Pancreatitis is an inflammatory process that may be either acute or chronic. Both acute and chronic pancreatitis involve tissue necrosis caused by activation of pancreatic enzymes, including trypsin and phospholipase A₂, as well as hemorrhage caused by pancreatic elastase. In acute pancreatitis, the gland can heal without impairment of function or morphologic changes but the condition may recur intermittently, leading to functional and morphologic loss. The severity of acute pancreatitis is indicated by a "Ranson score." Ranson and Imrie developed multiple prognostic criteria and demonstrated that patients with three or more identifiable risk factors at the time of admission to the hospital or during the initial 48 hours of hospitalization have an increased chance of mortality. Some of these criteria include:

• Age >55 years
• WBC >16,000/ml
• Hypocalcemia
• Hypoxemia
• Fluid deficit

In chronic pancreatitis, recurrent attacks result in progressive deterioration of the pancreatic structure and loss of exocrine and endocrine pancreatic function.

Pancreatic inflammation begins with parenchymal edema (acute edematous pancreatitis) and peripancreatic fat necrosis. It may progress to necrosis of the gland itself, evolving into hemorrhagic or necrotizing pancreatitis. Necrotizing pancreatitis can lead to the formation of pseudocysts (formed from enzymes being walled off by granulation tissue) and abscesses (bacterial seeding of pancreatic tissue). Because of the location of the pancreas in the retroperitoneal space and its lack of encapsulation, the inflammation spreads easily. In severe cases, pancreatic exudate containing toxins and activated pancreatic enzymes penetrates the retroperitoneum and induces chemical burns increasing the permeability of blood vessels. This causes extravasation of fluid from the circulatory system, hypovolemia, and shock. Most cases of pancreatitis are caused by either biliary tract disease or chronic use of alcohol.

• Biliary tract disease: Obstruction of pancreatic duct by biliary stone 
• Long-standing heavy alcohol consumption: Ethanol increases the protein content of the pancreatic juices. Over time, excess protein precipitates, forming plugs within small pancreatic ductules that block outflow. Ethanol also increases the permeability of the ductules so pancreatic enzymes can reach the parenchyma and damage the pancreas.
• Medications: Including azathioprine, sulfonamides, corticosteroids, NSAIDs, tetracyclines 
• Viral infections: Mumps, cytomegalovirus, hepatitis virus, EBV, rubella 
• Structural abnormalities: In pancreatic duct, common bile duct, or ampullary region; may be secondary to pancreatic carcinoma 
• Hypertriglyceridemia (exceeding 1,000 mg/U) 
• Abdominal or cardiopulmonary surgery (ischemic damage to the pancreas) 
• Trauma resulting in compression of the pancreas against the spine 
• Oxidative stress—See section entitled Complementary and Alternative Therapies for more details 

• Biliary tract disease 
• Binge alcohol consumption and chronic alcoholism 
• Race: In the United States incidence in African-Americans is 20.7 per 100,000 versus 5.7 per 100,000 for whites and 4 per 100,000 for Native Americans.
• Age: Peaks at 35 to 64 years 
• Recent surgery 
• Familial hypertriglyceridemia

• Severe, persistent, sharp abdominal pain, often radiating to the back 
• Nausea and vomiting 
• Fever 
• Sweating 
• Abdominal tenderness 
• Tachycardia 
• Tachypnea 

• Abdominal aneurysm 
• Intestinal obstruction 
• Inflammation of the gallbladder or bile ducts 
• Cholelithiasis 
• Gastroenteritis 
• Hepatitis 
• Mesenteric ischemia 
• Pancreatic cancer 
• Peritonitis 
• Perforated gastric or duodenal ulcer 
• Ectopic pregnancy 
• Appendicitis 
• Diverticulitis 

During an acute episode, patient is feverish and sweating. Pulse is usually 100 to 140 beats/min with shallow, rapid respiration. Patient appears acutely ill; sensorium may be blunted. Mild jaundice may be present.

