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The pancreas is a leaf-shaped spongy glandular organ located in the abdominal cavity. It has two anatomical components. The endocrine pancreas, represented by the islet cells, regulates intermediary metabolism of carbohydrate and fat. The exocrine pancreas, represented by the acinar cells, synthesizes an array of enzymes essential for digestion of food in the small intestine, and secretes bicarbonate required to neutralize gastric acid (Goldberg and Durie 1993).
Normally, digestion of pancreas by pancreatic enzymes is prevented by the following:
Enzymes are synthesized and secreted as inactive zymogens whose activation occurs only after reaching intestine.
All digestive enzymes are confined in vesicles within acinar cells.
Acinar cells synthesize and secrete trypsin inhibitor, a protein that inhibits activation of trypsinogen (Rhoades 2003).
Chronic pancreatitis (CP) disorders cause morphological derangement, intermittent inflammatory flares, chronic persistent pain, fibrotic obstruction of bile duct, duodenum, and portal mesenteric or splenic veins resulting in exocrine and endocrine failure (Warshaw, Banks et al. 1998). In simple words, pancreatic tissue is destroyed by the action of its own enzymes, causing inflammation and auto-digestion of the pancreas.
The TIGAR-O (Toxic-metabolic, Idiopathic, Genetic, Autoimmune, Recurrent and severe acute pancreatitis, Obstructive) classification system is based on risk factors for CP. Table 1 (Etemad and Whitcomb 2001; Sata, Koizumi et al. 2007).
CP has an annual incidence of about one person per 100,000 in the United Kingdom and a prevalence of 3/100,000. Alcohol misuse accounts for most cases, and it mainly affects men aged 40Â50 years. The quantity and duration of alcohol consumption correlates with the development of CP (Bornman and Beckingham 2001). Pancreatic cancer develops in roughly 4 percent of patients within 20 years of a diagnosis of CP (Steer, Waxman et al. 1995).
MODE OF INHERITANCE OF CP
Hereditary pancreatitis is a very rare form of CP, which has an early onset (Teich 2008). Itâ€™s cause has been identified as a mutation in the cationic trypsinogen gene (PRSS1) at locus 7q35 (Sharer, Schwarz et al. 1998), pancreatic secretory trypsin inhibitor (SPINK 1) mutations and cystic fibrosis transmembrane conductance regulator (CFTR) mutations (Teich 2008). Please refer Fig. 0 on the next page.
Fig. 0: Model of inherited pancreatitis. In the normal pancreas (left) trypsin that is prematurely activated within pancreas is inhibited by SPINK1 and in the second line by trypsin and mesotrypsin, preventing autodigestion. In inherited pancreatitis (right) mutations in PRSS1 or SPINK1 lead to an imbalance of proteases and their inhibitors, resulting in autodigestion (Teich 2008).
Fig. 1 demonstrates the pathogenesis of autodigestive fat necrosis in acute pancreatitis, repeated incidences of which lead to CP (Kloppel 1993).
TRADITIONAL THEORIES OF PATHOGENESIS
Oxidative stress theory: (Stevens, Conwell et al. 2004).
Oxidized by-products generated within the hepatocytes is secreted in the bile (Fig. 2) (Braganza 1983).
The bile is refluxed into the pancreatic ducts and causes oxidative damage to the acinar and ductile cells (EkstrÃ¶m and Ingelman-Sundberg 1989).
Chronic exposure to oxidative stress leads to fibrosis (Marshall and McLean 1971).
Toxic metabolic theory:
Alcohol is directly toxic to the acinar cell through a change in cellular metabolism.
Alcohol produces cytoplasmic lipid accumulation within the acinar cells, leading to fat degeneration, cellular necrosis, and fibrosis (Bordalo, Goncalves et al. 1977).
Stone and duct-obstruction theory: Kindly consider Fig. 3.
(A) In predisposed individuals, pancreatic fluid is lithogenic, leading to protein plug and stone formation.
(B) Accumulation of stones within the acinar cell complex produces ulceration and inflammation of the ductules.
(C) Ductular obstruction from epithelial inflammation and the stones leads to atrophy, exocrine insufficiency, and fibrosis (Sarles, Bernard et al. 1990).
The necrosis-fibrosis theory: Kindly consider Fig. 4.
(A) An episode of acute pancreatitis produces an acute inflammatory cell infiltrate in the peri-ductal areas.
(B) The healing phase of acute pancreatitis deposits collagen in the affected periductal areas.
(C) Extrinsic compression of the ducts by collagen obstructs the acinar cell complex.
(D) Worsening obstruction results in acinar cell atrophy, stasis, and secondary stone formation (Kloppel and Maillet 1991).
Typical symptoms of CP include: (Bornman and Beckingham 2001)
Severe dull epigastric pain radiating to the back, partly relieved by leaning forward.
Pain accompanied with nausea and vomiting.
