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Acute Pancreatitis inChildren

Downloaded from https://onlinelibrary.wiley.com/doi/ by Universität Bern, Wiley Online Library on [22/08/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License

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Acute Pancreatitis Associated withMetabolic, Infections andDrug-

Ali A. Aghdassi1, Mats L. Wiese1, Quang Trung Tran

Department of Medicine A, University Medicine Greifswald, Greifswald, Germany

LMU University Hospital, Munich, Germany

University of Medicine and Pharmacy, Hue University, Hue, Vietnam

1,3

, and Markus M. Lerch

Introduction

Immoderate alcohol consumption and gallstones are by far the most frequent etiologic factors for acute pancreatitis, accounting for up to 70% of all cases. The remaining 30% are patients where no triggering event can be identified (idiopathic pancreatitis, approximately 15%) and in 15%, rare causes are identified in association with acute pancreatitis. These include anatomical variants, metabolic disorders, drugs, tumors, genetic abnormalities, and infectious diseases. In this chapter we review some of the rarer causes of acute pancreatitis.

Metabolic Diseases

Hyperlipidemia and hypercalcemia are the best- known metabolic causes for acute pancreatitis. To a lesser extent, diabetic ketoacidosis (DKA), a severe complication of diabetes mellitus can cause pancreatitis.

Hypercalcemia

Hypercalcemia often results from primary hyperparathyroidism (pHPT), a disorder of the parathyroid glands that is defined by an inappropriate secretion of parathyroid hormone (PTH)[1]. Elevated calcium levels affect other organs, including the gastrointestinal tract. However, determination of the incidence of hyperparathyroidism- related pancreatitis is difficult because patients often harbor comorbidities such as concomitant alcohol abuse, cholecystolithiasis, or hypertriglyceridemia. In many cases a definite assignment of the etiology of acute pancreatitis is not possible because patients have additional

risk factors for acute pancreatitis has been observed in 1.5–6.8% of patients with primary hyperparathyroidism, for example. The highest incidences were reported from India where a higher predisposition for (tropical) calcific pancreatitis was also observed[2–4]. Mean serum calcium levels are higher in patients with primary hyperparathyroidism and coexisting acute pancreatitis (12.8–13.3 mg/dL) compared to individuals with hyperparathyroidism who do not develop pancreatitis (11.6–12.1 g/dL) [2,5,6]. After parathyroidectomy, the causative therapy for pHPT, risk of pancreatitis dramatically reduced[4].

Hypercalcemia resulting in acute pancreatitis may also be attributed to unrelated diseases of the parathyroid glands but these cases are extremely rare. Reports of secondary hypercalcemia due to either solid or hematologic malignant tumor disorders, including multiple myeloma[7] and iatrogenic causes of hypercalcemia such as calcium- containing infusions during cardiac surgery[8] or for parenteral nutrition[9] underline that high circulating calcium levels predispose to pancreatitis.

The molecular mechanisms of hypercalcemiapancreatitis are gradually being resolved. Ca important for intracellular signaling and homeostasis. Disturbances in intracellular calcium levels impair its signaling function and high cytosolic levels within the exocrine acinar cell trigger premature protease activation[10]. Blocking the uptake of calcium into the cells or chelation of intracellular ionized Ca2+ largely prevents digestive zymogen activation and pancreatic damage[11]. Mutations in the calcium- sensing receptor gene (CASR), encoding a G protein- coupled receptor regulating calcium homeostasis, were associated with chronic pancreatitis but are not directly related to acute pancreatitis

pancreatitis. A coincidence of

Related Diseases

induced

The Pancreas: An Integrated Textbook of Basic Science, Medicine, and Surgery, Fourth Edition. Edited by Hans G. Beger, Markus W. Büchler, RalphH. Hruban, Julia Mayerle, John P. Neoptolemos, Tooru Shimosegawa, Andrew L. Warshaw, David C. Whitcomb, and Yupei Zhao. © 2023 John Wiley & Sons Ltd. Published 2023 by John Wiley & Sons Ltd. Companion website: www.wiley.com/go/beger/thepancreas4e

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in pHPT patients [12]. Several clinical trials have been set up to investigate the possibility of reducing the incidence and severity of pancreatitis by interfering with the intracellular effects of calcium.

