Cationic Trypsinogen (PRSS1).

Chapter 19 - The Pancreas

Ralph H. Hruban MD

Robb E. Wilentz MD

Normal

The pancreas has important endocrine and exocrine functions, and diseases of the pancreas cause significant morbidity and mortality. Despite the physiologic importance of the pancreas,

the retroperitoneal location of the gland and the vague signs and symptoms associated with injury to the gland allow many diseases to progress relatively unnoticed for extended periods of

time. Diseases of the pancreas thus remain a continuing source of frustration in modern medicine.

The adult pancreas is a transversely oriented retroperitoneal organ extending from the "C" loop of the duodenum to the hilum of the spleen ( Fig. 19-1 ). On average, the pancreas measures

20 cm in length and weighs 90 gm in men and 85 gm in women.[1] Although the pancreas does not have well-defined anatomic subdivisions, the adjacent vasculature can be used to

separate the pancreas into three parts: the head, body, and tail.

The pancreatic duct system is highly variable. The main pancreatic duct, also known as the duct of Wirsung, most commonly drains into the duodenum at the papilla of Vater, whereas the

accessory pancreatic duct, also known as the duct of Santorini, most often drains into the duodenum through a separate minor papilla approximately 2 cm cephalad (proximal) to the major

papilla of Vater ( Fig. 19-2A ). In many adults, the main pancreatic duct merges with the common bile duct proximal to the papilla of Vater, thus creating the ampulla of Vater, a common

channel for biliary and pancreatic drainage. Owing to developmental variability, however, this ductal architecture can differ tremendously from patient to patient.

Embryologically, the pancreas arises from the fusion of dorsal and ventral outpouchings of the foregut.[1] During early embryonic development, the dorsal and ventral pancreatic primordia

rotate and fuse at approximately the seventh week of gestation to form a single gland.[2] The majority of the gland, including the body, the tail, the superior/anterior aspect of the head, and

the accessory duct of Santorini, is derived from the dorsal primordium. Although the ventral primordium gives rise only to the posterior/inferior part of the head of the pancreas, the ventral

primordium is important because it drains into the papilla of Vater. Fusion of the dorsal and ventral duct systems allows the majority of the gland to drain through the larger Vaterian

papilla.

Although the organ gets its name from the Greek pankreas, meaning "all flesh," the pancreas is, in fact, a complex lobulated organ with distinct exocrine and endocrine components. The

exocrine portion of the gland, which produces digestive

Figure 19-1Anatomic relationships of the pancreas seen in a cross-section of the abdomen at the level of the upper lumbar vertebrae. (From Go VW, et al (eds): The Pancreas: Biology,

Pathobiology, and Disease, 2nd ed. New York, Raven Press, 1993.)

Figure 19-2Pancreatic ductal anatomy. A, The normal ductal anatomy. B, The ductal anatomy in pancreatic divisum. (Adapted from Gregg JA, Monaco AP, McDermott WV: Pancreas

divisum: results of surgical intervention. Am J Surg 145:488–492, 1983.)

Figure 19-3Pancreatic acini, showing the radial orientation of the pyramidal exocrine acinar cells. The cytoplasm is devoted to the synthesis and packaging of digestive enzymes for

secretion into a central lumen.

TABLE 19-1-- Etiologic Factors in Acute Pancreatitis

Metabolic

Alcoholism

Hyperlipoproteinemia

Hypercalcemia

Drugs (e.g., thiazide diuretics)

Genetic

Mechanical

Trauma

Gallstones

Iatrogenic injury

••Perioperative injury

••Endoscopic procedures with dye injection

Vascular

Shock

Atheroembolism

Polyarteritis nodosa

Infectious

Mumps

Coxsackievirus

Mycoplasma pneumoniae

Of note, 10% to 20% of patients with acute pancreatitis have no known associated processes. Although this condition is currently termed idiopathic, a growing body of evidence suggests

that many, in fact, have a genetic basis. The genetic alterations associated with the development of pancreatitis therefore deserve special note.[22]

Cationic Trypsinogen (PRSS1).

Hereditary pancreatitis is an autosomal-dominant disease with an 80% penetrance characterized by recurrent attacks of severe pancreatitis usually beginning in childhood.[19] This disorder

is caused by germ line (inherited) mutations in the cationic trypsinogen gene (also known as PRSS1).[18] Most are point mutations, with G to A transitions, that result in an arginine (R) to

histidine (H) substitution (called R122H).[19] This mutation abrogates a critical failsafe mechanism, by affecting a site on the cationic trypsinogen molecule that is essential for the cleavage

(inactivation) of trypsin by trypsin itself.[23] When this site is mutated, trypsinogen and trypsin become resistant to inactivation, and the abnormally active trypsin activates other digestive

proenzymes, resulting in the development of pancreatitis.

Date: 2016-04-22; view: 617