Epigastric tenderness. Patients often avoid eating as it causes pain, leading to severe weight loss.
Excess fat in stools (steatorrhoea) which are pale, loose and offensive. Incontinence is caused in severe conditions.
90% desctruction of the functioning exocrine tissue results in steatorrhoea, low pancreatic lipase activity and mal-absorption of fat.
Development of overt diabetes mellitus (mild).
Hypoglycaemia due to lack of glucagon (Bornman and Beckingham 2001).
MANAGEMENT OF CP
Treatment of CP requires managing acute attacks of pain and controlling diabetes mellitus and fat mal-absorption (Bornman and Beckingham 2001).
Micronutrient antioxidants (selenium, Î² carotene, methionine, and vitamins C and E) to treat free radical damage.
Analgesics (tilidine, tramadol, morphine, meperidine, fentanyl).
Management of Steatorrhoea:
Pancreatic replacements (enteric coated microspheres) to control the loose stools.
H2 receptor antagonist and dietary fat restriction is advised for some patients.
Management of Diabetes mellitus:
Referral to diabetologist upon development of symptoms.
Treatment with oral hypoglycaemic.
Endoscopic procedures and surgery:
Endoscopic procedures are performed to remove pancreatic duct stones and stenting of strictures.
The normal pancreatic parenchyma is preserved to avoid diabetes mellitus and mal-absorption of fat.
Duodenal preserving resection of the pancreatic head (Beger procedure) and extended lateral pancreaticojejunostomy (Frey's procedure) are favoured. (Fig. 5).
Whipple's pancreato duodenectomy and total pancreatectomy is sometimes necessary (Bornman and Beckingham 2001).
Unlike in CP, pancreatic function returns to normal after attacks of acute pancreatitis. Therefore, pancreatic function tests are necessary to differentiate between acute and chronic presentations of the disease. A variety of exocrine pancreatic function tests have been developed, which can be categorized as: (Table 2) (Lankisch 1982).
Direct tests, in which pancreatic flow, bicarbonate, and enzyme secretion are measured in duodenal or pure pancreatic juice after exogenous hormonal stimulation of the pancreas.
Indirect tests, which use nutrients for endogenous stimulation of pancreatic enzyme secretion.
Faecal tests, which include microscopic inspection of stools and estimation of faecal trypsin, chymotrypsin, fat and nitrogen content.
Serum enzyme or isoenzyme estimation, with or without previous hormonal stimulation.
Table 2: Direct and indirect exocrine pancreatic function tests.
CLINICAL VALUE OF BIOCHEMICAL TESTS
The pancreas must be damaged significantly before functional loss is clinically recognized. Invasive tests of pancreatic function (intubation tests) are the gold standard for determining exocrine pancreatic function. Pancreatic function testing is not diagnostic of chronic pancreatitis, but rather serves as a sign of chronic pancreatitis and a measure of the severity of injury.
Pancreatic function testing serves three purposes: to diagnose pancreatic insufficiency, to aid in the evaluation of chronic pancreatitis and to provide a basis for rational treatment. Mechanistically, pancreatic insufficiency reflects either impaired enzyme synthesis capacity, altered release of enzymes and bicarbonate into the intestine, or intra-luminal impairment of pancreatic enzyme function or mixing (Etemad and Whitcomb 2001).
TYPICAL DATA FOR PATIENT WITH CHRONIC PANCREATITIS
Chronic alcoholism causes most cases of CP. Other causes are gallstones, hypercalcemia, hyperlipidemia, duct obstruction or inherited predisposition. Abnormal laboratory findings may result from pancreatic inflammation, pancreatic exocrine insufficiency, Diabetes Mellitus, bile duct obstruction, pseudocyst formation or splenic vein thrombosis (Chen 2006).
The clinical course, morphological features and laboratory findings of Hereditary CP (HCP) do not differ from those of patients with alcoholic CP (Teich 2008). A case report which was presented for a patient with autoimmune CP described typical laboratory findings (Horiuchi 1998). These findings have been incorporated in Table 4.
Table 4: Typical values found for patient with autoimmune CP (Horiuchi 1998). Additional comments have been added for significance of the test and their indications relevant to pancreatic disease.
In this case study, the definition, aetiology, incidence, mode of inheritance, pathology, clinical presentations and management of CP have been mentioned. Also, the biochemical laboratory tests, their significance in diagnosis and prognosis of the disease, and a typical set of laboratory results found for a patient with autoimmune CP have been included.
CP is a serious condition as it does not have any cure. Once the pancreas is damaged, it is not able to return to normal function (Tanaka 1990). Treatment is mainly directed towards preventing attacks, controlling pain and treating the complications (Warshaw, Banks et al. 1998). CP is associated with reduced life expectancy. Only half of the patients with a diagnosis of CP survive for longer than seven years following diagnosis. There is also an increased rate of pancreatic cancer in CP patients (Goldacre and Roberts 2004).