Hypertriglyceridemia

It is known that elevated lipid levels are associated with cardiovascular diseases. However, hyperlipidemia is a rare but well- established cause of acute pancreatitis as well. This is mostly related to hypertriglyceridemia, because hypercholesterolemia by itself does not cause acute pancreatitis. Hypertriglyceridemia and hyperlipidemia in general are becoming more common in industrialized countries and it has been reported that over

1.5% of the US population has severe hypertriglyceridemia (defined as a serum concentration of 500– 2000

mg/dL) [13]. Normal triglyceride levels for adults

should be less than 150 mg/dL[14].

Acute pancreatitis secondary to hypertriglyceridemia is seen in between 1.3% and 3.8% of patients [15–17]. Typically, triglyceride levels above 1000 mg/dL (or

11.4 mmol/L) precipitate acute pancreatitis with a risk of around 5%. Triglyceride levels exceeding 2000 mg/dL more than double that risk to 10–20%. In addition, data from a large Danish registry- based study indicate that even nonfasting mild to moderate triglyceride levels ≥177 mg/dL (2 mmol/L) increase the risk of pancreatitis so that dyslipidemia needs to be considered as a potential cause of acute pancreatitis more often than previously assumed[18].

Plasma triglycerides can be of exogenous or endogenous origin. Normally, dietary triglycerides are the main source and form the main lipid component in very- low density lipoproteins (VLDL). Once hydrolyzed in the small intestine they are absorbed and incorporated into chylomicrons and transported via lymphatic vessels to peripheral tissues for further utilization. Cells of all parenchymal tissues secrete lipoprotein lipases that hydrolyze triglycerides and surface components of chylomicrons and VLDL to release free fatty acids for energy supply. Fatty acids are converted to fatty acid ethyl esters (FAEE) by carboxylester lipase (CEL), an enzyme also expressed in pancreatic acinar cells. FAEE themselves exert toxic direct effects on cells and also raise intracellular Ca

concentrations that further promote cellular

damage[19].

Patients with hypertriglyceridemia often have a concomitant history of diabetes mellitus (72%), hyperlipidemia (I, IV, and V according to Fredrickson’s classification, 77%), alcohol abuse (23%), or gallstones (7%). Triglyceride levels are also elevated in the setting of DKA[16,20]. Typically, a lipid abnormality presents as a secondary factor (obesity, diabetes mellitus) whereas

isolated hyperlipidemia (usually type I or V) is much less common[21]. Moreover, mild to moderate hypertriglyceridemia is not infrequently seen in alcoholic pancreatitis patients as a secondary effect of excessive alcohol consumption and this is much more common than hyperlipidemia- induced pancreatitis in association with primary or inherited forms of hypertriglyceridemia. Clinically, alcohol abuse still needs to be ruled out as the cause of acute pancreatitis whenever hypertriglyceridemia is diagnosed [21,22]. Patients with familial chylomicronemia syndrome (FCS), a rare autosomal- re cessive disorder characterized by a loss of lipoprotein lipase (LPL) activity due to inactivating mutations of the LPL gene or genes encoding for proteins that regulate LPL activity such as apolipoproteins C- II and A- 5 (APOC2, APOA5), glycosylphosphatidylinositol- anchored highdensity lipoprotein binding protein 1 (GPIHBP1), and lipase maturation factor 1 (LMF1), have an increased risk of recurrent acute pancreatitis resulting from an excessive increase of plasma triglycerides by more than 10 to 100 times above the normal level[23].

