Chronic pancreatitis: clinical guidelines

List of Abbreviations

CFTR – cystic fibrosis transmembrane conductance regulator

ERAS – Enhanced recovery after surgery

FTS – Fast track surgery

HB_A1c – glycated hemoglobin

IL-1 – interleukin-1

IL-6 – interleukin-6

IL-8 – interleukin-8

ISGPS – International Study Group for Pancreatic Surgery

SPINK1 – serine protease inhibitor, Kazal type 1 (pancreatic secretory trypsin inhibitor)

TNF-α – tumor necrosis factor alpha

AIP – autoimmune pancreatitis

MPD – main pancreatic duct

CI – confidence interval

BMI – body mass index

PPI – proton pump inhibitors

CIT – cystic-inflammatory transformation

CT – computed tomography

PA – pseudoaneurysm

ICD-10 – International Classification of Diseases 10th Revision

MRI – magnetic resonance imaging,

MRCP – magnetic resonance cholangiopancreatography

HPF – high-power field

PD – pancreaticoduodenectomy

P – pancreas

PF – pancreatic fistula

RAS – Russian Gastroenterological Association

RCT – randomized controlled trial

ERCP – endoscopic retrograde pancreatocholangiography

DM – diabetes mellitus

TDB – terminal portion of the common bile duct

US – ultrasound examination

PFT – pancreatic function tests

CP – chronic pancreatitis

E SMPD – endoscopic main pancreatic duct stenting

EUS-PBZ – endoscopic ultrasonography of the pancreatobiliary zone

PUD – peptic ulcer disease

Terms and Definitions

Abscess formation – involvement of a secondary infection in the inflammatory process, leading to the formation of an abscess.

Pancreatic abscess – a cavity located within the pancreatic tissues, filled with purulent and necrotic masses.

Wirsungolithiasis – a calculus in the pancreatic duct.

Intraductal papillary mucinous neoplasm – a borderline malignant pancreatic neoplasm developing in its duct system, characterized by the presence of papillary proliferations of the mucosa and mucin production.

Cystic-inflammatory transformation (CIT) of the duodenum – an inflammatory and cystic lesion of its wall localized in the descending part of the duodenum, which is found in patients with CP.

Pseudoaneurysm – a cavity located outside a blood vessel that communicates with its lumen. A pseudoaneurysm is formed when the vascular wall is injured, resulting in a breach of its integrity.

Pancreatic hypertension – an increase in pressure within the pancreatic duct system due to impaired outflow of pancreatic juice. It manifests as dilation of the pancreatic duct.

Postnecrotic (false) pancreatic cyst (from Greek *kýstis* – bladder) – a cavity arising in the pancreatic tissue as a result of parenchymal necrosis, containing pancreatic juice and tissue detritus. True pancreatic cysts have an internal epithelial lining. The walls of false cysts (pseudocysts) lack such a lining and consist of fibrous tissue.

Steatorrhea – a pathological symptom characterized by the presence of an excessive amount of fat in the stool.

Pancreatic function tests – methods for determining the exocrine or endocrine function of the pancreas.

Chronic pancreatitis – a long-standing inflammatory disease of the pancreas manifested by irreversible morphological changes that cause pain and/or persistent loss of function.

Exocrine pancreatic insufficiency – a clinical syndrome that occurs when more than 90% of the active pancreatic parenchyma is destroyed.

Endoscopic papillasphincterotomy – incision of the sphincter apparatus of the major duodenal papilla using a papillotome via a duodenoscope.

Endoscopic retrograde cholangiopancreatography – an endoscopic examination consisting of cannulation of the major duodenal papilla via a duodenoscope and injection of a radiopaque agent into the bile and pancreatic ducts under fluoroscopic control.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Chronic pancreatitis (CP) – a polyetiological, long-standing inflammatory disease of the pancreas leading to irreversible morphological changes in the parenchyma and ducts of the organ, which cause pain and/or persistent loss of function [1–3]. In 2016, a new concept of the definition of CP was proposed, driven by the evolution of knowledge regarding etiology, pathogenesis, and early changes in the pancreas preceding the stage of atrophy and fibrosis. The modern definition views CP as a pathological fibro-inflammatory syndrome of the pancreas in which individuals with genetic predisposition, under the influence of environmental factors and/or other risk factors, develop a sustained pathological response to parenchymal injury or stress, leading in the late stage of CP to pancreatic atrophy and fibrosis, pain syndrome, duct deformation and strictures, calcifications, and exocrine and endocrine dysfunction [4].

1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)

Modern views on the etiology of CP are reflected in the TIGAR-O classification (Toxic-metabolic, Idiopathic, Genetic, Autoimmune, Recurrent and severe acute pancreatitis, and Obstructive) [5], according to the latest revision of which the following risk factors and etiological variants of CP are distinguished [6]:

Toxic/metabolic

- alcohol

- tobacco smoking

- hypertriglyceridemia

- hypercalcemia

- medications

- toxins

• - chronic kidney disease (end-stage)

• - oxidative stress factors (chemotherapy and radiation therapy, ischemia)

- metabolic

• diabetes mellitus

• - obesity, including visceral

• - diet (high red meat content, vegetarianism)

Genetic

- autosomal dominant

• PRSS1 (Serine Protease 1) – cationic trypsinogen mutations in codons 29 and 122 (hereditary pancreatitis)

• CEL (Carboxyl Ester Lipase) – MODY8 phenotype (Maturity Onset Diabetes of the Young)

- autosomal recessive

• CFTR (cystic fibrosis transmembrane conductance regulator), 2 mutations in *trans* position (cystic fibrosis)

• CFTR, <2 mutations in trans position (CFTR-associated disorders)

• SPINK1 (serine protease inhibitor, Kazal type 1), 2 mutations in trans position (familial pancreatitis)

- complex mutations (increased susceptibility to damage under the influence of external factors)

• CFTR (1 variant, or >1 in cis position)

• CTRC (chymotrypsin C)

• CASR (calcium sensing receptor)

• SPINK1 (1 variant, cis)

• CPA1 (carboxypeptidase A1)

• CEL or CEL-HYB (hybrid allele of the carboxyl ester lipase gene)

- modifier genes (have no phenotypic expression of their own, but exert an amplifying effect on the expression of other genes)

• PRSS1 (PRSS1 locus)

• CLDN2 (claudin2)

• SLC26A9 (sulfate/anion transporter)

• GGT1 (type I gamma-glutamyltransferase)

• ABO – blood group B

- hypertriglyceridemia syndromes

• LPL – lipoprotein lipase deficiency

• APOC2 – apolipoprotein C-II deficiency

• familial chylomicronemia syndrome

• multifactorial chylomicronemia syndrome

- Rare, non-neoplastic syndromes involving the pancreas

• Shwachman-Diamond syndrome

• Johanson-Blizzard syndrome

• Mitochondrial disorders (Pearson syndrome)

Autoimmune pancreatitis (AIP) (Appendix A3)

- AIP type 1, associated with IgG₄

• isolated

• with involvement of other organs (IgG₄-associated disease)

- AIP type 2,

• isolated

• combined with Crohn's disease

• combined with ulcerative colitis

• with involvement of other organs

CP as a consequence of recurrent and severe acute pancreatitis

• severe acute pancreatitis

• recurrent acute pancreatitis (more than 1 episode of acute pancreatitis)

Obstructive

• Oddi sphincter stenosis

• duct obstruction (by a tumor, stone, or periampullary duodenal cysts)

• pancreatic duct strictures (a complication of endoscopic procedures: papillosphincterotomy, stone extraction, etc.)

• pancreas divisum.

Idiopathic

• early onset (<35 years, mean age 20 years, pain present)

• late onset (>35 years, mean age 56 years, pain absent in 50% of patients; rapid development of calcification, exocrine and endocrine insufficiency)

Toxic factors

Alcohol is the cause of CP in 60-70% of cases. The daily alcohol consumption dose that leads to CP within 10-15 years is approximately 60-80 ml/day (Appendix G1). Gender, hereditary, and other factors may play a foundational role; therefore, the term "toxic pancreatitis" does not necessarily imply chronic alcoholism or the consequences of alcohol abuse [7, 8]. Smoking significantly potentiates the effect of alcohol (multiplicative effect), increasing the risk of developing and progressing CP [9, 10]. Observational study results indicate that the role of tobacco smoking in the genesis of CP may be even more substantial than that of alcohol [11].

Medications can cause acute and chronic pancreatitis; for example, cases of pancreatitis have been reported during treatment with asparaginase**, azathioprine**, didanosine**, methylprednisolone**, HMG-CoA reductase inhibitors, estrogens, fenofibrate**, valproic acid**, etc., which should be considered when taking the patient's medication history [12, 13].

Hypercalcemia is a risk factor for acute and chronic pancreatitis when total ionized calcium is elevated >12.0 mg/dL (3 mmol/L). Most cases of hypercalcemia-induced pancreatitis are associated with hyperparathyroidism or malignancies, and very rarely caused by a genetic disorder — familial hypocalciuric hypercalcemia (mutations in the CASR gene – calcium-sensing receptor gene) [14-17].

End-stage renal disease (stage 5) is among the known causes of CP due to reduced renal toxin excretion and electrolyte imbalances (e.g., hypercalcemia).

Metabolic factors

A definitive correlation between nutritional deficiency, the presence of specific foods in the diet, and the development of CP has not been established. A high red meat diet may be a risk factor for CP, while vegetarianism may reduce the risk of CP [8, 18].

It is currently well established that hypertriglyceridemia is a risk factor for acute and chronic pancreatitis. To diagnose acute hypertriglyceridemic pancreatitis (in the absence of other factors), serum triglycerides must be elevated above 1000 mg/dL (11.2 mmol/L). However, pancreatitis recurrence may occur at lower blood triglyceride elevations — 500 mg/dL (5.6 mmol/L) [19, 20], and even moderate hypertriglyceridemia increases the risk of pancreatitis [21].

Diabetes mellitus increases the risk of acute and chronic pancreatitis and can lead to pancreatic tissue atrophy and fibrosis with subsequent exocrine insufficiency [22, 23].

Hereditary factors

Cationic trypsinogen (PRSS1) gene mutations lead to the synthesis of pathologically active trypsin and the development of hereditary pancreatitis [24]. In patients with hereditary pancreatitis, symptoms typically appear much earlier (under the age of 20), the disease progresses rapidly, and the risk of pancreatic adenocarcinoma increases accordingly.

Maturity-onset diabetes of the young (MODY8) is associated with mutations in the carboxyl ester lipase (CEL) gene expressed by pancreatic acinar cells. Patients with MODY8 develop pancreatic exocrine dysfunction in childhood, followed by diabetes in adulthood [25].

Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene [26] and the trypsin inhibitor (PSTI or SPINK1) gene [27] have been identified in patients with idiopathic CP. In the mixed Russian population, the N34S mutation in the SPINK1 gene is significantly more common than in controls (14.6% vs. 2.9%, respectively; p<0.05). The odds ratio for developing idiopathic CP in the presence of the N34S mutation in this study was 4.6 [28]. The N34S mutation accounts for 10% or more of idiopathic CP cases [29].

Ductal obstruction

Conditions associated with the development of obstructive CP include sphincter of Oddi stenosis, main pancreatic duct strictures, presence of stones in the pancreatic ducts, pseudocysts, and tumors. It has not been definitively proven whether CP develops in the setting of pancreas divisum and sphincter of Oddi dysfunction.

Cystic-inflammatory transformation (CIT) of the duodenum is an inflammatory and cystic lesion of the duodenal wall localized in the descending part, which occurs in CP patients. Three mechanisms of CIT development are possible:

1. Inflammation of the dorsal part of the pancreatic head embedded in the duodenal wall, due to impaired secretion outflow via the accessory pancreatic duct (Santorini's duct);

2. Secondary spread of the inflammatory process from the pancreatic head to the paraduodenal fatty tissue and duodenal wall;

3. Rarely — a primary inflammatory-cystic lesion of truly heterotopic pancreatic tissue with secondary obstructive pancreatitis or concurrent development of CP in cases of alcohol abuse [30].

Immunological factors

Autoimmune pancreatitis (AIP) is a distinct form of pancreatitis that can occur in isolation or in combination with Sjogren's syndrome, inflammatory bowel disease, and many other autoimmune diseases [31]. In recent years, two types of AIP have been distinguished: type I and type II [32].

Type I AIP is morphologically represented by lymphoplasmacytic sclerosing pancreatitis, typically combined with elevated IgG₄ levels, and may be part of an IgG₄-related disease.

Type II AIP, or idiopathic periductal pancreatitis, is characterized by neutrophilic infiltration with microabscess formation and frequent association with inflammatory bowel disease [33].

Severe acute pancreatitis, recurrent acute pancreatitis, and chronic pancreatitis are viewed as a single continuum of pancreatic injury [34].

Following a first episode of acute pancreatitis, the development of CP was noted in 10% (95% CI, 4%-19%), and in recurrent acute pancreatitis — in 36% (95% CI, 20%-53%) [35].

In another retrospective study, after an initial episode of acute pancreatitis, recurrence was observed in 17% of patients, and chronic pancreatitis was diagnosed over a five-year follow-up period in nearly 8% of patients [36].

The risk of transformation into chronic pancreatitis after acute pancreatitis is higher in men and in cases of alcoholic etiology of pancreatitis [37].

1.3 Epidemiology of the Disease or Condition

The prevalence of CP in Russia is 27.4–50 cases per 100,000 population, and worldwide – 42–52 cases per 100,000 population [38–40]. The overall incidence of chronic pancreatitis in the world is 10 cases (95% CI 8–12) per 100,000 population per year [19]. CP typically develops at a mature age (35–50 years). In developed countries, the average age at diagnosis has decreased from 50 to 39 years; men suffer from CP twice as often as women, with a growing trend in the proportion of female patients (by 30%); primary disability among patients reaches 15% [19, 39–41].

Mortality after the initial diagnosis of CP is up to 20% within the first 10 years and over 50% after 20 years, averaging 11.9% [39, 40].

1.4 Features of Coding the Disease or Condition

K86.0 Alcoholic chronic pancreatitis

K86.1 Other chronic pancreatitis

K86.2 Cyst of pancreas

K86.3 Pseudocyst of pancreas

K86.8 Other specified diseases of pancreas

K90.3 Pancreatic steatorrhea

1.5 Classification of the disease or condition

Classification of chronic pancreatitis (V.T. Ivashkin et al., 1990) [42].

1. By etiology:

• Biliary-dependent

• Alcoholic

• Dysmetabolic

• Infectious

• Drug-induced

• Autoimmune

• Idiopathic

2. By clinical manifestations:

• Painful

• Dyspeptic

• Mixed

• Latent

3. By morphological features:

• Interstitial-edematous

• Parenchymal

• Fibro-sclerotic

• Hyperplastic

• Cystic

4. By clinical course pattern:

• Rarely relapsing

• Frequently relapsing

• With persistently present CP symptoms

5. Complications:

• Impaired bile outflow and duodenal content passage

• Portal hypertension (extrahepatic)

• Post-necrotic cyst

• False aneurysm of pancreatic arteries, gastrointestinal bleeding

• Endocrine disorders:

  pancreatogenic diabetes mellitus,

• Inflammatory changes: abscess, parapancreatitis, "enzymatic" cholecystitis, pneumonia, etc.

1.6 Clinical presentation of the disease or condition

The most typical clinical manifestations of CP are abdominal pain and symptoms of pancreatic exocrine insufficiency; however, in some cases, the clinical picture of the disease may manifest with complications.

Abdominal pain is the main symptom of CP. Pain is usually localized in the epigastrium with radiation to the back, worsening after meals and easing in a sitting position or when leaning forward. Pain is observed in 80–90% of patients, while 10–20% exhibit "painless pancreatitis" [43]. Pain attacks can be recurrent (type A: short-lived pain attacks lasting up to 10 days against the background of long pain-free periods); sometimes patients experience constant pain (type B: more severe and prolonged episodes with pain-free periods lasting 1–2 months, more commonly observed in alcoholic CP) [44].

Exocrine pancreatic insufficiency, manifesting clinically, occurs only when the functional activity of the gland decreases by more than 90%. Clinical manifestations of fat malabsorption are steatorrhea, flatulence, and weight loss (in 30–52% of patients). Alcoholic pancreatitis leads to exocrine insufficiency more frequently than pancreatitis of other etiologies [45]. In patients with alcoholic pancreatitis, signs of maldigestion occur on average 10 years after the onset of the first clinical symptoms.

Endocrine pancreatic insufficiency eventually develops in 70% of patients with CP in the form of impaired glucose tolerance. Diabetes mellitus occurs with a prolonged course of CP; the probability of developing diabetes mellitus gradually increases 10 years after the onset of CP manifestation [39, 46–48].

Pancreatogenic DM differs from type 1 and type 2 diabetes by a higher risk of hypoglycemia and a reduced frequency of ketoacidosis [49, 50]. Complications such as macro-/microangiopathy, nephropathy, neuropathy, and retinopathy are just as frequent as in type 1 diabetes. Today, pancreatogenic diabetes mellitus resulting from CP should be classified as type 3c [48, 50].

Clinical manifestations of CP vary significantly depending on its stage [51] (Table 1).

