1 Acute Pancreatitis – The Current Concept in Ethiopathogenesis , Morphology and Complications

B. Suresh Kumar Shetty1, Ramdas Naik2 , Adithi S. Shetty3, Sharadha Rai4, Ritesh G. Menezes5 and Tanuj Kanchan1 1Department of Forensic Medicine and Toxicology Kasturba Medical College, Mangalore, Manipal University, 2Department of Pathology, Kasturba Medical College, Mangalore, Manipal University, 3Department of Obstetrics & Gynaecology, K. S. Hegde Medical Academy, Mangalore, Nitte University, 4Department of Pathology, Kasturba Medical College, Mangalore, Manipal University, 5Department of Forensic Medicine and Toxicology, Srinivas Institute of Medical Sciences & Research Centre, Mangalore, India


Introduction
This chapter is a comprehensive approach on etiology, patho-phyosiological and complications of acute pancreatitis and its review will aid in evaluation of acute pancreatitis in-toto. Pancreatitis is the inflammation of the exocrine pancreas which results from injury to the acinar cells. It may be classified as either acute or chronic. Acute pancreatitis is the reversible injury to the pancreatic parenchyma associated with inflammation and is characterized by a recurrent episode of abdominal pain and elevated serum amylase and lipase levels.


The frequency of acute pancreatitis is inversely proportional to the size of gallstones. Persistence of stones in the bile duct or the ampulla of vater is associated with more severe disease. An impacted gallstone may allow the reflux of bile into the pancreatic duct or occlude the duct's orifice.

Pancreatic Obstruction
 It is a less common cause of acute pancreatitis. Sphincter of Oddi dysfunction and carcinoma of the pancreas are associated with acute pancreatitis and is usually of the mild type.

Genetic Factors
 About 10% to 20% of patients with acute pancreatitis have no known associated etiological processes. Though these are termed idiopathic, the evidence suggests that some may have a genetic basis.  Hereditary pancreatitis is characterized by recurrent attacks of severe pancreatitis usually developing in childhood. Most of these are caused by germline (inherited) mutations in the cationic trypsinogen gene (also known as PRSS1). In patients with these mutations, tryspin is inappropriately activated in the pancreas, which in turn activates other digestive proenzymes.  The serine protease inhibitor Kazal type 1 (SPINK1) gene codes for a pancreatic secretory trypsin inhibitor. This inhibits trypsin activity and prevents autodigestion of the pancreas by activated trypsin. Mutation in the SPINK1 gene leads to loss of function of the inhibitor gene and causes pancreatitis.
The other etiological factors for acute pancreatitis are shown in the Table.1.

Pathogenesis
The changes of acute pancreatitis are due to autodigestion of the pancreatic substance by inappropriately activated pancreatic enzymes. Inappropriate delivery of pancreatic proenzymes to the intracellular compartment containing lysosomal hydrolases may activate proenzymes. This mechanism may be responsible for injury due to alcohol or duct obstruction.  Primary acinar cell injury: Acinar cells may be directly damaged by certain viruses (e.g., mumps), drugs, alcohol, trauma to the pancreas, ischemia and shock.  Hyperstimulation of pancreas: This may be seen in association with consumption of alcohol or fat diet.  Reflux of bile: Infected bile or duodenal content may regurgitate into the pancreatic duct due to disruption of sphincter Oddi (e.g., gallstones). prophospholipase and proelastase into active forms. The actived enzyme lipase degrade fat cells and elastase damage the elastic fibers of blood vessels. Trypsin also activates kinin system, Hageman factor (factor XII), coagulation and complement systems.  Second phase: It involves the activation, chemoattraction and sequestration of neutrophils into the pancreas, resulting in an intrapancreatic inflammatory reaction of variable severity. Leukocyte release cytokines which is responsible for local inflammation and interstitial edema. Edema may decrease the local blood flow and cause further ischemic damage to acinar cells  Third phase: It is due to the effects of activated proteolytic enzymes and cytokines, released by the inflamed pancreas, on distant organs. Activated proteolytic enzymes, especially trypsin, not only digest pancreatic and peripancreatic tissues but also activate other enzymes such as elastase and phospholipase. The active enzymes protease digest cellular membranes and cause parenchymal cell necrosis. The activated lipase cause fat necrosis and the elastase disrupt the vessel wall leading to hemorrhage. Cell injury and death result in the liberation of bradykinin, vasoactive substances and histamine which produce vasodilation, increased vascular permeability, and edema with effects on many organs. Thus it may lead to systemic inflammatory response syndrome (SIRS) and acute respiratory distress syndrome (ARDS) as well as multiorgan failure.

Safety mechanism
The pancreas has many safety mechanisms to prevent autoactivation of zymogens. One of the known mechanism is the pancreatic secretory trypsin inhibitor (PSTI), which is found in secretory granules. It inhibits trypsin activity.

Morphology
The normal pancreas has a poorly developed capsule and lies close to adjacent structures, which includes the common bile duct, duodenum, splenic vein and transverse colon. Due to this, in acute pancreatitis these are also commonly involved in the inflammatory process. The morphological feature of acute pancreatitis varies from minimal inflammation and edema to severe extensive necrosis and hemorrhage.

