Etiology, pathogenesis, and diagnostic assessment of acute pancreatitis

Acute pancreatitis (AP) is an inflammatory condition of the pancreas that can lead to injury or destruction of acinar components and is clinically characterized by abdominal pain and elevated blood levels of pancreatic enzymes. The clinical spectrum is as diverse as its causes and pathogenesis, ranging from a relatively mild set of symptoms to a severe illness with potentially life-threatening complications. In the recent Atlanta classification revision, AP is differentiated into two types: interstitial edematous pancreatitis and necrotizing pancreatitis. AP is the most common diagnosis for hospitalization among the gastrointestinal (GI) conditions in the United States, accounting for as many as 300,000 hospitalizations per year. ^, The incidence is on an increasing trend during the past decades and has ranged from approximately 5 to 100 per 100,000 population per year. AP with its associated complications is a major cause of morbidity and mortality worldwide; mortality ranges from approximately 1% in mild cases to almost 30% in severe cases with persistent organ failure. ^, As a result, AP poses a huge financial healthcare burden as well. ^, In a recent study by Brindise et al., the incidence of AP was observed to increase from 9.48 to 12.19 per 1000 hospitalizations with cost of hospitalization increasing from $27,827 to $49,772 from 2002 compared with 2013 and an aggregate cost of over $2.6 billion per year in the US alone. ^, ^, In-hospital mortality and mean length of stay (LOS) has decreased from 2.99 to 2.04 per 100 cases and 6.99 to 5.74 days, respectively, in the same period.

Etiology and pathogenesis of acute pancreatitis

Gallstones and alcohol abuse together account for as many as 60% to 80% of all AP cases. ^, The relative frequency of each of these etiologies depends largely on the population being evaluated. In both the East and the West, biliary pancreatitis is more common in women, whereas alcoholic pancreatitis is more common in middle-aged men. ^, Approximately 10% of cases are caused by diverse causes, such as malignancy, hyperlipidemia, hypercalcemia, viral infection, drugs, and iatrogenic causes. As many as 30% of cases are idiopathic. ^,

Acute biliary pancreatitis

Between 4% and 8% of patients with gallstones eventually experience biliary pancreatitis secondary to migratory gallstones ( Fig. 55.1 A; see Chapters 33 and 37 ). ^, The incidence of acute biliary pancreatitis is higher in women than in men (69% vs. 31%) and increases with age. The natural history of acute biliary pancreatitis is different from that of alcohol-induced disease. There is a spectrum of severity similar to alcoholic pancreatitis, but if the patient recovers, endocrine and exocrine deficiencies are much less likely than in alcoholic patients, and in most cases the gland is histologically normal after clinical recovery.

FIGURE 55.1, Causes of acute pancreatitis.

Opie first observed an impacted gallstone at the papilla of Vater in two patients with severe pancreatitis in 1901. Since then, investigations have shown that the pathogenesis of biliary pancreatitis is multifaceted, with ampullary obstruction, biliopancreatic reflux, gallstone-related factors, and genetics each playing a role.

Experimental and clinical studies have shown that ampullary obstruction by gallstones not only initiates but also sustains and aggravates biliary pancreatitis. ^, On the other hand, Acosta et al. found small gallstones in the stool of 94% of patients with biliary pancreatitis compared with 8% of control subjects with gallstones who did not have pancreatitis, demonstrating that the crucial event is probably not the impaction of a stone in the common bile duct (CBD) but rather the passage of a gallstone of a suitable size through the ampulla of Vater. In the absence of an obstructing stone at the ampulla, based on findings of inflamed ampulla in patients operated on early (<36 hours after admission) for biliary pancreatitis versus those operated on late (>3 months after admission), it is hypothesized that local edema or spasm of the ampulla can also lead to obstruction of the pancreatic duct. Either way, transient obstruction increases pressures in the pancreatic duct, which then leads to extravasation of pancreatic juice in the interstitium and subsequent injury of the gland. Pancreatic hypersecretion after a meal may then enhance the increasing pressure in an already-obstructed duct from the migrating gallstone and intensify the injury. The causative role of transient obstruction by gallstones in pancreatitis is further supported by the observation that recurrent attacks of biliary pancreatitis can be prevented or reduced by endoscopic sphincterotomy. In patients with separate orifices of the CBD and pancreatic duct, biliary pancreatitis can still occur, likely because of the stone in the distal bile duct compressing the adjacent pancreatic duct directly or from the resulting edema.