Table 1. Determination of the clinical stage of CP with prognosis assessment

Complications of chronic pancreatitis

Approximately 1/3 of patients with CP have pancreatic pseudocysts [52]; they can be of various sizes, mostly asymptomatic, or provoke the clinical picture of compression of adjacent organs, causing upper abdominal pain. Spontaneous regression of pseudocysts in CP occurs less frequently than in acute pancreatitis [52]; in patients with alcoholic CP, spontaneous regression is described in 25.7% of cases, and asymptomatic persistence in 23% [53]. The risk of developing severe complications in the asymptomatic course of chronic pseudocysts is <10% [52].

Exacerbation of CP and recurrent attacks of acute pancreatitis against the background of CP can lead to pancreatic necrosis with the development of infectious complications (inflammatory infiltrates, abscesses, purulent cholangitis, septic conditions). Duodenal stenosis develops in less than 5% of cases. The main cause of duodenal obstruction is cystic-inflammatory transformation of the duodenum with the spread of inflammation to the paraduodenal tissue. Decompensated forms of gastric evacuation disorders rarely occur [54–56].

Edema and the development of pancreatic fibrosis may cause compression of the common bile duct with the development of obstructive jaundice (in 16–35% of patients). Jaundice can be constant or recurrent. The onset of jaundice is preceded by upper abdominal pain characteristic of CP exacerbation [57–59].

Portal hypertension, caused by compression or thrombosis of the portal, superior mesenteric, or splenic veins due to inflammation and fibrosis of the peripancreatic tissue, is observed in 7–18% of patients. Bleeding from esophageal or gastric phlebectasia is not a frequent complication of CP [60].

Gastrointestinal bleeding in patients with CP is a pathognomonic symptom of a false aneurysm (FA) of the branches of the celiac trunk and superior mesenteric artery. At the same time, gastroduodenoscopy does not reveal ulcerations in the stomach and duodenum, or esophageal phlebectasia. Blood discharge from the major duodenal papilla during duodenoscopy is recorded in 14% of cases [61].

The consequence of progressive pancreatic fibrosis and pancreatic maldigestion not controlled by enzyme replacement therapy is malabsorption syndrome with the development of micronutrient deficiency. Therefore, signs of essential macro- and micronutrient deficiency are also classified as complications of CP with pancreatic exocrine insufficiency [62, 63]. Patients with CP are primarily at risk for developing vitamin deficiencies (A, D, E, and K) [64, 65] and vitamin B_12. Osteoporosis is an established complication of CP [63].

Maldigestion in exocrine pancreatic insufficiency is a risk factor for the development of small intestinal bacterial overgrowth (SIBO) [66, 67]. SIBO occurs in 34–92% of patients with CP, being more frequent in patients with alcoholic CP than in patients with other forms of this disease [68, 69].

With a prolonged course of CP, the risk of developing PC increases [70, 71]. For patients with a five-year history of CP, the risk of developing cancer increases 8-fold [72]. According to a meta-analysis, mutations in the CFTR gene in CP are associated with a moderate risk of developing PC (OR 1.41; 95% CI 1.07-1.84; P = 0.013), whereas mutations in the SPINK1 gene do not increase the risk of cancer (OR 1.52; 95% CI, 0.67-3.45; P = 0.315) [29]. A precursor to PC may be pancreatic intraepithelial neoplasia (PanIN)—specific morphological changes in the duct walls [38].

Possible complications also include: erosive esophagitis, Mallory-Weiss syndrome, gastroduodenal ulcers (caused by a significant decrease in pancreatic bicarbonate production), and abdominal ischemic syndrome.

2. Diagnostics, medical indications and contraindications for diagnostic methods

Criteria for diagnosing the disease/condition:

The diagnosis of chronic pancreatitis is established on the basis of:

• anamnestic data (characteristic complaints of abdominal pain attacks and/or clinical signs of exocrine and/or endocrine pancreatic insufficiency, previous detection of chronic pancreatitis)

• physical examination (abdominal wall tenderness upon palpation in the projection area of the pancreas)

• laboratory examination (signs of exocrine and endocrine pancreatic insufficiency according to functional tests)

• instrumental examination (calcifications in the pancreatic parenchyma and ducts, pancreatic duct dilatation according to ultrasound, CT, MRCP, ERCP)

Comments: The diagnosis of chronic pancreatitis (CP) is recommended to be established based on reliable morphological criteria or a combination of morphological and functional criteria. CT, as well as MRCP and ERCP, are recommended as methods of choice to verify the diagnosis of CP. Verification of the diagnosis may require performing one or all of the most accurate methods, including follow-up dynamic studies after 6–12 months if the detected signs are insufficiently consistent with a diagnosis of CP.

2.1 Complaints and Anamnesis

Symptoms and medical history data characteristic of patients with CP are specified in subsection 1.6.

2.2 Physical Examination

Physical examination during an exacerbation of CP makes it possible to determine tenderness in the Chauffard's zone upon abdominal palpation, combined with moderate resistance of the anterior abdominal wall muscles; a positive Mayo-Robson sign is tenderness upon palpation in the left costovertebral angle.

2.3 Laboratory Diagnostics

• Determination of blood amylase and serum lipase activity are not absolutely specific markers of CP, but their determination is recommended for patients with CP on the first day of hospitalization and subsequently dynamically during the same hospitalization to diagnose complications and recurrence of acute pancreatitis against the background of CP [73–75].

LoR BGoE 2Level of recommendation validity – B. Level of evidence reliability – 2.

Comments: blood amylase and lipase levels in chronic pancreatitis (CP) may be slightly elevated, within normal limits, or below normal, which is explained by the focal nature of the inflammatory process and the severity of pancreatic fibrosis; unlike acute pancreatitis, which is characterized by elevated enzyme levels in the blood and urine. A persistently elevated blood amylase level suggests macroamylasemia (where amylase forms large complexes with plasma proteins that are not filtered by the kidneys, resulting in normal amylase activity in the urine) or extrapancreatic sources of hyperamylasemia (renal failure; salivary gland diseases (mumps, calculi, radiation sialadenitis); maxillofacial surgery complications; "tumor" hyperamylasemia (lung cancer, esophageal cancer, ovarian cancer); burns; diabetic ketoacidosis; pregnancy; kidney transplantation; brain trauma; drug use (morphine**); biliary tract diseases (cholecystitis, choledocholithiasis), peptic ulcer complications – perforation or penetration of ulcers.

• To diagnose exocrine pancreatic insufficiency in clinical practice in patients with CP, it is recommended to determine the activity of fecal pancreatic elastase-1 [76-79].

GCR BLEL 1Reliability grade of recommendations – B. Level of evidence – 1.

Comments: Direct methods

Classical tube-based methods for determining pancreatic juice volume and the concentration of enzymes and bicarbonates have extremely limited application in the diagnosis of CP due to invasiveness, high cost, low availability of stimulants (to date, these drugs are not approved for medical use in the Russian Federation), labor intensity, and poor patient tolerance. These methods cannot distinguish CP from pancreatic insufficiency without CP. Direct methods can only be used in clinical trials in highly specialized clinics. In certain complex cases, the technique is applicable for the differential diagnosis of steatorrhea.

Improvement of EUS-guided secretin stimulation testing allows, in addition to inspecting the pancreatic ducts, for timed collection of duodenal contents following secretin administration, thereby reproducing the classic secretin test via endoscopy. The problem with this method is the limited accumulated experience and lack of validation, which is reflected by the absence of this method in all current international clinical guidelines for the diagnosis of pancreatic insufficiency. In Russia, the main limitation to its use is the lack of a registered secretin preparation.

Indirect methods

Indirect pancreatic function tests indirectly assess impaired exocrine function; they are more accessible compared to direct methods, but have lower sensitivity and mainly detect late stages of exocrine insufficiency.

Determination of fecal fat content. Standard coprological examination with microscopy for neutral fat droplets has low sensitivity; therefore, when using it to verify steatorrhea and evaluate treatment efficacy, the analysis must be performed three times while taking the patient's diet into account.

The quantitative fecal fat assay was developed back in 1949 and is sensitive for diagnosing pancreatic insufficiency in late stages [38]. The test is performed on a 5-day high-fat diet in the absence of enzyme replacement therapy, with stool collected over 72 hours. Normally, the coefficient of fat absorption is at least 92% [80]. The quantitative fecal fat method is used primarily within clinical trials and is rather difficult to apply in routine clinical practice.

Determination of fecal elastase-1 activity. Elastase-1 maintains relative stability compared to other pancreatic enzymes during passage through the gastrointestinal tract. The greatest advantages lie in determining fecal elastase using the enzyme immunoassay method (via monoclonal antibodies): this method measures only human elastase, so test results are not affected by replacement therapy. The test is non-invasive and relatively inexpensive, but has low sensitivity in mild-to-moderate exocrine pancreatic insufficiency and low specificity in certain gastrointestinal pathologies unrelated to the pancreas [81]. For mild exocrine function insufficiency, the sensitivity of the method is 63%.

The diagnostic accuracy of fecal elastase determination decreases sharply in the presence of accelerated transit, diarrhea, or polyfecalism of any origin, leading to false-positive results (low elastase test values) due to enzyme dilution; a similar situation may occur with small intestinal bacterial overgrowth due to bacterial hydrolysis of elastase. The degree of exocrine pancreatic insufficiency can be assessed after relief/minimization of the main manifestations of exocrine pancreatic insufficiency (diarrhea, steatorrhea) during initial therapy with modern enzyme preparations.

A decrease in fecal elastase content indicates primary exocrine pancreatic insufficiency (0–100 µg/g – severe; 101–200 – moderate or mild) [82], which is an indication for lifelong, most commonly high-dose, enzyme replacement therapy. Determining elastase levels dynamically is practically pointless, since the number of remaining functionally active pancreatic cells capable of secretion cannot increase. The determination of fecal elastase-1 activity is recommended for diagnosing CP when imaging results are inconclusive, in which case exocrine pancreatic insufficiency serves as an indirect sign of CP.

Breath test. The breath test involves oral administration of a ¹³C-labeled substrate (a mixture of triglycerides), which is hydrolyzed in the intestinal lumen to a degree proportional to pancreatic lipase activity. Exhaled ¹³CO₂ is determined by mass spectrometry or infrared spectroscopy, but, as with other indirect tests, this assay has variable sensitivity and specificity depending on a large number of factors, which is why we can observe contradictory research results in recent years. It must be acknowledged that the improvement and standardization of this technique, the use of standard validated equipment, and strict adherence to the test methodology together open up broad prospects for its widespread use [80]. The lack of a substrate approved for use in Russia (¹³C-mixed triglycerides) currently makes it impossible to perform.

• All patients with chronic pancreatitis (CP) are recommended regular (at least once a year) assessment of glycated hemoglobin, fasting blood glucose, or an oral glucose tolerance test to evaluate pancreatic endocrine insufficiency [47].

LoR BGoE 2Level of recommendation validity – B. Level of evidence reliability – 2.

Comments: Diagnosis of endocrine insufficiency should be timely and thorough through regular (at least once a year) measurement of blood glycated hemoglobin, fasting blood glucose, or performing an oral glucose tolerance test. The optimal form of screening remains controversial [49]. An international expert committee recommended using HB_A1c (at a level of ≥6.5%) rather than blood glucose concentration for the diagnosis of diabetes [83].

2.4 Instrumental Diagnostics

The choice of imaging technique should be based on its availability, the appropriate skills of the personnel, and the invasiveness of the specific study.

• All patients with clinical symptoms characteristic of CP at their initial presentation to any specialist are recommended further targeted examination using diagnostic imaging methods to confirm or exclude CP [58, 84-86].

Level of Consensus – CLevel of Evidence – 5Level of Consensus – C. Level of Evidence – 5.

Comments: a characteristic clinical picture, along with abnormal results of pancreatic function tests, allows the clinician to consider the diagnosis of CP as probable or uncertain (i.e., clinical suspicion of CP), which requires the use of more accurate imaging methods to confirm the diagnosis.

Plain abdominal radiography can only detect pronounced calcification in the pancreatic projection. This method is obsolete. According to studies, plain radiography detected pancreatic calcification or intraductal calculi in 30-40% of cases, especially when examined in an oblique projection. Formally, such a finding previously excluded the need for further testing to confirm the diagnosis of chronic pancreatitis [87]. At the same time, it should be remembered that pancreatic calcinosis is most common in alcoholic and hereditary CP, and rarely in idiopathic pancreatitis [38]. Moreover, calcification can also occur in pancreatic cancer, which, combined with low sensitivity, prevents this technique from being recommended as competitive and diagnostically valuable.

• For initial screening of patients with clinical symptoms characteristic of CP, to exclude other causes of abdominal pain, transabdominal ultrasound (comprehensive ultrasound examination of the abdominal organs) is recommended due to the non-invasive nature of the method, ease of performance, and sufficient specificity in determining the main manifestations of CP: increased pancreatic size, dilated pancreatic duct, wirsungolithiasis, parenchymal calcinosis, and post-necrotic cysts [58, 84, 85, 88].

Level of Consensus – CLevel of Evidence – 1Level of Consensus – C. Level of Evidence – 1

Comments: transabdominal ultrasound acts as a primary screening method for unexplained abdominal pain. This method allows detection of free fluid in the abdominal cavity, assessment of the liver, biliary tract, and kidneys, diseases of which can mimic or accompany CP, and in some cases – to rule out surgical or gynecological diseases.

Ultrasound has insufficiently high sensitivity in the diagnosis of CP – 67% (95% CI: 53%-78%), which is definitely insufficient for diagnosing CP. The specificity of ultrasound in the diagnosis of CP is 98% (95% CI: 89%-100%) [89]. The examination should include inspection of all abdominal organs, the retroperitoneal space, and the small pelvis. Characteristic ultrasound signs of CP detected in B-mode include increased parenchymal echogenicity, structural heterogeneity due to multiple hyperechoic strands (fibrosis areas), presence of parenchymal calcifications and calculi in the pancreatic ducts, main pancreatic duct diameter greater than 2 mm, and post-necrotic cysts. Diffuse changes in the pancreatic parenchyma and an increase in its size without the changes listed above do not allow confirming the presence of CP [90]. Transabdominal ultrasound can confirm the diagnosis of CP at a late stage, detect pancreatic calcification and intraductal calcium stones (if their size exceeds 5 mm), pseudocysts, dilation of the main pancreatic duct and its side branches, and pancreatic parenchymal atrophy [49, 91, 92].

• Patients with a confirmed diagnosis of an asymptomatic pancreatic pseudocyst are recommended dynamic transabdominal ultrasound (comprehensive ultrasound examination of the abdominal organs) as part of a watchful waiting management strategy in order to timely diagnose potential complications [49, 91, 93].

Level of Consensus – CLevel of Evidence – 5Level of Consensus – C. Level of Evidence – 5.

Comments: due to its high sensitivity to fluid collections, ultrasound is the method of choice for monitoring patients with pancreatic pseudocysts.

• If there are no signs of CP on transabdominal ultrasound, it is recommended to continue the diagnostic workup by performing other instrumental examinations: contrast-enhanced abdominal CT with intravenous bolus injection, and, as indicated, MRI (magnetic resonance cholangiopancreatography / magnetic resonance imaging of the pancreas / magnetic resonance imaging of the abdominal organs / contrast-enhanced magnetic resonance imaging of the abdominal organs) and/or endoscopic ultrasonography of the pancreatobiliary zone (EUS) [86].

Level of Consensus – CLevel of Evidence – 5Level of Consensus – C. Level of Evidence – 5.

Comments: today, it can be stated that transabdominal ultrasound is unable to detect early-stage CP [94], being significantly inferior to MRI, CT, and EUS in image quality, spatial and contrast resolution. Thus, a negative ultrasound result does not even rule out the presence of pancreatic calculi. In various clinical situations, MRI of varying scope may be performed.

Table 2. Pancreatic changes in CP according to imaging methods [95]

• Abdominal CT with intravenous bolus contrast enhancement (mandatorily including native, arterial, venous, and delayed phases as required by the pancreatic protocol, with data recorded on digital media) is the method of choice in the diagnosis of CP and is recommended for all patients to detect specific pancreatic changes. CT is recommended for all patients suffering from CP no later than 2 weeks after initial presentation [49, 86, 96, 97].

This recommendation is intended for Level 3 medical organizations.

Level of Consensus – CLevel of Evidence – 4Level of Consensus – C. Level of Evidence – 4.

Comments: Contrast-enhanced CT of the abdominal cavity with intravenous bolus injection is the method of choice for the initial diagnosis of chronic pancreatitis (CP). It significantly surpasses transabdominal ultrasound in diagnostic value and is more accessible in Russia today compared to other methods, such as EUS and secretin-enhanced magnetic resonance cholangiopancreatography (MRCP). To effectively utilize all capabilities of CT and reliably diagnose edema, necrosis, and pancreatic tumors, it is essential to perform the scan with intravenous bolus enhancement across all phases of the contrast study. The native phase is required to detect pancreatic calculi, the arterial phase to visualize pseudoaneurysms in the splenic and gastroduodenal artery basins, the venous phase for differential diagnosis with other pancreatic diseases (type II IPMN), and the delayed phase to determine the degree of fibrous changes in the pancreatic parenchyma.

Contrast-enhanced CT allows for the detection of areas of pancreatic necrosis (absence of contrast agent uptake). The sensitivity of this method in diagnosing CP is 75–90%, and its specificity is 85–90% [49]. In acute exacerbations of CP, contrast-enhanced CT can confirm the diagnosis, assess the severity of the exacerbation, and detect complications. The Cambridge classification of CP severity based on CT and ultrasound data is presented in Appendix A3 (Table 4) [88].

