Pancreatitis

Disease Definition and Causes

Pancreatitis is inflammation of the pancreas (Pancreatitis; from pancreas – pancreas + itĭdis – inflammation). It can manifest with pain in the upper abdomen, swelling, unexplained weight loss, uncontrollable vomiting, and fatty stools, where the stool is difficult to flush and appears greasy.
There are two types of pancreatitis:

1. Acute Pancreatitis: It is acute inflammation not associated with infection, leading to the destruction of pancreatic cells. In this inflammation, pancreatic enzymes start to aggressively affect the pancreas, increasing the area of damage, and secondary infection joins the surrounding tissues and organs.
2. Chronic Pancreatitis: It is long-term inflammation of the pancreas, leading to irreversible changes in its tissue structure and ducts, resulting in pain and/or continuous deterioration of organ function.
   Prevalence of Pancreatitis
   In the last thirty years, the prevalence of acute and chronic pancreatitis has more than doubled worldwide. This increase may be associated with harmful habits such as smoking, alcohol use, in addition to lifestyle patterns and the quality of nutrition.
   Chronic pancreatitis is diagnosed in 27-50 people per 100,000 population. Chronic pancreatitis usually develops between the ages of 35-50, with men experiencing it at a rate twice that of women. After the initial episode of acute pancreatitis or exacerbation of chronic pancreatitis, about 15% of patients lose their ability to work. Within 10 years of the first exacerbation of chronic pancreatitis, up to 20% of patients die, and within 20 years – over 50%. These high mortality rates are associated with inadequate diagnosis, treatment ineffectiveness, including self-treatment, and also with high risks of complications such as abdominal poisoning, blood poisoning, fluid accumulation in the abdomen, cysts, pancreatic damage, etc.

Causes of Pancreatitis

Pancreatitis can occur for several reasons, including types of acute pancreatitis:

• Alcoholic pancreatitis and food poisoning: It occurs due to excessive alcohol consumption and imbalance in diet and quality.
• Biliary pancreatitis: It occurs due to the flow of bile into the pancreatic ducts, which often happens in cases of gallstones and sometimes in cases of diverticulitis, papillary inflammations, and pancreatic worms.
• Traumatic pancreatitis: It occurs due to direct injury to the pancreas, such as car accidents or as a complication of operations or diagnostic tests such as ERCP.
• Pancreatitis due to other causes: It can result from autoimmune diseases, circulatory failure, viral infections (such as mumps, hepatitis, cytomegalovirus), and the effect of certain medications.
  Regarding chronic pancreatitis, the causes include:
• Toxic/metabolic factors: Associated with alcohol intake, smoking, elevated levels of fats or calcium in the blood, chronic kidney failure, and the effects of drugs and poisons.
• Genetic factors: Occur when there is a genetic predisposition to pancreatitis.
• Autoimmunity: Occurs when the body’s immune system attacks the pancreas abnormally.
• Result of recurrent acute and/or severe inflammation: Such as inflammation due to necrosis, blood deficiency, radiation, etc.
• Obstruction: Narrowing (stenosis) of the Oddi muscle, or obstruction by a pancreatic tumor or cyst, or fibrosis of the pancreatic ducts after endoscopic procedures.
• Unknown cause (Idiopathic): Occurs without a known cause.

For Acute Pancreatitis Symptoms:

1. Pain in the upper abdomen (epigastric region), radiating to the back or surrounding the body.
2. Uncontrollable vomiting.
3. Muscle tension in the mid-abdominal area.

For Chronic Pancreatitis Symptoms:

1. Pain in the upper abdomen, sometimes radiating to the back, worsening after meals and alleviating with sitting or leaning forward.
2. Fat malabsorption, manifested in greasy stools that are difficult to flush, abdominal swelling and rumbling, unexplained weight loss over the last six months.
3. Impairment in pancreatic hormone functions, leading to decreased glucose tolerance and the development of diabetes.

In some rare cases, chronic pancreatitis can present as “pain-free,” where the affected individual may not feel pain but other symptoms appear.

