Chronic pancreatitis

Chronic pancreatitis is a long-lasting condition and slowly destroys the functions of the pancreas. Chronic pancreatitis represents the end result of a continuous, prolonged, inflammatory, and scarring process that affects the pancreas. The pancreas does not heal or improve. Instead, it gets worse over time, which can lead to permanent damage to your pancreas endocrine and exocrine tissues and in some cases, development of pancreatic cancer ¹, ². For example, the pancreas may lose its ability to produce insulin and glucagon and digestive enzymes (pancreatic digestive juices). As a result, you can develop glucose intolerance or diabetes. Chronic pancreatitis can also cause weight loss because your body may be unable to digest fat and key elements of food. Chronic pancreatitis different from acute pancreatitis, where the pancreatic inflammation is only short term. Most people with chronic pancreatitis have had 1 or more attacks of acute pancreatitis. Chronic pancreatitis is less common than acute pancreatitis, with about 86,000 hospital stays per year ³. In the US, chronic pancreatitis affects African Americans more frequently than caucasians ⁴. In addition, chronic pancreatitis due to alcohol is more common in males, whereas that due to hyperlipidemia is more common in females ⁴. The median age at diagnosis of chronic pancreatitis is 45.

The most common cause of chronic pancreatitis in adults is excessive alcohol consumption in developed countries ⁵, ⁶, ⁷, ⁸, ⁹, ¹⁰. Chronic pancreatitis was formerly thought that malnutrition in developing countries was a cause of chronic pancreatitis, but this myth has since been dispelled ¹¹. Cigarette smoking has been reported to be an independent risk factor for developing chronic pancreatitis ¹² and increases its rate of progression ¹³, ¹⁴.

The major risk factors for the development of chronic pancreatitis may be categorized according to the TIGAR-O system ¹⁵:

• T: Toxic-metabolic (e.g. alcohol)
• I: Idiopathic, recent guidelines recommend that cystic fibrosis needs to be ruled out in these patients before calling it idiopathic ¹⁶
• G: Genetic more commonly seen in children ¹⁷
• A: Autoimmune pancreatitis
• R: Recurrent pancreatitis. Repeated episodes of acute pancreatitis can lead to chronic pancreatitis.
• O: Obstructive (e.g. choledocholithiasis, pancreatic head tumor)

Complications of chronic pancreatitis include:

• chronic pain in your abdomen
• maldigestion, when you can’t digest food properly
• malnutrition and malabsorption
• problems with how well your pancreas works
• scars in your pancreas
• diabetes
• pancreatic cancer, which is more likely in people with both diabetes and pancreatitis
• osteopenia, osteoporosis and bone fractures

Diagnosing chronic pancreatitis relies on changes in diagnostic imaging and blood work in addition to clinical symptoms. The histologic hallmarks of chronic pancreatitis include scar tissue (fibrosis), chronic inflammation, and loss of acinar cells ². Because histologic diagnosis is rarely pursued given the potential for complications, there is a need for a noninvasive biomarker of pancreatic fibrosis. As defined by the International Study Group of Pediatric Pancreatitis: In Search for a Cure (INSPPIRE) consortium ¹⁸, chronic pancreatitis requires imaging findings characteristic of and consistent with chronic pancreatitis (specifically, radiographically evident calcifications, and pancreatic duct irregularities, such as strictures and dilations) along with 1 of the following 3: abdominal pain consistent with pancreatic origin, evidence of exocrine pancreatic insufficiency, or evidence of endocrine pancreatic insufficiency, or a pancreatic biopsy specimen demonstrating histological evidence of chronic pancreatitis.

In chronic pancreatitis, the pancreas is permanently damaged, but treatment can help control the condition and reduce any symptoms. People with chronic pancreatitis are usually advised to make lifestyle changes, such as stopping drinking alcohol and stopping smoking. They’re also given medicine to relieve pain. Surgery may also be an option for those experiencing severe pain.

People with severe pain or who are losing weight may need to stay in the hospital for:

• Pain medicines.
• Fluids given through a vein (IV).
• Stopping food or fluid by mouth to limit the activity of the pancreas, and then slowly starting an oral diet.
• Inserting a tube through the nose or mouth to remove the contents of the stomach (nasogastric suctioning) may sometimes be done. The tube may stay in for 1 to 2 days, or sometimes for 1 to 2 weeks.