• Abdominal contrast-enhanced CT with intravenous bolus injection is recommended as the most effective method for determining the localization of calculi and intraductal pancreatic stones, as well as for the differential diagnosis between CP and pancreatic tumors larger than 5 mm in patients with CP. The absence of pancreatic changes on CT does not rule out early-stage CP, but this probability is significantly lower compared to transabdominal ultrasound [85, 88, 89].

GSI CLoE 1Grading of Recommendations Assessment, Development and Evaluation (GRADE) – C. Level of Evidence – 1.

Comments: CT findings indicative of CP include glandular atrophy, presence of ductal calculi, pancreatic duct dilatation, intra- or peripancreatic cysts, thickening of the peripancreatic fascia, and splenic vein thrombosis [98]. CT may reveal signs suggestive of probable CP: structural heterogeneity, blurred margins, and pancreatic enlargement [99].

• In patients with recurrent abdominal pain and negative CT findings, endoscopic ultrasonography of the pancreatobiliary zone (EUS) is recommended for the differential diagnosis of CP and other inflammatory or tumor diseases of the pancreas, as well as to obtain information on the state of the duodenum in the presence of its cystic-inflammatory transformation [100-103].

Level of Consensus – CLevel of Evidence – 4Level of Consensus – C. Level of Evidence – 4.

Comments: Endoscopic ultrasonography is the most sensitive method for detecting early-stage CP [100, 101]. EUS is a minimally invasive imaging technique that is also used for therapeutic purposes [91]. The severity of CP is assessed according to the 2007 Rosemont classification [100, 101]. The Rosemont criteria include: 6 parenchymal features reflecting the state of the organ parenchyma, which are divided into major (A, B) and minor (Appendix A3) criteria: hyperechoic foci with shadowing, honeycomb lobularity, non-honeycomb lobularity, hyperechoic foci without shadowing, hyperechoic strands, and cysts; and 5 ductal criteria, which are also divided into major A and minor features: presence of calculi, main pancreatic duct dilatation, side-branch dilation, main duct irregularity, and hyperechoic duct walls. There are 4 diagnostic categories of CP certainty: consistent, suggestive, indeterminate, and normal. The use of elastography and/or contrast enhancement during EUS can increase the method's sensitivity in detecting CP and differentiating it from tumors [104].

Differential diagnosis between inflammatory and malignant masses, as well as the early detection of malignancy in patients with diagnosed CP, remains a challenge for all imaging modalities; however, EUS with fine-needle aspiration biopsy is the method that provides the most accurate tissue characterization [105].

Under endoscopic ultrasound guidance, a diagnostic puncture biopsy (ultrasound-guided percutaneous pancreatic biopsy) can be performed for cytological (cytological examination of pancreatic tissue microparticles) and histological verification of ambiguous areas for the differential diagnosis of CP, autoimmune pancreatitis, and tumor involvement [100-102].

• EUS is recommended for patients with suspected or established CP as the most informative method for diagnosing early CP (minimal-change CP), especially when combined with secretin stimulation, contrast enhancement, and pancreatic elastography; however, this method requires high specialist expertise and a strictly standardized approach [101, 104, 106].

GSI CLoE 3Grading of Recommendations Assessment, Development and Evaluation (GRADE) – C. Level of Evidence – 3.

Comments: EUS and secretin-stimulated MRCP are the most reliable imaging modalities for detecting early parenchymal and ductal changes in CP, as well as ductal anomalies [91, 106].

• Endoscopic ultrasonography of the pancreatobiliary zone is recommended for patients with suspected obstructive etiology of pancreatitis (clinical or radiological signs of pancreatic or biliary hypertension, endoscopic signs of major duodenal papilla abnormalities) [101, 104, 105]. This recommendation is intended for level 3 healthcare facilities.

GSI CLoE 3Grading of Recommendations Assessment, Development and Evaluation (GRADE) – C. Level of Evidence – 3.

• In patients with intolerance to iodine-containing contrast agents, MRI (magnetic resonance cholangiopancreatography / magnetic resonance imaging of the pancreas / magnetic resonance imaging of the abdominal cavity, performed separately or in combination depending on the clinical situation) is recommended to detect CP and differentially diagnose the causes of biliary and pancreatic hypertension. MRI findings indicative of CP include focal or diffuse signal intensity changes on T1W and T2W images (including with fat suppression), decreased contrast enhancement in the arterial and venous phases on dynamic MRI, and increased contrast enhancement in the delayed phase due to fibrous tissue enhancement [107-110] (this statement applies to level 3 healthcare facilities).

GCR BLEL 2Grade of Recommendation – B. Level of Evidence – 2.

• In patients with chronic pancreatitis and a newly detected pancreatic cystic lesion, MRI/MRCP (magnetic resonance cholangiopancreatography / magnetic resonance imaging of the pancreas / magnetic resonance imaging of the abdominal cavity, performed separately or in combination depending on the clinical situation) is recommended for differential diagnosis [107-110] (this statement applies to level 3 healthcare facilities).

GCR BLEL 2Grade of Recommendation – B. Level of Evidence – 2.

Comments: MRI is preferred in patients with intolerance to iodine-containing contrast agents. MRI findings indicative of CP include decreased signal intensity on T1- and T2-weighted images with fat suppression and reduced contrast enhancement. Magnetic resonance cholangiopancreatography (MRCP) allows fluid-filled structures—the pancreatic duct and pseudocysts—to be identified with high accuracy. Fluid inside a pseudocyst serves as a natural contrast agent, making it detectable on both standard MRI and MRCP. On T2-weighted and T2-STIR sequences, cysts exhibit a homogeneous hyperintense MR signal with clear, smooth margins. MRI also distinguishes the hemorrhagic component of fluid, which appears as a hyperintense MR signal on T1-FFE-weighted images due to the significant paramagnetic effect of methemoglobin [103, 107-111].

• MRCP is the most informative method for the differential diagnosis of the causes of biliary and pancreatic hypertension and is recommended for patients with CP to characterize ductal alterations [112].

Level of Consensus – CLevel of Evidence – 5Level of Consensus – C. Level of Evidence – 5.

Comments: since side branches are visualized in only 10–25% of cases [103, 107–110], this type of imaging has limited diagnostic value in early-stage chronic pancreatitis (CP). A disadvantage of MRI is that in the presence of calcifications (typical for CP), this method cannot match the high specificity of CT. However, the presence of areas with very low signal intensity suggests calcified zones characteristic of the inflammatory process [109, 110, 113] and can be valuable for a small group of patients in whom other diagnostic methods fail to confirm the suspected diagnosis of CP.

• MRCP and secretin-stimulated endoscopic pancreaticobiliary scintigraphy (ESBS) are recommended as the best imaging methods for diagnosing parenchymal and ductal changes in patients with early-stage CP. Dynamic MRCP with a secretin test is recommended as the primary non-invasive method for identifying initial morphological changes in the pancreatic ductal system and fluid collections, as well as for assessing the exocrine pancreatic reserve [114, 115]. This recommendation is intended for level 3 medical organizations.

GCR BLEL 3Grade of Recommendations — B. Level of Evidence — 3

Comments: The combination of MRI and secretin-stimulated MRCP is the most accurate method for verifying minimal-change chronic pancreatitis. The use of contrast enhancement significantly increases the sensitivity of the method in the differential diagnosis of CP and pancreatic tumors. MRCP allows fluid-filled structures—the main pancreatic duct (MPD) and pseudocysts—to be identified with high precision [114, 115].

• MRCP and ESBS are recommended as the most accurate diagnostic methods for pancreatic developmental anomalies in patients with CP [114].

Level of Consensus – CLevel of Evidence – 5Level of Consensus – C. Level of Evidence – 5.

Comments: Secretin-enhanced MRCP has very high sensitivity [114] and can be valuable in a small group of patients with early-stage ductal changes in CP, precancerous conditions (PanIN, intraductal papillary mucinous neoplasm), and pancreatic adenocarcinoma.

• Endoscopic retrograde cholangiopancreatography (ERCP) is not recommended as a diagnostic method for CP due to the risk of serious complications (acute pancreatitis, cholangitis, sepsis, retroduodenal perforation). ERCP in patients with CP should be considered a component of therapeutic endoscopic intervention (e.g., MPD stenting during an exacerbation or external fistula), rather than solely a diagnostic tool [103, 111].

Level of Consensus – CLevel of Evidence – 5Level of Consensus – C. Level of Evidence – 5.

Comments: ERCP is an invasive procedure with a high risk of severe complications. It allows a detailed assessment of the pancreatic duct and its branches (irregular duct dilation – "chain of lakes") and pseudocysts, and reliably establishes the diagnosis of CP. It may be most valuable in the absence of ESBS or when MRCP results are equivocal. A disadvantage of the method is the inability to assess the state of the pancreatic parenchyma. However, this technique in chronic pancreatitis should not be performed solely for diagnostic purposes. Criteria for evaluating pancreatograms in CP by ERCP and MRCP are provided in Appendix A3, Table 3.

2.5 Other Procedures

• Serum IgG₄ testing is recommended for patients with suspected autoimmune pancreatitis and for differential diagnosis with pancreatic neoplasms [116–118]. This recommendation is intended for level 3 medical organizations.

GCR ALEL 1Grade of Recommendations — A. Level of Evidence — 1

Comments: meta-analysis data show high specificity and relatively low sensitivity of elevated IgG₄ and IgG levels in the diagnosis of autoimmune pancreatitis and the differential diagnosis of focal pancreatitis from pancreatic tumors. Clinically significant serum parameters for diagnosing AIP and differential diagnosis with pancreatic cancer include hypergammaglobulinemia (based on protein fraction electrophoresis analysis A09.05.014), elevated IgG levels (blood immunoglobulin G test A09.05.054.004), and elevated serum IgG₄ levels [116, 117]. Timely detection is important

• Nutritional status assessment using clinical and laboratory methods (total protein, albumin, white blood cell count, differential leukocyte count [to determine the absolute lymphocyte count], hemoglobin level, retinol-binding protein, vitamin B₁₂ [cyanocobalamin], folic acid, transferrin, total magnesium, and zinc concentrations) is recommended for all CP patients upon hospital admission and during outpatient visits to assess disease severity and predict the risk of complications and adverse outcomes [63].

Level of Consensus – CLevel of Evidence – 4Level of Consensus – C. Level of Evidence – 4.

Comments: the assessment is based on calculating the body mass index (BMI), noting weight loss and its severity, and identifying indirect signs of trophic insufficiency during general physical examination—signs of anemia, trophic skin disorders, signs of kwashiorkor, etc. [121, 122]. Criteria for the clinical assessment of nutritional status are given in Appendix A3.

Laboratory assessment of nutritional status is widely available and informative for most Russian clinics, even when using a combination of simple tests: determining total protein, albumin, peripheral blood absolute lymphocyte count, and hemoglobin level.

• For a detailed assessment of nutritional status in a patient with CP, it is recommended to determine the concentrations of retinol-binding protein, vitamin B₁₂ (cyanocobalamin), folic acid, transferrin, total magnesium, and zinc [63].

Level of Consensus – CLevel of Evidence – 4Level of Consensus – C. Level of Evidence – 4.

Since 90% or more of CP patients with various markers of trophic insufficiency are underweight [121], the practitioner must be aware that even CP patients with normal or high BMI frequently develop trophic insufficiency, and weight loss is the most significant potential risk marker for the development of trophic insufficiency.

Sarcopenia is a fairly common complication of CP, observed in approximately 2 out of 5 patients [123].

• Patients with CP are recommended to undergo a single bone mineral density assessment (by X-ray densitometry) for the early diagnosis of osteoporosis developing secondary to exocrine pancreatic insufficiency and vitamin D malabsorption [49, 91].

Level of Consensus – CLevel of Evidence – 5Level of Consensus – C. Level of Evidence – 5.

Comments: osteoporosis is a proven complication of CP resulting from pancreatogenic malabsorption, including in the absence of overt signs of exocrine pancreatic insufficiency [62].

• Patients with CP and exocrine pancreatic insufficiency who have persistent clinical symptoms despite ongoing therapy are recommended to undergo a carbohydrate-load hydrogen breath test to diagnose small intestinal bacterial overgrowth (SIBO) [124–127].

Level of Recommendations – CLevel of Evidence – 4Level of Recommendations – C (Level of Evidence – 4)

Comments: the principle of breath tests is to measure the amount of hydrogen and/or methane in exhaled air after a carbohydrate load. The human body cannot produce these metabolites; therefore, their presence in exhaled air is due to microbial fermentation of carbohydrates in the small and large intestines, followed by absorption into the bloodstream and, after passing through the liver, excretion by the lungs [128]. Unlike small bowel aspirate culture, the breath test is an inexpensive, non-invasive, simple, and widely available method for detecting SIBO. The sensitivity of the glucose breath test ranges from 20 to 93%, and specificity from 30 to 86%, compared to the culture method. For the lactulose breath test, these figures are 31–68% and 44–100%, respectively [129].

3. Treatment, including drug and non-drug therapies, diet therapy, and pain management

3.1 Diet therapy

• All patients with CP are recommended to completely abstain from alcohol to reduce the frequency of severe complications and mortality [11, 53, 91, 130–133].

Level of Consensus – CLevel of Evidence – 4Level of Consensus – C. Level of Evidence – 4.

Comments: under abstinence, a reduction in symptom severity and pain relief have been noted in some cases, whereas continued alcohol consumption promotes disease progression [11, 53, 91, 130–133]. Exocrine pancreatic insufficiency generally does not progress with alcohol cessation [130]. Individuals who do not consume alcohol show a better response to pain-relief therapy [44, 71, 130, 131, 134–136]. Nevertheless, alcohol cessation does not always halt disease progression. To achieve cessation, addiction psychiatrists specializing in alcohol dependence should be involved, followed by psychological follow-up [49].

• All patients with CP are recommended to quit smoking in order to reduce/relieve pain and prevent the development of CP complications [136, 137].

Level of Recommendation – CLevel of Evidence – 4Level of recommendation validity – C. Level of evidence reliability – 4.

Comments: regardless of the clinical course features of chronic pancreatitis, patients are advised to quit smoking as a significant and independent risk factor for the development of chronic pancreatitis [136, 137]. In general, it is very difficult to isolate the independent role of smoking as an etiological factor and a factor influencing the course of chronic pancreatitis when alcohol abuse is present, since smoking and alcohol abuse frequently coexist [11, 133, 138].

• Patients with chronic pancreatitis are recommended frequent small meals with a high protein and carbohydrate content to improve nutrient absorption and correct nutrient deficiencies. The degree of fat restriction depends on the severity of malabsorption and the efficacy of enzyme replacement therapy [139].

Level of Consensus – CLevel of Evidence – 5Level of Consensus – C. Level of Evidence – 5.

Comments: frequent small meals are recommended: in small portions 5–6 times a day depending on the severity of the disease [139]. A high protein and carbohydrate content in the diet is preferred, provided it does not exacerbate pain and dyspeptic symptoms. The degree of fat restriction in exocrine pancreatic insufficiency depends on the severity of steatorrhea; in most cases, fats are not restricted, especially unrefined vegetable fats.

• In patients with severe exocrine pancreatic insufficiency who continue to experience severe, highly distressing steatorrhea leading to social maladaptation despite adequate replacement therapy, a diet containing less than 40–60 g of fat per day is recommended [121, 122, 140].

Level of Consensus – CLevel of Evidence – 5Level of Consensus – C. Level of Evidence – 5.

Comments: protein-energy malnutrition is common in patients with chronic pancreatitis and is multifactorial in origin, resulting from dietary intake restriction, malabsorption, diabetes mellitus, intestinal motility disorders, and concurrent chronic alcoholism [121, 122, 140]. Interventional studies investigating fat restriction in patients with pancreatic insufficiency have not been conducted. General guidelines for patients with severe exocrine pancreatic insufficiency include a daily diet with an energy value of 2500–3000 kcal and a protein intake of 1.0–1.5 g/kg/day [140]. Relief of steatorrhea should be achieved not by restricting fat intake (which is necessary for normal absorption of vitamins A, D, E, and K), but by prescribing adequate doses of enzyme replacement therapy.

Complex carbohydrates and dietary fibers can be beneficial in slowing the progression of DM and preventing small intestinal bacterial overgrowth syndrome. The intake of dietary fibers is often restricted in patients with CP based on the belief that fibers adsorb digestive enzymes in experiments, thereby affecting their action [141]. However, this notion is based on indirect data (e.g., triolein breath tests, the results of which can be influenced by delayed gastric emptying caused by fibers) [142].

• In patients with decompensated exocrine pancreatic insufficiency and/or a long-standing history of CP (more than 5 years), it is recommended to screen for (A, D, E, and K) vitamin deficiencies, and parenteral administration is indicated if necessary [91].

Level of Consensus – CLevel of Evidence – 5Level of Consensus – C. Level of Evidence – 5.

Comments: patients with CP may experience impaired absorption of vitamins (A, D, E, and K), which is accompanied by a decrease in their serum concentrations [143]. At the same time, clinical manifestations of hypovitaminosis are rare [62, 144]. Patients with CP may develop vitamin B₁₂ deficiency due to impaired cleavage of the vitamin B₁₂-haptocorrin complex (Castle's factor) by pancreatic proteases. Patients who abuse alcohol are also at risk of developing thiamine (vitamin B₁), riboflavin (vitamin B₂), and pyridoxine (vitamin B₆) deficiencies. If a deficiency in serum vitamin levels is detected, replacement vitamin therapy should be administered [63-65].

