The Paradox of the Pancreas

Politzki Print Productions: Hanover, 2003

Modlin, Irvin M MD, PhD; Mark Kidd PhD

PREFACE

It is difficult to know who first saw the pancreas but one can certainly imagine the consternation and the excitement at the first observation of the whitish yellow solid lobulated structure lying hidden behind the stomach. Some say it may have been the horoscopists or augers as they sought the meaning of the future in the entrails or the lobes of the liver. Others believe it may have the priests as they sacrificed animals to placate the gods of Assyria or Mesopotamia. Certainly the reference in the Talmud to the organ known as the “finger of god” suggests that the rabbis of old knew of the gland. Millennia later we continue to struggle with the nature of the gland and still seek to divine the meaning of its diseases. The passage of time has allowed the distinction of ducts and glands, enzymes and hormones and enabled us to vault from the nature of its secretions to the arcane assessment of the genomic diseases. Yet still we flounder in an immensity of uncertainty as to the very nature of the gland and the molecular basis of its diseases. Despite incredible endeavors by investigators it is fair to say that the pancreas still eludes us much of its function and disease remain like the dark side of the moon-much spoken about but little visible.

The great intellects of the Greeks of Alexandria recognized the unique nature of the organ comprised so unusually of flesh alone and termed it pan kreas. Although they had little direct evidence of its function they surmised that its location connoted a digestive responsibility. Others perhaps less philosophical and more practical minded proposed that its location behind the stomach indicated a role as a cushion to support and protect what was obviously the most important organ of digestion. This state of acceptance lasted for centuries although some consideration was given by philosophers to the notion that the soul might reside within the gland since it could not be identified elsewhere. Others less bothered by the possible sanctity of the gland removed it with alacrity from animals and noting its pure fleshy nature consumed it with gusto and sometimes “moutarde”. This pragmatic management of the pancreas led Nicholas Culpepper to name it the “sweetbread” and for the most part its exotic culinary assessment remained for many years the redeeming grace of the pancreas.

The anatomists of the sixteenth century such as the Flemish Vesalius provided true form to the pancreas and detailed in impeccable fashion its relationships to other organs. Wirsung of Padua identified the main duct and Santorini of Venice the minor but none sought to define the function of the “cushion of the stomach”. It would fall to Sylvius of Leiden in his search for the chemical basis of digestion to seek to define the secretory properties of the gland. Stimulated by his mentor, Regnier de Graaf of Delft developed canine pancreatic fistula models, syringes to drain the ducts and in so doing became the first to define the nature of pancreatic secretion. Unfortunately the limited chemical methodology of the times precluded any major advances in this area and the attention of physicians turned to the relationship of the gland to disease. The enlightened and erudite Morgagni in his quest to understand the malfunction of organs autopsied numerous unfortunates and elegantly linked symptomatology to the pathological consequences he noted in the affected organs. In so doing he was able to opine not only on the “scirrhous” nature of the pancreas in some of the deceased but also the presence of stones and their relationship to blockage of the ducts.

At this stage work with the pancreas attained an intellectual plateau of relatively low height as diverse investigators speculated for the most part on the nature of the gland and linked it to diverse symptomatology and while ascribing obscure functions to the organ. A particularly damaging set of experiments by Konrad Brunner of Schaffhausen (also known as the Swiss Hippocrates) especially dampened the ardor for pancreatic studies. Having successfully extirpated the pancreas of a number of dogs who then survived in apparently good health, he declared the pancreas to be unnecessary for life. The decision by this savant of medicine that the pancreas was not a “vital” organ vitiated further interest in the gland for some time. Further damage was done by the innovative proposal of Sömmerring of Berlin that the pancreas was nothing more than a “salivary gland in the belly” and few saw an exciting investigative path in the pursuit of saliva.

Fortunately Mehring and Minkowski in repeating the pancreatic excisional surgery of Brunner a century later differed from him in their assessment of the outcome and observed the sugar overflow in the urine thus concluding that the basis of diabetes lay within the pancreas. At this stage Laguesse recollected the strange collections of cells in the pancreas that had been described by the medical student Langerhans and proposed that these islets were related to the genesis of the “sugar disease”. Further observations by Opie of Baltimore regarding the relationship of fibrotic damage to the islets in patients who perished of diabetes led to the inescapable conclusion that the pancreas was not only involved in digestion but also played a pivotal role in glucose homeostasis. The subsequent exciting experimental foray of the orthopedic surgeon, Banting and the medical student Best led to the isolation and identification of insulin and the development of a rational therapeutic strategy for the management of diabetes.