Opie proposed in 1901 that bile reflux into the pancreatic duct caused by stone obstruction of the common biliary pancreatic channel initiates the inflammation. Since then, however, the evidence suggests that the common channel focus is invalid. Under physiologic circumstances, the pressure in the pancreatic duct is 3-fold higher than in the CBD, thereby preventing reflux of bile into the pancreatic duct. During ampullary obstruction, the pressure gradient between the biliary tree and the pancreatic duct may reverse. Nonetheless, although sterile refluxate can cause an increase in the permeability of the pancreatic ductal system through activation of pancreatic enzymes, it does not lead to pancreatitis and would remain a harmless event. ^, However, when there is temporary biliary and pancreatic obstruction, followed by decompression and flow of infected bile at high pressure into the pancreatic duct, AP is induced.

Contributing to the pathogenesis of biliary pancreatitis are factors that facilitate the passage of gallstones from the gallbladder into CBD and then through the ampulla. A recent study showed that small gallstone diameter (<5 mm), wide cystic duct (>5 mm) and high stone load (>20 gallstones) were significant risk factors for biliary pancreatitis. Other gallstone-associated features that increase the risk for development of biliary pancreatitis include mulberry shape and irregular surfaces. ^, Excess cholesterol crystals in the gallbladder and good emptying of the gallbladder are also associated with an increased risk of pancreatitis.

In recent years, variations or mutations in the genes that encode pancreatic enzymes or their inhibitors have been suggested as potential risk factors for development of AP. SPINK1 encodes a potent inhibitor of trypsin activity within the pancreas, and it has been found that mutations in SPINK1 are significantly higher in patients with AP (all causes) compared with a healthy control group. A case of recurrent biliary pancreatitis has reportedly been associated with a mutation in ABCB4 gene, which encodes a multidrug resistance protein involved in the transport of phosphatidylcholine across the canalicular membrane of hepatocytes.

Acute alcoholic pancreatitis

Alcoholic pancreatitis is more common in men, which may be secondary to greater alcohol intake in men rather than a gender-based difference in susceptibility. The peak age for presentation of alcoholic pancreatitis is uniformly 40 to 60 years. Incidence and prevalence also differ in terms of race and geographic distribution. The average daily alcohol consumption among patients with alcoholic pancreatitis averages 100 to 150 g/day. Although the risk for pancreatitis increases with greater doses of alcohol, epidemiologic studies shows that clinically evident pancreatitis develops in only a minority of heavy drinkers. ^, On the other hand, findings consistent with pancreatitis have been reported in as many as 75% of autopsies performed on alcohol abusers. These observations suggest that alcohol alone may not cause pancreatitis unless accompanied by additional genetic and/or environmental factors. As such, it is probable that alcohol sensitizes the pancreas, with these additional genetic and environmental factors then initiating pancreatitis. Interestingly, binge drinking in the absence of long-term, heavy alcohol use does not appear to precipitate AP and the type of alcohol intake (e.g., wine vs. beer) does not change risk.

