From Billroth and Sippy to Helicobacter: A Century in the Management of Peptic Ulcer

Introduction

Major resectional gastric surgery in 1881 by Theodor Billroth was done before the role of vagus nerves on gastric secretion was known by Pavlov. Schwarz’s dictum of “no acid no ulcer” lead to Sippy’s 1915 diet regimen therapy. Lester Dragstedt in 1945 introduced truncalvagotomy reducing the mortality of partial gastrectomy. It was modified by selective and highly selective procedures. With an aim of further acid reduction, few surgeons performed extended gastric resections or vagotomy combined with antrectomy.

Introduction of histamine (H2) receptor antagonists in 1974 and proton pump inhibitors (PPI) resulted in better ulcer healing with less surgical interventions. Discovery of Helicobacter pylori (H Pylori) by Warren and Marshall in 1984 lead to the infective etiology. H Pylori eradication therapy evolved as the front line management of peptic ulcer disease.

Late Nineteenth Century And Early Twentieth Century Gastric Surgery

Theodor Billroth
1829 – 1894

Ivan Pavlov
1849 – 1936

Abdominal surgery blossomed after introduction of anaesthesia in 1846 by William Morton and Joseph Lister’s antiseptic surgery in 1867. Theodor Billroth from Vienna in 1881 performed the first gastric resection with gastroduodenal anastomosis (Billroth I procedure) for cancer. Billroth II operation was discovered accidentally in 1885 when Billroth did gastrojejunostomy only to bypass an inoperable antral carcinoma. Patient recovered well and the tumour was later resected, gastric remnant and duodenal stump were closed (Billroth II procedure).

Billroth II operation was further modified by Hungarian surgeon Eugene Polya in 1940 and later by Hofmeister and Finsterer to narrow the gastro-jejunal anastomosis. Polyagastrectomy attained undisputed leadership as the surgical treatment of peptic ulcer for many years.

Extended gastric resections as exceptionally high measured gastrectomy, by Visick¹ and less extensive procedures as antrectomy appeared among further modifications.
Smithwick and Farmer from Boston University in 1946 performed bilateral truncalvagotomy combined with distal gastric resection. In 1952 Edward of Nashville, unaware of the former contribution, performed truncalvagotomy with 40% gastric resection and termed as “antrectomy” ^2-3.

The Role of Vagus Nerves, Gastric Acid Reduction

Bertram Welton Sippy
1866 – 1924

Lester Reynold Dragstedt
1893 – 1975

Initial procedures for peptic ulcer surgery were empirical and subsequent evolution has been guided by demonstration of physiologic mechanisms controlling gastric secretions. The aim of any operation for chronic duodenal ulcer is to reduce substantially the amount of acid production by the stomach.

Russian physiologist Ivan Pavlov won the Nobel Prize in Physiology or Medicine in 1904 for discovery of the role of vagus nerves in gastric acid secretion. Dragutin Karl Schwarz from Croatia in 1910 introduced “no acid no ulcer” dictum in etiology of peptic ulcer disease.

Bertram Welton Sippy from Wisconsin USA, ardent believer of Schwarz’s dictum introduced Sippy’s diet in 1915. The diet regimen was hourly milk and cream supplemented by frequent large doses of antacids, often periodic gastric aspirations for a specified period of time. A generation of physicians found this as an effective mean for rapid healing of peptic ulcers. Long term use resulted in renal failure, hypercalcemia and milk alkali syndrome. It is now regarded as an obsolete diet used in the initial stages of peptic ulcer treatment.

In 1958 gastric atrophy and achlorhydria was induced by gastric mucosa cooling with a balloon perfused with cold fluid at 0 to 5ºC by Wangensteen in USA⁴. The gastric hypothermia method was terminated as ulcer healing was not accelerated and common complications as pneumonia, septicaemia and generalised hypothermia were seen.