Mechanism of Disease Development:
During the progression of pancreatitis, the following processes occur:

1. Injury to pancreatic cells due to its enzymes causing damage as a result of oxidation (oxidative stress).
2. Abnormal immune reaction of the body due to disturbances in fat metabolism (lipid metabolic syndrome).
3. Development of blood capillary thrombosis, i.e., closure of their paths by blood clots.
4. Decrease in oxygen supply to pancreatic cells.
5. Shift in acid-base balance towards oxidation (acidosis).
6. Acceleration of metabolic processes (metabolism).
7. Damage to cell membranes and blood vessels in the pancreas.

Numerous infective factors contribute to these harmful processes in pancreatitis development, which can be categorized into primary, secondary, tertiary, and quaternary factors.

Primary factors impacting are the pancreas’ own enzymes, which exacerbate deterioration when the pancreas is damaged or dysfunctional.

• These enzymes include: proteases and chymotrypsin, which break down pancreatic tissue proteins, and phospholipase A2, which destroys cell membranes.

Secondary factors impacting:

• The activation of pancreatic enzymes by specific proteins in the blood that control blood pressure and coagulation, and participate in inflammation and pain development (the kallikrein-kinin system). Thus, substances like bradykinin, histamine, and serotonin are activated, increasing blood vessel permeability, leading to edema, increased fluid and cellular elements’ extravasation from vessels, and formation of small clots in tiny blood vessels.

Tertiary factors:

• Disruption of fluid transfer in pancreatic tissues triggers defensive cells (such as macrophages, mononuclear cells, neutrophils) to release large amounts of cytokines, contributing to immune suppression.

Quaternary factors:

• Cytokines and enzymes increase intestinal wall permeability, allowing bacteria and toxins to penetrate from the digestive system into the large venous and lymphatic systems, and then to targeted organs: liver, lungs, kidneys, heart, brain, stomach, intestines.

Organ dysfunction and infectious factors lead to a complementary covenant development, where each disorder increases the general condition’s risk.

Classification and Stages of Pancreatitis Development:

• Mild: No pancreatic necrosis or organ failure occurs. Patients experience abdominal pain and uncontrollable vomiting, along with increased muscle tension in the abdominal area.
• Moderate: One of the following signs appears: fluid accumulation or infiltration around the pancreas, limited necrosis, and/or organ failure for up to 48 hours. Symptoms include continuous fever and diarrhea.
• Severe: Bacterial necrosis of the pancreas and/or continuous functional failure develop. Patients experience fever, diarrhea, and severe pain in the upper abdominal parts, and symptoms persist for more than 48 hours.

About 80-85% of acute pancreatitis cases indicate a mild form, which is easier to manage and rarely causes complications. This form may present with pain or discomfort in the upper abdomen, nausea, and digestive disturbances, sometimes accompanied by diarrhea.

Approximately 15-20% of acute pancreatitis cases indicate a necrotizing (pancreatic) form. The necrotic form is characterized by periods of life-threatening complications and is divided into two stages during the intermediate and severe periods:

Early stage:

• A: The first 7 days of the disease. During this period, necrotic foci form in the pancreatic tissue or in the surrounding tissues, leading to toxemia. It can result in dysfunction of many organs and the development of cardiopulmonary, respiratory, renal, and hepatic failure. Difficulty breathing, changes in blood pressure, general fatigue, increased pain in the upper abdomen, and fever occur.

B: From 7 to 14 days of the disease. The body reacts to the necrotic accumulations formed in the pancreas and surrounding tissues: sudden fever rises, infiltration around the pancreas occurs (i.e., inflammatory fluids accumulate), accompanied by pain in the upper abdomen.

Late stage (from the third week of the disease to several months). An isolated fluid accumulation forms in the pancreatic area, and pseudocysts develop. In case of infection, pancreatic tissues and surrounding tissues die, leading to the development of purulent complications. These complications can progress to abscesses in the abdominal cavity and in fat spaces, peritoneal membrane inflammation, bleeding in the digestive tract, and the formation of abscesses, wound inflammation, blood poisoning, and other complications affecting various body functions.

Chronic Pancreatitis Classification:

Based on Etiology:

1. Biliary: Resulting from gallstones or bile duct obstruction, cysts, tumors, or specific muscle disorders like Oddi’s sphincter dysfunction.
2. Alcoholic: Caused by consuming over 60-80 ml of alcohol per day for 10-15 years, combined with smoking.
3. Metabolic: In cases of chronic kidney failure, thyroid gland overactivity, injury resulting from vascular diseases like arteriosclerosis, among others.
4. Infectious: Presence of parasites like amoebas and others.
5. Drug-induced: Persistent warnings in medical leaflets about the risk of pancreatitis due to medication, though there are no conclusive data yet on any specific drug definitively causing the condition.
6. Autoimmune: Isolated or associated with syndromes like Sjogren’s syndrome, inflammatory bowel diseases like Crohn’s disease and ulcerative colitis, and many other autoimmune diseases.
7. Idiopathic: Of unknown cause.

