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By: K. Gambal, M.B. B.CH. B.A.O., Ph.D.

Vice Chair, College of Osteopathic Medicine of the Pacific, Northwest

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Genotype-phenotype correlation and frequency of the 3199del6 cystic fibrosis mutation among I148T carriers: Results from a collaborative study. Pathology of cystic fibrosis: review of the literature and comparison with 146 autopsied cases. Towards the ideal quantitative pancreatic function test: analysis of test variable that influence validity. Pancreatic function in infants identified as having cystic fibrosis in a neonatal screening program. Mutations in the cystic fibrosis transmembrane regulator gene and in vivo transepithelial potentials. Introduction About a decade ago, a question was raised about glyburide, a widely used sulfonylurea, as a possible cause for acute pancreatitis (Blomgren). Since then, several systemic reviews reveal the incidence of acute pancreatitis in patients with type 2 diabetes 1. Five years after the concern was raised about glyburide and soon after the first of the incretin based, exenatide, had gained a significant market share, reports of pancreatitis again began to surface. Examination of two different insurance data bases, again reveal no real increase over other agents used to treat type 2 diabetes. This chapter will cover the wide variety of drugs that have been associated with acute pancreatitis as well as the studies that substantiate increase in acute pancreatitis in type 2 diabetes. The rate of acute pancreatits in incretin based agents and other agents as mentioned above seems the same as the rate in the population of type 2 diabetic as a whole. Background In 2002 Blomgren reported the association of acute pancreatitis with obesity and glyburide therapy in type 2 diabetic subjects (Blomgren). The first of a new class of incretin-mimetic agents, exendatide (Byetta) was introduced for the treatment of diabetes in 2005 and by 2006 the first report of acute pancreatitis was made by Denker (Denker) and soon others began to immerge. Perhaps, the fact that the pathway involved with each of these new types of agents has the potential to affect the gastrointestinal tract, there was concern that this might be responsible for precipitating acute pancreatitis. Diabetic comorbidities of hypertriglyceridemia and obesity may increase their risk for acute pancreatitis. New etiologies continue to be described as evidenced by the report by Frulloni and colleagues of an autoimmune pancreatitis identified by a novel antibody directed at an epitope homologous to a protein from Helicobacter pylori (Frulloni). Type 2 diabetes is associated with obesity and hyperlipidemia, each of which has been considered a risk factor for pancreatitis (Trivedi, Blomgren).

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Nonspecific mild reactions are relatively common, with a sensation of warmth or nausea. Symptoms of immediate reactions range from pruritus, rhinitis, and urticaria to hypotensive anaphylactic reactions. A typical pretreatment regimen consists of prednisone 50 mg 13, 7, and 1 hours before the procedure and diphenhydramine 50 mg 1 hour before the procedure. The addition of ephedrine 25 mg or albuterol 4 mg 1 hour to the procedure may also be considered but should be balanced against risk in patients with cardiovascular disease. It should be noted that premedication does not eliminate the possibility of a reaction and that severe reactions may still occur. Corticosteroid with or without cyclosporine has been used as pretreatment, but it is unclear how efficacious these approaches are. Premedication with corticosteroids and antihistamines has been utilized for drug allergic reactions, but breakthroughs have been reported and the true efficacy of this approach is unknown. Nephrogenic systemic fibrosis is a devastating complication of gadolinium agents in patients with renal dysfunction. Screening for renal function prior to gadolinium use has markedly reduced these reactions. Most adverse reactions to local anesthetics are due to nonallergic factors such as vasovagal responses, toxic or idiosyncratic reactions due to inadvertent intravenous epinephrine, or anxiety. Based on patch testing, there is cross reactivity among the benzoate esters (which do not cross-react with amides) but not among the amides. It is not known what, if any, relevance this has on immediate-type reactions to local anesthetics. If the reaction history is consistent with a possible type I reaction, skin testing followed by graded challenge tests may be performed using the same (epinephrine-free) local anesthetic that is intended to be used. Placebo administration is often important in testing patients as they often react due to anxiety regarding the test. Also, very rare patients may have positive skin tests to methylparabens in local anesthetics, and some of these may be false positive. In these situations, preservative-free local anesthetic should be used for skin testing/graded challenge. Cancer chemotherapeutics Drug allergic reactions have been reported for most chemotherapeutic agents with a wide spectrum of reactions and severity. In the taxane family, paclitaxel and docetaxel have a high frequency of causing first-dose anaphylactoid reactions. Pretreatment with corticosteroids and antihistamines is effective at reducing the rate of these reactions to approximately 2% to 4%. A suggested premedication regimen includes dexamethasone 20 mg (oral or intravenous), 12 and 6 hours before dosing, and diphenhydramine 50 mg and cimetidine 300 mg or ranitidine 50 mg, both administered intravenously 30 minutes before treatment. Patients who react despite premedication can undergo an induction of drug tolerance procedure.