The direct effect of alcohol on the pancreatic duct and the acinar cells has been studied. Alcohol increases secretion of two nondigestive proteins, lithostathine and glycoprotein GP2, in the pancreas, which precipitate within the ducts and form aggregates that eventually enlarge and calcify to form intraductal calculi. ^, Whether these protein plugs and ductal calculi play a role in the initiation of alcoholic pancreatitis is yet to be determined, although it is accepted that these events have the potential to facilitate disease progression. In animal studies, chronic administration of alcohol has been found to increase the pancreatic content of the digestive enzymes trypsinogen, chymotrypsinogen, and lipase, as well as the lysosomal enzyme cathepsin B. Trypsinogen can be activated by cathepsin B within acinar cells, leading to a cascade of autodigestion characteristic of pancreatitis. The pancreas can metabolize alcohol via both oxidative and nonoxidative pathways, yielding the toxic metabolites acetaldehyde and fatty acid ethyl esters (FAEEs), respectively. ^, Oxidative alcohol metabolism results in the generation of reactive oxygen species (ROS) as a byproduct and, at the same time, depletion of the ROS scavenger glutathione. The products of alcohol oxidation (acetaldehyde and ROS) and those of nonoxidative metabolism of alcohol (FAEEs) have all been reported to cause acinar cell injury. Clinical and experimental studies have demonstrated that oxidant stress from the metabolism of alcohol induces destabilization of zymogen granules and lysosomes, resulting in pancreatic injury. Similarly, FAEEs from nonoxidative metabolism of alcohol destabilize lysosomes in acinar cells, thus increasing the potential for contact between lysosomal and digestive enzymes, leading to their intracellular activation and autodigestion of the gland. This is mediated by the sustained increases in intracellular calcium levels, leading to trypsinogen activation, alterations in endoplasmic reticulum (ER) luminal environment, activation of mitochondrial permeability transition pore (MPTP), and depletion of ATP leading to cellular necrosis. Ethanol itself can affect cellular autophagy, an important cellular process by which unneeded or damaged cellular components are sequestered in autophagic vacuoles and targeted to the lysosome for degradation. This is postulated to result in the accumulation of large vacuoles within acinar cells, one histologic characteristic seen in pancreatitis. Furthermore, it has been shown that the induction of pancreatic stellate cells by ethanol or acetaldehyde leads to their transformation to highly proliferative myofibroblast-like cells. This leads to accumulation of extracellular matrix proteins, which can lead to fibrosis. Furthermore, stellate cells can induce the synthesis of cytokines and growth factors involved in their activation, resulting in an autocrine loop that may explain the inability of the pancreas to fully recover from injury in the presence of continued alcohol ingestion, leading to chronic pancreatitis (CP).

Despite the many pathways of direct toxic injury of alcohol to the pancreas, the low numbers of patients with alcoholism in whom pancreatitis develops suggests that a susceptibility factor, environmental or genetic, is at play to provide a second hit for triggering clinical pancreatitis. Among the environmental factors studied, smoking has garnered the most interest. A recent cohort study showed that smoking was a dose-dependent risk factor for alcoholic pancreatitis after controlling for age, gender, body mass index (BMI), and alcohol consumption. As for genetic factors, to date, studies on hereditary factors as well as mutations in genes related to digestive enzymes and their inhibitors have shown no conclusive association with alcoholic pancreatitis. A potential cofactor that does have relevance to the clinical situation is bacterial endotoxemia. A recent study has demonstrated a key role for lipopolysaccharide, an endotoxin found in the cell wall of gram-negative bacteria, in the initiation and progression of alcoholic pancreatitis.

Nonbiliary and nonalcoholic acute pancreatitis

Although less frequent, there are a variety of other etiologic factors that have been found to cause AP, accounting for as many as one-quarter of the cases. Improved understanding of AP, coupled with advances in genetics, molecular biology, and pathology, has shed new light on its pathogenesis; AP is often the result of a complex interaction between host and environmental factors. This section examines some of these nonbiliary and nonalcoholic causes of AP.

Metabolic causes

Hypertriglyceridemia.

Hypertriglyceridemia is well documented and accounts for 1% to 10 % of all AP cases. ^, ^, AP secondary to hypertriglyceridemia seldom occurs unless it is severe (defined as >10 mmol/L fasting), although the exact pathophysiologic mechanism is unclear. ^, The prevalence of AP development among dyslipidemia patients is approximately 5% and 20% of patients, with serum triglycerides levels higher than 1000 and 2000 mg/dL, respectively. The clinical course of AP from hypertriglyceridemia is often similar to other causes of AP; however, the morbidity and mortality are reported to be significantly higher in these patients.