3.2 Conservative treatment

Conservative treatment of patients with CP aims to relieve symptoms and prevent the development of complications. There are 6 main objectives of conservative therapy for CP [49]:

1. cessation of alcohol consumption and smoking cessation, regardless of the presumed etiology of the disease, daily alcohol doses and the number of cigarettes smoked per day, duration of alcohol consumption and tobacco smoking;

2. determining the cause of abdominal pain and attempting to reduce its intensity;

3. treatment of exocrine pancreatic insufficiency;

4. identification and treatment of endocrine insufficiency in early stages before the development of complications;

5. nutritional support;

6. screening for pancreatic adenocarcinoma, especially in hereditary (familial) pancreatitis, a positive family history of pancreatic cancer, a long-term history of proven chronic pancreatitis, and age over 60 years.

Relief of abdominal pain

• For patients with chronic pancreatitis experiencing intense pain syndrome, it is recommended to prescribe analgesics periodically or in courses via an available route of administration (e.g., paracetamol**), or non-steroidal anti-inflammatory and antirheumatic drugs (M01A). If ineffective, tramadol** should be preferred. The duration of continuous analgesic therapy should not exceed 3 months (with monitoring of the patient's condition, blood biochemical parameters, primarily alanine aminotransferase, aspartate aminotransferase, and gamma-glutamyl transferase activity in the blood), after which a reassessment of therapeutic and/or diagnostic tactics is required [145].

LE RGoE 5Level of Evidence – C. Grade of Recommendation – 5.

Comments: Paracetamol** is prescribed orally at 1000 mg × 3 times/day, tramadol** – orally at 400 mg/day. Within 3 months, the pain should stop or become significantly less frequent, making it possible to take analgesics on demand (Algorithm 3). If there is postprandial exacerbation of pain, analgesics should be taken 30 minutes before meals to minimize postprandial pain amplification [49, 91]. If the patient's pain is not related to food intake, analgesics should be taken after meals to reduce the risk of gastric mucosal damage.

• To reduce manifestations of concomitant depression, lessen pain severity, and potentiate the effect of analgesics, it is recommended to prescribe antidepressants—non-selective monoamine reuptake inhibitors [49].

Level of Consensus – CLevel of Evidence – 5Level of Consensus – C. Level of Evidence – 5.

Comments: these drugs can alter the sensitivity of the central nervous tissue and visceral nerves, which is hypothesized to play a role in the development of pain in chronic pancreatitis. Antidepressants—non-selective monoamine reuptake inhibitors—have a wide profile of adverse events due to potential cardiotoxicity and anticholinergic effects. Since the analgesic effects of antidepressants are class-specific, selective serotonin reuptake inhibitors can be considered as an alternative [49], although there are currently no randomized controlled trials demonstrating their efficacy.

• To relieve refractory pancreatic pain in patients with chronic pancreatitis, pregabalin** is recommended, which is also used in the treatment of neuropathic pain [146, 147].

GCR BLEL 2Grade of Recommendation – B. Level of Evidence – 2.

Comments: the drug has analgesic and anxiolytic effects, which can be an additional positive effect for some patients [146, 147].

• Enzyme replacement therapy is not recommended for the relief of pancreatic pain, but may be important in reducing symptoms of abdominal discomfort associated with exocrine pancreatic insufficiency [148-150].

GGR BLE 1Grade of Recommendations — B. Level of Evidence — 1.

Comments: data from meta-analyses of randomized clinical trials have not revealed a positive effect of enzyme replacement therapy in the treatment of pancreatic pain.

• In case of ineffectiveness of conservative therapy (abdominal pain for 3 months) or the need for opioid analgesics for 2 weeks (due to the high risk of dependence), as well as when suspecting the development of chronic pancreatitis complications, consultation with a surgeon and an endoscopist is recommended to evaluate the likelihood of pain relief using endoscopic or surgical treatment methods [281].

Level of Evidence CGrade of Recommendation 5Level of Recommendation – C. Level of Evidence – 5.

Treatment of exocrine and endocrine pancreatic insufficiency

Clinically significant impairment of fat and protein digestion occurs only when pancreatic functional activity decreases by more than 90% [46]. Surgical intervention (resection) on the pancreas may also cause the development and/or aggravation of exocrine pancreatic insufficiency [152, 153] and necessitate lifelong enzyme replacement therapy. Adequate and timely treatment helps prevent serious complications and reduces mortality associated with malnutrition.

Enzyme replacement therapy. The goal of replacement therapy is to enable the patient to ingest, digest, and absorb normal amounts of essential nutrients and micronutrients. Clinical indications for enzyme replacement therapy in chronic pancreatitis (CP):

• verified steatorrhea;

• chronic diarrhea, polyfecalia;

• nutritional deficiency;

• history of pancreatic necrosis, severe CP (pancreatic parenchyma calcification or intraductal calcifications combined with main pancreatic duct dilation) [154];

• history of pancreatic surgery disrupting normal food passage (classical pancreaticoduodenectomy, lateral pancreaticojejunostomy with a Roux-en-Y limb);

• status post any pancreatic surgery with signs of exocrine insufficiency.

• Enzyme replacement therapy is recommended for patients with CP and exocrine pancreatic insufficiency, as it improves fat digestion and absorption [91, 155, 156].

GPP ALoE 1Grading of Recommendations Assessment, Development, and Evaluation (GRADE) level – A. Level of Evidence – 1.

Comments: patients with clinically apparent steatorrhea (unformed, greasy, foul-smelling voluminous stools) are recommended to receive enzyme replacement therapy based on clinical findings [91, 155].

• All patients with CP and clinical or biochemical signs of trophic deficiency, including those without overt steatorrhea [80, 152], are recommended to receive enzyme replacement therapy to normalize nutritional status (levels of vitamins (A, D, E, and K), prealbumin, and ferritin), as well as to prevent osteoporosis caused by vitamin D malabsorption [62, 144].

Level of Evidence CGrade of Recommendation 5Level of Recommendation – C. Level of Evidence – 5.

Comments: to monitor treatment efficacy in international practice, laboratory methods for assessing fat digestion are used: quantitative fecal fat stool test (in clinical trials), ¹³C-mixed triglyceride breath tests (in research and routine practice) [80]. Both methods are currently unavailable in Russia. At the same time, using BMI and laboratory markers of trophic status (serum retinol-binding protein, vitamin B₁₂, transferrin, total magnesium, zinc, and absolute lymphocyte count) is equally effective and more accessible [121, 122, 157, 158].

• Enzyme replacement therapy is recommended to improve the quality of life in patients with CP [159–162].

GCR BLEL 2Grade of Recommendation – B. Level of Evidence – 2.

Comments: a reliable correlation has been established between improved quality of life scores, weight gain, and a reduction in fecal fat excretion [159–162].

• All patients with CP undergoing enzyme replacement therapy are recommended to take pancreatin** during or immediately after meals [156, 163, 164].

GPP BLoE 1Grading of Recommendations Assessment, Development, and Evaluation (GRADE) level – B. Level of Evidence – 1

Comments: clinical studies have demonstrated the superiority of taking pancreatin preparations** immediately after or during meals compared to taking them before or between meals.

• Patients with CP for the treatment of malabsorption due to exocrine pancreatic insufficiency are recommended to use encapsulated enteric-coated microparticulate pancreatin** (minimicrospheres, microtablets, etc.) [149, 160, 165, 166].

LoR BGoE 2Level of recommendation validity – B. Level of evidence reliability – 2.

Comments: enteric-coated microparticles are significantly more effective than tablet formulations in treating steatorrhea due to improved pharmacokinetics, which ensures a higher probability of enzyme contact with chyme and a larger contact surface area [167].

• In patients with clinical symptoms of exocrine pancreatic insufficiency, the recommended minimum initial dose of encapsulated pancreatin** is 40–50 thousand units per main meal (3 times a day) and a half-dose (20–25 thousand units) for snacks (total frequency at least 5 times a day) [149, 156, 164, 168].

GPP ALoE 1Grading of Recommendations Assessment, Development, and Evaluation (GRADE) level – A. Level of Evidence – 1.

Comments: prescribing an average of 40–50 thousand units per main meal and 20–25 thousand units per snack leads to the normalization of fat absorption, significant weight gain, and normalization of retinol-binding protein and prealbumin levels in the majority of patients with CP [49, 80, 91].

• All patients with CP receiving enzyme replacement therapy are recommended to have their initial treatment efficacy assessed by weight gain and symptom reduction 6 months after starting therapy (outpatient stage); however, any doubt regarding the efficacy of replacement therapy should be regarded as an indication for laboratory and instrumental monitoring of enzyme replacement therapy [169, 170].

Level of Consensus – CLevel of Evidence – 5Level of Consensus – C. Level of Evidence – 5.

Comments: clinical parameters such as resolution of diarrhea and normalization of dyspeptic symptoms are often used as criteria for assessing the efficacy of enzyme replacement therapy [91]. At the same time, stool normalization occurs in many patients at enzyme doses that are insufficient to normalize fat digestion.

• In cases of insufficient efficacy of initial doses of enteric-coated enzyme preparations, an increase in the dose of pancreatin** is recommended. If maldigestion symptoms persist despite high doses of the drug (400–500 thousand units/day), the administration of gastric acid suppression therapy – proton pump inhibitors (PPIs) in standard doses – is recommended [152, 156, 171–173].

GPP ALoE 1Grading of Recommendations Assessment, Development, and Evaluation (GRADE) level – A. Level of Evidence – 1.

Comments: patients with persistent symptoms despite taking initial doses of modern enteric-coated digestive enzyme preparations (40–50 thousand units per main meal and 20–25 thousand units per snack) should have their doses of pancreatin** minimicrospheres or microtablets doubled (higher doses may also be prescribed) or be prescribed gastric acid-suppressing drugs [167] to improve fat emulsification [152, 171, 172]. PPIs in standard doses are the preferred agents (e.g., #omeprazole** 20 mg twice daily). There are a few small studies demonstrating the efficacy of this approach in patients with severe pancreatic insufficiency [172, 174, 175].

• In the presence of persistent steatorrhea despite adequate enzyme replacement therapy in patients with CP, it is recommended to rule out other causes of diarrhea, particularly those associated with small intestinal bacterial overgrowth (SIBO), which is common in CP [176], protozoan infections, and celiac disease.

Level of Consensus – CLevel of Evidence – 4Level of Consensus – C. Level of Evidence – 4.

• In patients with severe pancreatic insufficiency following acute necrotizing pancreatitis, in the presence of calcifying pancreatitis, or in patients with significantly reduced fecal elastase-1 levels (less than 200 mcg/g), lifelong enzyme replacement therapy with encapsulated pancreatin** preparations at an adjusted dose is recommended [91, 154].

Level of Consensus – CLevel of Evidence – 5Level of Consensus – C. Level of Evidence – 5.

Comments: in confirmed CP with signs of nutritional deficiency (weight loss, muscle wasting, osteoporosis, signs of hypovitaminosis), the prescription of enzyme replacement therapy may be indicated even without verified steatorrhea [91, 154].

• When treating patients with diabetes mellitus secondary to CP, it is recommended to monitor blood glucose levels to prevent complications, avoiding hypoglycemia and ketoacidosis [49, 83].

Level of Consensus – CLevel of Evidence – 5Level of Consensus – C. Level of Evidence – 5.

Comments: when diabetes develops as an outcome of severe pancreatic parenchymal fibrosis, oral hypoglycemic agents play no significant role [49, 83]. The majority of patients with pancreatogenic diabetes mellitus and unresponsiveness to appropriate diet require insulin therapy [50]. The diet for pancreatogenic diabetes mellitus is similar to that for type 1 diabetes mellitus, except for the need to correct malabsorption, vitamin, and micronutrient deficiencies; prescribing frequent small meals helps prevent hypoglycemia [91].

Comments: empirical antibiotic therapy in patients with suspected SIBO without a confirmed diagnosis is not justified, as it exposes them to an unjustified risk of antibiotic resistance, antibiotic-associated diarrhea, and Clostridiodes difficile-associated disease [177]. Nevertheless, antibacterial therapy is the preferred strategy for eradicating small intestinal bacterial overgrowth. Treatment efficacy is determined by the clinical picture. The most effective antibacterial drugs for eradicating small intestinal bacterial overgrowth include rifaximin, ciprofloxacin** (bacterial GI infections), metronidazole** (infections caused by Bacteroides spp. (including B. fragilis, B. distasonis, B. ovatus, B. thetaiotaomicron, B. vulgatus)), and norfloxacin (for GI infections) [66].

Comments: probiotics are live microorganisms that confer a health benefit on the host when administered in adequate amounts. The efficacy of probiotics depends on the constituent bacterial strains [180]. According to a recent Cochrane review with a meta-analysis of 31 RCTs, probiotic administration also reduces the risk of C. difficile-associated diarrhea by 60% compared to placebo or no probiotic support (OR=0.40; 95% CI 0.30-0.52) [178].

Treatment of autoimmune pancreatitis (AIP)

• In the presence of clinical symptoms, all patients with autoimmune pancreatitis are recommended to receive immunosuppressive therapy (e.g., glucocorticoids H02AB, antineoplastic agents, and immunomodulators). In the absence of complaints, persistent abnormalities in blood biochemical parameters (elevated liver or pancreatic enzymes, markers of cholestasis) are also indications for initiating active therapy [120, 181, 182].

Level of Evidence CGrade of Recommendation 5Level of Recommendation – C. Level of Evidence – 5.

Comments: systemic immunosuppressive therapy is indicated for patients with symptoms of AIP (pancreatic pain, obstructive jaundice), or with a focal pancreatic mass on instrumental studies for differential diagnosis from cancer, or with cholestasis in cases associated with IgG4-related sclerosing cholangitis. The administration of treatment to completely asymptomatic patients remains controversial. Spontaneous remission according to clinical studies is possible in 10-25% of cases [183-185].

To induce AIP remission, oral glucocorticoids (#prednisolone**) are recommended at a dose of 0.6-1.0 mg/kg/day for 2-4 weeks, followed by a gradual dose reduction of 5 mg every 2 weeks over 3-6 months. Second-line therapy (in case of contraindications to corticosteroids or steroid resistance) is #rituximab**. The total duration of induction therapy should be at least 12 weeks.

During systemic corticosteroid therapy, remission was achieved in 96% of patients with type 1 AIP and 92% with type 2 AIP.

In addition to glucocorticoids, #rituximab** (mouse/human chimeric monoclonal antibodies specific to the CD20 antigen of B lymphocytes) is the only drug that induces AIP remission.

#Rituximab** is prescribed at a dose of 375 mg/m² weekly for 4 weeks followed by maintenance infusions every 2-3 months (oncohematology protocol), or 1000 mg twice with a 15-day interval every 6 months (immunology/rheumatoid arthritis protocol) [119, 120, 181, 186-188].

Comments: the remission induction stage is defined as meeting each of the following criteria after 6 months of treatment: (1) ≥50% reduction in IgG₄ levels; (2) reduction of the glucocorticoid dose to a maintenance dose of ≤10 mg/day; and (3) absence of relapse during systemic corticosteroid tapering over 6 months [182, 189].

• Due to the high recurrence rate, especially in type 1 AIP, it is recommended to prescribe maintenance therapy with low doses of glucocorticosteroids (equivalent to 2.5-7.5 mg of oral #prednisolone** daily) or immunosuppressants (#azathioprine**, #mercaptopurine**, #methotrexate**, #mycophenolate mofetil**), or #rituximab**. Thiopurines (#azathioprine**) and #mycophenolate mofetil** are prescribed concurrently with ongoing glucocorticoid therapy for 6-8 weeks, followed by continuation of immunosuppressant monotherapy [119, 120, 181, 182, 190, 191].

Level of Evidence CGrade of Recommendation 5Level of Recommendation – C. Level of Evidence – 5.

Comments: maintenance therapy in the high-risk AIP relapse group is recommended for a duration of 12 months to 3 years. Factors indicating a high risk of AIP relapse after treatment include: type 1 AIP compared to type 2 AIP, high pretreatment serum IgG₄ levels (4 times the upper limit of normal or higher), high serum IgG₄ levels during systemic corticosteroid therapy, association with IgG₄-related sclerosing cholangitis, diffuse enlargement of the pancreas, and multi-organ involvement [188, 191-193]. #Rituximab** is administered (375 mg/m² of body surface area) once weekly for 4 weeks, and then every 2-3 months, or as two infusions of 1000 mg with a 15-day interval every 6 months [1, 2]. #Azathioprine** is recommended at doses of 2-2.5 mg/kg/day orally [3]. To prevent relapse, #azathioprine** can be used in combination with glucocorticoids (#prednisolone** 5-7.5 mg/kg/day) [4]. When prescribing long-term maintenance therapy with thiopurines, it must be remembered that these drugs increase the risk of lymphoproliferative disorders by more than 5-fold (2.01-13.9), especially in men older than 65 years [5]. Therapy with #mycophenolate mofetil** should be initiated at a dose of 1 g/day, which can be increased to 1.5-2 g/day, while closely monitoring complete blood count parameters [6]. As with #azathioprine**, many patients on low doses of #mycophenolate mofetil** (1 g/day) experience a relapse. #Methotrexate** is prescribed after the induction course of glucocorticoid therapy at an initial dose of 10 mg/week, then increased to 20 mg/week [7, 8].

3.3 Surgical Treatment

Surgical treatment: indications and methods

In complicated disease courses, endoscopic or surgical treatment is indicated [91]. The decision to perform an intervention should be made in a center specializing in conservative and surgical treatment of pancreatic diseases.

