Pancreatitis: common but forgotten causes

Introduction

As the Great Hippocrates said: “A physician shall keep in mind all medicines that he/she prescribed to patients and keep in mind what effect they had in each patient depending on peculiarities of this patient and the disease. In medicine, this composes an origin, middle, and end.”

The quantity of patients with inflammatory enteropathies has been continuously increasing. The main position in this pathology is occupied by ulcerative colitis, Crohn’s colitis. According to the data of Belousova et al., the growth of its quantity (an almost 1.5-fold increase) has been noted in recent years, and this is possibly connected with improving diagnostics [1].

Aminosalicylates (5-ASA) remain agents of first-line treatment of inflammatory enteropathies. The last decade thoroughly enriched the collection of drug products for treating the bowels. In clinical recommendations, biological substances, such as TNF-alpha inhibitors, ustekinumab, were included. Nonetheless, the data for 5 years published in Gut in 2018, which assessed the results of treating ulcerative colitis in 22 European countries and Israel, demonstrated that the number of surgical interventions and cases of the disease severe course was not substantially different from that observed 20 years ago. It means that the introduction of biological therapy has not changed the disease natural course so far. Furthermore, the majority of patients (80.7% (95% CI 75.5–85.1%)) participating in clinical trials of immunodepressants and biological drugs continues to receive 5-ASA.

Despite the economic availability of aminosalicylates, they have disadvantages, too. In more than 40% of patients who took these products, clinical and/or endoscopic relapses (302/743 in the studies where aminosalicylates were compared with placebo, 416/871 in the studies where 5-aminosalicylates were compared with sulfasalazine) were revealed. So, the search for optimal therapy of ulcerative colitis proceeds. Intolerance of the 5-ASA group is found in less than 20% of patients with ulcerative colitis [2]. Among the possible side effects, pancreatitis development was noted.

According to the data of some authors, patients with such a reason for pancreatitis development occur in 6–8% of cases [3]. A potentially broad spectrum of medicines may cause pancreatitis, including azathioprine, sulfanilamides, furosemide, metronidazole, tetracycline, valproic acid, and compounds of 5-aminosalicylic acid (5-ASA) [2, 4, 5].

In the discussed clinical case, pancreatitis development occurred in the setting of a drug product exposure.

The 32-year-old female patient K. had been followed up by a gastroenterologist since June 2020, when she sought medical advice with complaints of diarrhea of up to 5–7 times per day with blood admixtures at every defecation. After conducting total colonofiberscopy with biopsy, she was diagnosed with “ulcerative colitis, new-onset, complete form, high activity.” According to the medical advice, the patient began to take a drug product based on 5-aminosalicylic acid without the sulfapyridine moiety in the mesalazine molecule in a tableted dosage form (1.5 g per os and 1 g per anum a day). After a week in the setting of drug product administration, she noted the manifestation of abdominal pain without sharp localization, without any connection with food intake, and without dyspeptic symptoms in a form of nausea and vomiting with no changes in the frequency of defecation. Having linked the symptoms with the start of product administration, the patient discontinued the therapy and, after the consultation with the gastroenterologist, began to take mesalazine in a granulated dosage form from 1 g per os a day. During the week of administration, she noted relapsing abdominal pain. However, due to the symptom poverty, she continued the therapy by gradually increasing the dose up to 3 g a day. After the week of administration of 3 g of the drug product in a granulated form, the patient again noted the abdominal pain intensification and relapse of dyspeptic symptoms in a form of nausea, which provoked her to discontinue the prescribed treatment again. In June 2020, the patient applied to the gastroenterological center of the specialized polyclinic of the Regional Clinical Hospital No. 2 with complaints of discomfort in the bowels before every defecation, distention, borborygmus, looseness of up to 5 times a day with blood admixtures at almost every defecation, the bodyweight reduction by 6 kg for the last month. The results of biochemical testing methods showed increased levels of blood amylase (up to 424 U/L), blood lipase (up to 2016.8 U/L), C-reactive protein (22.1 mg/L), and urine amylase (17 409 U/L). In the hemogram, the erythrocyte sedimentation rate was accelerated up to 77 mm/hour. In the standard coprological survey, there were no signs of steatorrhea.