At about the same time considerable investigation was being undertaken in establishing the chemical nature of digestion. Schwann in the laboratory of Muller in Berlin had identified pepsin in the stomach and Kühne had described trypsin. Similarly it had become apparent that different enzymes were responsible for the dissolution of carbohydrates, lipids and proteins. It had long been speculated that aberrations in digestion might be linked to pancreatic dysfunction and anecdotal evidence provided by physicians such as the Dutchman, Fles recounted how eating raw pancreas could cure malnutrition and diarrhea. Serious experimental work by individuals including Engesser led to the conclusions that the digestive ferments of the pancreas could be replaced by organotherapy and diverse pancreatic extracts were produced in order to support the function of the gland in persons presumed to be suffering from such a malady. Lack of sophisticated chemical knowledge precluded a serious understanding of the stability of the enzymes and a muddled period of medical science then ensued where arguments about enzyme stability were confused with pH optima and peptic digestion. Further work on the subject by Kühne had led to the elucidation of a variety of pancreatic enzymes and established the specificity of their catalytic effects on food products. The nature of these biochemical events was further characterized by Michaelis and Menten of Berlin who elegantly defined the chemical basis of the reactions and established the scientific basis of enzymology. Unfortunately considerable controversy existed as to the efficacy of enzyme preparations and eminent gastroenterologists such as Ewald vigorously criticized the different products available despite good evidence of their clinical utility. Subsequent rigorous experimental work by Abelman in Germany as well as the group of Ivy in Chicago demonstrated unequivocally that pancreatic exocrine deficiency led to dramatic losses in the absorption of fat and protein but also that replacement with enzyme supplements was capable of dramatic reversal of the malnutrition and steatorrhea.

At the turn of the 19^th century the exploration of the mechanics of digestion led to a substantial interest in both the structure of the various involved organs and how their function might be regulated. Heidenhain of Breslau and Golgi of Pavia defined the basics of structure. Pavlov of Russia determined that nervism was the dominant regulator while Bayliss and Starling of London argued to the contrary that chemical messengers were the keys to function. The doctrine of neural regulation led to the award of a Nobel prize to Pavlov, while the discovery of secretin as the first hormone by Starling led to the foundation of the discipline of endocrinology. A century of expansion of the subject of neuro hormonal regulation of acinar and ductal function has unfortunately led us no closer to therapeutic intervention in pancreatic disease although for a brief moment it appeared that somatostatin might provide such a window of opportunity. The utility of the agent sadly remained limited to the therapy of the orphan disease of rare pancreatic endocrine tumors. Fortunately the identification of insulin by Banting and Best led to a major advance in the management of diabetes although little further progress has been made in the elucidation of the integrated function of the islets or the role of the numerous other cells that comprise the endocrine organ embedded within the pancreas.

Although much progress had been made in the elucidation of pancreatic secretion in the last fifty years of the nineteenth century, advances in the diagnosis and management of pancreatic disease lagged far behind. Infective conditions were rarely diagnosed prior to post mortem and if perchance a surgeon were to intervene, death was a certain end result. Indeed the eminent physician, Naunyn referred to visceral surgery as little more than a pre mortem autopsy and most surgeons followed the wise advice of Nicholas Senn of Chicago who advocated the avoidance of pancreatic surgery (noli me tangere) at all costs. Mayo Robson of Leeds at the turn of the century opined that one might consider such an endeavor only if the patient collapsed-presumably he considered operating on the pancreas as a “coup de grace” for the departing patient. Indeed the early years of the twentieth century reflected a paucity of pancreatic surgery and only a few stalwarts such as Codivilla of Italy, Kausch of Berlin, Halstead of Baltimore and Whipple of New York exhibited the temerity necessary to address the pancreas surgically. The difficulty encountered in controlling the bleeding, the unreliability of the anastomoses and the absence of antibiotics culminated in a fearsome mortality. Fortunately the work of Doisy and Dam led to the advent of vitamin K and the specter of bleeding receded enough to enable one stage resections and allow for some reasonable improvement in operative survival. Thus by the nineteen thirties pancreatic resections were being undertaken for neoplasia and other intrepid surgeons began to consider dealing with the sphincter of Oddi directly believing that its malfunction in some way played a role in the development of the fibrotic disease of the pancreas. This poorly defined entity was better defined by Comfort of Rochester, Minnesota who opined on the criteria necessary to diagnose the disease loosely identified as “chronic pancreatitis”. The demonstration of stones, strictures and dilated ducts drove surgeons to the conclusion that such problems could be dealt with by resection, removal or drainage and an almost infinite variety of permutations and commutations of such surgical procedures were thereafter described.