Complications of chronic pancreatitis include: 1) persistent pain syndrome refractory to medical therapy; 2) pancreatic duct hypertension due to pancreatolithiasis or pancreatic duct strictures; 3) symptomatic post-necrotic pancreatic cysts; 4) obstructive jaundice caused by compression of the terminal common bile duct; 5) portal hypertension due to compression of the splenoportal confluence or splenic vein thrombosis; 6) persistent impairment of food passage through the duodenum; 7) pseudoaneurysm of the celiac trunk and superior mesenteric artery basins [170, 194-198]. Against the background of these complications, pancreatogenic ascites and/or pleural effusion may occur; in patients operated on for pancreatitis or who suffered pancreatic trauma, pancreatic fistulas requiring surgical treatment may develop [199-202]. An absolute indication for surgical treatment is the inability to rule out pancreatic cancer.

In the treatment of symptomatic pseudocysts, surgical and endoscopic methods, as well as EUS-guided transluminal stenting, are effective [53]. Surgical treatment of pseudocysts may involve a Roux-en-Y jejunal loop anastomosis, as well as lateral pancreaticojejunostomy in case of concomitant pancreatic duct dilation greater than 5-7 mm [203].

Recurrent jaundice or clinical signs of cholangitis are indications for endoscopic stent placement, which is a safe and effective procedure (with a complication rate of 4 to 7%) [204]. Although jaundice resolves shortly after stent implantation, complete resolution of the bile duct stricture is achieved in only a small fraction of patients, particularly in calcifying pancreatitis. Better results are achieved with staged placement of multiple stents [100].

In case of duodenal lumen stenosis, treatment should begin with conservative anti-inflammatory therapy. If there is no effect and evacuation disorders persist, or other complications of chronic pancreatitis are present, pancreatoduodenal resection is indicated [205].

RCTs comparing the efficacy of surgical and endoscopic biliary drainage in chronic pancreatitis have not been conducted.

Thus, in the absence of data suggesting pancreatic cancer, surgery should be the treatment of choice for biliary strictures with clinical manifestations of jaundice lasting for more than one month. The optimal procedure has not yet been established. Various operations are performed, ranging from biliary bypass (choledocho- or hepatojejunostomy) to pancreatoduodenal resection. If an inflammatory mass is present and/or cancer is suspected, resection of the pancreatic head should be performed in all cases [91].

In the uncomplicated course of the disease, invasive interventions are aimed at correcting morphological changes in the pancreatic duct system (strictures, calculi), inflammatory changes in the parenchyma, or performing neurolysis.

Pain relief. Prospective RCTs comparing the efficacy of conservative and surgical pain management in chronic pancreatitis have not been conducted. Studies evaluating pain dynamics after surgical treatment have noted high variability in the effect (from 47% to 80% of patients) [44, 132].

• In patients with verified chronic pancreatitis, it is recommended to address the issue of surgical intervention in the following conditions: - severe refractory abdominal pain leading to a decrease or loss of working capacity; - lack of response to conservative treatment for 3 months; - risk of developing dependence on analgesics and/or psychotropic drugs; - occurrence of chronic pancreatitis complications requiring invasive management (bleeding, duodenal obstruction, symptomatic pseudocysts, etc.); - suspected pancreatic cancer [135, 206-213].

Level of Evidence – 1. Grade of Recommendation – A.

Comments: in seven randomized trials and meta-analyses [135, 206, 209-213], a total of 302 patients showed a significant reduction in pain after pancreatic resection [207, 208]. In patients with asymptomatic chronic pancreatitis and duct dilatation (>7 mm), surgical decompression of the pancreatic duct is not mandatory, but it may be performed to prevent the progression of exocrine and endocrine insufficiency [91]. If cancer cannot be ruled out, resection is indicated to obtain material for histological examination. Untimely diagnosis of pancreatic cancer significantly worsens the prognosis [214].

• Surgical treatment for patients with chronic pancreatitis is recommended when sequential conservative management fails for 3 months (strict diet adherence, therapy with encapsulated pancreatin**, vitamins, analgesics including tramadol**, antidepressants, pregabalin**), along with a significant decrease in quality of life and impaired working capacity [49].

Level of Evidence – 5, Grade of Recommendation – C.

Comments: the decision to perform an intervention must be carefully weighed, taking into account the risk assessment of early and long-term complications. Other causes of upper gastrointestinal pain must be ruled out.

Endoscopic treatment

• Endoscopic treatment is not recommended for patients with asymptomatic dilatation of the pancreatic duct [91].

Level of Consensus – CLevel of Evidence – 5Level of Consensus – C. Level of Evidence – 5.

Comments: there are no studies evaluating the effect of endoscopic treatments on the endocrine and exocrine function of the pancreas in such patients [91].

• Endoscopic treatment is recommended in patients with pain and pancreatic duct dilatation to relieve pain [215, 216].

GPP CLoE 4Level of Recommendations — C. Level of Evidence — 4.

Comments: prospective studies demonstrate the efficacy of endoscopic treatment in patients with pain and pancreatic duct dilatation [215, 216].

Endoscopic pancreatic duct stenting

• Lithoextraction and mechanical lithotripsy are recommended for solitary pancreatic duct stones (virsungoliths) with a diameter of no more than 5 mm located in the pancreatic duct at the level of the head of the organ [84, 215, 216].

Level of Evidence – 4, Grade of Recommendation – C.

Comments: extracorporeal shock wave lithotripsy (in the presence of radiopaque calculi in the main pancreatic duct) is used for virsungolith fragmentation, potentially followed by ERCP, endoscopic pancreatic sphincterotomy and lithoextraction, or contact lithotripsy (mechanical, laser, or electrohydraulic) [84, 111, 217-221].

• Endoscopic pancreatic duct stenting (EPDS) using non-absorbable plastic pancreatic stents is recommended for patients with a dominant stricture and pre-stenotic duct dilatation of at least 6 mm. It is recommended to place one or several 7 Fr, 8.5 Fr, or 10 Fr stents with replacement at intervals of 2 to 5 months, depending on the diameter and number of stents, maintaining the final total diameter for a period of at least 1 year. Prior to stenting, endoscopic pancreatic sphincterotomy, mechanical and/or balloon dilatation of the stricture are recommended. The presence of multiple strictures is a contraindication to duct stenting [84, 111, 217, 222].

Level of Evidence CGrade of Recommendation 5Level of Recommendation – C. Level of Evidence – 5.

Comments: pancreatic duct stenting is advisable in the presence of significant strictures—an increase in duct diameter to more than 6 mm distal to the stricture. The presence of multiple strictures and multiple pancreatolithiasis is a contraindication to pancreatic duct stenting. Successful stenting requires pancreatic sphincterotomy and stricture dilatation, removal of stones, and treatment of pancreatic duct strictures. Stenting is performed using non-absorbable plastic pancreatic stents with a diameter of 7, 8.5, 10 Fr, the length and shape of which are selected individually. Occlusion of plastic pancreatic stents occurs after 2-5 months depending on their diameter and number, which necessitates their replacement [217, 223, 224]. Complications of pancreatic duct stenting (acute exacerbation of pancreatitis, proximal or distal stent migration, pancreatic abscess) are observed in 6-39% of cases [84, 111].

In case of pain recurrence, repeat endoscopic procedures have high efficacy [225]. Endoscopic drainage can be offered as the method of choice in patients with minor pancreatic parenchymal changes and the absence of multiple complications of chronic pancreatitis, as well as in patients with contraindications to surgery or those refusing it, and it can also serve as a preliminary stage to evaluate the efficacy of planned surgical treatment [210].

In patients with frequent pain attacks, sphincterotomy can be performed to improve pancreatic juice outflow. However, data on the efficacy of this method for treating pain in patients without duct dilatation and obstruction are lacking.

Currently, there are two strategies for pancreatic duct stenting:

• stent removal after 6-12 months regardless of the resolution of the pancreatic duct stricture;

• subsequent stent replacements until the stricture disappears.

Pain relief within 12 months after stenting is observed in 2/3 of patients, but complete resolution of strictures is noted in only a small proportion of patients [225]. A promising approach is precise measurement of the distal pancreatic duct stricture with phased placement of stents of increasing diameter (size increase of 2-4 units every 6 months). Following the final removal of a stent placed according to this technique, stricture resolution was observed in 95% of cases [226]. At the same time, such aggressive endoscopic treatment with sequential placement of multiple plastic pancreatic stents can lead to stricture resolution in 44-90% of cases, followed by a recurrence-free course within 13-48 months after pancreatic stent removal.

• If endoscopic pancreatic duct stenting fails or severe abdominal pain recurs, surgical treatment is recommended for patients [91, 100, 227, 228]. Evaluation of long-term outcomes among patients receiving endoscopic and surgical treatment has shown that resection procedures provide superior outcomes [229-231].

Level of Evidence – 4, Grade of Recommendation – C.

Comments: treatment of asymptomatic and uncomplicated pseudocysts is not indicated, regardless of their size [52]. Endoscopic drainage may be preferable to surgery because it has a better risk-benefit profile, being a less invasive method that provides drainage of equivalent efficacy [91].

Endoscopic treatment of external and internal pancreatic fistulas

• Endoscopic pancreatic duct drainage for pancreatic fistulas is recommended for patients with a duct defect confirmed by fistulography and MRCP in order to bridge the area of duct injury with a stent [223, 232].

GPP CLoE 4Level of Recommendations — C. Level of Evidence — 4.

Comments: external pancreatic fistulas generally occur after external drainage of post-necrotic pancreatic pseudocysts, and less commonly after pancreatic surgery. One of the rare complications of chronic pancreatitis is internal pancreatic fistulas opening into the abdominal and occasionally thoracic cavity. Stenting (drainage) with coverage of the duct injury site should be pursued. Placing a stent or silicone drain for nasopancreatic drainage proximal to the defect, as well as isolated wirsungotomy, are also possible but less effective. The recommended stenting period in the absence of a stenosing intraductal component (strictures) is at least 6 weeks [233].

Drainage procedures for post-necrotic/parapancreatic pancreatic cysts

Indications for the drainage of a post-necrotic cyst include a size greater than 5 cm, abscess formation, pain, impaired bile or gastric outflow, portal hypertension, and perforation of the post-necrotic cyst into the abdominal cavity. Asymptomatic post-necrotic cysts less than 5 cm in diameter with an unformed capsule and no communication with the pancreatic duct tend to resolve spontaneously, and therefore patients should be managed conservatively with active surveillance [232, 234, 235]. Elimination of cysts can be achieved via endoscopic internal drainage into the lumen of the duodenum or stomach, as well as by an "open" surgical approach.

• External drainage of a post-necrotic cyst (external drainage of pancreatic pseudocysts) is recommended only in cases of abscess formation, absence of a formed capsule, or when a more complex intervention is unfeasible due to the patient's critical condition or technical reasons [232, 234, 235].

Level of Evidence CGrade of Recommendation 5Level of Recommendation – C. Level of Evidence – 5.

Comments: ultrasound-guided external drainage is a forced measure and is indicated only for abscess formation, rupture of the cyst into the abdominal cavity, or an extremely grave condition of the patient. The outcome of external drainage of a post-necrotic cyst is typically the formation of an external pancreatic fistula, which frequently requires subsequent surgical treatment [85]. The surgical management strategy is determined by the severity of the cyst wall, the presence or absence of sequestra and infection within the cyst lumen, technical equipment availability, and the skill level of the surgical team.

• Endoscopic internal drainage of a post-necrotic pancreatic cyst is recommended for cyst sizes greater than 5 cm with no tendency to regress within 6 weeks of onset, a cyst wall thickness greater than 5 mm, absence of large sequestra in the lumen, and close apposition of the cyst cavity to the gastric or duodenal wall [234, 235].

GPP CLoE 4Level of Recommendations — C. Level of Evidence — 4.

Comments: endoluminal approach under endoscopic ultrasound guidance is recommended, as it allows for selecting a safe puncture path. Fully covered self-expanding nitinol stents (Polymer-metal biliary stent*** covered) with internal fixation elements to prevent stent migration should be used for drainage. Alternatively, at least 2 plastic biliary stents with bilateral "double-pigtail" anchors (Non-absorbable polymeric biliary stent) can be used. Stents should not be removed until instrumental confirmation of cyst wall collapse and no earlier than 1–2 months after implantation. This method achieves success in 92% of cases. However, short-term outcomes are superior to long-term ones: recurrence occurs in 8.5–23% and complications in 14.4% [217, 232].

Transpapillary access with cystoduodenal stenting is used for small (up to 5 cm) fluid collections communicating with the pancreatic duct at the level of the head [217, 232].

• Open cystopancreatojejunostomy (creation of a pancreato(cysto)jejunostomy) or via mini-access is recommended for large post-necrotic cysts of any localization with a well-formed capsule and large sequestra [236, 237].

GOM ALOE 1Grade of Recommendation – A. Level of Evidence – 1.

Comments: cystopancreatojejunostomy ensures recovery in 90–100% of cases in the absence of fibrotic changes in the pancreatic parenchyma proximal to the post-necrotic cyst. Postoperative complications occur in 20% of cases [235, 236]. Minimally invasive approaches should be preferred. Anastomosis of the cyst should be performed with a Roux-en-Y jejunal limb at least 70 cm long using a single-layer continuous over-and-over suture with a synthetic monofilament absorbable thread. The Roux limb of the jejunum is placed retrocolically; if the transverse mesocolon is shortened or involved in an inflammatory infiltrate, it is placed antecolically. End-to-side enteroenterostomy is constructed at the level of the first vascular arcade of the jejunum. The cyst walls are partially excised and routinely submitted for pathological examination to rule out a cystic pancreatic neoplasm. Laparoscopic cystopancreatojejunostomy should be performed only in centers with the requisite laparoscopic expertise.

Treatment of biliary hypertension in chronic pancreatitis

• Endoscopic management of biliary hypertension in chronic pancreatitis is recommended in cases of clinically significant cholangitis and obstructive jaundice. Biliary stenting is a temporary measure performed using multiple plastic biliary stents (non-absorbable polymeric biliary stent***). Stents must be replaced every 3 months. The course of treatment lasts for at least 1 year after achieving the placement of the maximum possible number of stents within the biliary tree lumen [217, 232, 238].

GCR ALEL 2Grade of Recommendation – A. Level of Evidence – 2.

Comments: if prior endoscopic stenting is ineffective and the patient fails to comply with the treatment regimen, endoscopic treatment is contraindicated. Patients require active surveillance due to the risk of septic complications associated with stent occlusion or migration. Uncovered and covered nitinol biliary stents (uncovered metal biliary stent***, polymer-metal biliary stent***) must not be used as a definitive treatment method due to their short functional lifespan and the impossibility of endoscopic removal. Despite high short-term clinical efficacy (up to 92%), the long-term efficacy of endoscopic stenting compared to surgery is low (31–62%), which is why biliary stenting is recommended for preoperative preparation or when surgery is declined [217, 232, 238].

Surgical treatment for pancreatic duct stones (wirsungolithiasis) and pancreatic hypertension

• Longitudinal pancreaticojejunostomy is recommended in the presence of ductal hypertension and dilatation of the pancreatic duct due to strictures or stones at the level of the pancreatic neck, body, and tail, and in the absence of fibrotic degeneration of the head and uncinate process. In the presence of a cyst and pancreatic hypertension, a combination of interventions—longitudinal cystopancreatojejunostomy on a Roux-en-Y excluded limb—is possible [84, 111, 196, 197, 236].

GOM ALOE 1Grade of Recommendation – A. Level of Evidence – 1.

Comments: longitudinal pancreaticojejunostomy effectively relieves ductal hypertension at the level of the body and tail of the pancreas. This procedure is ineffective in the presence of fibrotic degeneration of the pancreatic head and uncinate process, or stones/strictures in the terminal pancreatic duct. Since chronic pancreatitis most frequently causes the most severe sclerotic changes in the pancreatic head, indications for longitudinal pancreaticojejunostomy arise infrequently. The pancreatic duct is unroofed along its entire length—from the head to the tail. Capillary bleeding is controlled by electrocoagulation, and bleeding arterial and venous vessels are suture-ligated. Stones are removed from the main pancreatic duct and its tributaries. If locating the pancreatic duct is difficult, or to assess the radicality of the procedure, intraoperative ultrasound should be performed. The pancreatic parenchyma is not resected, even in the presence of intraparenchymal calcifications. The pancreaticojejunostomy with an isolated Roux jejunal limb is formed using a continuous suture with synthetic monofilament absorbable thread. The Roux limb is brought up through an opening in the transverse mesocolon.

Resection procedures in chronic pancreatitis

Pancreatic resection techniques are currently well-established and prioritized, as they allow for the radical management of chronic pancreatitis complications caused by fibro-cystic degeneration of the head or distal parts of the pancreas [84, 111, 196, 197, 236]. Several variants of pancreatic head resection exist, each with strict indications [84, 111, 196, 197, 236, 239–241].

• Partial resection of the pancreatic head with longitudinal pancreaticojejunostomy (Frey procedure) is recommended for fibrotic transformation of the pancreatic head and pancreatic hypertension caused by wirsungolithiasis or duct strictures [84, 111, 196, 197, 236, 239].

GOM ALOE 1Grade of Recommendation – A. Level of Evidence – 1.