As a rule, in the first stage of acute pancreatitis, transient hyperglycemia is developed, which is most commonly caused by increasing basal and stimulated secretion of hyperglycemic-glycogenolytic factor, and in 15% of cases, persistent hyperglycemia occurs. In case of a favorable outcome, the level of glucose will be normalized. With extensive lesions of the pancreas, deep necroses, and in case of repetitive relapsing acute pancreatitis, diabetes mellitus may develop, which is characterized by true hypoinsulinemia and hyperglucagonemia with the necessity of insulin therapy. According to literature data, 1% of all cases of diabetes mellitus are developed in the setting of acute pancreatitis [6, 7, 8]. In this patient, with repetitive control, hyperglycemia and glucosuria in fasting conditions were not revealed.

In addition to laboratory studies, control abdominal sonography was performed. Judgment: ultrasound markers of bathygastry, gastrostasis, changes in the pancreas (average dimension of 32 × 17 × 25 mm), parenchyma of medium echogenicity, homogeneous echotexture, no focal changes and space-occupying masses, non-enlarged pancreatic duct), hepatobiliary disorders were not revealed using the results of the study. Judgment of esophagogastroduodenoscopy: incompetence of cardia; superficial gastritis; cicatricial ulcerative deformation of the duodenal bulb, erosive bulbitis. For the first time, the antibodies against Helicobacter pylori were revealed.

Diagnosis: drug-induced pancreatitis associated with administration of mesalazine; ulcerative colitis, complete form, high activity; duodenal ulcer disease associated with Helicobacter pylori, evanescent remission; erosive bulbitis. Prednisolone 40 mg a day with a gradual decrease in the dose down to complete discontinuation, multienzyme drug products 25,000–40,000 U as a single dose, proton pump inhibitors 40 mg a day, and antispasmodics were prescribed. When controlling laboratory indicators and clinical patterns, the authors noted a positive clinical effect of the conducted treatment. After the week of administration, diarrhea and pain syndromes were jugulated, and therewith the patient did not notice the relapse of dyspepsia manifestations. Control laboratory indicators: after the week, the levels of blood lipase and amylase, as well as urine amylase, were reduced by 3 times as compared with the initial values. After a month of therapy with controlling laboratory studies, it was found that the changed indicators had almost achieved the normal values. To the treatment, 6-mercaptopurine 50 mg a day (chronic usage with due regard to body weight) was added. In the setting of the drug product administration, after two weeks, with controlling clinical manifestations and laboratory indicators, no negative changes were revealed.

At present time, the 5-ASA drug products remain base agents for the treatment of patients with ulcerative colitis even with existing side effects. They proved their effectiveness both in worsening and in maintaining remission [4, 9]. In 30% of patients, when administering sulfasalazine, unfavorable manifestations, such as leukopenia with agranulocytosis, nephratonia, and toxicoallergic skin lesions, were noticed [10, 11]. The development of these unfavorable manifestations is connected with the presence of the sulfapyridine moiety in the molecule, the toxicity of which had been already confirmed [12, 13]. The problem with toxicity was solved by creating mesalazine-based drug products without sulfapyridine moiety, the mechanism of action of which is currently under investigation [14]. At present time, the majority of leading European gastroenterologists are committed to a conventional ascending approach to the therapy of patients with inflammatory enteropathies, namely stepwise application of the group of drug products (Step-up therapy): mesalazine products and/or corticosteroids (in combination with antibiotics, prebiotics, and probiotics, if necessary) → immunosuppressants → products of biological therapy [15]. The authors also, in their prescription, were committed to this approach, and this demonstrated its effectiveness.

Conclusions

The application of 5-ASA for the treatment of ulcerative colitis may be accompanied by a number of side effects, including the development of pancreatitis. Medicinal therapy together with other etiological factors (autoimmune, alcoholism, mucoviscidosis, pancreatic duct obstruction) remains an underestimated cause of pancreatitis, and this needs to be considered in real clinical practice.