Diagnosis of hypertriglyceridemia- induced pancreatitis needs to be established early after disease onset because serum triglycerides levels usually fall rapidly after fasting periods and hypocaloric intravenous volume therapy[21].

It still remains controversial whether hypertriglyceridemia- induced pancreatitis tends to have a more severe course. Some data indicate that severe acute pancreatitis and organ complications may be more frequent in the presence of hypertriglyceridemia[22].

Initial treatment of hypertriglyceridemia- induced pancreatitis is the same as for other etiologies andincludes fluid resuscitation, analgesia, and controlled oral food intake. In cases of severe acute pancreatitis and sustained excessive elevation of triglyceride levels lipid apheresis might be considered as a therapeutic option but a clear benefit has not been consistently shown[24]. Emphasis should be laid on lifestyle modifications and lipid- lowering agents, fibrates in the first line, to prevent further attacks of pancreatitis[14]. In patients with FCS, a therapy with volanesorsen, an antisense oligonucleotide targeting APOC3mRNA can be used as an adjunct therapy when conventional triglyceride lowering agents failed[23].

Diabetic Ketoacidosis

Acute pancreatitis can arise as a severe complication of diabetic ketoacidosis (DKA) with a risk of high mortality. Unfortunately, it is often overlooked because abdominal pain or peritoneal irritation can result from ketoacidosis and hyperlipasemia/- amylasemia might be unspecifically elevated. Acute pancreatitis occurs in at least

Infectious Diseases 201

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10–15% of patients with DKA [20]. It has also been reported during non- ketoacidotic hyperosmolar coma but this is very rare. The pathogenesis of acute pancreatitis in DKA is often attributed to hypertriglyceridemia that frequently occurs in parallel. Normally, hypertriglyceridemia is transient and resolves once DKA is corrected[20]. Insulin, fluid resuscitation under control of glucose, and electrolyte balance are key elements in the management of DKA. Plasmapheresis is used in refractory cases complicated by severe hypertriglyceridemia.

Bariatric Surgery

The number of bariatric surgeries performed annually is constantly growing. Besides weight loss an improvement of obesityrelevant intention. In the context of acute pancreatitis, it is noteworthy that there is some evidence of so- called “post- bariatric pancreatitis.” Currently, a few case reports of post- bariatric pancreatitis as an early complication following laparoscopic gastric bypass or sleeve gastrectomy exist. Consistently in these cases, pancreatitis developed within a few days after surgery. Intraoperative manipulation of peripancreatic tissue, compromised pancreatic microcirculation, edema, and spasm of major papilla as well as small bowel or outlet obstruction caused by blood clots have been suggested as triggers. Since pancreatitis as a short- term complication of bariatric surgery is rarely seen, the exact mechanisms remain to be elucidated. Data from a historical cohort of patients who underwent Rouxen- Y gastric bypass, sleeve gastrectomy, adjustable gastric banding, and revisional procedures showed a higher incidence of acute pancreatitis than in the general population[25]. The risk of acute pancreatitis is higher after vertical sleeve gastrectomy compared to Roux- en- Y gastric bypass surgery [26]. However, it is believed that this risk increase is primarily driven by biliary disease

associated metabolic diseases is becoming a

caused by sludge or gallstones as a result of rapid post- surgery weight loss, especially after sleeve gastrectomy. Hence, post- bariatric pancreatitis is likely seen exclusively as an acute complication after surgery, whereas in the longer term, pancreatitis may be caused by other and more common etiologies, first of all biliary.

Infectious Diseases

Data regarding the influence of microorganisms on acute pancreatitis and their incidence are rare and almost exclusively based on case reports. Sometimes it is not entirely clear whether other causes have been ruled out. Patients with acute pancreatitis based on an infectious agent often have a coexistent immunocompromising disorder or diabetes. The microbes involved include bacteria, viruses, fungi, and parasites (Table22.1)[27].