This is confounded by the frequent presence of other factors coexisting in some of these patients, such as poorly controlled diabetes mellitus, obesity, alcohol abuse, pregnancy, and hypothyroidism. Triglyceride-induced AP is associated with types I, IV, and V hyperlipidemia. A common theory is that excess triglycerides are hydrolyzed by pancreatic lipase and released in the pancreatic microvasculature, resulting in high concentrations of free fatty acids (FFAs), which overwhelm the binding capacity of albumin and self-aggregate to micellar structures with detergent properties. This promotes acinar cell and pancreatic capillary injury, which results in ischemia and forms an acidic milieu that starts the vicious cycle of triggering more FFA toxicity. At the same time, the ischemia is exacerbated by the increased viscosity of blood from the elevated levels of chylomicrons. The damage to the acinar cells and microvasculature leads to amplification of inflammatory mediators and free radicals, ultimately leading to necrosis, edema, and inflammation of the pancreas. ^, ^,

Mild to moderate hypertriglyceridemia (<5 mmol/L) occurs in almost half of patients in the early phase of AP from any etiology, but some speculate that this is an epiphenomenon rather than a true precipitant because of the high prevalence of hypertriglyceridemia in the general population. ^, Some studies have proposed a genetic predisposition to hypertriglyceridemic AP. Lipoprotein lipase deficiency associated with chylomicronemia is a rare autosomal recessive disorder caused by multiple/different lipoprotein lipase gene mutations, characterized by high fasting plasma triglyceride levels. The frequency of mutations in cationic trypsinogen (PRSS1) , serine protease inhibitor Kazal type 1 (SPINK1) , cystic fibrosis transmembrane conductance regulator (CFTR) , and tumor necrosis factor superfamily member 2 (TNF2) genes were studied in 128 patients with hypertriglyceridemia with or without AP. The prevalence of polymorphisms in CFTR and TNF genes was found to be significantly higher in those with hypertriglyceridemia.

Hypercalcemia.

Hypercalcemia is a rare cause of AP, with a reported prevalence of 1% to 4%. There is no clear pathophysiologic mechanism, but elevated parathyroid hormone (parathormone, PTH) and hypercalcemia could be responsible for calcium deposit in the pancreatic ducts. Hypercalcemia-induced cellular injury occurs through activation of pancreatic enzymes by a trypsin-mediated mechanism, resulting in acinar cell damage, pancreatic autodigestion, and subsequent pancreatitis. Another mechanism is the formation of pancreatic calculi, which, by modifying pancreatic secretion, may lead to protein plug formation, resulting in ductal obstruction. Acute hypercalcemia also increases the permeability of the pancreatic ductal membrane, allowing enzymes to leak and injure the pancreatic parenchyma. Parathormone may have direct toxic effects on the pancreas as well. Coexistence of primary hyperparathyroidism and AP has widely been reported, with a prevalence of 1.5% to 13%, but a causal relationship remains unclear. ^, Hypercalcemia results from calcium infusion during total parenteral nutrition and occurs in patients with myeloma, leukemia, vitamin D poisoning, disseminated cancer, or severe hyperthyroidism, all of which have been associated with pancreatitis. ^, ^, Reciprocally, treatment of the hypercalcemia, regardless of the cause, has been reported to resolve the AP.

Inborn errors of metabolism.

AP has been associated with a variety of inborn errors of metabolism; these entities are rare but more common in neonatal and pediatric patients. These familial disorders cause hyperlipidemias, disorders of branched-chain amino acid degradation, homocystinuria, hemolytic disorders, acute intermittent porphyria, and several amino acid transporter defects. AP also has been reported in patients with type I glycogen storage disease (von Gierke). The mechanism is not clear, but the common physiobiochemical processes are hyperlipidemia, lactic acidosis, hypoglycemia, and hyperuricemia, any of which could initiate pancreatitis. Other metabolic conditions associated with AP are maple syrup urine disease, cystathionine β-synthase deficiency, 3-hydroxy-3-methylglutaryl-CoA lyase deficiency, pyruvate kinase deficiency, cystinuria, lysinuric protein intolerance, and other cationic aminoacidurias. In the majority of these diseases, pancreatitis is not common, and its pathogenesis is poorly understood.