Clinical Phenomena:

1. Painful: Pain in the epigastric region, radiating to the back and/or showing neuralgic character.
2. Digestive: Nausea, regurgitation, vomiting tendency, heartburn, swelling, digestive system disorders, etc.
3. Varied: Symptoms from the above points.
4. Latent: Manifests covertly, rarely detected during routine check-ups.

Nature of Clinical Evolution:

1. Rare Recurrent: Episodes recur less than once every 3 months.
2. Frequently Recurrent: More than once every 3 months.
3. With Steady Symptoms.

Clinical Stages:

1. Preclinical Stage: Signs appear only according to ultrasound examination results. Prognosis depends on the cause of pancreatic sclerosis, the severity of inflammation, and the body’s response to it.
2. First Stage: Onset of initial symptoms (repeated pain episodes, recurrent pancreatitis attacks, deteriorating quality of life). Symptom duration ranges from 4-7 years. Expectations: Increased risk of pancreatic clots formation and other complications due to worsening inflammation.
3. Second Stage: Persistent symptoms (repeated pain, decreased elastase-1 enzyme in feces, pre-diabetes). At this stage, the body doesn’t receive enough nutrients.
4. Third Stage: Continued Symptoms (repeated pain, decreased elastase-1 enzyme in feces, pre-diabetes). At this stage, the body doesn’t receive enough nutrients.
5. Fourth Stage: Pancreatic sclerosis (pain becomes less severe, enzyme deficiency worsens, pancreatic inflammation exacerbates). Expectations: Weight and muscle loss may occur, diabetes may develop, with an increased risk of pancreatic cancer.

These classifications illustrate the progression and causes of pancreatic sclerosis, in addition to the nature of clinical phenomena and stages. Always consult a physician for accurate diagnosis and proper management.

Complications of Pancreatitis:
Complications of pancreatitis include mechanical jaundice – obstructive jaundice (in 16-35% of patients) obstructing the flow of bile and the passage of duodenal contents (food from the stomach mixed with bile from the liver and gallbladder, as well as pancreatic juice from the pancreas), pseudocysts, hormonal disorders, pancreatic necrosis with gland development, cysts, parapancreatitis, cholecystitis, pneumonia, peritonitis, pleurisy, and other diseases. About two-thirds of patients with chronic pancreatitis carry asymptomatic pseudocysts.

Also, malabsorption syndrome appears with a deficiency of essential nutrients, possibly due to the growth of connective tissue and the appearance of fibrous changes in the pancreas, in addition to taking enzyme preparations uncontrollably. Deficiencies in vitamins A, D, E, K, and B12 often occur, leading to the development of osteoporosis.

The risk of pancreatic cancer increases eightfold in patients with pancreatitis over five years. Rare complications such as corrosive esophagitis, intestinal malabsorption syndrome, Mallory-Weiss syndrome, gastric and duodenal ulcers, left abdominal click syndrome, portal vein hypertension, and bleeding from the stomach or esophagus are also possible.

Diagnosis of Pancreatitis:
The diagnosis of pancreatitis includes physical examination, palpation, laboratory tests, and tools.

Diagnosis of Acute Pancreatitis:
Examination: The patient is anxious, with a body temperature often between 37.1 and 39 degrees Celsius, accelerated heart rate, and purple spots on the face (Mondor’s sign) – these spots are associated with the effect of enzymes and circulatory disorders. Bluish spots (cyanosis) can also be seen on the abdominal sides of the body (Gray-Turner sign), and around the navel (Cullen’s sign), and dryness of the tongue may occur.

Palpation: Pain in the chest cage area, and rarely, severe pain may be felt when pressure is applied to the abdomen and intensifies sharply when the hand is pulled away (Shtikken – Blomberg sign). The abdominal artery pulse may not be felt (Foskrescinski’s sign), and there may be sensitivity when palpating the tail of the pancreas area (Mayo-Robson sign), and in the area of the thoracic vertebrae: eighth and ninth – on the left and ninth and eleventh – on the right (Kaka’s sign).