Bacteria

Numerous bacterial pathogens have been mentioned as causing acute pancreatitis but mostly they are described in single case presentations. Rep orts exist on Mycoplasma,

Legionella, Leptospira, Salmonella, Campylobacter, and Brucella species as well as Mycobacteria tuberculosis. The

pathogenesis of acute pancreatitis is most likely related to released bacterial toxins. Antimicrobial treatment was initiated upon diagnosis of bacteria- related acute pancreatitis in the majority of cases. However, some reports mention a resolution of pancreatitis with only symptomatic treatment.

Viruses

Of all the infectious agents, most reports exist on mumps virus and its relation to acute pancreatitis. Paramyxovirus causes mumps and although this disease usually has a

Table22.1 Infectious agents associated withacute pancreatitis.

Bacteria Viruses Fungi Parasites

Mycoplasma pneumoniae Paramyxovirus Candida spp. Ascaris lumbricoides

Legionella pneumophila Hepatitis virus A- C, E Aspergillus Toxoplasma gondii

Salmonella enteriditis Human immunodeficiency virus (HIV) Cryptosporidium parvum

Campylobacter jejuni Varicella zoster virus

Leptospira interrogans Herpes simplex virus Strongyloides stercostalis

Brucella melitensis Cytomegalievirus Fasciola hepatica

Mycobacterium tuberculosis Influenza virus (H1N1)

coxsackie virus

Plasmodium falciparum

Coronavirus (SARS- CoV- 2)

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mild course, pancreatitis was reported in around 4% of mumps patients[28,29].

The association between hepatitis A, B, and C viruses and acute pancreatitis has also been described. Hepatitis E infections are increasingly diagnosed in Western countries and reports on associated acute pancreatitis have been published [30]. Acute pancreatitis usually has a favorable outcome when related to viral hepatitis.

Human immunodeficiency virus (HIV)- positive patients with the diagnosis of acquired immune deficiency syndrome (AIDS) are also at risk for acute pancreatitis. So far, data are not conclusive whether these patients suffer from a more severe course of the disease. Severe acute pancreatitis was reported in 10–50% of patients with AIDS[31]. Modern therapeutic regimens for HIV/AIDS are associated with a much lower incidence of acute pancreatitis and a lesser degree of severity than earlier regimes that included the use of high pentamidine and didanosine concentrations.

In humans, group B coxsackie virus infections affect many organs including the heart, the central nervous system, and the pancreas. In addition, the association of this member of the picornaviridae family with acute pancreatitis has already been investigated in experimental animal models.

Gastrointestinal symptoms are observed in patients infected by severe acute respiratory distress coronavirus 2 (SARS- CoV- 2). So far, small retrospective and casecontrol studies suggest that acute pancreatitis is an infrequent complication of COVID- 19 infection and the proposed underlying pathomechanisms seem to make this association plausible. However, a true increase in the incidence of acute pancreatitis during the COVID- 19 pandemic has not been firmly demonstrated [32]. Moreover, diagnosis of acute pancreatitis must be clearly differentiated from a sole elevation of serum pancreatic enzymes, which occurs more frequently[33]. Cytotoxic effects, disturbed immune reactions, a penetration of

CoV- 2mediated by ACE2 receptors to the pan-

SARScreas and virus- associated coagulopathies are currently being discussed as causative mechanisms.

Other suspected viruses include varicella zoster virus, causing chickenpox[34], influenza[35], herpes simplex, Epstein–Barr, and cytomegalovirus[27].

Fungi

Data on fungal infections causing acute pancreatitis are extremely rare; more often fungi manifest as a late infectious complication of severe acute pancreatitis with infected necrosis. Among them Candida spp. is the most common fungal microorganism that is seen secondary to pancreatitis [36]. Aspergillus species are discussed as a potential causative agent for pancreatitis as well [27].