Comments: pancreatic head resection with longitudinal pancreaticojejunostomy (Frey procedure) ensures reliable relief of pancreatic hypertension and removal of the major part of the sclerotic pancreatic head tissue, as proposed in the modified version of the operation introduced in 2003 [241]. The pancreatic duct is opened along its entire length. The tissue of the head and uncinate process is excised, preserving no more than 5 mm of parenchyma adjacent to the duodenal wall, the intramural part of the common bile duct, and the portal vein; calculi are removed from the main pancreatic duct and side branches as thoroughly as possible. The volume of the resected head parenchyma must exceed 50%. An anastomosis is formed between the edges of the resulting cavity in the pancreatic head and the opened pancreatic duct and a Roux-en-Y jejunal loop using a continuous over-and-over suture with absorbable synthetic monofilament suture material. The Roux limb, at least 60 cm in length, is brought through the transverse mesocolon. This operation does not provide complete exposure of the terminal part of the common bile duct and the portal vein from the pancreatic tissue. Due to the large wound surface area in the resection zone of the head, uncinate process, and the incised pancreatic duct, there is a risk of early hemorrhage into the lumen of the anastomosis in the immediate postoperative period [240, 241]. Laparoscopic or robot-assisted variants of the Frey procedure are challenging due to the difficulty of assessing the radicality of the intervention; further studies of long-term outcomes are necessary to determine their feasibility.

• The Bernese modification of pancreatic head resection (duodenum-preserving pancreatic head resection (atypical)) is recommended in the presence of not only fibrous degeneration of the head parenchyma but also biliary hypertension [197, 239-242].

Level of Evidence CGrade of Recommendation 5Level of Recommendation – C. Level of Evidence – 5.

Comments: in the Bernese modification of pancreatic head resection, the volume of resected pancreatic tissue is increased due to the complete excision of the parenchyma adjacent to the intramural part of the common bile duct [242]. In the presence of biliary hypertension and obstructive jaundice, the lumen of the bile duct may be opened. The resulting flaps of the bile duct wall are sutured to the remaining pancreatic tissue. The pancreatic duct, if it contains stones or strictures, is incised as in the Frey procedure. The Roux-en-Y jejunal loop is sutured along the perimeter of the resected head, uncinate process, and the pancreatic duct. A disadvantage of this operation is the risk of a common bile duct stricture developing inside the anastomotic cavity [111, 198]. If there is an extensive stricture of the common bile duct, opening its lumen within the cavity formed after head resection is unadvisable. The most reliable method to relieve biliary hypertension is the creation of a hepaticojejunostomy using a Roux-en-Y isolated jejunal loop.

• Beger's subtotal pancreatic head resection (duodenum-preserving pancreatic head resection (atypical)) is recommended in the presence of the aforementioned complications combined with portal hypertension caused by compression of the confluence of the superior mesenteric and splenic veins [111, 198, 240-242].

GOM ALOE 1Grade of Recommendation – A. Level of Evidence – 1.

Comments: the pancreas is mobilized in the region of the neck, beneath which a tunnel is created, exposing the anterior surface of the confluence of the superior mesenteric and splenic veins. The portal and superior mesenteric veins are dissected free from the scar sheath that surrounds and compresses them. The tissue of the head and uncinate process is resected, leaving a strip of parenchyma along the medial wall of the duodenum and the terminal part of the common bile duct no more than 5 mm thick. The stump of the body of the gland and the remaining parenchyma along the duodenal wall are anastomosed to the Roux-en-Y jejunal loop with two anastomoses, whereas if the volume of the proximal pancreatic stump is small, its anastomosis with the intestine is not required [240-242].

• Pancreaticoduodenal resection is recommended in cases where the presence of a malignant tumor of the pancreatic head cannot be ruled out, as well as in cases of fibro-inflammatory transformation of the duodenum combined with persistent duodenal stenosis refractory to conservative therapy [197, 236, 240-245].

Level of evidence – 1, strength of recommendation – A.

• Distal pancreatic resection is recommended in cases where the presence of a tumor in the tail of the pancreas cannot be ruled out, or in the presence of a post-necrotic pancreatic cyst replacing the parenchyma of the distal part of the organ [197, 236].

GOM ALOE 1Grade of Recommendation – A. Level of Evidence – 1.

Comments: distal pancreatic resection in chronic pancreatitis is performed when the presence of a tumor in the tail of the pancreas cannot be ruled out; in rare cases, for post-necrotic cysts completely replacing the tail of the pancreas, provided there is no impairment of secretion outflow through the pancreatic duct in the body and head of the pancreas. When performing distal pancreatic resection, in cases where the splenic vessels can be separated from the walls of the post-necrotic cyst, splenectomy should be avoided. In the presence of subhepatic portal hypertension caused by splenic vein thrombosis with gastric varices, splenectomy combined with one of the resection-drainage procedures is indicated [197, 236].

• When performing a resectional procedure for chronic pancreatitis, it is recommended in all cases to perform an urgent pathomorphological examination of the biopsy (surgical) material of the pancreas [56, 91].

Level of Evidence CGrade of Recommendation 5Level of Recommendation – C. Level of Evidence – 5.

Endovascular interventions for pseudoaneurysms of the celiac trunk and superior mesenteric artery basins

• Patients with pseudoaneurysms of the branches of the celiac trunk and superior mesenteric artery communicating with the pancreatic duct (type 1 pseudoaneurysms) are recommended a two-stage treatment approach: Endovascular occlusion of the aneurysm sac using microcoils followed by radical surgical treatment of the complications of chronic pancreatitis. In the presence of type 2 pseudoaneurysms not communicating with the pancreatic duct, an endovascular procedure aimed at closing the aneurysm cavity (endovascular occlusion of the aneurysm sac using microcoils) or artery stent-grafting with a covered nitinol stent (placement of a stent in the vessel, peripheral artery stent, bare-metal***), which will be the final stage of treatment, can be performed [61, 246, 247].

GPP CLoE 4Level of Recommendations — C. Level of Evidence — 4.

Comments: patients with type 1 pseudoaneurysms at the time of diagnosis are often in severe condition due to anemia caused by recurrent gastrointestinal bleeding. Due to the severity of the patients' condition, radical surgical treatment is impossible. At the first stage of treatment, it is necessary to achieve cessation of recurrent bleeding through urgent endovascular intervention [61, 246, 247]. The following options for endovascular interventions are recommended: occlusion of the artery distally and proximally to the neck of the aneurysm; occlusion of the aneurysm sac and the afferent artery; stent-grafting of the artery with a covered stent at the level of the neck of the aneurysm. Endovascular exclusion of the pseudoaneurysm from the bloodstream eliminates recurrent gastrointestinal bleeding. However, due to the communication of the type 1 pseudoaneurysm cavity with the lumen of the pancreatic duct, the action of pancreatic juice leads to the lysis of thrombotic masses 2-3 weeks after embolization (except in cases where covered stent-grafting has been performed) [61]. Following intensive preparation aimed at correcting anemia and hypoproteinemia, a radical surgical procedure must be performed to address the complications of chronic pancreatitis that led to the development of the pseudoaneurysm.

Postoperative complications

Operations for chronic pancreatitis are accompanied by a high rate of postoperative complications, reaching 20-40% [248]. In cases where the pancreatic parenchyma has not lost its exocrine activity at the time of surgery, there is a real threat of postoperative pancreatitis and pancreatic fistula formation [236]. Extensive pancreatic head resections with a large wound surface area create conditions for early hemorrhage into the lumen of the pancreaticojejunostomy.

Postoperative pancreatitis is a frequent complication following pancreatic surgery. Macroscopic manifestations of pancreatitis in the form of glassy edema of the parapancreatic adipose tissue and even foci of fat necrosis can be detected during surgery itself [248]. In the immediate postoperative period, clinical signs of pancreatitis include manifestations of endogenous intoxication (persistent tachycardia in the absence of hypovolemia, acrocyanosis, suppression of spontaneous breathing), discharge of brownish exudate with a high amylase content from the abdominal cavity via drainage tubes, gastrostasis, and paralytic ileus. These symptoms indicate the development of severe pancreatitis. A biochemical marker of pancreatitis is an elevation of blood amylase levels above 150 U/L. Treatment of postoperative pancreatitis should be conservative and carried out in an intensive care unit [249, 250].

• In postoperative pancreatitis, patients who have undergone pancreatic surgery are recommended to receive intensive conservative therapy in the intensive care unit to eliminate signs of hyperamylasemia and endogenous intoxication [248].

GPP CLoE 4Level of Recommendations — C. Level of Evidence — 4.

Comments: the regimen of basic conservative therapy includes antibiotic therapy for the prevention and treatment of septic complications; medical suppression of pancreatic, gastric, and duodenal secretion; correction of hypovolemia along with water-electrolyte and metabolic disorders; improvement of blood rheological properties; prevention and treatment of gastrointestinal functional insufficiency; analgesic and antienzymetic therapy. In pancreatonecrosis, it is advisable to use extracorporeal detoxification methods [248-250].

• For the prevention of complications, patients who have undergone pancreatic surgery are recommended to receive somatostatin and its analogues in accordance with the specific drug's prescribing information [251].

GCR CLEL 2Grade of Recommendations — C. Level of Evidence — 2.

Comments: the use of octreotide** in patients with postoperative pancreatitis reliably reduces the serum levels of pro-inflammatory mediators and cytokines (TNF-α, IL-1, IL-6, IL-8), and also decreases the systemic inflammatory response level [203].

• For pancreatic fistulas, it is recommended to perform conservative therapy and dynamic monitoring while ensuring adequate outflow of pancreatic secretion. The presence of a pancreatic fistula poses a real threat of erosion bleeding [199-201].

GPP CLoE 4Level of Recommendations — C. Level of Evidence — 4.

Comments: a pancreatic fistula is a consequence of postoperative pancreatitis, against the background of which leakage of pancreatoduodenal anastomoses or the pancreatic stump after distal resections occurs [201]. According to the revised 2017 ISGPF classification, pancreatic fistulas are divided into 3 types: clinically insignificant pancreatic fistula (formerly type A according to the 2005 ISGPF classification), B, and C (Appendix A3) [252, 253].

• In postoperative non-massive bleeding, it is recommended to administer conservative therapy aimed at correcting hemodynamics and the hemostatic system. To clarify the source of bleeding, it is recommended to perform abdominal computed tomography with intravenous bolus contrast enhancement and/or abdominal vessel angiography [254-259].

Level of Evidence — 4. Grade of Recommendations — C.

• If a bleeding artery is detected during angiography, it is recommended to perform endovascular embolization of the vessel [254-259].

Level of Evidence — 2. Grade of Recommendations — B.

• In massive bleeding and the impossibility of endovascular intervention, it is recommended to perform relaparotomy to identify the source of bleeding. In soft tissue bleeding and in the absence of pancreatonecrosis or necrotic parapancreatitis, hemostasis can be achieved by suture ligation. In erosion bleeding from major vessels (mesenteric-portal trunk, splenic vein, celiac trunk and superior mesenteric artery basins) resulting from postoperative pancreatonecrosis, it is recommended to perform total duodenopancreatectomy and splenectomy [254-259].

Level of Evidence — 2. Grade of Recommendations — B.

Comments: the probability of bleeding after pancreatic resection reaches 10%, with a mortality rate of 1.2% [257, 258]. Adequate external drainage of the surgical area reduces the risk of erosive bleeding.

Bleeding after pancreatic resection should be classified according to the recommendations of the International Study Group on Pancreatic Surgery (ISGPS) [253, 254], taking into account the following factors:

1 – time of onset of bleeding – the first 24 hours after surgery completion – early bleeding; later than 24 hours – late bleeding, usually erosive;

2 – severity of bleeding – patient's condition, hemoglobin level, and the need for blood component transfusion;

3 – source and localization of bleeding – intraluminal (into the lumen of the gastrointestinal tract) or intra-abdominal bleeding [252-254].

Time of onset of bleeding (ISGPS, 2007):

• early – occurs within the first 24 hours after surgery, caused by technical factors: inadequate intraoperative hemostasis, coagulopathy, vessel wall injury by electrocoagulation during lymph node dissection;

• late – occurs more than 24 hours after the end of surgery; causes of bleeding include postoperative pancreatitis and pancreatic fistula, intra-abdominal abscesses, ulceration at the anastomosis site, and formation of an arterial pseudoaneurysm [253].

In a multicenter study conducted by E. Yekebas (2007) based on the analysis of 1,669 pancreatic resections, the ISGPS severity classification of bleeding was modified [259].

1. “Sentinel bleeding” is characterized by short-term output of a small amount of blood through abdominal drains or a nasogastric tube; coffee-ground vomiting or melena may occur; clinical manifestations of acute blood loss (tachycardia, drop in blood pressure) are absent, and hemoglobin does not drop by more than 15 g/L. The bleeding stops spontaneously, and there is no need for blood transfusion. However, recurrent bleeding is possible within 12 hours.

2. Mild post-resection bleeding is characterized by blood output through abdominal drains, a drop in hemoglobin level up to 30 g/L, with or without clinical manifestations of acute blood loss.

3. Severe post-resection bleeding is characterized by a drop in hemoglobin level of more than 30 g/L and pronounced clinical manifestations of acute blood loss [253].

Early postoperative bleeding. A specific feature of operations for chronic pancreatitis (longitudinal pancreatojejunostomy, Frey's procedure, Bern modification of pancreatic head resection) is the creation of a large wound surface on the pancreatic parenchyma and a significant length of the jejunal wall incision used for anastomosis. As a result, bleeding into the lumen of the anastomosis from both the pancreatic parenchyma and the jejunal wall may occur in the immediate postoperative period. Clinical manifestations include severe upper abdominal pain due to overdistension of the Roux limb with blood, general symptoms of acute blood loss, and melena.

Early mild bleeding into the lumen of the pancreatojejunostomy is treated conservatively. In case of massive bleeding, emergency angiography followed by embolization of the bleeding vessel should be performed. If endovascular intervention is not feasible, relaparotomy is performed. During relaparotomy, it is necessary to take down the anterior lip of the pancreatojejunostomy, oversew the bleeding vessel, and re-create the anastomosis. Enterotomy through the anterior lip of the anastomosis is unacceptable, as this inevitably leads to suture dehiscence due to impaired blood supply to the intestinal wall.

Late postoperative bleeding. Late bleeding, being erosive, poses a real threat to the patient's life and requires conservative therapy in mild cases, and emergency endovascular intervention with embolization of the eroded vessel or emergency relaparotomy in massive cases [260]. During relaparotomy, the condition of the pancreatoduodenal anastomosis, the pancreatic stump, and parapancreatic tissue must be taken into account. Bleeding may have stopped at the time of surgery, which significantly complicates identifying its source. Postoperative pancreatonecrosis and necrotic parapancreatitis combined with erosive bleeding from major vessels are unfavorable factors and, as an exceptional measure, may require pancreatic extirpation and splenectomy.

4. Medical Rehabilitation and Sanatorium-Resort Treatment

• Patients with preserved exocrine pancreatic function after the resolution of an exacerbation of chronic pancreatitis are recommended to be prescribed pancreatin** capsules at a total daily dose of 100,000–150,000 IU/day for 3–6 months [96].

GCR BLEL 2Grade of Recommendation – B. Level of Evidence – 2.

• When exocrine pancreatic insufficiency develops in patients with chronic pancreatitis, lifelong enzyme replacement therapy with pancreatin** is recommended, often with the addition of PPIs (e.g., #omeprazole** 10 to 40 mg twice daily) to enhance the efficacy of digestive enzyme preparations [161, 261-266].

GPP CLoE 4Level of Recommendations — C. Level of Evidence — 4.

Comments: the further prognosis for patients with CP is determined by the potential development of complications requiring surgical correction (which are accompanied by corresponding intraoperative mortality rates). The standardized mortality ratio for patients with CP is 3.6:1 (i.e., patients with any form of CP die 3.6 times more often than individuals of the same age in the general population) [267].

• All patients scheduled for surgery for CP are recommended to receive prophylaxis of infectious complications with systemic broad-spectrum antibacterial drugs 30 minutes before surgery (in the absence of medical contraindications) [256, 268, 269].

GPP CLoE 4Level of Recommendations — C. Level of Evidence — 4.

Comments: postoperative rehabilitation of patients with chronic pancreatitis follows the principles of enhanced recovery after surgery (ERAS). Recent studies have demonstrated that the ERAS program reduces the length of hospital stay by 30-50%, while also reducing the incidence of postoperative complications by 40% [256, 269-271].

• All patients who underwent surgery for complicated forms of chronic pancreatitis are recommended early mobilization in the postoperative period to reduce the risk of postoperative complications [269-272].

LoR BGoE 2Level of recommendation validity – B. Level of evidence reliability – 2.

Comments: bed rest increases the risk of deep vein thrombosis, atelectasis, and hypostatic pneumonia, contributes to microcirculatory disorders, and increases the risk of cardiovascular complications in the postoperative period [53]. The patient can be mobilized and brought to an upright position within the first 4 hours after surgery [46, 49]. Early physical mobilization is of particular importance for patients at high risk of postoperative complications. Early mobilization implies transferring patients from the intensive care unit to the specialized ward on the day following surgery, provided the early postoperative course is uneventful, with independent ambulation within the ward.

• All patients who underwent surgery for complicated forms of chronic pancreatitis are recommended multimodal analgesia for pain-free mobilization and enhanced recovery [269-272].

GCR BLEL 2Grade of Recommendation – B. Level of Evidence – 2.

Comments: the multimodal analgesia strategy provides a parallel effect on all links of pain pathogenesis and includes the administration of paracetamol** alongside one of the neuroaxial or regional analgesia modalities.