Abdomen is invariably tender, particularly left upper quadrant and epigastrum. Upper abdomen may be rigid and/or distended as well. Bowel sounds may be diminished or absent.

In severe cases, the flanks or periumbilical area may be bluish due to leakage of blood from the pancreas in hemorrhagic pancreatitis. Lung auscultation, especially of the left lung, may reveal basilar rales from contiguously spreading inflammation.

• CBC: WBC usually > 12,000/ml with the differential shifted towards segmented polymorphs
• Elevated blood glucose secondary to decreased insulin release, increased glucagon release, and increased glucocorticoids and catecholamines from adrenal glands
• BUN, creatinine, and electrolytes usually out of balance due to movement of fluids into the interstitium
• Low calcium levels in 25% of patients with pancreatitis
• Serum amylase and lipase: Fractionation of total serum amylase into its isoamylases (p-type and s-type) is now possible in most commercial laboratories. P-type amylase greater than three times normal is particularly suggestive of pancreatitis, although elevated p-type is also seen in renal failure and other conditions. Lipase is more specific than amylase and elevation is generally diagnostic of pancreatitis; elevation of lipase is associated with more severe pancreatitis and higher mortality rate. Severity of pancreatitis does not correlate with level of elevation of amylase.
• Elevated triglycerides
• Serum bilirubin: Elevated in 15% to 25% of patients as pancreatic edema compresses common bile duct
• Markedly elevated LDH indicates poor prognosis (one of Ranson's criteria)
• Low albumin seen in 10% of cases

• Plain X rays: Kidney, urethra, bladder, and upright position; rule out air under diaphragm; peripancreatic calcifications may be noted in chronic pancreatitis; x-rays are normal > 50% in the cases of pancreatitis
• Chest X ray: May reveal atelectasis or pleural effusion
• Ultrasound: May detect biliary stones; overlying gas often prevents clear visualization of pancreas
• CT: Particularly contrast enhanced dynamic CT (CECT), provides best visualization of pancreas in most patients; rule out abscess or pancreatic pseudocyst

• Urinary para-aminobenzoic acid test for chymotrypsin activity; low excretion in patients with chronic pancreatitis
• CT-guided aspiration of necrotic areas: If exudate reveals organisms on Gram's staining or culture, prompt extensive surgical debridement of infected retroperitoneal tissue is necessary. Absent such intervention, mortality with retroperitoneal infection is close to 100%.
• EKG may show changes simulating MI in case of acute pancreatitis
• HIDA scan in acute pancreatitis to evaluate gallbladder and biliary tree

Mild edematous pancreatitis can usually be treated conservatively with IV fluid resuscitation and fasting, along with careful monitoring, until symptoms subside. Nasogastric suction reduces gastric secretion and prevents gastric contents from entering the duodenum; however, the procedure is considered elective because there is no proven benefit to the practice in terms of overall clinical outcome. Parenteral nutrition should be provided within a few days. Signals indicating that more aggressive therapy is needed include:

• Hypotension
• Oliguria
• Hypoxemia
• Hemoconcentration

Treatment for pancreatitis from hypertriglyceridemia includes:

• Weight loss
• Exercise
• Lipid-restricted diet
• Control of blood sugar if diabetic
• Avoidance of alcohol and medications that can elevate triglycerides (e.g., thiazide diuretics and beta blockers.)

• Analgesics: Meperidine (50 to 100 mg IM every 3 to 4 hours as needed in patients with normal renal function) preferred over morphine to reduce spastic effect on sphincter of Oddi
• Antibiotics: To treat documented infections with particular organisms, antibiotics such as ampicillin (250 to 500 mg IM/IV every 6 hours for adults and 25 to 50 mg/kg/day divided every 6 to 8 hours for children) and third generation cephalosporins (ceftriaxone IM/IV 1 to 2 g/day or divided bid for adults, 50 to 75 mg/kg/day divided every 12 hours for children). Imipenem has been used to prevent infection of sterile pancreatic necrosis. No benefit to antibiotics in mild to moderate pancreatitis

• Infected pancreatic necrosis should be treated by surgical debridement.
• Surgery may also be required to drain an abscess.
• Surgical intervention is indicated to achieve hemostasis in cases of hemorrhagic pancreatitis.
• A resection may be considered to relieve refractory pain in chronic pancreatitis with localized disease if the main pancreatic duct is not dilated. This operative approach should be reserved for patients abstaining from alcohol and those who would be able to manage diabetes if it resulted or intensified from the resection.
• Endoscopic retrograde cholangiopancreatography (ERCP) may be performed for severe gallstone pancreatitis.