Most fungal infections involving the pancreas are superinfections of pancreatic or extrapancreatic necrosis and thus secondary events. Once they occur they have a negative effect on outcome and mortality. Prior antibiotic treatment of (bacterially) infected necrosis does not appear to increase the rate of fungal infection of necrosis.

Parasites

Some case reports exist on acute pancreatitis caused by

Toxoplasma, Cryptosporidium, Ascaris, Plasmodium falciparum infections, or helminths (Strongyloides). An

immunomediated mechanism is discussed as being the underlying mechanism but even immunocompetent individuals can develop pancreatitis. For parasites such as Ascaris lumbricoides, Fasciola hepatica, and Clonorchis sinensis the disease mechanism is identical to that of gallstone- induced pancreatitis: impaction in the duodenal papilla and obstruction of the pancreatic duct. They account for up to 5% of cases of “biliary” pancreatitis in some parts of Asia and China and endoscopic removal of the parasite from the papilla remains the therapy of choice.

Drug- Related Diseases

According to the World Health Organization (WHO) more than 525 drugs have been reported to cause acute pancreatitis as a potential side- effect. It is expected that the number of medications will increase in parallel with the approval of new drugs and accumulating case reports[37]. However, the level of evidence differs as knowledge is essentially extrapolated from case reports with varying strength in quality [38]. By definition, case reports only produce the lowest level of evidence in epidemiologic studies. Moreover, drug- related acute pancreatitis is usually not accompanied by other clinical or laboratory signs of adverse drug reactions such as a rash, lymphadenopathy, or eosinophilia. Therefore diagnosis is often difficult to establish[39]. A rechallenge with the suspected drug and induction of an additional attack of pancreatitis (after initial withdrawal) allows researchers to conclude potential causality but is not definitive proof. Apart from this challenge, ethical considerations limit the use of rea drug in order to trigger a second attack of pancreatitis with its potential complications. The incidence of druginduced pancreatitis is low and is estimated to account for

0.1–2% of all cases[40,41]. Very young and older people, women, and patients suffering from immunosuppressive disorders (such as HIV) or inflammatory bowel disorders are at higher risk. Risk increases in these groups by up to fourfold and is most probably based on immune- mediated

exposure to

Drug- Related Diseases 203

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reactions and the type of drugs prescribed for these disorders[37,38,42].

There are many different ways currently in use to classify drugs according to their risk of causing adverse events. With regard to acute pancreatitis the classification model of Badalov and coworkers from 2007 is currently the most frequently used. It subdivides drugs into four groups (class I–IV), based on the quality of published evidence for each agent reported as having caused acute pancreatitis[43]:

● Class I: Group with highest level of evidence and the

presence of a positive rechallenge test for the drug.

Class I drugs can be further subdivided into those in

which other potential causes for acute pancreatitis

(i.e., alcohol, gallstones, hypertriglyceridemia) have

been ruled out (Ia) and those where other causes were

not excluded in the relevant reports (Ib).

● Class II: At least four case reports for the particular

drug are required. In addition, ≥75% of the cases must

show a consistent drug latency, meaning that time of

onset of pancreatitis is within a reasonable time frame

after drug consumption. The mean interval between

initial drug intake and start of symptoms is around

5weeks, with a wide range of 2 to 36weeks[44].

● Class III: At least two case reports exist but there is

neither a consistent latency among the cases nor a

published rechallenge test.

● Class IV: Weakest level of evidence based on a single

case report, no rechallenge test was done.

Alternatively, drug- related adverse effects are classified by application of the Bradford Hill criteria. Nine different criteria evaluate the evidence of causation and one of them is the claim for biologic plausibility, meaning that the proposed causality must have been shown in an experimental laboratory setting[45].

A third classification system groups drugs according to a definite, probable, or possible causality for an adverse reaction. The main characteristics include: (i) a reasonable temporal relationship from drug intake to onset of symptoms, (ii) a known underlying pharmacologic mechanism, (iii) presence or absence of other causes for the particular side- effect, and (iv) recurrent disease after rechallenge[46]. Depending on the quality of the case report, it can happen that a suspected medication might be classified once as a definite and once as a probable risk factor[38].