• All patients who underwent surgery for complicated forms of chronic pancreatitis are recommended early resumption of enteral nutrition for enhanced recovery [269-272].

GCR BLEL 2Grade of Recommendation – B. Level of Evidence – 2.

Comments: oral intake of water in volumes up to 1000 ml against the background of ongoing infusion therapy on the day following surgery; from day 2 – increase in fluid intake volume up to 1500 ml with a decrease in intravenous infusion volume, initiation of enteral nutrition; complete discontinuation of infusion therapy, enteral nutrition.

• All patients who underwent surgery for complicated forms of chronic pancreatitis are recommended early removal of catheters (central venous, urinary) and abdominal drains [269-272].

LoR BGoE 2Level of recommendation validity – B. Level of evidence reliability – 2.

Comments: prolonged postoperative nasogastric intubation is associated with a high risk of gastroesophageal reflux, pneumonia, and atelectasis, as well as delayed recovery of gastrointestinal motility [272], and therefore should not be used routinely in the postoperative period. A nasogastric tube inserted intraoperatively for upper GI decompression should be removed at the end of anesthesia, or in rare cases (when there is a risk of gastrostasis) – on the first postoperative day. Abdominal drain removal should be performed on the 4th–5th postoperative day if the drainage volume does not exceed 100 ml and its amylase content does not exceed twice the normal limit. In the presence of signs of a pancreatic fistula, the drainage tube is not removed until drainage output completely ceases.

• All patients operated on for complicated forms of chronic pancreatitis are recommended administration of a heparin group drug at a prophylactic dose 12 hours before surgery and for up to 4 weeks after surgery to prevent thromboembolic events [269-272].

GCR BLEL 2Grade of Recommendation – B. Level of Evidence – 2.

Comments: prolonged surgeries increase the risk of thromboembolism, therefore deep vein thrombosis prophylaxis is indicated for almost all patients when planning extensive pancreatic surgery. Mechanical thromboprophylaxis (elastic and dynamic compression) is recommended for all hospitalized patients [272].

5. Prevention and Dispensary Observation

Prevention of CP is based on the extrapolation of cohort epidemiological data, according to which limiting alcohol consumption and tobacco smoking (an absolute ban for individuals with a history of acute pancreatitis or a confirmed diagnosis of CP) can be assumed to be a factor reducing the risk of CP progression. In individuals with symptomatic cholelithiasis, attacks of chronic calculous cholecystitis, and biliary pancreatitis, timely cholecystectomy can be considered a method for preventing subsequent attacks of pancreatitis.

Empirical recommendations regarding dietary prevention and the need to abandon almost everything, including coffee, chocolate, and fats of any origin, are not currently scientifically substantiated. It is possible (since it has not been sufficiently studied) that other factors associated with nutrition may be more significant in provoking CP exacerbation — obesity, overeating, and postprandial hypokinesia (causing high intra-abdominal pressure), chronic dietary antioxidant deficiency, hypercholesterolemia, the combined effect of dietary factors, ethanol, and tobacco smoke components, etc. At the same time, one must remember the flip side of the coin, when some highly compliant patients meticulously follow a strict diet to prevent recurrent attacks of pancreatitis (these are usually individuals without an alcohol history, non-smokers) and drive themselves to nutritional deficiency with manifestations of multivitamin deficiency, kwashiorkor, anemia, etc.

• Thus, based on the results of a number of experimental, epidemiological, and pilot studies, as well as empirical long-term experience, all patients with CP can be recommended the following lifestyle modification measures to prevent disease exacerbations: frequent small meals (4-5 times a day, in even portions with an equal distribution of fat-containing foods in the diet), avoidance of overeating; creation of a balanced diet limiting saturated fats and cholesterol; inclusion of a sufficient amount of dietary fiber (plant cellulose) in the diet; adequate physical activity; consumption of a diverse diet with low saturated fat and cholesterol content (unrefined vegetable fats are somewhat restricted only in overweight individuals); selection of a diet with sufficient dietary fiber found in grain products, vegetables, and fruits; finding a balance between food intake and physical activity (to stabilize weight aiming for an ideal body mass index adjusted for age) [49, 269-271].

Level of Evidence CGrade of Recommendation 5Level of Recommendation – C. Level of Evidence – 5.

• All patients suffering from CP are recommended complete abstinence from alcohol to reduce the frequency of exacerbations and mortality [44, 134, 273].

Level of Consensus – CLevel of Evidence – 4Level of Consensus – C. Level of Evidence – 4.

Comments: cessation of alcohol intake contributes to the reduction of CP symptoms, primarily reducing/completely relieving abdominal pain, and slowing down the development of exocrine pancreatic insufficiency [44, 134, 273].

• All patients suffering from CP are recommended complete smoking cessation to reduce pain syndrome and prevent the development of CP complications [136].

GCR CLOE 5Grade of Recommendation – C, Level of Evidence – 5

Comments: all patients with CP are recommended to quit smoking as a significant and independent factor in the development of CP [136].

• Patients with cholelithiasis are recommended surgical treatment: cholecystectomy, endoscopic lithoextraction from the common bile duct to prevent attacks of biliary pancreatitis [84, 270].

Level of Evidence CGrade of Recommendation 5Level of Recommendation – C. Level of Evidence – 5.

• Patients who have undergone invasive interventions for chronic pancreatitis are recommended dispensary follow-up by a general practitioner, general practice physician (family doctor), or gastroenterologist at their place of residence; after surgical treatment, a comprehensive examination once a year [58, 84, 91].

Level of Evidence CGrade of Recommendation 5Level of Recommendation – C. Level of Evidence – 5.

For effective primary prevention of chronic pancreatitis, one could hope for the viability of the idea of universal dispensary follow-up of the population for the timely detection of biliary tract pathology, hyperlipidemia, stigmas of latent alcohol abuse, etc. However, to date, this idea has not found practical application in any country worldwide, as its implementation involves high financial costs. Pharmacoeconomic studies could provide an answer regarding the feasibility of such a tactic, but awaiting their initiation, given the growing yet relatively low prevalence of chronic pancreatitis in the population, must currently be considered unrealistic.

6. Organization of Medical Care

Stages of medical care delivery

Outpatient stage: identification of individuals with suspected chronic pancreatitis, ordering diagnostic procedures, establishing the diagnosis of chronic pancreatitis, prescribing conservative therapy followed by dynamic follow-up. In case of ineffectiveness of conservative therapy, referral for surgical treatment.

Inpatient stage

Inpatient treatment of patients with chronic pancreatitis must be implemented through a three-tier system of medical care delivery.

Tiers of inpatient care delivery to the population

First tier: medical organizations whose structure includes units providing primary health care and/or specialized (excluding high-tech) medical care to the population within the boundaries of the municipality.

Scope of medical care at the first tier: conservative therapy for chronic pancreatitis during an exacerbation, referral to second-tier facilities to perform palliative interventions in the event of biliary hypertension, duodenal obstruction, and post-treatment/rehabilitation of patients following surgeries performed in second- and third-tier hospitals. Patients with urgent complications requiring specialized high-tech medical care (transcatheter embolization/occlusion to stop portal or arterial bleeding, pancreatic duct stenting) are referred to third-tier hospitals, bypassing the second tier.

Indications for hospitalization in a first-tier hospital: clinical presentation of an exacerbation of chronic pancreatitis, performing laboratory and ultrasound diagnostics, and conservative therapy.

Criteria for discharge from a first-tier hospital: relief of pain syndrome, normalization of laboratory parameters (total amylase, pancreatic amylase, urinary amylase, leukocyte count).

Second tier: medical organizations whose structure includes departments and/or centers providing specialized (excluding high-tech) medical care to the population of several municipalities, as well as emergency hospitals.

Scope of medical care at the second tier: performing palliative surgeries for biliary tract obstruction, subcompensated and decompensated duodenal obstruction, and transfer from a first-tier hospital upon the development of conditions requiring intensive care and surgical intervention (bleeding from pseudoaneurysms).

Indications for hospitalization in a second-tier hospital: presence of the biliary obstruction symptom complex, subcompensated or decompensated duodenal stenosis, and severe persistent pain syndrome.

Criteria for discharge from a second-tier hospital: clinical and laboratory signs of resolution of obstructive jaundice after the intervention, restoration of gastric emptying, and relief of pain syndrome.

Third tier: medical organizations whose structure includes units providing high-tech medical care involving technically complex procedures associated with a high risk of perioperative complications, requiring the collaborative work of diagnostic, surgical, endoscopic, anesthesiology-resuscitation, and interventional radiology services, which must be available around the clock. This condition can only be met in high-volume centers.

Indications for hospitalization in a third-tier hospital: complicated course of chronic pancreatitis (persistent pain syndrome unresponsive to medical therapy; pancreatic ductal hypertension due to Wirsungolithiasis or pancreatic duct strictures; post-necrotic pancreatogenic pancreatic pseudocysts; obstructive jaundice caused by compression of the common hepatic duct; portal hypertension with bleeding from phlebectasias due to compression of the confluence of the superior mesenteric and splenic veins; persistent impairment of food passage through the duodenum; pseudoaneurysms of arteries in the celiac trunk and superior mesenteric artery basins, suspected malignancy, and external and internal pancreatic fistulas) requiring surgeries such as pancreatic resection, pancreatoduodenectomy, distal pancreatectomy, or endovascular interventions.

Criteria for discharge from a third-tier hospital: satisfactory postoperative condition and absence of complications [269, 271].

Management tactics for a general practitioner and gastroenterologist in chronic pancreatitis

The management tactics for a patient with chronic pancreatitis are based on several important components:

1. Establishing the diagnosis of chronic pancreatitis (i.e., confirming or ruling out chronic pancreatitis, which presents difficulties in the early stages of the disease);

2. Attempting to determine the etiology of chronic pancreatitis (since etiological treatment is the most effective);

3. Determining the stage of chronic pancreatitis (which dictates the choice of treatment tactics and influences the prognosis);

4. Diagnosing pancreatic insufficiency (which forms the basis for choosing the regimen of enzyme replacement therapy and insulin therapy, drug dosages, or recognizing the need for surgical treatment);

5. Developing a treatment plan (in some cases, through a multidisciplinary consensus with surgeons, endoscopists, and endocrinologists);

6. Determining the prognosis taking into account the initial clinical scenario and the chosen medical strategy.

The diagnosis of "definitive chronic pancreatitis" (Algorithm 1) is established using highly informative imaging modalities based on morphological signs combined with clinical manifestations (if ultrasound is insufficiently informative, CT at a minimum). If neither ultrasound nor CT confirms the diagnosis, the patient may be monitored and treated with a presumptive diagnosis of chronic pancreatitis. Thus, once the diagnosis of chronic pancreatitis is reliably established, the first stage involves an attempt at etiological (most effective) intervention. First and foremost, this applies to etiological forms requiring timely and specific intervention—systemic corticosteroids for autoimmune pancreatitis, surgical or endoscopic decompression for obstruction, etc. In the presence of exocrine pancreatic insufficiency, it is advisable to determine its type—primary (with decreased elastase-1 levels under proper stool collection conditions) or secondary (with normal elastase levels), which will determine the duration of enzyme replacement therapy. The duration of a course of encapsulated pancreatin** in secondary pancreatic insufficiency is determined by the time required for symptom resolution and the possibility of identifying and eliminating secondary causes of insufficiency (e.g., small intestinal bacterial overgrowth syndrome). In case of steatorrhea relapse after discontinuation or dose reduction of pancreatin**, despite normal fecal elastase-1 values, lifelong enzyme replacement therapy is also necessary. A patient with low fecal elastase-1 values in the absence of conditions for a false-positive result is indicated for lifelong enzyme replacement therapy. In the presence of a persistent pain course resistant to combined pharmacotherapy using pancreatin**, analgesics, and pregabalin** for 3 months, it is advisable to discuss the patient collectively with surgeons and endoscopists regarding endoscopic or surgical treatment. The prescription of narcotic analgesics carries a high risk of addiction, which dictates making a timely decision on the potential need for endoscopic and/or surgical treatment.

Due to the impossibility of adequate morphological verification of CP for various reasons, as well as the fact that ultrasound is currently the most common method for assessing the state of the pancreatic parenchyma in Russia, the diagnosis of "chronic pancreatitis" in some patients is considered probable or possible depending on the medical history and clinical presentation (Algorithm 2). A similar situation arises when CT data are insufficient, and in some cases even EUS, for establishing a diagnosis of CP (uncertain, possible CP, or clinical suspicion of CP). In the presence of / suspicion of exocrine pancreatic insufficiency, it is also advisable to determine its type—primary (with decreased elastase-1) or secondary (with normal elastase levels), which will determine the duration of enzyme replacement therapy and allow us to state with greater confidence the presence of CP (a combination of unconvincing imaging criteria and pancreatic insufficiency). The course of pancreatin capsules** in secondary pancreatic insufficiency is also determined by the time frame for symptom resolution and the ability to identify and eliminate secondary causes of insufficiency (e.g., small intestinal bacterial overgrowth syndrome). Due to the lack of certainty regarding the "pancreatic" type of diabetes, the choice of a hypoglycemic agent should be decided in conjunction with an endocrinologist. In the absence of an effect from conservative methods aimed at pain relief, unlike the situation with "definite CP", it is advisable, first of all, to clarify the diagnosis of CP using reliable methods for assessing pancreatic morphology (EUS, CT, MRCP) prior to consulting a surgeon.

7. Additional Information

Factors influencing the outcome of surgical treatment for chronic pancreatitis

Up to 20% of operated patients are dissatisfied with the outcome of surgical treatment [272]. This primarily applies to the recurrence or persistence of pain after surgery [272, 274]. Factors influencing the effectiveness of surgical treatment are not yet fully understood. One of them is considered to be the volume of pancreatic head resection. According to a 2016 meta-analysis including 323 patients after various modifications of resection-drainage interventions on the pancreas, it was noted that in all cases, surgical treatment had a satisfactory outcome [275, 276]. However, none of the publications included in the meta-analysis described a methodology for objectively assessing the volume of pancreatic head resection.

Another potential factor influencing the treatment outcome is the timing of the surgical intervention. Surgical intervention for CP performed in the early stages of the disease (up to 3 years from the initial manifestation) leads to better long-term outcomes. Recently, isolated single-center studies have emerged noting the advantage of surgical treatment for CP in the early stages from the initial manifestation of the disease (up to 3 years) [275, 276].

Prognosis of the course of CP

Currently, there is no prognostic system for the course of chronic pancreatitis approved by the professional community. Large cohort studies and meta-analyses are needed to more accurately determine the factors influencing the outcome of CP.

It is obvious that when predicting the course of CP, it is necessary to rely on data regarding the patient's physical condition (BMI), the influence of toxic factors (alcohol, smoking), laboratory test data (blood glycated hemoglobin, C-reactive protein, albumin levels), the state of the pancreas (presence of post-necrotic cysts and calculi), and the presence of biliary strictures.

To objectively assess the patient's condition over time, questionnaires are widely used, such as the visual analogue scale (VAS) (Appendix G2), the numerical rating scale for pain (NRS) (Appendix G3), as well as quality of life (QoL) questionnaires SF-36 (Appendix G4) and QLQ-C30 (Appendix G5) [276-278].

To slow down fibro-inflammatory processes in the pancreas and improve patient condition, lifestyle modification is necessary, including complete cessation of alcohol, adherence to dietary recommendations, and adequate enzyme replacement therapy [268].

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

Alekseenko, Sergey Alekseevich, Doctor of Medical Sciences, Professor (Khabarovsk). There is no conflict of interest.

Anischenko, Maria Alexandrovna, Candidate of Medical Sciences (Moscow). There is no conflict of interest.

Bagnenko, Sergey Fedorovich, Doctor of Medical Sciences, Professor, Academician of the Russian Academy of Sciences (Saint Petersburg). There is no conflict of interest.

Bordin, Dmitry Stanislavovich, Doctor of Medical Sciences, Professor (Moscow). There is no conflict of interest.

Bykov, Mikhail Ilyich, Doctor of Medical Sciences, Professor (Krasnodar). There is no conflict of interest.

Budzinsky, Stanislav Alexandrovich, Doctor of Medical Sciences (Moscow). There is no conflict of interest.

Buriev, Ilya Mikhailovich, Doctor of Medical Sciences, Professor (Moscow). There is no conflict of interest.

Vishnevsky, Vladimir Alexandrovich, Doctor of Medical Sciences, Professor (Moscow). There is no conflict of interest.

Galperin, Eduard Israilevich, Doctor of Medical Sciences, Professor, Full Member of the Russian Academy of Natural Sciences (Moscow). There is no conflict of interest.

Glabay, Vladimir Petrovich, Doctor of Medical Sciences, Professor (Moscow). There is no conflict of interest.

Goltsov, Valery Remirovich, Doctor of Medical Sciences (Saint Petersburg). There is no conflict of interest.

Dyuzheva, Tatyana Gennadievna, Doctor of Medical Sciences, Professor (Moscow). There is no conflict of interest.

Ivashkin, Vladimir Trofimovich, Doctor of Medical Sciences, Professor, Academician of the Russian Academy of Sciences, President of the Russian Gastroenterological Association. President of the Regional NGO "Scientific Society for the Promotion of Clinical Research of the Human Microbiome". There is no conflict of interest.

Karmazanovsky, Grigory Grigorievich, Doctor of Medical Sciences, Professor, Corresponding Member of the Russian Academy of Sciences (Moscow). There is no conflict of interest.