Chronic renal failure and dialysis-related causes

AP can be caused by and associated with end-stage renal disease, including chronic renal failure and dialysis-related complications. Although rare, AP contributes to significant morbidity and mortality in patients whose health is already compromised. The diagnosis of AP is also confounded by renal dysfunction caused by altered levels of pancreatic enzyme estimation and the contribution of pancreatic damage from dialysis and uremia. Multiple studies attempting to determine the incidence of AP in dialysis patients have demonstrated mixed results. However, the incidence of pancreatitis is generally accepted to be significantly higher in patients undergoing peritoneal dialysis (PD) versus those receiving hemodialysis (HD). ^, In a recent large prospective cohort study of 2603 HD patients who were followed for 4 consecutive years after initial diagnosis of chronic HD, it was shown that the incidence of AP was more than three times higher in patients receiving HD compared with the general population. These results conflicted with older small retrospective studies reporting similar rates of AP between HD and the general population. ^, Based on postmortem studies, pancreatic abnormalities are reported in as many as 60% of patients undergoing long-term dialysis. Toxic substances in PD dialysate, alterations in serum calcium and PTH levels, and coexisting bacterial and viral infections are postulated factors that can initiate AP. The increase in various GI hormones in patients with end-stage renal disease, such as cholecystokinin, glucagon, and gastric inhibitory polypeptide, can stimulate hypersecretion of pancreatic enzymes such as trypsin, which can also initiate AP. Local accumulation of calcium in the pancreas from calcium in the PD solution has also been postulated. Another mechanism is peritoneal infusion of a large amount of nonphysiologic fluid under high intraabdominal pressure, which renders the pancreas more susceptible to parenchymal injury and hypoxemia, inducing premature activation of proteolytic enzymes, with higher risk of AP. These and other factors are cited to explain why the incidence of AP is higher in patients with PD than in patients with HD.

In conventional HD, there is a risk of hypotension, which is referred to as intradialytic hypotension. It is defined as a decrease of systolic blood pressure greater than or equal to 20 mm Hg or a mean arterial pressure by 10 mm Hg. This can lead to mesenteric ischemia via ischemic-reperfusion injury, a well-established cause of AP. Furthermore, excess GI hormones are not cleared in HD, increasing the risk of AP as mentioned above.

Drug-induced and toxin-induced pancreatitis

Drug-induced pancreatitis (DIP) is a rare entity with a reported incidence of 0.1% to 2% of AP cases. ^, In a World Health Organization (WHO) database, 525 different drugs were listed to cause AP as an adverse effect. Epidemiologic studies report that at-risk populations for DIP include the elderly and pediatric age-groups, females, and patients with inflammatory bowel disease or human immunodeficiency virus (HIV). Management and prevention of DIP requires an updated, evidence-based database of drugs associated with pancreatitis because prompt withdrawal of the offending agent is necessary along with supportive care. Little is clear, especially in patients on multidrug therapy; much controversy exists about the precise causes of DIP, and most theories center around a few mechanisms. Accumulation of a toxic metabolite/intermediary and hypersensitivity reactions cause immune-mediated injuries and pancreatic duct constriction, localized angioedema effect in the pancreas, and arteriolar thrombosis. ^, Adverse effects of drugs causing hypercalcemia or hypertriglyceridemia are also mechanisms for DIP. The family of drugs often reported to cause AP are the angiotensin-converting enzyme (ACE) inhibitors, antidiabetic agents, statins, 5-ASA and derivatives, antibiotics (e.g., metronidazole, tetracycline), and valproic acid. Table 55.1 summarizes the various classifications and drugs. ^, A recent publication developed a data-driven classification system, based loosely on the system developed by Badalov et al., that reclassified drugs into six classes based on: (1) evidence of a positive rechallenge, (2) a simplified measure of the rigor of causality assessment conducted, and (3) the consistency of the latency for drugs for cases in which a positive rechallenge or rigorous causality measurement was not reported. ^,