The right diet is important for people with chronic pancreatitis to keep a healthy weight and get the correct nutrients. A nutritionist can help you create a diet that includes:

• Drinking plenty of liquids
• Limiting fats
• Eating small, frequent meals (this helps reduce digestive symptoms)
• Getting enough vitamins and calcium in the diet, or as extra supplements
• Limiting caffeine

Your doctor may prescribe pancreatic enzymes. You must take these medicines with every meal, and even with snacks. The enzymes will help you digest food better, gain weight and reduce diarrhea.

Avoid smoking and drinking alcoholic beverages, even if your pancreatitis is mild.

Other treatments may involve:

• Pain medicines or a surgical nerve block to relieve pain
• Taking insulin to control blood sugar (glucose) level
• Steroid medicine is recommended for people with chronic pancreatitis caused by problems with the immune system because it helps to relieve the inflammation of the pancreas.

Surgery may be performed if a blockage is found. In severe cases, a part of or the entire pancreas may be removed.

Figure 1. Chronic pancreatitis (contrast material–enhanced CT image of chronic pancreatitis)

Footnote: Images in a 49-year-old patient with history of alcohol abuse, chronic pancreatitis and cirrhosis. (a) Oblique axial contrast material–enhanced CT image shows moderately to markedly irregular pancreatic duct contour (white arrow) and stricture in pancreatic neck causing upstream ductal dilatation (black arrow). Distribution of findings is greater than 70% because there are features of chronic pancreatitis involving entire pancreas. Relatively less enhancement of parenchyma is shown in region of head compared with body and tail. Delayed enhancement pattern is nonspecific; however, it can be seen with fibrosis. (b) Oblique coronal contrast-enhanced CT image shows head, neck, and body of pancreas with more than seven coarse calcifications (arrow). Largest pancreatic duct caliber is measured as shown with white line. (c) Axial contrast-enhanced CT image shows measurement of pancreatic thickness in patient with pancreatic duct dilatation, measured perpendicular to longitudinal axis of parenchyma at level of lateral margin of adjacent vertebral body (VB) or upstream to pancreatic duct calculus or stricture. Splenic vein (SV) and artery in measurement should be avoided.

What is acute pancreatitis?

Acute pancreatitis is inflammation of the pancreas. Acute pancreatitis happens when digestive enzymes start digesting the pancreas itself. Acute pancreatitis occurs suddenly and is a short-term condition, meaning it appears suddenly and lasts for days ¹⁹, ²⁰. Most people with acute pancreatitis get better, and it goes away in several days with treatment. But some people can have a more severe form of acute pancreatitis and go on to develop serious complications, which requires a lengthy hospital stay. Acute pancreatitis is different to chronic pancreatitis, where the pancreas has become permanently damaged from inflammation over many years. Acute pancreatitis affects men more often than women. Acute pancreatitis is becoming more common, for reasons that are not clear ²¹. Acute pancreatitis is the cause of up to 275,000 hospitalizations in the United States per year, incurring nearly $2.6 billion in hospitalization costs ²², ²³, ²⁴. The incidence of acute pancreatitis in children is at 10–15 cases per 100,000 children ²⁵. While mild acute pancreatitis carries a mortality of <1%, mortality rates for severe pancreatitis can reach as high as 30% ²⁶. Drugs are responsible for 0.1%-2% of acute pancreatitis incidents. The majority of drug-induced pancreatitis cases are mild to moderate in severity; however, severe and even fatal cases can occur. Although pancreatitis is rare in children, the number of children with acute pancreatitis has grown.

Repeat episodes of acute pancreatitis may lead to chronic pancreatitis. Other complications of acute pancreatitis include:

• dehydration
• bleeding
• infection

Most cases of pancreatitis are caused by overuse of alcohol ²⁷, ²⁸. Alcohol use is responsible for up to 70% of cases of acute pancreatitis in the United States. About 5 to 8 drinks per day for 5 or more years can damage the pancreas ²⁹. Gallstones are the next most common cause of acute pancreatitis ³⁰, ³¹. When the gallstones travel out of the gallbladder into the bile ducts, they block the opening that drains bile and enzymes. The bile and enzymes “back up” into the pancreas and cause swelling. Besides overuse of alcohol and gallstones, other causes of pancreatitis include:

