Modern Management of Duodenal Ulcer

Chronic peptic ulcer of the duodenum is a common disease. It causes the loss of over two million working days per annum in the U.K. In Scotland, its sufferers occupy over one hundred thousand bed days, and, along with benign gastric ulcer it kills almost four hundred Scots per year.1,2' By the age of fifty about ten per cent of the male Scottish population will have been affected by it. If it is not rare, neither is it new. The term peptic ulcer was first used in 1882 by Quincke, believing that pepsin was the prime culprit. Bilroth first performed his operation in 1881, so we have nearly a century of operative experience to draw from. Yet despite this, there is still controversy over how this condition should be managed. Until recently our drug therapy was ineffective in altering the natural history of the disease, and even now has little place in recurrent ulceration. And trying to untangle the mass of surgical literature with many surgeons each promoting the virtues of one of the various manoeuvres, with at least nine major and a multitude of minor variants on offer, is not easy. Copyright Royal Medical Society. All rights reserved. The copyright is retained by the author and the Royal Medical Society, except where explicitly otherwise stated. Scans have been produced by the Digital Imaging Unit at Edinburgh University Library. Res Medica is supported by the University of Edinburgh’s Journal Hosting Service: http://journals.ed.ac.uk ISSN: 2051-7580 (Online) ISSN: 0482-3206 (Print) Res Medica is published by the Royal Medical Society, 5/5 Bristo Square, Edinburgh, EH8 9AL Res Medica, New Series No. 1, 1978/79: 16-21 doi:10.2218/resmedica.v0i1.916 PRINCIPLES AND PRACTICE MODERN MANAGEMENT OF DUODENAL ULCER


MODERN MANAGEMENT OF DUODENAL ULCER
Alan Boyd B.Sc.

Introduction.
Chronic peptic ulcer of the duodenum is a com m on disease.It causes the loss of over tw o million working days per annum in the U.K. In Scotland, its sufferers occupy over one hundred thousand bed days, and, along with benign gastic ulcer it kills almost four hundred Scots per year.1,2'B y the age of fifty about ten per cent o f the male Scottish population will have been affected by it.
If it is not rare, neither is it new.The term peptic ulcer was first used in 1882 b y Quincke, believing that pepsin was the prime culprit.Bilroth first performed his operation in 1881, so we have nearly a century of operative experience to draw from.
Yet despite this, there is still controversy over how this condition should be managed.Until recently our drug therapy was ineffective in altering the natural history of the disease, and even now has little place in recurrent ulceration.And trying to untangle the mass of surgical literature with m any surgeons each prom oting the virtues of one of the various manoeuvres, with at least nine major and a multitude of minor variants on offer, is not easy.
A n d w hy should this be?Largely because we still do not fully understand its multi-factorial aetiology, when applied to the individual.M any factors have been implicated, most now well founded, but some still a little dubiously, but we are still not in a position to relate these to each patient, and treat his disease specifically, even if we had the means.A n d on the surgical side the differing emphasis placed on the balance between effectiveness and sequelae, both morbid and mortal, compounded by the natural variations between surgeons' techniques and abilities, as well as patient variables have served to m uddy the waters for those seeking clear cut answers.
However, in the last few years new develop ments have arisen, both in the medical and surgical managements which promise to radically improve the outlook for our patients.The advent of Histamine H 2 receptor antagonists has given us a potent and specific means of reducing acid secretion, and the development of Highly Selective Vagotom y offers a less ablative approach with a marked reduction in the side effects so long associated with gastric surgery, and it is on these that I shall concentrate.

