzyme release resulting in damage.224T225 That
glandins, and that 95% inhibition of prostaglandin syn- this may be the case in NSAID-induced enteropathy is
thesis can be achieved without apparent damage.201,202 supported by the findings that macroscopic damage is
At the same time, others have suggested that intestinal limited when neutrophil recruitment is prevented by
lesions can be produced by inducing antibody produc- induction of neutropenia or following administration
tion to cycle-oxygenase, the implications being that it of antibodies to adherence molecules that interfere
is the primary initial target of NSAID-related dam- with neutrophil migration.218*2’9 Sulfasalazine226 and
age.203 metronidazole217 reduce inflammation in NSAID en-
Once the intestinal barrier has been broken, the se- teropathy, and at the same time there is decreased in-
quence of events is determined by the interplay be- testinal blood loss although there is no significant de-
tween luminal aggressive factors and mucosal de- crease in the abnormal intestinal permeability; these
fense.“’ In animals, there is no doubt about the findings are in general agreement with the above hy-
importance of luminal bile acids, food ingestion, and pothesis. The above puts a number of important obser-
bacteria on NSAID-induced damage, although their vations into perspective and forms a logical testable
precise interaction is uncertain.204-214 It has been par- multistage pathogenic framework for the development
ticularly difficult to explain the predominantly middle of NSAID-induced inflammation, which may be rele-
and distal small intestinal location of the macroscopic vant, in particular the second stage, to other intestinal
damage. Conceivably, this may relate to regional varia- disease.
tions in the concentration of NSAIDs and the impor-
Management. It should be emphasized that all
tance of luminal aggressive factors.
of the studies relating to management have been specif-
The importance of bile is suggested by the finding
ically designed to study the possible pathogenesis of
that bile duct ligation greatly reduces the prevalence of
the enteropathy or its resemblance to classic inflamma-
the lesions.209 Luminal concentration of bile acids in-
tory bowel disease, and none have been subjected to
creases distally while food is absorbed, which may per-
evaluation by acceptable trials. Indeed, because
turbate damaged enterocyte membranes and thus act
NSAID-induced enteropathy is not known with cer-
synergistically with the biochemical damage.‘“’ As
tainty to be associated with an increased mortality (un-
most NSAIDs are conjugated and secreted in bile to a
like the gastroduodenal side effects), it is unlikely that
significant degree (20%60% of an intravenously ad-
prevention or treatment will become serious clinical
ministered dose), the findings could also be explained
options for the majority of patients receiving these
by selective delivery of large concentrations of
drugs. There are nevertheless three therapeutic op-
NSAIDs to the distal small intestine where bacterial
tions, namely to stop NSAID treatment, to prevent the
deconjugation is significant.215-2’7
enteropathy, or to treat it.
Feeding animals after the NSAID dose clearly en-
hances the macroscopic damage.“’ While this has The possibility of discontinuing NSAID therapy is
usually been ascribed to environmental agents or bacte- usually impractical because patients require the drugs
ria playing a pathogenic role in the damage, the expla- for control of pain and synovitis. The lowest possible
nation may simply be that ingested food causes bile dose of NSAIDs should be used, and there is a case for
secretion with the above consequences. Finally, the abandoning rigorous fixed-dose regimens.
role of bacteria has been inferred by the almost univer- The possibility of preventing the enteropathy de-
sal findings that very few lesions are found in the pends on the knowledge of its pathogenesis, which
germ-free animal and that pretreatment with antimi- may involve a complex biochemical mechanism fol-
crobials reduces the damage.204~206-209 Curiously, treat- lowed by a tissue reaction. It also follows that the more
ment, instead of prophylaxis, with the same antimi- specific the intervention and the earlier in the patho-
crobials does not facilitate healing in animals,‘l’ genesis of the enteropathy it is applied, the greater
although metronidazole is therapeutic in humans.218 potential it has. The prospect of preventing the dam-
Also, the neutrophil appears to be the main effector age with concomitant prostaglandins is not good be-
cell in NSAID-induced small intestinal damage, and it cause very large doses have to be given to reduce the
may be that microbial invasion of the mucosa provides permeability changes induced by single doses of indo-
1842 BJARNASON ET AL. GASTROENTEROLOGY Vol. 104, No. 6

methacin,‘44 and despite this many subjects still have Conclusion

increased intestinal permeability. Furthermore, when NSAIDs remain extremely useful antirheu-
normal therapeutic doses of misoprostol are given matic drugs, but it is clear that the full story of
with indomethacin for a week’48,‘51 there is no evi- NSAIDs and the intestine has yet to be told. This re-
dence of protection, suggesting that the biliary compo- view shows that the idea of a site specific gastroduo-
nent (not covered by simultaneous ingestion of the denal organ damage is simplistic and incorrect. Indeed
two) may be sufficient to cause damage. the introduction of NSAID formulations to circum-
The situation is similar for glucose-citrate formula- vent the gastroduodenal damage (enteric coating, sus-
tions of indomethacin, which effectively prevent the tained release, etc.) may be transferring the problem
increased intestinal permeability caused by indometh- out of sight of the traditional endoscopist. The realiza-
acin following single doses.i4” However, it still fails to tion of the magnitude of gastrointestinal damage
prevent the permeability changes or the development caused by NSAIDs should encourage active research
of the enteropathy when taken long term (unpublished into means by which to minimize these side effects.
observations), presumably for the same reasons de-
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Received September 23, 1992. Accepted January 19, 1993.
Address requests for reprints to: lngvar Bjarnason, M.D., Depart-
ment of Clinical Biochemistry, King’s College School of Medicine and
Dentistry, Denmark Hill, London SE5 9PJ, England.