Total parenteral nutrition as primary treatment in Crohn's disease - RIP? - Gut
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Gut: first published as 10.1136/gut.29.10.1304 on 1 October 1988. Downloaded from http://gut.bmj.com/ on July 30, 2021 by guest. Protected by copyright.
Gut, 1988, 29, 1304-1308
Leading article
Total parenteral nutrition as primary
treatment in Crohn's disease - RIP?
The unpredictable course of Crohn's disease presents the clinician with
many questions concerning therapy, most of which remain unanswered.
Ideally prospective, controlled, randomised trials can indicate optimal
methods of treatment, but the clinical variability of this disease of unknown
aetiology has made such trials difficult to design and to undertake. Since
Crohn's disease was first described over 50 years ago, the aims of therapy
have remained the same, to stop the acute attack swiftly and then delay
relapse for as long as possible, preferably without recourse to surgery.
Several trials of medical treatment have been reported. Two controlled
prospective randomised studies'2 indicated that steroids and sulfasalazine
were the best drugs in the treatment of the acute attack. Steroids and
sulfasalazine together would maintain remission in up to 40% of patients
over two years, compared with only 10% on placebo.2 Azathioprine 2.5 mg/
kg/d has been shown to have a significantly beneficial effect in maintaining
patients in remission.4 Metronidazole has also been reported to have a
place in the treatment of active disease.' None of these treatments, however,
is without a substantial incidence of side effects.56
In the late 1960s and early 1970s interest focussed on total parenteral
nutrition (TPN) when various reports indicated that the nutritional state of
severely ill patients could be maintained, or even improved, whilst allowing
more time for medical therapy to induced remission of the acute attack. TPN
could be used in patients in whom medical therapy had failed to improve
their general condition before surgery.7 It was observed that TPN obviated
the need for surgical intervention in some patients.7'0 It was postulated that
the 'bowel rest' achieved as a result of the TPN might be in itself of primary
importance`'0 in the treatment of inflammatory bowel disease. The principle
of 'bowel rest' using surgical techniques such as ileostomy to divert intestinal
contents from the inflamed bowel and thus allow healing, had been
suggested before,"'4 although such diversion was applicable only when the
disease was confined to the colon.
One of the great problems in judging published results of TPN in Crohn's
disease has been that interpretation of the benefits and mechanisms of action
have been confused by the differing aims and methods by which data have
been collated in various studies. Examples of these pitfalls include studies
which examine both Crohn's disease and ulcerative colitis;'517 19-22 studies
which are uncontrolled and/or non-randomised;'517 3 and retrospective
reviews.'1212425 'Drug resistance' and 'failure of medical therapy' are often
not formally defined.'5 17 122 The importance of clearly defining such terms
has been emphasised elsewhere.26
In this issue of Gut Greenberg et al, report a prospective, randomised,
controlled trial of bowel rest and nutritional support in the management of
Crohn's disease. Patients with Crohn's disease 'unresponsive to medical
1304Gut: first published as 10.1136/gut.29.10.1304 on 1 October 1988. Downloaded from http://gut.bmj.com/ on July 30, 2021 by guest. Protected by copyright.
Totalparenteral nutrition as primary treatment in Crohn 's disease - RIP? 1305
management' (with steroid doses before entry stated) were randomised to
21 days of nutritional support in three groups: TPN with nothing by mouth, a
nasogastrically administered, defined formula, whole protein containing
diet, or partial parenteral nutrition supplying some of the nutritional
requirements with ad libitum oral food. Remission of disease was defined as
a modified Crohns Disease Activity Score' 24 of less than 150 on day 21. All
patients who remitted were maintained on a dose of 15 mg steroids daily and
followed up at one year. There was no significant difference in outcome
between the three groups with respect to the number of remissions of acute
disease (58-71%), or the number of patients still in remission at one year
(42-56%). This new study thus dispels the idea that 'bowel rest' plays an
essential part in the induction and subsequent maintenance of remission in
active Crohn's disease and this is in accordance with the earlier work of Lochs
et al.27 It must be emphasised, however, that this report specifically shows
that 'bowel rest' in the conventional sense of withholding nutrients from the
intestinal mucosa, is not a prerequisite to achieving remission in those
patients who are also receiving medical treatment. The authors record the
daily doses of steroids in each group before entry into the study (TPN 24±3
mg; defined formula diet 23±3 mg; partial parenteral nutrition 21±3 mg).