Uncomplicated Chronic Duodenal Ulcer
Conventional wisdom has it that the initial management of duodenal ulcer, in the absence of life threatening complications, should be con servative in all cases, and nothing has appeared in recent years to change this.
Adm ission to hospital is preferable, as bed rest still remains a corner stone of therapy and the release from domestic tensions and pressures may aid this.This alone is enough to bring relief of sym ptom s within a few days to m any patients, a fact which must be borne in mind when assessing the efficiency of drugs.Eighty per cent of patients will remit symptomatically for a greater or lesser period without specific treatment.
Stopping sm oking has been proven to speed healing of gastric ulcers, but the evidence in duodenal ulcer is less conclusive.Empirically, however it seems sensible and is retained by most clinicians.
A s for diets, the milk-fish diet of the past has been discredited, with hourly m ilk feeding having shown to increase acid secretion, and no evidence of increased healing being found.Dietary advice should now be limited to avoiding those foods and alcohol which aggravate sym ptom s and to taking regular smallish meals.3Drug treatment has evolved considerably in recent years, and there is now much evidence that healing can be accelerated as well as sym ptom s alleviated.The drugs available fall into five categories according to site of action.
1. Antacids.Providing purely sym ptom atic relief, these were the main stay of treatment until the newer drugs arrived.They remain useful adjuvant therapy for relief of symptoms, and should be allowed freely.
Total titration of gastric acidity is neither practical4 nor necessary.What is required is rapidity plus freedom from side effects, which is best achieved by balancing the cathartic and constipating effects of magnesium and alum inium compounds.
2. Anticholinergics.These are m any and various yet differ little in their effects or side-effects.They are less effective than antacids for sym ptom s and have no evidence for a healing action.5Since their role in maintenance therapy for the prevention of recurrence is also contested5 they must be of declining usefulness in tod ay's treatment.
3. Antipepsins.These synthetic sulphated m uco polysaccharides eg.amylopectin are claimed to interfere with auto digestion b y pepsin.They are very expensive and not generally available though they m ay have an effect on recurrence6 , again disputed and requiring further evaluation.
4. Mucosal Barrier Fortifying Agents.The first of the new generation compounds, this group has three contenders.Carbenoxolone is a liquorice derivative, whose mode of action is not clear, but which m ay stimulate m ucus production.When it first appeared in produced very poor results in duodenal ulcer (Doll, 1962), though effective in gastric ulcers, but it has recently been re examined in the belief that effective concentrations had previously not been realised in the duodenum and now a degree of endoscopically proven healing has been show n.5 But it has serious disadvantages in terms of side effects producing salt and water retention and potassium loss.Conventional diu retics worsen the potassium loss and spironolactone blocks its therapeutic effect which m ust limit its use in duodenal ulcer.Deglycyrrhinized liqhorice has not been shown to speed healing, but chelated Bism uth has, to a m inor degree5

Histamine H 2 Antagonists.
Histamine is thought to be an intermediate messenger in the acid and pepsin secreting pathway in the gastric mucosa both for vagal and gastrin stimulated secretion.The receptor for this is pharmacologically different from that mediating bronchial and sm ooth muscle contraction and is designated H 2 .The first drug to be developed was Burim am ide w hich was show n experimentally on dogs to reduce acid secretion.However it lacked potency and could only be given parenterally, and was replaced b y Metiamide w hich was put on trial.The largest published trial was the International Multicentre Trial8 w hich followed sixty seven patients with endoscopically confirmed duodenal ulcer in a metiamide v. placebo randomised controlled trial.
Ulcer healing in six weeks was significantly increased compared to placebo (Table 1).It also produced a statistically significant reduction in antacid consum ption and daytime pain, measured b y a self scoring system.
This difference was greater than has been shown for the other groups of ulcer healing drugs.