• Heredity — Hereditary pancreatitis is a rare genetic disorder that predisposes a person to develop the disease, usually before age 20 ³².
• Genetic causes — Mutations of the cystic fibrosis gene is the most widely recognized genetic cause.
• Blockage of the duct that drains digestive enzymes from the pancreas — If the enzymes don’t drain properly, they can back up and damage the pancreas. Blockage can be caused by gallstones, scarring from prior surgery, tumors, pancreatic cancer or abnormalities of the pancreas or of the shape or location of the pancreatic duct. If the blockage is found early, surgery or a procedure called endoscopic retrograde cholangiopancreatography (ERCP) to relieve the blockage may help to prevent damage to the pancreas. Endoscopic retrograde cholangiopancreatography (ERCP), a procedure used to treat gallstones, also can lead to pancreatitis.
• Autoimmune pancreatitis — For unexplained reasons, some people develop antibodies that attack their own pancreas.
• Very high blood triglyceride levels (hypertriglyceridemia) – most often above 1,000 mg/dL ³³, ³⁴, ³⁵, ³⁶.
• Damage to the ducts or pancreas during surgery
• After certain procedures used to diagnose gallbladder and pancreas problems (endoscopic retrograde cholangiopancreatography, ERCP) or ultrasound guided biopsy ³⁷, ³⁸
• Injury to the pancreas from an accident
• Overactive parathyroid gland (hyperparathyroidism)
• Reye syndrome
• Use of certain medicines (especially estrogens, corticosteroids, sulfonamides, thiazides, and azathioprine) ³⁹, ⁴⁰
• Certain infections, such as viral infections (e.g. mumps, cytomegalovirus, coxsackie B virus) that involve the pancreas
• Smoking. Although heavy smokers tended to be heavy drinkers, smoking itself was a significant risk factor for acute pancreatitis, recurrent acute pancreatitis and chronic pancreatitis ⁴¹, ⁴²

Sometimes, a cause for pancreatitis is never found. This is known as idiopathic pancreatitis.

The most common symptoms of acute pancreatitis include ⁴³:

• suddenly getting severe pain in the center of your abdomen (belly) that radiates to your back
• feeling or being sick (nausea and vomiting)
• a high temperature of 38°C (100.4°F) or more (fever)

Acute pancreatitis is usually diagnosed in hospital, where you’ll receive treatment and be monitored for any complications. A doctor will ask you about your symptoms, family history and may feel your abdomen – it will be very tender if you have acute pancreatitis. They’ll also do a blood test, and sometimes a CT scan, to help confirm the diagnosis.

At first, it can be difficult to tell whether your acute pancreatitis is mild or severe. You’ll be monitored closely for signs of serious problems, such as organ failure.

You may have further tests to help determine the severity of your condition and assess your risk of developing more serious complications. These may include:

• a CT scan of your abdomen – where a series of X-rays are taken to build up a more detailed image of your pancreas
• a MRI scan of your abdomen – where strong magnetic fields and radio waves are used to produce a detailed image of the inside of your body
• an ultrasound scan of your abdomen – where sound waves are used to create a picture of your gallbladder to detect gallstones, and a picture of your pancreas

A diagnosis of acute pancreatitis requires 2 out of 3 criteria ⁴⁴, ⁴⁵:

• Abdominal pain consistent with pancreatitis,
• A serum amylase or lipase three or more times the upper limit of normal, and
• Findings consistent with pancreatitis on cross-sectional abdominal imaging [in adults: computed tomography (CT) or magnetic resonance imaging (MRI); in children CT, MRI or in some cases transabdominal ultrasound (TUS)].

Acute pancreatitis is treated in hospital, where you’ll be closely monitored for signs of serious problems and given supportive treatment, such as fluids, painkillers (analgesics), oxygen and nutrition ⁴⁶. Treatment for acute pancreatitis aims to help control the condition and manage any symptoms you may have. You may be given fluids directly into a vein (intravenous fluids), pain relief, liquid food through a tube in your abdomen and oxygen through tubes in your nose. A nil-by-mouth regimen to rest the gut, routine use of prophylactic antibiotics, and avoidance of early opiate analgesia have been invalidated in randomised trials, and do not feature in international guidelines ⁴⁷, ⁴⁸, ⁴⁵.

Most people with mild acute pancreatitis get better within a week and are well enough to leave hospital after a few days.

Recovery can take longer in severe cases, as some people can develop complications.

Those with severe acute pancreatitis can develop complications that require further treatment and may need to be admitted to a high-dependency unit or intensive care unit (ICU). Recovery may take much longer from severe acute pancreatitis, and there’s a risk it could be fatal ⁴⁹.

What is hereditary pancreatitis?

