Nicholas Senn (bottom left) (1844 Y 1908) of Chicago contributed significantly to the elucidation of pancreatic function and disease. He used skillful laboratory experimentation and clinical observation not only addressing the mechanisms of acute pancreatitis but also providing rational insight into the validity of surgical techniques for its treatment. As such, he was especially responsible for bringing the dangers of pancreatic surgery and the diseases of the pancreas to the attention of US surgeons. 

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... by Reginald Fitz (1843 Y 1913), who thought the origin was bacterial infection and H. D. Rolleston who proposed it to be a solar plexus Y related event. Robert Langerhans postulated that it was pancreatic ferment that resulted in necrosis of fat tissue, and Simon Flexner, in 1897, suggested that this ferment was lipase. In a seminal article published in 1889, Reginald Fitz of Boston presented the first systematic analyses of acute pancreatitis (Fig. 5). 28 Fitz was born in Chelsea, Mass, and entered Harvard College in 1858 but left in his junior year to work in a copper mine. 39 He returned in 1862 to complete BA and MD degrees and then proceeded to Europe, where he acquired a unique blend of training in both clinical medicine and pathology under the guidance of such illustrious scientists as Rokitansky, Skoda, and Billroth. Fitz also worked in the laboratory of Rudolf Virchow (1821 Y 1902), where he became an expert in micros- copy and also brought to the United States Virchow’s teaching that disease is an expression of aberration in normal cellular function. Having returned to Massachusetts, as an instructor in Pathology and later as Shattuck Professor of Pathologic Anatomy, he pioneered integration of clinical information with pathologic findings, and his perspicacity led to significant advances in surgical pathology including characterization of acute appendicitis, intestinal obstruction, complications of Meckel diverticulum, and acute pancreatitis. In 1889, at the New York Pathological Society’s Middleton- Goldsmith lecture, Fitz presented his article entitled B Acute Pancreatitis: A Consideration of Hemorrhage, Hemorrhagic, Suppurative, and Gangrenous Pancreatitis, and of Disseminated Fat Necrosis [ in which he systematically reviewed the clinical symptoms in 53 cases of pathologically documented acute pancreatitis. 28 In addition, he detailed the various hemorrhagic, suppurative, and gangrenous changes in acute pancreatitis and their pathological differentiation. He further commented on various etiologies such as gall stones, alcohol, perforating gastric ulcer, and trauma. Quite remarkably, Fitz also described pancreatic abscess, splenic vein thrombosis, and a likely pseudocyst of the pancreas as associated complications of acute pancreatitis. In this paper, Fitz also proposed a relationship between pancreatic hemorrhage and pancreatitis and a causal link between disseminated fat necrosis and acute pancreatitis. By his systematic analysis of the various facets of acute pancreatitis, Fitz laid the foundation for antemortem diagnosis of this disease and greatly facilitated subsequent pancreatic research at the turn of the 20th century. Interestingly, Fitz initially advocated a conservative approach to the surgical management of patients with acute pancreatitis, noting that B an operation I in the early stages of this disease, is extremely hazardous. [ 40 However, his recommendation later changed to early laparotomy as performed for other causes of acute abdomen. Despite the accumulating knowledge on pancreatitis, it was not until the middle of the 20th century that an understanding of the differences between acute and chronic pancreatitis was appreciated. However, there were multiple descriptions of pancreatic concretions in the 18th and 19th centuries. In 1678, de Graaf recounted previous reports of pancreatic stones by his contemporaries. After this, there were also numerous reports of pancreatic lithiasis at the time of autopsy by various authors including Bonet, Morgagni, and Johann Friedrich Meckel (1724 Y 1774). 5 In 1799, Matthew Baillie (1761 Y 1823) of London published plates that clearly depicted pancreatic ductal concretions, ductal dilatation, and changes of chronic pancreatitis. 41 At the turn of the 19th century, Sir Arthur Mayo Robson (1853 Y 1933) of Leeds presumed the etiology to be of bacterial infection; however, the distinction among acute, subacute, and chronic was still controversial. 42,43 In 1946, Comfort, 44 at the Mayo Clinic, provided a significant analysis of the clinical entity of chronic pancreatitis and, in so doing, produced the seminal manuscript on the subject that has, for 50 years, remained the critical commentary on the disease. One of the contemporaries of Reginald Fitz who contributed extensively to the advancement of our knowledge of the pancreas was Nicholas Senn (1844 Y 1908), a surgeon who was born in Sweden but later moved to the United States and attended the Chicago Medical School. 