J -67
Metiamide 1.3g/day 73 ) Table 1_______________________________________ However Metiamide had several side effects, the most serious of which was bone marrow depression w hich led to one death.This led to the toxic thiourea group being replaced by a cyanoguanidine group and the new drug cimetidine was released for trial.
The results published so far seem to indicate that cimetidine is both effective and free from major side effects though of course it will be some time before the latter can be stated categorically.
Pouder9 produced complete healing in all of a series of ten patients on cimetidine 8 0 0 or 1600mg/day, for six weeks.Heggie10 produced healing in seventeen of nineteen patients (90%), on 400m g t.d.s.
Bodem ar and W alan11 showed ninety per cent healing in a series of forty-four patients, as against thirty-six per cent on placebo, on a regime of 2 0 0 or 300m g q.i.d.They also followed acid secretion, antacid consum ption and self assessed sym ptom s and found a statistically significant reduction in all three.Marginally better results were found on the higher dose.
Cim etidine has undoubtably been a great breakthrough.These series showed ulcer healing and sym ptom atic relief in ninety per cent of patients, a far better result than has been achieved b y other drugs.Antacids failed to heal ulcers faster than methyl cellulose, the control chosen for one trial.
However, one major problem still remains, namely that of recurrence, since the now standard six week course does not alter the natural history.In the series b y Heggie10 seven of his seventeen patients with healed ulcers had a recurrence within a m onth of stopping treatment.Trials of continuous cimetidine as a prophylactic measure on a dose of 400mg/day, taken at night, are now under way, but early results indicate that this is not fully effective.12 Fortunately cimetidine, being as yet free from side effects, may, with long term therapy (for life?), offer an answer to recurrence for many sufferers, but evaluation o f this is based on a few trials with small numbers of patients followed for relatively short periods, and an answer cannot yet be given.
Therefore, the treatment of recurrent or persistent ulceration is still surgical.The indications, which have not altered for some time, are reasonably clear.They are: a. intractable pain, or recurrence of pain with frequent loss o f work b. complications -pyloric stenosis, perforation or bleeding c. presence for five years or more.
The last is a little more controversial but it has been stated than an ulcer present for five years in unlikely to heal and that the risk from complications of having an ulcer for five years is similar to that of an operation.
The present authors of " Bailey and L o v e " suggest that patients should "e a r n " their operation, since unless they have suffered from some pain or a complication they m ay be ungrateful if significant sym ptom s arise from surgery.But this may change at least in degree in future years if recent developments hold good.
Having decided on surgery the choice is wide and a short survey of the alternatives may be useful.The aim of operation is to reduce the am ount of acid bathing the duodenum w hich can be achieved by bypassing it, removing a part of the secretory apparatus or b y removing the stimulus to secretion both neural and endocrine.
The earliest operations were gastrectomies with duodenal or jejunal anastomosis.This was fairly effective but had numerous side effects and a high mortality.Sectioning of the vagi at the oesophageal hiatus was introduced, thus removing both direct and gastrin mediated secretion.However the vagi control gastric em ptying and gastric stasis was produced necessitating a drainage procedure either by pyloroplasty (at least four methods), gastrojejunostomy or antrectomy which also has the virtue of removing the gastrin mediated stimulus to secretion.
B y the mid sixties m any surgeons had become dissatisfied with these operations.M an y variants had been tried but despite long experience few good results were obtained and new w ays to deal with the problem were sought.
With titles like T h e Surgeon's Dilem m a'1 the papers of the period set out the problem.Partial gastrectomy had the lowest recurrence rate but serious side effects and a significant mortality.Vagotom y and drainage was safer but had a higher recurrence rate and a different though no less debilitating set of side effects.
This led to the development of a selective vago tom y to overcome of the post vagotom y sym ptom s by leaving intact the hepatic and coeliac branches, and, most recently, a highly selective vagotom y which leaves the antrum innervated as well, allowing ' normal gastric emptying so that no drainage procedure is necessary.
The reasons for dissatisfaction were not hard to see.Table 2 lists the incidence of side effects and recurrence found in four of the more popular procedures.Five hundred and eight patients were followed for five to eight years in the Leeds Y o rk trials.13 -14 Uncharacteristically this series produced only one operative death (in the truncal vagotom y and pyloroplasty group) partly due to selecting out of high risk patients and partly due to the great experience of all the participants.Sim ilar results were obtained in Glasgow 15 and in Am erica by the Veterans' administration who followed 1357 patients.16These results showed that on ly major gastric resection carried a higher m ortality -nearly 2 % as against 0 .6%-0 .9% for other operations.With their low mortality they pointed towards truncal vagotom y and gastro jejunostomy or antrectomy as the best operations in experienced hands and called for a halt in the drift towards vagotom y and pyloroplasty which was steadily growing in popularity due in part to its more physiological approach.
Nevertheless this still produces a considerable and unacceptable burden of sequelae, even in the best hands.The first major trial o f selective vagotomy was by Kennedy in Belfast who followed one hundred patients with truncal vagotomy and drainage or selective vagotomy and drainage and produced a reduction in post operative diarrhoea from 30% to 8%, a statistically significant result ( a rare event in most o f the surgical papers on duodenal ulcer ), with similar results fo r recurrence and other symptoms.
Most attention soon turned however to highly selective vagotomy which on a theoretical basis offered much by not interfering with gastric emptying and by not requiring the alimentary tract to be opened.It was firs t performed as early as 1957 by G riffith and Harkins on an experimental basis but they included a drainage procedure.Andrup in Copenhagen and Johnston in Leeds were the first to perform it w ithout drainage.Soon many people were trying it and reporting their results which, often, were very poor fo r a number o f reasons.But many of these bad early results pointed to errors o f technique and procedure and are worth looking at.