Laboratory Tests:

• Complete blood count.
• Complete urine analysis.
• Chemical blood analysis (total protein, total and direct bilirubin, AST, ALT, urea, creatinine, glucose, coagulation, C-reactive protein, amylase, and lipase; key markers that may indicate acute pancreatitis are amylase and lipase).
  Instrumental Examination:
• Abdominal ultrasound. Signs of acute pancreatitis: pancreatic enlargement, fuzzy borders, presence of fluid in the abdominal cavity and in the peritoneal cavity, and other manifestations.
• Computerized tomography (CT) or magnetic resonance imaging (MRI) of the abdominal cavity organs. They allow assessing the severity of the condition and are performed in cases where conservative treatment does not lead to improvement. MRI is preferred, but if not feasible or contraindicated (such as presence of metal in the body), CT is performed.
• Endoscopic ultrasound (EndoUSI) – in case of suspicion of gallstones in pancreatitis associated with the gallbladder.
• Laparoscopy – when it is difficult to make a diagnosis using the above-mentioned tests.

Diagnosis of Chronic Pancreatitis:

Laboratory Tests:

• Chemical analysis of blood and urine – increased levels of alpha-amylase and lipase indicate chronic pancreatitis.
• Stool analysis for pancreatic elastase 1 – to determine the deficiency of pancreatic exocrine enzymes.
• Analysis of free fats in stool – not very informative in diagnosing chronic pancreatitis.
• Blood tests for glycosylated hemoglobin (HbA1c), fasting glucose level, and glucose tolerance test – to diagnose pre-diabetes or diabetes.
• Blood antibody tests to determine IgG4 – to detect autoimmune pancreatitis.

Instrumental Examination:

• Abdominal ultrasound and small pelvis space ultrasound – in case of pancreatitis, pancreatic enlargement, areas of fibrosis, and calcifications can be seen, as well as other distinctive signs.
• Contrast-enhanced computed tomography (CT) of abdominal cavity organs – performed when there are no clear signs of pancreatitis on ultrasound.
• Endoscopic ultrasound (EndoUSI) – helps differentiate chronic pancreatitis from other inflammatory diseases and tumors in the pancreas.
• Magnetic resonance imaging (MRI) – used to evaluate changes in the pancreatic gland and check for any calcifications.
• Cardiac exclusions – to rule out cardiac causes of pain.
• Other tests depending on clinical condition and medical history.

Treatment of Pancreatitis:

• In case of acute pancreatitis, all patients are transferred to the surgery department where basic treatment is provided, including fasting for a day, detoxification treatment (administration of necessary medications intravenously), and taking medications that reduce smooth muscle tone and decrease bile acid secretion. This treatment is carried out to avoid surgery like laparoscopy or any other individually determined methods.
• Rehabilitation after acute pancreatitis treatment includes exposure to ultraviolet rays (UV), solux, electromagnetic heating of the abdominal area, clay applications, and introduction of iodine preparations into the abdominal area using a constant electric current. These methods are described in clinical recommendations, but there are not enough studies confirming their effectiveness.
• In case of chronic pancreatitis, it is advised to consult a physician as self-treatment may lead to complications and patient death. It is preferable to quit alcohol and smoking, eat small meals throughout the day, and increase protein and carbohydrate intake.
• The physician may prescribe vitamins A, D, E, K, B1, B2, B6, B12 as needed. Pain relievers or nonsteroidal anti-inflammatory drugs may also be prescribed in case of severe pain, and antidepressants may be prescribed to reduce pain and enhance the effect of pain relievers.
• In case of exacerbation and development of complications, surgical treatment or endoscopic therapy may be necessary.

Sources:

1. Russian Society of Surgeons. Chronic Pancreatitis: Clinical Recommendations. — Moscow, 2020. — 81 p.
2. Russian Society of Surgeons. Acute Pancreatitis: Clinical Recommendations. — Moscow, 2020. — 38 p.
3. Tsisyk A.Z., Kruglik N.A., Romashkevichus S.K. Latin for Pharmaceutical Faculty Students: Educational and Methodical Guide in 2 Parts. Part 2. — Minsk: BSMU, 2012. — 108 p.