Hereditary pancreatitis is a rare genetic condition characterized by multiple recurrent episodes of inflammation of the pancreas (pancreatitis), which can progress to chronic pancreatitis. Hereditary pancreatitis is a rare cause of acute, recurrent acute, and chronic pancreatitis ⁵⁰. Hereditary pancreatitis symptoms include recurring bouts of severe abdominal pain, nausea, and vomiting, that usually require opiate analgesia for pain relief ⁵¹. Onset of symptoms typically occurs before the age of ten years, but can begin at any age ⁵², ⁵⁰, ⁵³. In the United States, it is estimated that at least 1,000 individuals are affected with hereditary pancreatitis. People with hereditary pancreatitis develop chronic pancreatitis, a constantly inflamed pancreas. This leads to symptoms which may include fatty stools, weight loss, and poor absorption of nutrients from food.

Adults with hereditary pancreatitis are at an increased risk for type 1 diabetes, pancreatic exocrine failure and pancreatic cancer (adenocarcinoma of the pancreas) ⁵⁴, ⁵⁵, ⁵⁶, ⁵⁷. Pancreatic cancer is the 4th most leading cause of cancer deaths among Americans. Individuals with hereditary pancreatitis appear to have a 40% lifetime risk of developing pancreatic cancer ⁵⁸. This increased risk is heavily dependent upon the duration of chronic pancreatitis and environmental exposures to alcohol and smoking. One recent study suggested that individuals with chronic pancreatitis for more than 25 years had a higher rate of pancreatic cancer when compared to individuals in the general population ⁵⁸. This increased pancreatic cancer rate appears to be due to the prolonged chronic pancreatitis rather than having a gene mutation (all cationic trypsinogen mutations). It is important to note that these risk values may be higher than expected because these studies on pancreatic cancer use a highly selective population rather than a randomly selected population.

Hereditary pancreatitis was first recognized by Comfort and Steinberg as a clinical syndrome in 1952 ⁵⁹ and mutations in the cationic trypsinogen (serine protease 1) gene (PRSS1 gene) on chromosome 7q were identified as major etiological factors in 1996 ⁶⁰, ⁵⁴, ⁶¹, ⁶². More than twenty pathogenic PRSS1 gene mutations have since been described, accounting for 80% of all cases of hereditary pancreatitis in people of European ancestry ⁶⁰, ⁵⁴, ⁶¹, ⁶². The two most commonly identified pathogenic PRSS1 mutations are p.R122H and p.N29I (90%), while less common mutations include A16V, R122C, N29T, D22G, and K23R ⁶³, ⁶⁴. Other implicated genes include those that encode serine protease inhibitor Kazal‐type 1 (SPINK1, on chromosome 5q32), cystic fibrosis transmembrane conductance regulator (CFTR), chymotrypsin C (CTRC), and A‐type carboxypeptidase (CPA1) ⁵⁴, ⁶¹, ⁶⁵. Modifier genes, such as the calcium‐sensing receptor gene (CASR), also influence the risk of hereditary pancreatitis ⁶⁶.

In most cases, hereditary pancreatitis is due to a PRSS1 gene that is not working correctly and is inherited in an autosomal dominant pattern ⁶², ⁶⁷, ⁶⁸. Internationally, the majority of PRSS1 mutations have been identified in the USA ⁶⁹ and Europe ⁶³, though few have also been reported from Japan ⁷⁰, South America ⁷¹ and Thailand ⁷².To date, hereditary pancreatitis has not been reported in patients of African ancestry ⁶⁰.

In hereditary pancreatitis, inflammation is initially restricted to the acinar and ductal cells, leading to pancreatic exocrine insufficiency; the pancreatic islets are affected only late in the disease process ⁵² and patients require pancreatic enzyme replacement long before diabetes develops ⁷³, ⁷⁴. As many as 60% of people with symptomatic pancreatitis will ultimately require surgical interventions (including endoscopic procedures) because of severe abdominal pain, with unavoidable loss of pancreatic function ⁵⁷, ⁷⁴.

Hereditary pancreatitis diagnosis is based on the symptoms, a clinical history and exam, and the results of genetic testing. Criteria for genetic testing for hereditary pancreatitis, when patients meet one or more of the following criteria ⁷⁵:

• A family history of idiopathic chronic pancreatitis, recurrent acute pancreatitis, or childhood pancreatitis
• Relatives with known mutations associated with hereditary pancreatitis
• Unexplained pancreatitis in a child
• Idiopathic chronic pancreatitis in patients <25 years old
• Recurrent acute pancreatitis of uncertain etiology
• Patients who are eligible for enrollment in approved research trials

At this time, there is no cure for hereditary pancreatitis. Patients with hereditary pancreatitis should be managed in the same way as patients who present with pancreatitis from other causes ⁵⁰. Treatment is focused on managing the symptoms and may include medications, surgery, and surveillance for diabetes and cancer. Patients may be prescribed pancreatic enzyme supplements to treat maldigestion, insulin to treat diabetes, analgesics and narcotics to control pain, and lifestyle changes to reduce the risk of pancreatic cancer (for example, no smoking and no drinking alcohol).