TABLE 55.1

Classifications of Drug-Induced Acute Pancreatitis (AP) and Common Drugs and Toxins Reported in the Literature ^a

ASSOCIATIONS	DEFINITE			PROBABLE	POSSIBLE
Definitions Karch & Lasagna, 1975	1. Drug reaction that follows a reasonable temporal sequence from administration of the drug that follows a known response pattern
	2. That is confirmed by cessation of the drug (dechallenge)				2. That could have been produced by patient’s clinical state or other modes of therapy administered to patient
	3. That is confirmed by reappearance of the symptoms on repeated exposure to the drug (rechallenge)			3. That could not be explained by the known characteristics of patient’s clinical state
Definitions Mallory & Kern, 1980	Criteria 1. Pancreatitis develops during the treatment with a suspected drug. 2. There is no evidence of any other etiologic factors. 3. Symptoms disappear after withdrawal of the drug. 4. Recurrence of pancreatitis on reintroduction of the pharmacologic agent.			Criteria fulfilled without proof of recurrent pancreatitis after rechallenge of the pharmacologic agent	Single case reports on pancreatitis
DEFINITION/CLASS	CLASS 1A	CLASS 1B		CLASS II	CLASS III	CLASS IV
Badalov et al., 2007	At least 1 case report, evidence of positive rechallenge Exclusion of other causes of AP.	At least 1 case report with positive rechallenge Other causes such as alcohol, gallstones, hypertriglyceridemia, and other drugs were not excluded.		At least 4 case reports with a consistent latency period for 75% or more of cases	At least 2 cases in the literature No consistent latency among cases No rechallenge	Not fitting into cases described earlier Single case report in published literature, without rechallenge
Wolfe et al., 2020	At least 1 case report in humans, with positive rechallenge; All other causes ruled out ^b	At least 1 case report in humans, with positive rechallenge; All other causes not ruled out ^b	At least 1 case report in humans, without positive rechallenge; All other causes not ruled out ^b	At least 2 cases in humans reported in literature, without positive rechallenge; All other causes not ruled out, Consistent latency ^c	At least 2 cases in humans, reported in literature without positive rechallenge; All other causes not ruled out; Inconsistent latency ^c	At least 1 case in humans reported in literature, drugs not fitting into earlier described classes
DRUGS
Wolfe et al., 2020; Badalov et al., 2007 Jones MR, 2015 Kaurich, 2008 Hung, 2014 Nitsche et al., 2010 Trivedi & Pitchumoni, 2005 Mallory & Kern, 1980	5-acetylsalicylic acid (mesalamine 6-mercaptopurine (6-MP) Acetaminophen All-trans retinoic acid Azathioprine Azodisalicylate/ olsalazine Bezafibrate Captopril Carbimazole Cimetidine Codeine Dapsone Erythromycin Fluvastatin Furosemide Interferon-alpha Isoniazid Lisinopril L-asparaginase Metformin Methimazole Methylprednisolone ^a Metronidazole Nitrofurantoin Orlistat ^a Piroxicam ^a	Amiodarone Ampicillin Antilymphocyte Globulin ^a Carbamazepine Ciprofloxacin ^a Clomiphene Clothiapine ^a Clozapine Cytarabine ^a Dexamethasone Didanosine Diphenoxylate + atropine Eluxadoline ^a Enalapril Everolimus ^a Growth Hormone ^a Hydrochlorothiazide Lamivudine