To assess the probability of a causal relationship between a drug and an adverse event, also the Naranjo criteria can be used. Besides questions on existing conclusive reports on the specific drug reaction, assessment of symptoms after drug discontinuation, and information on serum concentrations of the drug, this algorithm also considers whether alternate causes of acute pancreatitis have been excluded[47].

The underlying mechanism of drug injury on the pancreas is likely based on idiosyncratic reactions. This type of reaction is characterized as being unpredictable, doseindependent, and with varying latency. From a pathophysiologic point of view idiosyncratic reactions are often mediated by an immunologic or cytotoxic mechanism of the specific compound or its metabolites. Unfortunately, they are difficult to reproduce in experimental animal models, whereas effects of intrinsic toxicity are mimicked more easily. Intrinsic toxicity implies organ damage in a dose- dependent way and is usually seen as toxicity after drug overdoses. With regard to the pancreas there are only a few reports based on an intrinsic mechanism covering acetaminophen, erythromycin, and carbamazepine[43]. A list of drugs often named in association with acute pancreatitis is given in Table22.2.

In addition, some of the most frequently cited drugs and their corresponding potential pathophysiologic mechanisms are discussed here.

Nonsteroidal anti-

inflammatory drugs (NSAID) have been proposed to induce acute pancreatitis, probably due to inhibition of prostaglandins. Prostaglandins seem to have a protective and membrane- stabilizing effect on pancreatic cells, as shown in experimental models[37,48]. The highest risks were reported for diclofenac (odds ratio [OR] 5.0) and the lowest for naproxen (OR

1.1). Use of selective COX- 2inhibitors can lower the risk for acute pancreatitis[38,49]. Conversely, given prophylactically as suppositories unselective NSAID have been shown to lower the rate of endoscopic cholangiopancreatography (ERCP)- induced pancreatitis, at least in very high- risk patients.

Estrogens, which are also used in oral contraceptives, may induce acute pancreatitis by reducing lipoprotein lipase activity, which then increases serum triglycerides and fatty acids. These components are known to be precipitating factors for acute pancreatitis[50].

Angiotensin- converting enzyme (ACE) inhibitors such as captopril, enalapril, lisinopril, and others decrease degradation of bradykinins that are released during acute pancreatitis. Bradykinins cause a local angioedema that could favor tissue edema or pancreatic duct obstruction and subsequent organ damage. There is also evidence fora direct toxic effect of ACE inhibitors on the pancreas[51,52].

Several studies report on the side- effects of azathioprine and 6- mercaptopurine, and these include acute pancreatitis. Interestingly azathioprine- induced pancreatitis is nearly never reported outside the field of inflammatory bowel disease (IBD), especially Crohn’s disease [38]. Presumably the drug’s toxicity is associated with the underlying disease. Affected individuals carry an up to 8- to 13fold increased risk of acute pancreatitis [53,54]. With regard to 6- mercaptopurine, 3.25% to 6% of patients with IBD being treated with that drug develop acute

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Table22.2 List ofdrugs withassociation toacute pancreatitis.

Definite association Probable association

Asparaginase Cyclopenthiazide

Azathioprin Oxaliplatin

Carbamazepine Mesalazine

Cytarabine Rifampin

Didanosine Octreotide

Enalapril Metformin

Erythromycin Hydrochlorothiazide

Estrogens Propofol

Furosemide Tamoxifen

Lamivudine

Mercaptopurine

Mesalamine

Opiates

Pentamidine

Pravastatin

Steroids

Sulfasalzine

Trimethoprim/Sulfmethaxazole

Tetracycline

Valproic acid

Immune checkpoint inhibitors

Source: Adapted from Nitsche C et al., Curr Gastroenterol Rep 2012 and Hung WY et al., 2014.

pancreatitis[55,56]. It is noteworthy that 5- aminosalicylic acid (OR 0.7) and sulfasalazine (OR 1.5), which are also frequently used for IBD treatment, were not associated with significantly increased pancreatitis risk in a recent report[57].