Dietary recommendations to help control pain with digestion include the consumption of small meals throughout the day that are high in carbohydrates and low in protein and fat. Pancreatic enzymes such as Creon, Pancrease, and Violiase are helpful in providing improved digestion and a reduction in diarrhea and pain for some patients with more advanced disease.

Exposure to smoking and alcohol are known to dramatically increase the risk for pancreatic attacks among individuals with hereditary pancreatitis. Smoking is strongly discouraged as it doubles the risk for pancreatic cancer ⁷⁶. Similarly, alcohol consumption is not recommended for these patients as no safe amount of alcohol use has been documented, because alcohol is a known risk factor for both acute and chronic pancreatitis. Therefore it is recommended that all hereditary pancreatitis patients avoid smoking and alcohol consumption. Though harder to control, dietary fat and emotional stress are considered triggers and should also be avoided ⁶⁴. Finally, the risk and benefit of the use of medications that have been associated with drug-induced pancreatitis (eg, ACE inhibitors, HMG co-A reductase inhibitors, and selective serotonin reuptake inhibitors) should be individualized to the patient ²³.

Overall survival in hereditary pancreatitis PRSS1 carriers appears to be similar to the general population ⁶⁰, ⁷⁷. However, if a patient with hereditary pancreatitis develops pancreatic cancer, it usually presents 20 years earlier than in the general population and thus results in an earlier and increased mortality ⁷⁸. Cancer was the most frequent cause of death in PRSS1 carriers (32.4%), of which less than half (42%) were from pancreatic cancer ⁷⁹, ⁸⁰. Interestingly, non-malignant pancreatic disease was mentioned on death reports as the second most common cause (21.6%), followed by cardiovascular disease (13.5%), which was different than the only other report on hereditary pancreatitis causes of death ⁷⁷.

Pancreas anatomy

The pancreas is a large gland that sits behind the greater curvature of the stomach and close to the first part of the small intestine (the duodenum). The pancreas is shaped a bit like a fish with a wide head, a tapering body, and a narrow, pointed tail. In adults it’s about 12–15 cm (5–6 inches) long and 2.5 cm (1 in.) thick but less than 2 inches (5 centimeters) wide. The pancreas is both an endocrine and exocrine gland (see Figures 1 and 2).

The pancreas has 3 parts, the head, body, and tail.

• the wide end is called the head. The head of the pancreas is on the right side of the abdomen (belly), behind where the stomach meets the duodenum (the first part of the small intestine).
• the bit in the middle is called the body. The body of the pancreas is behind the stomach.
• the thin end is called the tail. The tail of the pancreas is on the left side of the abdomen next to the spleen.

About 99% of the pancreas is exocrine tissue made up of small clusters of glandular epithelial cells called acinar cells (acini), which secretes 1,200 to 1,500 mL of pancreatic juice per day – that are released into the small intestines to help you digest foods (especially fats). The digestive enzymes are first released into tiny tubes called central ducts. These merge to form larger ducts, which empty into the pancreatic duct (duct of Wirsung). The pancreatic duct merges with the common bile duct (the duct that carries bile from the liver), and empties into the duodenum (the first part of the small intestine) at the ampulla of Vater (also known as the hepatopancreatic ampulla). The ampulla of Vater (hepatopancreatic ampulla) is where the pancreatic duct and bile duct join together to drain into the duodenum, which is the first part of the small intestine. The passage of pancreatic juice and bile through the hepatopancreatic ampulla (ampulla of Vater) into the duodenum of the small intestine is regulated by a mass of smooth muscle surrounding the ampulla known as the sphincter of the hepatopancreatic ampulla, or sphincter of Oddi. The other major duct of the pancreas, the accessory duct (duct of Santorini), that branches from the main pancreatic duct and opens independently into the duodenum about 2.5 cm (1 in.) superior to the hepatopancreatic ampulla (ampulla of Vater) at the minor duodenal papilla. The accessory duct (duct of Santorini) bypasses the sphincter and allows pancreatic juice to be released into the duodenum even when bile is held back.