Hydrocortisone Ifosfamide Indalpine ^a Losartan Mefenamic acid ^a Meglumine antimoniate Methyldopa Mirtazapine	Adefovir dipivoxil ^a Amoxicillin + clavulanic acid ^a Artesunate ^a Atorvastatin Axitinib ^a Boceprevir ^a Bortezomib ^a Canaglifozin ^a Candesartan ^a Celecoxib ^a Clarithromycin Danazol Dexfenfluramine ^a Diclofenac Diethylstilbestrol ^a Dilantin ^a Dimethyl fumarate ^a Doxycycline ^a Ezetimibe ^a Finasteride Flurbiprofen ^a Gadolinium ^a Glicazide ^a Glimepiride ^a Ibuprofen ^a Indomethacin	Ceftriaxone Clofibrate ^a Exenatide ^a Isotretinoin Levetiracetam ^a Sitagliptin ^a	Acetylsalicylic acid ^a Gold Nivolumab ^a Ondanseton ^a Tacrolimus ^a	Ado-trastuzumab Emtansine ^a Albiglutide ^a Alendronate Amineptine ^a Benazepril Brentuximab vedotin ^a Calcium carbonate ^a Capecitabine Chlorthalidone Ciprofibrate ^a Cisplatin Clomipramine ^a Clonidine ^a Demeclocycline ^a Doxylamine succinate ^a Ertapenem ^a Estramustine Phosphate ^a Famcyclovir Gatifloxacin ^a Gemfibrozil Granisetron ^a Interleukin-2 Lacosamide ^a Lamotrigine Linagliptin ^a Linezolid ^a
	Pravastatin Prednisone Premarin Procainamide Pyritinol Ramipril Ranitidine Rosuvastatin Simvastatin Sorafenib ^a Sulindac Tamoxifen Telaprevir ^a Tetracycline Tigecycline ^a Thalidomide ^a Trimethoprim-sulfamethoxazole Vemurafenib^ Valproic acid	Nelfinavir Octreotide Omeprazole Oral contraceptive Oxyphenbutazone Paclitaxel Paromomycin ^a Pentamidine Perindopril ^a Prednisolone Propofol Quetiapine ^a Rifampicin ^a Risperidone Salazopyrine ^a Saxagliptin ^a Stibogluconate Sulfasalazine Valsartan ^a Voriconazole ^a	Interferon beta Irbesartan Itraconazole ^a Ixazomib ^a Ketoprofen Ketorolac Lanreotide ^a Lenvatinib ^a Liraglutide ^a Meprobamate ^a Metolazone Minocycline Naltrexone ^a Naproxen Nilotinib Olanzapine ^a Pantoprazole ^a Propylthiouracil ^a Riluzole ^a Rofecoxib ^a Secnidazole ^a Sirolimus ^a Theophylline ^a Tiaprofenic acid ^a Tinidazole ^a Vedolizumab ^a Vildagliptin ^a			Lixisenatide ^a Loperamide ^a Lovastatin Maprotiline ^a Methandrostenolone ^a Micafungin ^a Miltefosine ^a Mizoribine ^a Montelukast ^a Mycophenolate mofetil ^a Nifuroxazide ^a Norfloxacin ^a Pazopanib ^a Phenformin ^a Phenolpthalien Polyethylene glycol bowel Preparation ^a Pregabalin ^a Procetofene ^a Rasburicase ^a Rifampin Ritonavir Roxithromycin Stavudine ^a Sunitinib ^a Tacalcitol ^a Telmisartan ^a Tocilizumab ^a Ursodeoxycholic acid ^a Venlafaxine ^a Zidovudine ^a Ziprasidone ^a
ASSOCIATIONS	DEFINITE			PROBABLE	POSSIBLE/SHOWN IN ANIMAL STUDIES
Toxins (sources) Khurana & Barkin, 2001	Ethyl alcohol (antifreeze, organic solvent) Methanol (solvent, nail vanish, gasoline additive) Organophosphate insecticides (pesticide, agricultural sprays, household insecticides, herbicides) Scorpion’s venom			Alpha toxin ( Clostridium perfringens, Staphylococcus aureus ) Diesel exhaust fumes (diesel engines) Pentachlorophenol (paper, leather, wood preservatives, fungicide) Tricholorethylene (degreaser for metals, veterinary anesthetic)	Aflatoxin (contaminated food, peanuts, grains) Carbon tetrachloride (organic solvent, dry cleaning, fire extinguishers, refrigerants) Cobalt (metal alloys) Neutral red (coloring agent, tropical viricide)