One major early fault in technique was an incomplete oesophageal clearance and this was illustrated by poor results in a number of studies.Kronberg in Copenhagen18 produced excellent results for dumping, diarrhoea and epigastric fu ll ness but a recurrence rate of 22%, after one year.Hellenbeck19 in America managed to reduce their incidence o f recurrence from 15.4 to 6% (one from seventeen) by increasing their oesophageal skeletonisation from two to seven and a half centimetres above the cardia.Similarly, another study by Kronberg compared fo u r techniques fo r the operation w ith lower recurrence when the oesophagus was adequately cleared, finally adopting the technique o f Goligher which was superior fo r both recurrence and symptoms.Another problem, shown by Sohlaurg21 in Bergen passes a comment which is pertinent to most of what has been discussed so far, namely that good results depend on experience operators.The Bergen study included a large number of junior operators some of whom had only assisted at one such operation before undertaking it themselves.Though few o f their results could be considered good, they steadily worsened w ith the increasing inexperience o f the operators.It must be remembered that most o f the good results both for the more established and the more recent operations have been obtained by very experienced surgeons w ith a special interest in, and performing large numbers of, the particular operation and so their results w ill be hard to repeat, though this is balanced, in part at least, by the fact that the new operation is young and should improve w ith age as has been the case with most procedures as further improvements in fine technique are developed.
In order to assess the place o f highly selective vagotomy (HSV) in the modern management of duodenal ulcer, we must have the answers to three questions: i Is it safe?ii.what are its post operative consequences?iii. is it effective?Its safety is least in doubt.Johnston in Leeds 2 2 sent a questionnaire to all the surgeons he knew to be doing HSV's and received replies covering 5539 patients.This showed an overall m ortality of 0.31%, compared to 0.8% in 6490 cases of truncal vagotomy and drainage, and 1.6% in 1725 cases of truncal vagotomy and antrectomy from other collected series.The only specific m ortality related to this operation was from upper gastric necrosis which accounted fo r five deaths (0.09%), and prompted Johnston to advocate the reperitonisation o f the lesser curvature as well as careful preservation of vascalature not sacrificed necessarily in the procedure.
Reports of post operative sequelae vary, but largely agree that they are significantly less than fo r other procedures.The figures in Table 3 for incidences of diarrhoea and dum ping compare extremely favourably with those in Table 2.The problem of poor drainage leading to epigastric fullness and gastric stasis was anticipated, but reports vary enormously.Goligher puts epigastric fullness at 2 9% , Sayers at 8% , but Goligher claimed that all but one of his patients could eat a normal meal w ithout discomfort.Johnston's mammoth collected series put gastric stasis, both early and late, at 1.3%, with a reoperation required to provide drainage in 0 .8% Barium and other studies have shown that in general liquids drain a little faster than usual and solids a little slower.
The series b y Ly n d o n also showed that, although all their patients gave a negative Hollander test one week post operation, this was rapidly changed to a positive rate of 9 4 % after three years.However, the level of peak acid output on insulin stimulation was only 1 0 % of the pre-op level, and offered no prognostic indicator for recurrence.
The incidence of recurrence with this operation in general is still not clear.Since it probably takes two to three years for a surgeon to familiarise himself with the operation and perfect his tech nique before he can reasonably compare it with his performance of more established procedures, and then takes at least five to ten years of follow up before reliable rates of recurrence can be established, and since no one has this length of experience, it would be foolish to make a final judgement on figures now available.Nevertheless some inferences can be drawn.
Table 3 also shows recurrence rates for most of the large series published to date and these vary from 1 -9% .Undoubtably these figures will rise w ith time as the follow up lengthens.The best result (1% -a t 5 years b y Lyn do n ) compares very favourably with any other method but in general this has not been widely achieved.We can say for certain that it will not pro ve as effective as vagotom y and antrectom y or larger gastric resections but that it could equal results for vago tom y and gastro-jejunostomy and will probably be more effective than vagotom y and pyloroplasty.Com parisons with selective vagotom y and drain age are few, but four randomised controlled trials reported by A n d ru p 23 suggest ' near parity on recurrence but a strong advantage for the highly selective procedure as regards sequelae, though these again suffer from small numbers and a short follow up.
Thus, H S V offers an attractive proposition to those favouring minimal intervention in the first instance, being very safe and largely free from side effects, and w ho consider acceptable the possibility of a slightly higher incidence of re currence perhaps necessitating a further operation at a later date.Those w ho consider surety as the prime consideration must opt for one of the established procedures with vagotomy, preferably selective, plus antrectomy offering probably the best choice.If it were I on the table, I would want a surgeon of the form er kind.

Sum m ary
O n confirm ation of the diagnosis of duodenal ulcer medical treatment should be instituted.Th is will consist of bed rest, stopping smoking, a m inim ally altered diet and drug therapy in the form of cimetidine 1.3 g/day in divided doses with additional antacids as required.This will produce healing in about 9 0 % of cases within six weeks.Thereafter cimetidine 4 0 0 mg/day may be useful as prophylaxis.For persistent or recurrent ulcers (or for complications, with which I have not dealt here) surgical treatment is required.The choice of operation will continue to depend on the surgeons preference but the new operation of H S V , if it maintains or improves its reliability as it develops, must continue to grow in popularity, offering as it does both greater safety and greatly fewer post operative symptoms.