Some might argue that higher doses could have induced remission without
nutritional support.
The case for TPN as a primary therapy in Crohn's disease is thus confused
in this and other studies by either prior, or concurrent administration of
standard medical treatment. So far there is no prospective randomised
controlled trial comparing TPN alone with standard medical therapy in
acute Crohn's disease. The data of Greenberg et al, indicate that such a trial
is not needed because the premise that bowel rest (as achieved by TPN) is
essential, or beneficial in achieving remission of acute Crohn's has now been
shown to be invalid.
Specific ways in which bowel rest can promote healing of affected bowel
have been proposed.2829 It has been postulated that bowel damage occurs in
relation to the antigenicity of intraluminal contents, possibly in association
with disordered immunological function which is secondary to the disease
and may be associated with malnutrition. It would follow that improvement
of nutrition with a resultant normalisation of immunological function")3 and
withholding of antigenic foDd proteins,32 or decreased intraluminal concen-
trations of bacteria33 might directly benefit the gut. It is also reported that
administration of TPN may result in functional change of the intestinal
microflora, although the clinical significance of such changes is unclear.-
The potential disadvantages of TPN and 'complete bowel rest' must be
considered. Even in specielised centres there is a small, but definite
morbidity associated with this technique, whatever the indications for using
it.35 The theoretical disadvantages of using TPN as primary therapy for
Crohn's disease must be borne in mind. There is now much evidence that
glutamine is essential for the normal structure and function of the intestine.-'
Commercial TPN solutions do not contain glutamine and villous atrophy is
well recognised in patients receiving TPN.37 There is increasing evidence
that fermentable fibre within the gut lumen may stimulate epithelial cell
proliferation in the small and large intestine, possibly by a mechanism
involving production of volatile fatty acid and release of plasma entero-
glucagon.38 Glutamine and fibre therefore may promote gut healing.Gut: first published as 10.1136/gut.29.10.1304 on 1 October 1988. Downloaded from http://gut.bmj.com/ on July 30, 2021 by guest. Protected by copyright.
1306 Payne-James and Silk
Treatment with TPN and 'bowel rest' denies the acutely inflamed intestine
these substrates.
These considerations are important when considering enteral diets as
primary therapy in Crohns disease. The potential benefits of elemental diets
have been reported by several investigators.394' More recent controlled
studies have confirmed the efficacy of this treatment.42 An elemental diet
may supply glutamine at the same time as improving nutritional status, but
lacks fermentable fibre. It would be interesting to determine whether a fibre
supplemented, glutamine rich, chemically defined elemental diet has any
additional therapeutic advantage in Crohn's disease.
The evidence at present indicates that TPN in Crohn's disease should be
restricted to supportive, rather than used as primary therapy. It is
undoubtedly useful in some circumstances, particularly in the treatment of
specific complications of Crohn's such as intestinal obstruction related
to stricture formation, or short bowel syndromes following repeated
resection. Available data seem to suggest that most of the benefit of TPN is
related to the improvement of nutritional state. Theoretical and practical
reasons dictate that the way forward in the development of more effective
(and perhaps safer), alternatives to drugs in the treatment of acute Crohn's
disease must be the evaluation of enteral diets in prospective, randomised
controlled trials. There have been many opportunities for evaluation of
TPN in this disease, but its advocates have taken too long to achieve positive
results. The report of Greenberg et al may be a nail, if not the final nail, in
the coffin of TPN as primary therapy in the treatment of acute Crohn's
disease.
J J PAYNE-JAMES AND D B A SILK
Department of Gastroenterology and Nutrition,
Central Middlesex Hospital,
Acton Lane,
London NWJO 7NS
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