5 He initially worked at the Cook County Hospital in Chicago and Milwaukee (Wis- consin) Hospital before proceeding to Munich for further training in surgery before finally returning to Rush Medical College as professor of surgery. In 1886, Senn presented an extensive account of his surgical experiments on the pancreas at the meeting of the American Surgical Association as an article entitled B Surgery of the pancreas, as based upon experiments and clinical re- searches [ (Fig. 6). 5,45 Starting with a review of the available surgical literature on the pancreas, Senn noted that the only operations available were either excision of retention cysts or formation of external pancreatic fistulas to drain such cysts. 45 He detailed a series of animal experiments, of which one was transection of the pancreas followed by suturing to prevent hemorrhage. In this experiment, Senn concluded that the con- tiguous portion of the pancreas continued to secrete digestive juices and that extravasation of the pancreatic juice from the distal end of the gland into peritoneum did not have adverse consequences. He also disproved the prevailing notion of dead pancreatic tissue being a highly putrescible substance leading to infection by crushing a segment of the pancreatic glands of 2 cats under aseptic conditions. He concluded that the affected part of the gland is absorbed and replaced by connective tissue while the rest of the gland functions normally. Presciently, he also noted that if the outlet of the pancreas is affected, it leads to ductal obstruction from scarring and destruction of the gland. His other experiments dealt with partial and total pancreatectomy, effects of the introduction of pancreatic juice into the peritoneal cavity, and the circulation, pancreatic fistulae, and gangrene of the pancreas. His observations on total pancreatectomy led him to caution against this operation because it could lead to B damage or necrosis of the duodenum. [ Senn recommended operative debridement of the gangrenous pancreas ex- trapolating case reports, which noted spontaneous recovery from gangrene of the pancreas by sloughing of the gland through the duodenum. Indeed, his experiments laid the foundation for future experimental work in pancreatic diseases, provided guiding principles for pancreatic surgery, and led him to being recognized as the father of experimental pancreatology. 5 In 1896, Hans Chiari invoked a role for pancreatic enzymes in the pathogenesis of pancreatic necrosis and proposed a theory of tryptic autodigestion initiated by activation by bile as initially proposed by Claude Bernard or alternatively by enterokinase as had been suggested by Nicholas Petrovich Shepovalnikov 3,46 in 1889. Gerhard Katsch (1887 Y 1961), in 1939, expanded this concept based on Heidenhein’s original 1875 recognition of the inactive forms of enzymes in pancreatic cells. He described the phenomenon of Fermentengleisung (derailment of enzymes) whereby circulating activated pancreatic enzymes resulted in damage to the lungs, kidneys, and capillaries. Similar explanations for hypocalcemia, fat necrosis, capillary permeability, pulmonary surfactant damage, and myocardial depression were considered by a variety of investigators 5 between 1944 and 1970. None has proved to be more persuasive than the role of superimposed infection that Sir Berkeley Moynihan (1856 Y 1936) 47 had empha- sized as early as 1925. Despite nearly a century of inquiry into the mysteries of the cataclysmic cascade of pancreatic enzyme activation, the key initiating factors and the subsequent mechanisms of glandular damage as well as the varied pathophysiological consequences of acute pancreatic inflammation are still poorly understood. The principal factor that leads to pancreatic injury is believed to be pathological activation of intracellular digestive enzymes, possibly as a result of colocalization of pancreatic zymogens with lysosomal enzymes to produce active trypsin. 48 Disruption of the pancreatic acinar cell membrane is also postulated as a key initiating event in the pathogenesis of acute pancreatitis. 49 Recent work has highlighted the role of disruption of protective mechanisms such as specific trypsin inhibitors (eg, serine pro- tease inhibitor Kazal type 1), compartmentalization of enzymes, and low intracellular Ca 2+ concentrations, which prevent pathologic activation of trypsinogen. 50 In addition, the down- stream enzymatic, inflammatory, and cell death pathways and the consequent activation of the systemic inflammatory response syndrome in severe acute pancreatitis have received considerable attention, especially with regard to the extrapancreatic facets of the disease. However, contemporary understanding of the pathogenesis is mostly derived from animal models and at the present time, the degree to which these models reflect human disease remains limited. 51 Although these advances have greatly enhanced the management of patients with severe acute pancreatitis, targeted therapeutic modalities that prevent or limit the degree of inflammation have not come to fruition. Up until the mid 20th century, it was not appreciated that acute pancreatitis was a disease with multiple etiologies that required different approaches for diagnosis and treatment. Now, gallstones are considered to be responsible for 35% to 40% of cases of acute pancreatitis, and alcohol is an etiologic factor in approximately 30% of acute attacks of ...