Oxidative Stress

The oxidative stress hypothesis is the theory that oxidative stress and the subsequent depletion of glutathione (GSH) stores are the pivotal instigating factors in pancreatitis. The failure to maintain sufficient antioxidant levels with increased free radical activity may lead to chronic pancreatitis. In addition, free radicals are thought to:

• Play a role in pancreatic edema formation
• Contribute to pancreatic necrosis
• Disrupt exocytosis
• Divert highly pro-inflammatory products into the interstitium

The transsulfuration pathway of methionine metabolism, essential to the integrity of the pancreatic acinar cells, is particularly vulnerable to free radical attack, which depletes methyl groups, ATP, and GSH. Evidence is emerging that antioxidant therapy may successfully inhibit or minimize oxidative stress as well as alleviate the pain associated with chronic pancreatitis (McCloy 1998; Schulz et al. 1999).

The impact of antioxidant deficiency on risk of development of pancreatitis may be of particular relevance in areas of the world with low soil concentrations and/or low dietary intake of antioxidants—e.g., vitamin C and selenium levels are reduced in certain parts of South Africa (Segal et al. 1995).

Studies have identified the following as causative factors in persistent oxidative stress in patients with chronic pancreatitis (Schulz et al. 1999):

• Cytochrome P450 induction
• Regular occupational exposure to volatile petrochemicals
• Habitually low intakes of vitamin C and the essential amino acid methionine;. methionine and vitamin C are considered necessary for maintaining adequate GSH stores

Carotenoids, ascorbic acid, and other antioxidants may be destroyed by cooking and processing of foods; antioxidants are found only in minimal levels in refined and processed foods. Lending further support to the oxidative stress theory, alcohol-induced pancreatitis is linked to depletion of antioxidants as evidenced by decreased glutathione stores and increased free radicals (Aleynik et al. 1999).

In addition, people with chronic pancreatitis have lower serum levels of the following nutrients (McCloy 1998; Morris-Stiff et al. 1999):

• Vitamin E 
• Selenium 
• Vitamin A
• Carotenoids including beta-carotene and lycopene (found in tomatoes) 

This finding further supports the possibility that oxidative stress plays a role in the pathogenesis of pancreatitis; the question arises as to whether antioxidant supplementation will impact the course of pancreatitis.

Antioxidant Supplementation:

A placebo-controlled trial investigated the benefits of antioxidant therapy in reducing the disabling pain of chronic pancreatitis. Twenty patients (15 with chronic pancreatitis and 5 with recurrent acute pancreatitis) completed a 20-week, double-blind, placebo-controlled, crossover trial. Active antioxidant therapy consisted of the following daily amounts in divided doses:

• Selenium 600 mcg
• Beta-carotene 9000 IU 
• Vitamin C 540 mg
• Vitamin E 270 IU
• Methionine 2 grams 

Compared with the control group, patients who received the antioxidant therapy exhibited significant clinical improvement including reduction of pain (see paragraph that follows). Vitamin C and methionine were considered by the authors to be the components responsible for clinical improvements (McCloy 1998). Two additional randomized, placebo-controlled, crossover trials, using S-adenosylmethionine (SAMe) alone or in combination with selenium and beta-carotene, failed to show improvement in clinical outcomes. SAMe is an initial metabolite in the methionine metabolic pathway (see description in earlier subsection entitled Oxidative Stress) (McCloy 1998).