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If the lesion is prominent, incisional biopsy or excision is indicated to exclude malignant lymphoma. Some patients with lesions classified pathologically as lymphoid hyperplasia eventually develop extraophthalmic foci of systemic lymphoma, so patients with this type of conjunctival lesion are usually treated with relatively low-dose external beam radiation therapy to the affected eye or eyes and monitored periodically over the ensuing years for signs of systemic lymphoma. Invasive clinical and pathologic features are generally evident, and regional and distant metastases are potential sequelae. Squamous Cell Carcinoma of Conjunctiva Squamous cell carcinoma of the conjunctiva is an acquired malignant neoplasm composed of very atypical neoplastic cells arising from the stratified squamous epithelium. It usually affects middle-aged to elderly persons except in xeroderma pigmentosum, in which it tends to develop early in life. If neglected or particularly aggressive, conjunctival squamous cell carcinoma can invade the sclera and extend intraocularly, or invade the orbit. At the time of surgery, cryotherapy to the conjunctiva surrounding and the sclera 260 underlying the excisional defect is frequently performed to reduce the chance of local tumor recurrence. If clinical examination or pathologic study of the excised specimen suggests residual neoplasia, supplemental topical therapy with mitomycin C, 5-fluorouracil, or interferon alpha-2b is frequently provided. Leukoplakic type of squamous cell carcinoma of the limbal conjunctiva; the surface white plaque (leukoplakia) is a result of focal hyperkeratosis. Gelatinous type of squamous cell carcinoma of the limbal conjunctiva with prominent conjunctival blood vessels extending to the tumor. Papillary type of squamous cell carcinoma of the limbal conjunctiva with prominent conjunctival blood vessels extending to the tumor. It tends to be highly invasive and frequently extends into the orbit by the time it is diagnosed. Mucoepidermoid carcinoma of conjunctiva, manifesting as papillary type anteriorly and subepithelial nodule posteriorly. Conjunctival Melanoma Conjunctival melanoma is an acquired malignant neoplasm that arises from the intraepithelial melanocytes of the conjunctiva. It is almost exclusively unilateral but may be multifocal in some patients if it arises from pre-existing primary acquired melanosis (see earlier in this chapter). It affects both males and females with equal frequency, but it is much more common in Caucasians than in non-Caucasians. It can arise from any region of the conjunctiva (limbal, bulbar, forniceal, palpebral, or caruncular), but it is most common near the limbus in the interpalpebral area.

Syndromes

• Nausea
• Do not smoke in bed.
• Use insulin at the same time each day, as directed by the doctor.
• Bronchitis
• Pancreatitis
• Swelling of the hands and face

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There is no significant correlation between the magnitude of serum amylase elevation and severity of pancreatitis. Serum lipase has a longer half life than amylase and therefore tends to remain elevated for longer. Urinary clearance of pancreatic enzymes from the circulation increases during pancreatitis; therefore, urinary levels may be more sensitive than serum levels. Several tests can help differentiate biliary pancreatitis from other causes of pancreatitis. Currently, these new markers have limited clinical availability, but there is significant interest in better understanding markers of immune response and pancreatic injury because these could be valuable tools for reliably predicting the severity of acute pancreatitis and supplementing imaging modalities. It also can detect extrapancreatic ductal dilations and reveal pancreatic edema, swelling, and peripancreatic fluid collections. But abdominal ultrasonography seldom visualizes the pancreas in patients with acute pancreatitis due to air in the distended loops of the small bowel. The finding of gallstones and dilatation of the extra-hepatic biliary tree on cross-sectional abdominal imaging further support to the diagnosis of gallstone pancreatitis. Pancreatic changes include diffuse or focal parenchymal enlargement, edema, or necrosis with liquefaction. Peripancreatic involvement includes blurring or thickening of the surrounding tissue planes. An early discrimination between mild edematous and severe necrotizing forms of the disease is of the utmost importance to provide optimal care to the patient. Although clinically mild pancreatitis is usually associated with interstitial edema, severe pancreatitis is associated with necrosis. Ultrasound image of the gallbladder demonstrates multiple dependent gallstones (curved arrow) with acustic shadowing (straight arrows). The patient had elevated pancreatic enzyme levels and underwent cholecystectomy because of gallstone pancreatitis. Sigmoid configuration of the main pancreatic duct with distal dilation of both main and dorsal ducts, suggesting the presence of an obstructive condition at the level of both major and minor papillae. Scoring systems in acute pancreatitis A variety of scoring systems have been proposed for accurate assessment of the severity of acute pancreatitis. Out of these 11 objective parameters, five are measured at the time of admission, whereas the remaining six are measured within 48 hours of admission. Morbidity and mortality of the disease are directly related to the number of signs present. This grading system assesses severity on the basis of quantitative measures of abnormalities of multiple variables, including vital signs and specific laboratory parameters, coupled with the age and chronic health status of the patient. A score of eight or more at admission is usually considered indicative of severe disease.

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