Era of Vagotomy Operations

The story of vagotomy began with Exner in 1912 for the treatment of tabetic pain. In 1923 Laterjet reported the use of vagotomy in treatment of duodenal ulcer. Inconclusive report, unavailable results and concept ahead of its time, the matter was soon forgotten⁵. Dragstedt and Owen’s report from University of Chicago on trans-thoracic section of vagus nerves for duodenal ulcer in 1943 resulted in much interest and validity of the new approach was investigated⁶. Early vagotomy operations without drainage were complicated by gastric stasis and in 1947 Dragstedt performed trans-abdominal approach with gastrojejunostomy⁷.
Pyloroplasty originally performed by Heineke in 1886 and Mikulicz in 1888 depended mostly upon the advent of vagotomy. Alternately a wide variety of gastric outlet procedures, such as Wineberg modification of Heineke-Mikuliczpyloroplasty, the Finney pyloroplasty and the Jaboulaygastroduodenostomy have been used in an attempt to improve gastric emptying.
Frankkson in 1948 first performed bilateral selective vagotomy in an attempt to avoid the complications of total abdominal nerve section8.This introduction of selective vagotomy was forgotten until Charles Griffith in United States and Harold Burge in England dedicated their efforts with well documented papers^9-10. Randomised controlled trial showed selective vagotomy with drainage procedure has more complete vagal denervation than truncalvagotomy but no obvious advantage was seen between the two groups¹¹.

Highly selective vagotomy (Parietal cell vagotomy or Proximal gastric vagotomy) with preserved innervated antrum and without a drainage procedure was introduced in 1970 by Amdrup and Jensen from Copenhagen and Johnston and Wilkinson from Leeds^12-13. It was introduced to minimise the drainage procedure induced side effects of dumping and diarrhoea yet preserve protective and inhibitory mechanisms in the antrum and duodenum.

Partial Gastrectomy or Vagotomy?

Many comparative studies and controlled trials appeared between gastric resection and various types of vagotomy. One great advantage of vagotomy with drainage over partial gastrectomy in treatment of duodenal ulcer is its lower mortality rate of under 1% ^14-15. Higher mortality of around 3 to 4% was seen in partial gastrectomy^16-17.
Unfortunately recurrent ulceration is more common with vagotomy and drainage procedure compared to partial gastrectomy. The cause of recurrence is not a direct complication of vagotomy but usually is due to incomplete section of vagal nerves as high as 20% after Hollander’s insulin test¹⁸. Postoperative Maximal Acid Output (MAO) studies reported reduction of gastric acidity around 50% after partial gastrectomy, 60 to 70% after truncalvagotomy or antrectomy^19-20.

Antrectomy combined with truncalvagotomy removes two principle drives, vagal-cholinergic drive and antral gastrin release with 1% recurrent ulceration rate 5 to 10 years after operation21. The operation resulted in 95% acid reduction but postoperative morbidity increased with the two combined procedures ^19-20.

Alimentary dysfunction as postoperative dumping, diarrhoea and weight loss were studied after the two types of surgical procedures. In Leeds and York study, early dumping was more common in partial gastrectomy than vagotomy, the incidence of diarrhoea was more common in vagotomy than the partial gastrectomy group17. Partial gastrectomy patients tend to have lower optimum body weight¹⁷.

McKelvey (1970) stated that post-vagotomy diarrhoea, dumping and other alimentary dysfunctions resulted from the drainage procedure rather than vagotomyit self²².

Highly selective vagotomy (Parietal cell vagotomy) “without drainage procedure” aims to lessen the postoperative symptoms including post-vagotomy diarrhoea²³. Highly selective vagotomy after more than 10 years has been associated with bowel dysfunctions and 7% overall ulcer recurrence rate ²⁴.

The obvious advantages between partial gastrectomy and various types of vagotomy are marginal¹⁶. From the year 1950 to 1975, due to indifferent same postoperative complications with other types of selective vagotomy, therapeutic pendulum swings to and fro between partial gastrectomy and truncalvagotomy. Proponents of partial gastrectomy still perform the Polya type of gastrectomy but majority of surgeons prefer truncalvagotomy as an appropriate operation for duodenal ulcer.