Drug list adapted from Wolfe et al (2020).

a The associations for new drugs are not reported in Badalov et al. (2007)

b Causes such as alcohol, hypertriglyceridemia, gallstones, and other drugs.

c Consistent latency defined as greater than 75% of cases falling into the same latency category (category 1: < 24 hours, category 2: 1–30 days, category 3: >30 days)

Toxins are reported causes of AP, but this is rare. Many cases may, in fact, be erroneously labeled “idiopathic pancreatitis.” Mechanisms may be similar to how certain drugs can initiate AP. The commonly reported toxins include scorpion’s venom, organophosphate anticholinesterase insecticides, organic solvents, pentachlorophenol, and diethyl glycol (see Table 55.1 ). ^, Data on AP associated with herbal or alternative medicines are limited. Reports documenting saw palmetto–induced AP postulate that saw palmetto ( Serenoa repens, extract of American dwarf palm tree fruit) stimulates estrogen receptors, which may result in hypertriglyceridemia or induce a hypercoagulable state that leads to pancreatic necrosis. Saw palmetto also inhibits cyclooxygenase, which is associated with the development of AP. ^,

The challenge with DIP lies in the lack of a standardized definition for the diagnosis of DIP. Although AP diagnostic criteria have been generally accepted, a recent review of DIP noted a substantial difference in criteria used by researchers to determine causality for DIP and an inconsistent application of the standard criteria for AP diagnosis. This potentially leads to challenges in classifying drugs with respect to their association with DIP. Furthermore, this can lead to information bias from misdiagnosis of other GI disease as AP and incorrect attribution of cause to a drug when it is not. ^,

Infectious causes

A variety of bacterial, viral, and parasitic infections have been established to cause AP, but the true incidence is not known, although it has been postulated to up to 10% of AP may be attributed to an infectious etiology. The value of treating the infectious agent to reverse pancreatitis is also not well established. Diagnostic criteria have been defined to evaluate the relationship between the microorganism and AP, based on histologic and imaging evidence of pancreatitis and combined with laboratory data on the infectious agent, after exclusion of the common causes ( Table 55.2 ). AP may manifest as a mild interstitial form, which constitutes 80% of patients and has a low morbidity and mortality rate (<1%). In 20% of patients, however, they may develop a more severe form characterized by an early vasoactive and toxic phase, and a late, more septic phase. Each organism works in a peculiar way to cause AP.

TABLE 55.2

Diagnostic Criteria for Infectious Causes of Acute Pancreatitis

Modified from Parenti DM, Steinberg W, Kang P. Infectious causes of acute pancreatitis. Pancreas . 1996;13(4):356–371.

CRITERIA	DEFINITE	PROBABLE	POSSIBLE
Pancreatitis	Evidence of pancreatitis at surgery, autopsy, or Radiologic evidence	Threefold increase in amylase and/or lipase and Characteristic symptoms (e.g., abdominal pain, tenderness)	Threefold increase in amylase and/or lipase without characteristic symptoms
Infection	Organism identified in pancreas or pancreatic duct by stain or culture	Culture of organism from blood or pancreatic juice or Serologic diagnosis (Fourfold or greater rise in titer) with Characteristic clinical or epidemiologic setting	Culture of organism from other body sites or Serologic diagnosis (Fourfold or greater rise in titer)

Bacterial causes.

Pancreatitis caused by bacteria has been reported with hematogenous, lymphatic seeding or ascending infection of the pancreatic duct from the biliary tree or the GI tract. Mycoplasma pneumoniae has been implicated as a cause of pancreatitis from antibody detection. ^, Studies in the 1970s have reported high Mycoplasma antibody titer in patients with AP. ^, ^, Nevertheless, the exact mechanism and relationship between AP and Mycoplasma infection remains unclear; postulated factors include ascending infection of Mycoplasma organisms, seeding via the hematogenous or lymphatic routes, autoimmune-mediated response to Mycoplasma infection, and an organ-specific toxin. Other pathogenic bacteria, such as Leptospira interrogans, Campylobacter jejuni, Salmonella typhi, Salmonella paratyphi Brucella, Yersinia enterocolitica, Y. pseudotuberculosis, Legionella, Nocardia, Mycobacterium tuberculosis, and M. avium, have been reported as causes of sporadic cases of AP. ^,

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