Kardasheva, Svetlana Stanislavovna, Candidate of Medical Sciences, Associate Professor (Moscow). There is no conflict of interest.

Korolev, Mikhail Pavlovich, Doctor of Medical Sciences, Professor, Chairman of the Russian Endoscopic Society (Saint Petersburg). There is no conflict of interest.

Krasilnikov, Dmitry Mikhailovich, Doctor of Medical Sciences, Professor (Kazan). There is no conflict of interest.

Kriger, Andrey Germanovich, Doctor of Medical Sciences, Professor (Moscow). There is no conflict of interest.

Kucheryavy, Yury Alexandrovich, Candidate of Medical Sciences, Associate Professor (Moscow). There is no conflict of interest.

Maev, Igor Veniaminovich, Doctor of Medical Sciences, Professor, Corresponding Member of the Russian Academy of Sciences (Moscow). There is no conflict of interest.

Maistrenko, Nikolai Anatolyevich, Doctor of Medical Sciences, Professor, Academician of the Russian Academy of Sciences (Saint Petersburg). There is no conflict of interest.

Marina F. Osipenko, MD, PhD, Professor, Novosibirsk. No conflict of interest.

Alexey V. Okhlobystin, MD, PhD, Associate Professor (Moscow). No conflict of interest.

Elena A. Poluektova, MD, PhD, Professor (Moscow), Vice President of the Interregional Public Organization «Scientific Society for the Promotion of Clinical Study of the Human Microbiome». No conflict of interest.

Mikhail I. Prudkov, MD, PhD, Professor (Yekaterinburg). No conflict of interest.

Simanenkov Vladimir Ilyich, Doctor of Medical Sciences, Professor, Member of the Russian Gastroenterological Association. No conflict of interest.

Evgeny G. Solonitsyn, MD, PhD (Saint Petersburg). No conflict of interest.

Anatoly I. Ulyanin, Gastroenterologist, General Practitioner (Moscow). No conflict of interest.

Andrey V. Fedorov, MD, PhD, Professor (Moscow). No conflict of interest.

Evgeny D. Fedorov, MD, PhD, Professor, President of the Russian Endoscopic Society (Moscow). No conflict of interest.

Igor B. Khlynov, MD, PhD, Associate Professor. Chief Gastroenterologist of the Ural Federal District (Yekaterinburg). No conflict of interest.

Marina V. Chikunova, MD, PhD, Assistant Professor, Department of Faculty Therapy, Yekaterinburg. No conflict of interest.

Alexey V. Shabunin, MD, PhD, Professor, Academician of the Russian Academy of Sciences (Moscow). No conflict of interest.

Sergey G. Shapovalyants, MD, PhD, Professor (Moscow). No conflict of interest.

Arkady A. Sheptulin, MD, PhD, Professor (Moscow). No conflict of interest.

Oleg S. Shifrin, MD, PhD, Professor (Moscow). No conflict of interest.

Appendix A2. Methodology for Developing Clinical Guidelines

The purpose of these guidelines is to provide practicing physicians with current concepts of the etiology and pathogenesis of chronic pancreatitis, and to introduce the current diagnostic and treatment algorithms for chronic pancreatitis.

Target audience of these clinical guidelines:

1. Gastroenterologists

2. Internists

3. General practitioners (family physicians)

4. Endoscopists

5. Surgeons

Scale for assessing levels of reliability of evidence (LRE) for diagnostic methods (diagnostic interventions)

Rating scale for levels of evidence (LE) for prevention, treatment, and rehabilitation methods (preventive, therapeutic, and rehabilitative interventions)

Grading system for the levels of evidentiary certainty (LEC) of recommendations for prevention, diagnostic, treatment, and rehabilitation methods (preventive, diagnostic, therapeutic, and rehabilitative interventions)

Procedure for updating clinical guidelines

The guideline updating mechanism provides for their systematic revision at least once every three years, as well as upon the emergence of new evidence-based data on the diagnosis, treatment, prevention, and rehabilitation of specific diseases, or in the presence of justified additions/comments to previously approved clinical guidelines, but no more frequently than once every 6 months.

Appendix A3. Reference Materials

These clinical guidelines have been developed taking into account the following regulatory and legal documents:

1. Federal Law of the Russian Federation No. 323-FZ dated November 21, 2011, «On the Fundamentals of Public Health Protection in the Russian Federation».

2. Order of the Ministry of Health of the Russian Federation No. 804n dated October 13, 2017 (as amended on July 12, 2018) «On approval of the nomenclature of medical services».

3. Order of the Ministry of Health of the Russian Federation No. 148n dated March 5, 2020, «On introducing amendments to Section II "Nomenclature of Medical Services" of the nomenclature of medical services approved by Order of the Ministry of Health of the Russian Federation No. 804n dated October 13, 2017».

Diagnostic criteria for autoimmune pancreatitis (HISORt system)

The HISORt system includes the following categories of features [32]:

• histological features («Histology») – periductal lymphoplasmacytic infiltrate with obliterating phlebitis, storiform fibrosis, and/or lymphoplasmacytic infiltrate with storiform fibrosis and a large number of IgG₄-positive cells ≥10 per high-power field (HPF);

• imaging findings («Imaging»): diffuse pancreatic enlargement with delayed rim-like contrast enhancement, diffuse irregularity of the main pancreatic duct (MPD);

• serological markers («Serology»): elevated serum IgG4 level (8–140 mg%);

• other organ involvement («Other organ involvement»): bile duct strictures, retroperitoneal fibrosis, salivary/lacrimal gland involvement, mediastinal lymphadenopathy;

• response to treatment («Response to steroid therapy»): positive response to administration of 30–40 mg/day of #prednisolone** for 1 month.

The diagnostic criteria provide the following probability levels for the diagnosis of autoimmune pancreatitis:

Level A: typical histological features

Presence of one or more of the following features:

• tissue sample with characteristic features of lymphoplasmacytic sclerosing pancreatitis;

• ≥10 IgG4-positive cells per HPF in the setting of lymphoplasmacytic infiltration.

Level B: typical laboratory and instrumental findings

Presence of all features:

• diffuse pancreatic enlargement according to computed tomography and magnetic resonance imaging (CT, MRI) with delayed contrast enhancement and a rim («capsule»);

• diffuse lumen irregularity of the MPD on endoscopic retrograde cholangiopancreatography (ERCP);

• elevated serum IgG₄ level.

Level C: positive response to glucocorticoids (H02A Systemic corticosteroids)

Presence of all features:

• exclusion of all other causes of pancreatic damage;

• elevated serum IgG₄ level or involvement of other organs confirmed by the detection of a large number of IgG₄-positive cells;

• resolution of/significant improvement in pancreatic or extrapancreatic abnormalities during steroid therapy (H02A Systemic corticosteroids).

Rosemont diagnostic criteria for EUS

Criteria for the diagnosis of CP based on EUS findings:

Definite CP

• 1 major A criterion (+) ≥3 additional criteria

• 1 major A criterion (+) major B criterion

• 2 major A criteria

Probable CP*

• 1 major A criterion (+) <3 additional criteria

• 1 major B criterion (+) ≥3 additional criteria

• ≥5 additional criteria (any)

Indeterminate CP**

• 3-4 additional criteria, absence of major criteria

• Single major B criterion or in combination with <3 additional criteria

Normal

• <2 additional criteria***, absence of major criteria

_______________________________________________________________________

Note:

*Diagnosis of CP by EUS should be performed in appropriate clinical settings.

**Confirmation by an additional imaging method (ERCP, CT, MRI, or pancreatic function tests – PFTs) is required.

***Except for cysts, MPD dilation, hyperechogenic foci without shadowing, and side branch dilation.

ERCP classification data in CP [58]

Table 3. Classification of pancreatograms in CP

Classification of CP severity based on CT and ultrasound data [58]

Table 4. Cambridge classification of CP based on CT and ultrasound results (81)

Main anthropometric indicators of nutritional status [234]

Mid-arm muscle circumference is calculated by the formula

MAMC (cm) = MU (cm) - 0.314 × TSFT (mm)

MU – mid-arm circumference, TSFT – triceps skinfold thickness

Nutritional status according to TSFT and MAMC:

Nutritional status by BMI

Diagnostic criteria for postoperative pancreatic fistulas following pancreatic surgery, ISGPF2017

Nomenclature of medical services used in the diagnosis and surgical treatment of chronic pancreatitis, as amended by Order of the Russian Ministry of Health No. 217n of April 16, 2019,

Laboratory diagnostics:

• B03.016.002 General (clinical) blood count

• B03.016.003 Complete blood count (detailed)

• B03.016.004 General clinical blood biochemistry test

• B03.016.005 Biochemical blood test for lipid metabolism disorders

• B03.016.006 General urinalysis

• B03.016.010 Coprological examination

• B03.016.017 Comprehensive determination of blood fatty acid concentration

• B03.027.027 Panel of tests for the diagnosis of malignant neoplasms of the pancreas

• A09.05.045 Determination of blood amylase activity

• A09.05.046 Determination of blood alkaline phosphatase activity

• A09.05.180 Determination of pancreatic amylase activity in blood

• A09.28.027 Determination of alpha-amylase activity in urine

• A09.30.009 Determination of amylase activity in peritoneal fluid

Instrumental Diagnostics:

• B03.052.001 Comprehensive ultrasound examination of internal organs

• A06.30.005 Computed tomography of the abdominal organs

• A06.30.005.002 Computed tomography of abdominal and retroperitoneal organs with intravenous bolus contrast enhancement

• A06.30.005.003 Computed tomography of the abdominal organs with intravenous bolus contrast enhancement

• A06.30.005.004 Spiral computed tomography of the abdominal organs with intravenous bolus contrast enhancement, multiplanar and three-dimensional reconstruction

• A06.30.008 Fistulography

• A06.30.008.001 Computed tomography fistulography

• A05.30.005 Magnetic resonance imaging of the abdominal organs

• A05.30.005.001 Magnetic resonance imaging of the abdominal organs with intravenous contrast enhancement

• A05.14.002 Magnetic resonance cholangiography

• A05.15.001 Magnetic resonance imaging of the pancreas

• A05.15.002 Magnetic resonance cholangiopancreatography

• A03.16.001 Esophagogastroduodenoscopy

• A03.16.002 Placement of a nasointestinal tube

• A04.14.003 Endosonography of the pancreatobiliary zone

• A04.16.003 Endosonography of the duodenum

  Surgical and endoscopic treatment

• A16.15.010 Pancreatoduodenal resection

• A16.15.010.002 Pylorus-preserving pancreatoduodenal resection

• A16.15.010.003 Robot-assisted pancreatoduodenal resection

• A16.15.010.004 Robot-assisted pylorus-preserving pancreatoduodenal resection

• A16.15.001.002 Endoscopic pancreatic resection

• A16.15.001.003 Partial resection of the pancreatic head with pancreatojejunostomy (Frey procedure)

• A16.15.002 Suture of pancreatic injury

• A16.15.004 Cystoenterostomy

• A16.15.006 Transduodenal sphincterowirsungoplasty

• A16.15.007 Wirsungoduodenostomy

• A16.15.008 Longitudinal pancreatojejunostomy

• A16.15.009.001 Spleen-preserving distal pancreatic resection

• A16.15.009.002 Distal pancreatic resection with splenectomy

• A16.15.015 External drainage of pancreatic cysts

• A16.15.015.001 Ultrasound-guided drainage of pancreatic cysts

• A16.15.015.002 Ultrasound-guided transcatheter treatment of pancreatic cysts

• A16.15.015.003 Ultrasound-guided occlusion of pancreatic cysts

• A16.15.016 Occlusion of pancreatic fistulas

• A16.15.016.001 Occlusion of external pancreatic fistulas

• A16.15.016.002 Disconnection of internal pancreatic fistulas

• A16.15.017 Excision of pancreatic cysts

• A16.15.019 Creation of pancreato(cysto)jejunostomy

• A16.15.020 Reconstructive interventions for chronic pancreatitis

• A16.14.031.003 Choledochojejunostomy

• A16.14.032 Biliary duct stenting

• A16.14.032.001 Endoscopic wirsungotomy

• A16.14.032.002 Video-endoscopically guided biliary duct stenting

• A16.15.021 Endoscopic stenting of the main pancreatic duct

• A03.16.002 Placement of a nasointestinal tube

• A16.12.041.001 Endovascular vessel occlusion using microcoils

• A16.12.041.002 Endovascular occlusion of aneurysm cavity using microcoils

Appendix B. Physician Action Algorithms

Algorithm 1. Management tactics for a patient with a confirmed diagnosis of chronic pancreatitis

Algorithm 2. Management tactics for a patient with a probable diagnosis of chronic pancreatitis

Algorithm 3. Examination and treatment tactics for a patient with chronic pancreatitis presenting with dominant abdominal pain

Algorithm 4. Surgeon's tactics in chronic pancreatitis

Appendix C. Patient Information

If pancreatitis is suspected, a comprehensive examination is necessary to establish an accurate diagnosis (in the first two to three years of the disease, many laboratory and instrumental parameters may be within normal limits, and clinical signs are not specific to this disease alone). Treatment of chronic pancreatitis involves: dietary compliance, analgesic therapy, vitamin supplementation, enzyme replacement therapy, management of diabetes mellitus and other endocrine disorders, and timely treatment of cholelithiasis.

Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools

Appendix G1. Paddington Alcohol Test

Russian title: Paddington Alcohol Test

Original title (if applicable): The Paddington Alcohol Test

Source Patton R, Hilton C, Crawford MJ, Touquet R. The Paddington Alcohol Test: a short report. Alcohol and alcoholism. 2004;39(3):266-8.

Type (underline):

• rating scale

• index

• questionnaire

Purpose: assessment of alcohol consumption

Contents

Paddington Alcohol Test

Key: The Paddington Alcohol Test (PAT) [279] takes little time and is comparable in sensitivity to AUDIT; it is considered positive (alcohol abuse) if there is a positive response to the 3rd and/or 4th question.

Notes:

Appendix G2. Visual Analog Scale (VAS)

Russian title: Visual Analog Scale (VAS)

Original title (if applicable): Visual analogue scale (VAS)

Source (official developers' website, validation publication): http://img.medscape.com/article/742/580/VAS.pdf

Type (underline):

• rating scale

• index

• questionnaire

Purpose: assessment of pain intensity

Content (template):

Key (interpretation): Each centimeter on the scale corresponds to one point. Thus, pain from 0 to 2 points is classified as mild, from 2 to 4 as moderate, from 4 to 6 as severe, from 6 to 8 as very severe, and up to 10 cm as excruciating.

Explanatory notes: The visual analogue scale is a 10 cm line. Its starting point corresponds to the absence of pain – "no pain", and the end point corresponds to the maximum possible pain intensity – "excruciating pain". The patient is asked to choose a point on the line that corresponds to the intensity of pain they are currently experiencing. The distance from the start of the line to the marked point is measured and rounded to the nearest whole number.

Appendix G3. Digital Pain Rating Scale

Russian title:

Original title (if applicable): Numeric rating scale (NRS)

Source (official developers' website, validation publication): https://www.sciencedirect.com/topics/medicine-and-dentistry/numeric-rating-scale

Type (underline):

• rating scale

• index

• questionnaire

Purpose: assessment of pain intensity

Content (template):

Graphic representation of the numerical rating scale for pain.

Key (interpretation): The NRS consists of a sequential series of numbers from 0 to 10. Patients are asked to rate pain intensity using numbers: 0 – no pain, 5 – moderate pain, and 10 – the worst pain imaginable.

Explanatory notes: An alternative to the VAS is the Numeric Rating Scale (NRS). The advantage of the NRS is that it can be used both in graphical format and verbally (including during telephone interviews).

Appendix G4. Quality of Life Assessment Questionnaires

Russian title:

Original title (if applicable): Short form 36 (SF-36)

Source (official developers' website, validation publication): https://www.rand.org/health-care/surveys_tools/mos/36-item-short-form.html

Wehler M, Reulback U, Nichterlein R et al. Health-related quality of life in chronic pancreatitis: a psychometric assessment. Scan J Gastroenterol 2003; 38:1083 – 9 [280].

Type (underline):

• rating scale

• index

• questionnaire

Purpose: assessment of quality of life

Content (template):

Key (interpretation): http://abdugaliev.ru/proj/medcalc/sf36__

Explanatory notes: Quality of life (QoL) is a universally accepted indicator of a patient's condition that allows for the objectification of subjective sensations. QoL is determined using questionnaires developed through special studies. The questionnaire was created for patients with chronic diseases and is not nosology-specific. The QLQ-C30 questionnaire was originally designed to assess the quality of life of cancer patients, but studies have demonstrated its applicability to patients suffering from CP [280].

Appendix G5. Quality of life assessment questionnaires.

Russian title:

Original title (if applicable): EORTC QLQ-C30

Source (official developers' website, validation publication): https://qol.eortc.org/ Fitzsimmons D, Kahl S, Butturini G et al. Symptoms and quality of life in chronic pancreatitis assessed by structured interview and the EORTC QLQ-C30 and QLQ-PAN26. Am J Gastroenterol 2005; 100: 918 – 26

Type (underline):

• rating scale

• index

• questionnaire

Purpose: assessment of quality of life

Content (template):

Key (interpretation): https://www.eortc.org/app/uploads/sites/2/2018/02/reference_values_manual2008.pdf

Explanatory notes: The QLQ-C30 questionnaire was originally designed to assess the quality of life of cancer patients, but conducted studies have proven the feasibility of its use among patients suffering from chronic pancreatitis.