3- Hydroxy- 3- methylglutaryl- coenzyme A (HMGCoA) reductase inhibitors (commonly known as statins), such as simvastatin, pravastatin, and atorvastatin are thought to have direct toxic effects and in a number of cases drug interactions involving cytochrome P450 3A4 (CYP3A4) seem to contribute to pancreatitis. However the overall risk for acute pancreatitis is rather low with an OR ranging from 1.01 to 2.02, so statins seem to be of low importance for drug- induced pancreatitis[58].

Nucleoside reverse transcriptase inhibitors such as didanosine, lamivudine, and stavudine have a toxic effect on the pancreas. In addition they cause metabolic disturbances[52]. HIV patients with a low CD4 count are at a higher risk[38].

Asparaginase is a cytostatic drug and commonly used for treatment of non- Hodgkin lymphoma

and acute lymphoblastic leukemia. Asparaginaseassociated acute pancreatitis was reported from 5–13 % in these therapies occurring in both children and adults with similar risk while pancreatitis- related complications were most frequently observed in adolescents. Re- administration of asparaginase is related with a high rate (up to 44%) of recurrence of acute pancreatitis and therefore should be carefully considered before rechallenging[59].

Consumption of valproic acid or other anti- epileptic drugs is associated with an increased risk for acute pancreatitis, presumably mediated by direct toxic effects and an increase of reactive oxygen species[38,52]. According to recent studies and in contrast to older reports, selective serotonin reuptake inhibitors (SSRI) do not increase the risk of acute pancreatitis[60].

Soon after introduction of incretin mimetics (glucagon-

like peptide- 1 [GLP- 1] agonists) safety concerns arose about the potential of acute pancreatitis as a side- effect, especially for exenatide and sitagliptin. Reports were also released on dipeptidyl- peptidase- 4 (DPP- 4) inhibitors[61,62]. Recent analyses failed to find an unequivocal effect on the incidence of pancreatitis and were explained by the fact that people with diabetes already are at increased risk of developing acute pancreatitis[37,63,64]. A higher prevalence of gallstone disease or hypertriglyceridemia is also seen in this patient group [65]. Summing up, the role of incretin mimetics is not conclusively answered: preexisting risk factors such as diabetes mellitus and cardiovascular disorders explain most pancreatitis cases in this group and the large safety trials on DPP- 4 inhibitors have largely calmed the initial concerns about an association with pancreatitis.

Immune checkpoint inhibitors are directed against cytotoxic T- lymphocyte- associated- antigen 4 (CTLA4), programmed cell death protein 1 (PD- 1) or its ligand 1 (PD- L1), which are expressed on T cells, antigen presenting and tumor cells, respectively. They are increasingly used for treatment of a growing number of malignant tumors and for some entities combinations of checkpoint inhibitors exist. Due to the higher number of prescriptions immune-

related adverse events are observed more frequently. Pancreatic injury is observed in up to 4% of patients being treated with immune checkpoint inhibitors[66], most often manifested by an asymptomatic increase of serum lipase and amylase but occasionally also by acute pancreatitis. Treatment consists of discontinuation and in severe cases of immune- mediated reactions steroid treatment is required.

Very few case reports exist on drug- induced acute

pancreatitis after penicillin- type antibiotics and these

References 205

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belong to class IV group because usually no rechallenge has been done after discontinuation of the medication[67].

For all drug- associated forms of pancreatitis management consists of drug discontinuation and supportive care, as for other types of acute pancreatitis. If necessary, a drug of a different class will be selected for further therapy. However, drug- induced pancreatitis remains a

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