Ninety-four patients who would have otherwise been considered surgical candidates due to intractable pain from pancreatitis were identified, received antioxidant therapy in lieu of surgery, and were followed for an average of 30 months. During this period the following results were observed:

• 78% became pain-free 
• 7% had a substantial reduction in pain 

The total number of hospital days was significantly lower than the year preceding initiation of antioxidant therapy. The author concludes that antioxidant therapy is an effective alternative. In fact, the author reports that pancreatic surgery for pain management has become obsolete at the Manchester Royal Infirmary in England since the institution of antioxidant therapy (McCloy 1998).

Patients suffering from acute or chronic pancreatitis may develop nutritional deficiencies secondary to post-prandial abdominal pain, steatorrhea, anorexia, altered motility, and malabsorption. Authors of a review of nutritional management for patients with pancreatitis came to the following conclusions (Scolapio et al. 1999):

• Oxidative stress and depletion of antioxidants play a significant role 
• Depletion of GSH stores and other sulfhydryl compounds does precipitate lipid peroxidation in pancreatitis
• Replacement of combined antioxidants (selenium, methionine, and vitamins A, C, and E) is needed to reduce pain and inflammation in both acute and chronic pancreatitis
• Deficient magnesium levels may be present, especially in alcoholic patients; intravenous administration of magnesium may be necessary to restore adequate levels.
• Fat-soluble vitamins should be evaluated carefully as they are likely to be deficient with concurrent malabsorption
• Vitamin B₁₂ may also be low secondary to pancreatic insufficiency and is best administered via intramuscular injection

Soybeans:

A recent animal study revealed that alcohol-induced pancreatic oxidative stress was opposed by polyenylphosphatidylcholine (PPC), a mixture of polyunsaturated phosphatidylcholines (PCs) extracted from soybeans. PPC protected against the depletion of GSH in alcohol-fed rats. The antioxidant activities of PCs are not fully understood. However, they appear to be related to a capacity to trap free radicals as they become assimilated into membranes and to repair damage in the membranes (called the "radical sink" hypothesis). Their lack of side effects and high degree of efficacy may make PPC and its PC species ideal orally active antioxidants; with further study of these soy extracts, this may include a role in preventing pancreatic damage (Aleynik et al. 1999).

• Emblica officinalis (Indian gooseberry) is a traditional Ayurvedic medicinal plant used in pancreas related disorders. The fruit is used for medicinal purposes and is the richest natural source of vitamin C. A study evaluated the effect of pretreatment with E. officinalis for experimentally-induced acute necrotizing pancreatitis in dogs. The outcome was significantly better in the E. officinalis pretreated group compared with controls. Necrotizing pancreatitis was averted in the pretreatment group (Thorat et al. 1995). These findings are in keeping with the oxidant stress hypothesis and also, perhaps, the radical sink hypothesis as outlined in the Complementary and Alternative Therapies and Nutrition sections.

Traditional Chinese Medicines

Case reports suggest that Traditional Chinese medicines are effective in the prevention and treatment of pancreatitis. Some of these herbal remedies include:

• Licorice root (Glycyrrhiza glabra)
• Ginger root (Zingiber officinale)
• Ginseng root (Panax ginseng)
• Peony root (Paeoniae lactiflora) 
• Cinnamon Chinese bark (Cinnamomum aromaticum)

These herbs are also commonly used in Western and Ayurvedic treatment of gastrointestinal disorders (Qi et al. 1995).