More than 20 years after operation for benign peptic ulcer, the risk of gastric carcinoma is three to six times greater than expected in patients with gastrojejunostomy²⁵. It was seen both in vagotomy and partial gastrectomy patients, probably due to mucosal reaction after enterogastric reflux²⁶.

The presence of many types of operations for a particular surgical condition indicates that no method is perfect and it is really true with regard to surgical management of chronic duodenal ulcer till the discovery of H₂ recepterantagonists.

H2 Receptor Antagonists and Proton Pump Inhibitors

Smith, Kline & French (SK&F) team noted that classical antihistamines did not suppress the acid production and a second type of receptor (H₂ receptor) existed for H⁺ production of the parietal cell. Cimetidine was developed by Dr James W Black at GlaxoSmithKline (previously SK&F) in 1971. It was first marketed in 1976 as Tagamet, the first blockbuster drug. Sir James Black was awarded with Nobel Prize in Physiology or Medicine in 1988. Peptic ulcer research field was more emphasised and drug companies converge on gastric acid inhibition as a cure for peptic ulcer disease. Ranitidine and Famotidine are also produced later.

In 1970 the enzyme H⁺/K⁺ AdenosineTriphosphatase (H⁺/K⁺ATPase) was discovered as the final step in acid production by the parietal cell. PPI drug as Omeprazole was discovered in 1979 and launched to the European market in 1988 as Losec, a potent drug for reducing gastric acid production. New generation of PPIs include Pantoprazole, Rabeprazole, Esomeprazole and Lansoprazole. PPI drugs bring down the acid output to nil and heal ulcers more rapidly than H₂ blockers. Compared to H₂ blockers, PPI drugs have longer duration of action with better inhibition of gastric acid production ²⁷.

Among gastroenterologists, “no acid no ulcer” concept appears to be resolved with antisecretory drugs. With better ulcer healing by medical treatment using H₂ blockers and PPI, less elective operations for peptic ulcer were noted since after 1980s ²⁸. However when treatment is withdrawn ulcers recur. The cause of recurrence is due to receptor up-regulation after long term H₂ receptorblockage or hypergastrinaemia after treatment with PPI.

Paradigm Breaking Discovery of Infective Etiology, Helicobacter Pylori

Barry Marshall

Robin Warren

Helicobacter pylori, Gram-negative spiral-shape bacterium that colonises the stomach, previously known as Campylobacter pylori was discovered in 1982 by pathologist Robin Warren and physician Barry Marshall from Perth, Western Australia. Robin Warren noted that the bacilli were present in the antral mucosa of all patients with active chronic gastritis, duodenal ulcer and gastric ulcer but not in the normal gastric mucosa 29. The finding was published in the Lancet in 1983.

Initial reports of an association between the bacterium and gastritis were faced with great scepticism by the scientific community. But Marshall proved with experimental studies that H pylori infection as the cause of histological gastritis fulfilled Koch’s postulates.

Clinical trials showed that eradication of Helicobacter by antibiotics reduce gastritis and prevent the relapse of peptic ulcer disease ^30-31.Marshall and Warren were awarded with Nobel Prize in Physiology or Medicine in 2005.

Conclusion

The story of evolution in treatment of peptic ulcer disease dated back from Billroth’s gastric resections in late nineteenth century to discovery of H pylori in late twentieth century for 100 years. More understanding of physiology in gastric acid reduction lead to various types of surgical procedures. Discovery of H2 receptor antagonists, proton pump inhibitors and finally H pylori eradication revolutionised the management of peptic ulcer disease with extremely less surgical interventions.

The human body reveals its innermost secrets only to those who have the patience and understanding to discover them. The pioneer work of many researchers, scientists and clinicians who contributed the progress in management of peptic ulcer disease will not be forgotten.

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Dr Myint Tun, M.B.B.S.(Ygn), M.Med.Sc.(Surg), FRCS Edin
Consultant Surgeon, Jivitadana Sanggha Hospital, Yangon
Assoc. Professor in Department of Surgery (Retd), Universiti Putra Malaysia
Sr Lecturer in Departments of Surgery (Retd), IM (1), IM (2) and IM Mandalay