The advent of antibiotics and the discovery of blood groups facilitated the development of extensive surgery such that pancreatic resection was addressed with more enthusiasm. The path established by Kausch and Whipple was thus opened to many as intrepid visceral operators sought vainly to remove tumors and cure patients of neoplasia. Although the excision of adenocarcinoma was to prove relatively fruitless in terms of improving long term survival the palliative effects of surgery encouraged further development of the technique and modifications such as “pylorus preservation” were deemed by some to confer a putative advantage. The identification of a less aggressive type of malignancy as connoted by neuro endocrine tumors led to more successful pancreatic surgery as insulinomas and gastrinomas were identified and removed with far better results.

A major drawback in the management of pancreatic disease was the fact that the location of the gland as well as the late presentation of symptoms rendered early diagnosis of disease problematic. Conventional radiology was of little value and the identification of pancreatic disease was problematic until the development of endoscopic retrograde pancreatography and papillotomy by Kawai and Classen. The subsequent introduction of computerized axial tomography by Hounsfield and thereafter magnetic resonance imaging led to a dramatic increase in the facility with which the topographic state of the pancreas could be defined. The further amplification of endoscopic techniques to include ultrasonography and fine needle aspiration further augmented the diagnostic armamentarium and enabled the specific identification of pancreatic disease. Despite advances in localization and identification the genesis of conditions such as acute pancreatitis remained a mystery. Some patients recovered despite therapy and others perished irrespective of it. Surgery was limited to dramatic drainage of necrotic material (ghoulishly termed necrosectomy) and represented little more than extensive attempts at incision and drainage permitted by the advances in anesthetic technique and amplification of intensive care expertise. Similarly the lesion perceived as chronic pancreatitis was addressed surgically with modest success based mostly on the fact that surgery was being undertaken on a gland that had already perished. Desperate to identify some treatable lesion surgeons then seized upon the hoary favorite of former times and cystic lesions became the vogue. Relatively rare and for the most part benign as their parotid counterparts (the pancreas is little more than a salivary gland in the abdomen), their successful excision excited extraordinary enthusiasm as the specter of adenocarcinoma was banished from surgical consciousness.

Thus by the turn of the 20^th century surgery could be deemed to have made spectacular technical progress without having impacted much upon any pancreatic disease process. Physiology and molecular biology had similarly advanced and while secretory regulation and its mechanics were better understood little beneficial therapeutic intervention had derived from the elucidation of the arcana of the cell. Pancreatic organ and islet cell transplantation continued to be of allure but their promise remained much like that of an unidentified Nirvana or the dulcet tones of the unidentified damsel in Coleridge’s Xanadu. Similarly gene therapy was much bruited in the hallways of academe but translation into clinical efficacy still remained an indistinct shadow on a sunlit horizon. Interestingly enough the two discoveries of the turn of the 19^th century pancreatic enzyme supplementation and insulin remained the most effective and predictable agents in the treatment of pancreatic disease.

This text tells the tale of those who sought for pancreatic wisdom and defines the trials and tribulations of their efforts. None were in vane for all knowledge is progress. Nevertheless a sanguine assessment of the current status of the “sweetbread” can only lead to one conclusion. We have progressed far since the days of Wirsung but we have much to learn.

“Therapeutics is the noblest pearl and the supreme treasure, and it holds first place in medicine; and there is nothing on earth that can be valued more highly than the curing of the sick”.

– The Merciful Physician, Man and his Body

– Paracelsus I/2,430.

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