Controlled animal studies of herbal combination remedies coincide with these case reports. Rats with induced chronic pancreatitis were treated prophylactically and following development of pancreatitis with either the herbal formula Saiko-keishi-to, a protease inhibitor (camostat mesilate), or other herbal medicine combinations. Saiko-keishi-tocontains nine herbal components:

• Bupleurum (Bupleurum falcatum L)
• Pinelliae tuber (Pinellia ternata)
• Chinese Skullcap (Scutellaria baicalensis) 
• Licorice root (Glycyrrhiza glabra)
• Cinnamon Chinese bark (Cinnamomum aromaticum)
• Peony root (Paeoniae lactiflora)
• Jujube (Zizyphi jujuba) 
• Asian ginseng (Panax ginseng)
• Ginger root (Zingiber officinale)

The group that received Saiko-keishi-to had significantly improved histologic scores compared to the other groups. The authors suggest that the following mechanisms of action contributed to this improvement; the pharmacologic effects are listed with the particular herbs likely responsible (Motoo et al. 2000):

• Anti-inflammatory (Bupleri radix as well as the combination of the herbs)
• Secretin-stimulating (Glycyrrhizae glabra)
• Increased microcirculation (Panax ginseng)
• Free radical scavenging (Panax ginseng)
• Proton pump inhibition (Paeoniae lactiflora) 
• Suppression of exocrine pancreatic and gastric acid secretion (combination of the herbs)
• Improve pancreatic ischemia (combination of the herbs)

It is likely that the herbs work together to achieve these outcomes and may not be effective individually or in a different combination (Motoo et al. 2000). For the most appropriate treatment, including how to effectively combine herbal remedies, it is best to have a patient evaluated by a specially trained herbalist or licensed and certified practitioner of Traditional Chinese Medicine.

Although the value of acupuncture in the treatment of pancreatitis is controversial, there are case reports of successful use of acupuncture to alleviate pain from either pancreatitis or pancreatic malignancy. In acupuncture terminology, acute pancreatitis is generally differentiated into one of three conditions:

• Stagnation of liver qi
• Damp heat in liver and spleen
• Upward disturbance by roundworms (seen in rural, mountainous regions)

In all three situations, the treatment principles are designed to:

• Promote liver function
• Regulate qi
• Eliminate heat, particularly damp heat

Depending on the clinical picture, the following may also be required:

• Clearing the interior of the body of excessive heat 
• Invigorating the spleen
• Eliminating roundworms

For stagnant liver qi, the author recommends that patients receive two treatments per day with needles retained for 40 minutes and manipulated every 10 minutes. Emotional changes may contribute to liver qi stagnation as well as disharmony of liver and stomach. Similarly, exposure to exogenous wind, cold and damp can contribute to functional disturbances of liver, gallbladder, and spleen as well as stagnation of qi (Su 1987).

Despite the report just outlined, a review of the current literature finds inconclusive results in applying acupuncture, transcutaneous electrical nerve stimulation (TENS), and electroacupuncture in the case of pancreatitis. There is some evidence that TENS reduced pain and frequency of attacks in a small group of patients (six) with chronic and acute pancreatitis (Diehl 1999). However, a prospective, randomized study comparing electroacupuncture to sham acupuncture, and TENS to sham TENS, did not demonstrate positive pain relief with either electroacupuncture or TENS (Ballegaard et al. 1985). A study comparing patients receiving only surgical intervention with a group receiving combined Traditional Chinese Medicine, including acupuncture, and Western medicine demonstrated a reduced mortality rate in the latter group. However, this study was limited by its nonrandom allocation of treatment and control groups (Qi et al. 1995; Diehl 1999).

Managing chronic pancreatitis to avoid acute attacks and further damage involves a low-fat diet, abstinence from alcohol, and avoidance of abdominal trauma. In addition, hypertriglyceridemic patients should lose weight, exercise, and avoid medications that increase triglycerides (e.g., thiazide diuretics and beta-blockers). Recent reports suggest the contribution of oxidative stress to development of pancreatitis, low levels of antioxidants in people with pancreatitis, and possible benefit from antioxidant supplementation in the prevention and/or treatment of pancreatitis. (See section entitled Complementary and Alternative Therapies for more details.)

• Pancreatic infection: usually gram-negative bacterial infection of necrotic tissue; requires prompt extensive surgical debridement. 
• Pancreatic pseudocyst: arises within obstructed duct or necrotic tissue; death may be caused by infection, hemorrhage, or rupture.
• Systemic multi-organ failure: heart failure, respiratory failure, renal failure, shock; thought to be due to circulating toxins. 
• Diabetes: pancreatic B cell injury may lead to hyperglycemia. 