Acute interstitial or edematous pancreatitis:
It is a mild and reversible form of acute pancreatitis. It is usually managed medically.
Microscopy: It shows interstitial edema and mild infiltratation of polymorphonuclear leukocytes, without any necrosis or hemorrhage. There may be focal areas of fat necrosis in the substance of the pancreas and in peripancreatic fat. Fat necrosis is due to the action of lipase on triglycerides which releases fatty acids from the fat cells. These fatty acids combine with calcium and form insoluble salts and this process is known as saponification. The insoluble salts impart a granular blue appearance to the involved fat cells.

Acute necrotizing pancreatitis
It is the severe form of acute pancreatitis in which the acinar, ductal tissues and islets of Langerhans show necrotic changes [ Figure.2.] Hemorrhage:Vascular injury due to the enzyme elastase can lead to hemorrhage into the parenchyma of the pancreas, which shows areas of red-black areas of hemorrhage in the substance of pancreas. Peritoneal cavity: In majority of cases, the peritoneal cavity contains a serous, slightly turbid, brown-tinged fluid in which globules of fat (derived from the action of enzymes on adipose tissue) can be seen [ Figure.3].

Fig. 3. Peritoneal Cavity In Acute Pancreatitis
 Microscopy:  Edema: It is due to leakage through microvasculature.  Acute inflammation  Enzymatic fat necrosis: It appears granular blue with ghost outlines.  Proteolytic destruction of pancreatic parenchyma: Acinar and ductal tissues as well as the islets of Langerhans are necrotic.  Destruction of blood vessels (elastase) and subsequent interstitial hemorrhage.

Acute hemorrhagic pancreatitis
It is the most severe form of acute pancreatitis. It usually occurs in the middle aged and is associated with high morbidity and mortality. Microscopically, it shows extensive parenchymal necrosis accompanied by hemorrhage within the pancreas.
The above features linked with the clinical features, laboratory findings and recent investigative procedures help in diagnosing acute pancreatitis with ease. The effective treatment modalities in recent years will insist on efficient interpretation of pathophysiology in acute pancreatitis so as to ensure a speedy recovery from the cause.

Clinical features
Abdominal pain is the major manifestation of acute pancreatitis. The pain may vary from mild and tolerable to severe, constant and incapacitating distress. Characteristically, the pain is steady and intense, located in the epigastrium and periumbilical region. It often radiates to the upper back as well as to the chest, flanks, and lower abdomen . Anorexia, nausea, vomiting and abdominal distention due to gastric and intestinal hypomotility and chemical peritonitis also frequently accompany the pain.
Full-blown acute pancreatitis usually present with sudden calamitous onset of an "acute abdomen" and is a medical emergency. Many of the systemic features of severe acute pancreatitis are due to release of toxic enzymes, cytokines, and other mediators into the circulation and activation of the systemic inflammatory response. These mediators result in leukocytosis, hemolysis, disseminated intravascular coagulation, fluid sequestration, acute respiratory distress syndrome, and diffuse fat necrosis. Peripheral vascular collapse and shock with acute renal tubular necrosis may also occur.

Laboratory findings
Marked elevation of serum amylase levels during the first 24 hours, followed within 72 to 96 hours by a rising serum lipase level.
Hyperglycemia is common and is due to multiple factors, including decreased insulin release, increased glucagon release, and an increased output of adrenal glucocorticoids and catecholamines. Glycosuria occurs in 10% of cases.
Hypocalcemia may result from precipitation of calcium soaps in necrotic fat; if persistent, it is a poor prognostic sign.
Hypertriglyceridemia occurs in 15 to 20% of patients, and serum amylase and lipase levels in these individuals are often spuriously normal.
Direct visualization of the enlarged inflamed pancreas by radiography is useful in the diagnosis of pancreatitis.

Treatment
In the majority of patients (85-90%) acute pancreatitis is self-limited and subsides spontaneously, usually within 3-7 days after treatment is started. About 5% with severe acute pancreatitis die from shock during the first week. Acute respiratory distress syndrome and acute renal failure are dangerous complications The key to the management of acute pancreatitis is "resting" the pancreas by total restriction of oral intake and by supportive therapy. Conventional mode of treatment include 1. Analgesics for pain, 2. Intravenous fluids and colloids to maintain normal intravascular volume, and 3. No oral alimentation.
The nasogastric suction has no clear-cut advantages in the treatment of mild to moderately severe acute pancreatitis. Therefore, it must be considered elective rather than mandatory. The drugs which block pancreatic secretion have not found to be of any benefit. For this and other reasons, anticholinergic drugs are not indicated in acute pancreatitis.

Role of antibiotics:
The benefit of antibiotic prophylaxis in the treatment of necrotizing acute pancreatitis remains controversial. It was observed that there is no benefit of antibiotic prophylaxis with regard to the risk of developing infected pancreatic necrosis.

Conclusion
These features linked with the clinical features, laboratory findings and recent investigative procedures will help in diagnosing acute pancreatitis with ease. The effective treatment modalities in recent years will insist on efficient interpretation of patho-physiology in acute pancreatitis so as to ensure a speedy recovery from the cause.