In mild edematous pancreatitis (Ranson score 0 to 2), with inflammation confined to the organ itself, the prognosis is excellent. Mortality in such cases is less than 5%. With severe necrosis and hemorrhage, or where inflammation is not confined to the pancreas (Ranson score 3 to 5 or greater), mortality is 10% to 50% or higher; this is due to the likelihood of infection and systemic complications. In chronic pancreatitis, recurring attacks tend to become more severe.

Aleynik SI, Leo MA, Aleynik MK, Lieber CS. Alcohol-induced pancreatic oxidative stress: protection by phospholipid repletion. Free Radic Biol Med. 1999;26(5-6):609-619.

American Gastroenterological Association. Medical position statement: treatment of pain in chronic pancreatitis. Gastroenterology. 1998;115(3):763-764.

Ballegaard S, Christophersen SJ, Dawids SG, Hesse J, Olsen NV. Acupuncture and transcutaneous electric nerve stimulation in the treatment of pain associated with chronic pancreatitis: a randomized study. Scand J Gastroenterol. 1985;20(10):1249-1254.

Beers MH, Berkow R, eds. The Merck Manual of Diagnosis and Therapy. Whitehouse Station, NJ: Merck & Co. 1999:269-275.

deBeaux AC, O'Riordain MG, Ross JA, Jodozi L, Carter DC, Fearon KC. Glutamine-supplemented total parenteral nutrition reduces blood mononuclear cell interleukin-8 release in severe acute pancreatitis. Nutrition. 1998;14(3):261-265.

Diehl DL. Acupuncture for gastrointestinal and hepatobiliary disorders. J Altern Complement Med. 1999;5(1):27-45.

Khoury G, Deeba S. Pancreatitis. In: Adler J, Brenner B, Dronen S, et al., eds. Emergency Medicine: An On-line Medical Reference. Accessed at www.emedicine.com/cgi-bin/foxweb.exe/showsection@d:/em/ga?book=emerg&sct=GASTROINTESTINAL on September 1, 2000.

McCloy R. Chronic pancreatitis at Manchester, UK. Focus on antioxidant therapy. Digestion. 1998;59(suppl 4):36-48.

Morris-Stiff GJ, Bowrey DJ, Oleesky D, Davies M, Clark GW, Puntis MC. The antioxidant profiles of patients with recurrent acute and chronic pancreatitis. Am J Gastroenterol. 1999;94(8):2135-2140.

Motoo Y, Su SB, Xie MJ, Taga H, Sawabu N. Effect of herbal medicine Saiko-keishi-to (TJ-10) on rat spontaneous chronic pancreatitis. Int J Pancreatol. 2000;27(2):123-129.

Qi QH, Xue CR, Wang PZ. Analysis of treatment in 84 cases of severe pancreatitis [in Chinese]. Chung Kuo Chung Hsi I Chieh Ho Tsa Chih. 1995;15(1):28-30.

Schulz HU, Niederau C, Klonowski-Stumpe H, Halangk W, Luthen R, Lippert H. Oxidative stress in acute pancreatitis. Hepatogastroenterology. 1999;46(29):2736-2750.

Scolapio JS, Malhi-Chowla N, Ukleja A. Nutrition supplementation in patients with acute and chronic pancreatitis. Gastroenterol Clin North Am. 1999;28(3):695-707.

Segal I, Gut A, Schofield D, Shiel N, Braganza JM. Micronutrient antioxidant status in black South Africans with chronic pancreatitis: opportunity for prophylaxis. Clin Chim Acta. 1995;239(1):71-79.

Su XM. The treatment of acute pancreatitis by acupuncture. J Chin Med. 1987;No. 25:24-25.

Thorat SP, Rege NN, Naik AS, et al. Emblica officinalis: a novel therapy for acute pancreatitis—an experimental study. HPB Surg. 1995;9(1):25-30.