The endocrine part of the pancreas consists of groups of cells that are closely associated with blood vessels. These remaining 1% of the cell clusters form “islands” of cells called pancreatic islets (Islets of Langerhans). The Islets of Langerhans cells secrete the hormones glucagon, insulin, somatostatin, and pancreatic polypeptide (PP). Islets of Langerhans main cell types are alpha cells (20%), beta cells (70%), and delta cells (5%). The pancreatic islets alpha cells secrete the hormone glucagon, and beta cells secrete the hormone insulin (Figure 2). Both insulin and glucagon are important hormones which help control blood sugar levels and are released directly into the bloodstream.

The Islets of Langerhans Delta (δ) cells, or D cells, secrete somatostatin (growth hormone–inhibiting hormone) concurrently with the release of insulin by the beta cells. Somatostatin is a peptide hormone that inhibits the secretion of glucagon and insulin by the nearby alpha and beta cells. Somatostatin also work with amylin to limit the secretion of stomach acid.

Other, minor types of pancreatic cells, about 5% of the total, are called pancreatic polypeptide (PP) and G cells. Pancreatic polypeptide (PP) cells secrete pancreatic polypeptide, a hormone that may inhibit the exocrine activity of the pancreas.

Pancreatic islets (Islets of Langerhans) are relatively concentrated in the tail of the pancreas, whereas the head is more exocrine. Over 90% of pancreatic cancers arise from the ducts of the exocrine portion (ductal carcinomas), so cancer is most common in the head of the pancreas.

Figure 2. The pancreas

Figure 3. Pancreas cell types

Footnotes: Exocrine pancreatic acinar cells constitute most of the pancreatic tissue, these cells produce digestive enzymes which are transported via the pancreatic ducts. The endocrine pancreas is illustrated with all cell types; alpha, beta, delta, pancreatic polypeptide (PP) and epsilon. The endocrine pancreas cells are arranged in compact Islets of Langerhans and secrete a number of classical and ‘nonclassical’ peptides, as depicted.

Figure 4. Pancreas location

Figure 5. Relationship of the pancreas to the liver, gallbladder, and duodenum

Pancreas function

The pancreas has two main functions—to make insulin and to make digestive juices, or enzymes, to help you digest food in the intestine. About 99% of the pancreas is exocrine tissue made up of small clusters of glandular epithelial cells called acinar cells (acini), which secretes 1,200 to 1,500 mL of pancreatic juice per day – that are released into the small intestines to help you digest foods (especially fats). The cells of the secretory acini exhibit a high density of rough ER (endoplasmic reticulum) and secretory vesicles (zymogen granules). The acini open into a system of branched ducts that eventually converge on the main pancreatic duct. This duct runs lengthwise through the middle of the gland and joins the bile duct at the hepatopancreatic ampulla (ampulla of Vater). The hepatopancreatic sphincter (sphincter of Oddi) thus controls the release of both bile and pancreatic juice into the duodenum. Usually, however, there is a smaller accessory pancreatic duct (duct of Santorini) that branches from the main pancreatic duct and opens independently into the duodenum at the minor duodenal papilla, proximal to the major papilla. The accessory duct (duct of Santorini) bypasses the hepatopancreatic sphincter (sphincter of Oddi) and allows pancreatic juice to be released into the duodenum even when bile is held back.

Pancreatic juice is an alkaline mixture of water, enzymes, zymogens, sodium bicarbonate, and other electrolytes. The acini secrete the enzymes and zymogens, whereas the ducts secrete the sodium bicarbonate. The bicarbonate buffers HCl (hydrochloric acid) arriving from the stomach.

Sodium bicarbonate buffers the hydrochloric acid arriving from the stomach, with the reaction:

• HCl + NaHCO3 ⟶ NaCl + H2CO3 (carbonic acid).

The carbonic acid then breaks down to carbon dioxide (CO2) and water. CO2 is absorbed into the blood and ultimately exhaled. What is left in the small intestine, therefore, is salt water—sodium chloride (NaCl) and H2O. Sodium bicarbonate is therefore important in protecting the intestinal mucosa from hydrochloric acid (HCl) as well as raising the intestinal pH to the level needed for activity of the pancreatic and intestinal digestive enzymes.

The pancreatic zymogens are trypsinogen, chymotrypsinogen and procarboxypeptidase. When trypsinogen is secreted into the intestinal lumen, it is converted to trypsin by enteropeptidase, an enzyme on the brush border of the duodenum. Trypsin is autocatalytic—it converts trypsinogen into still more trypsin. Trypsin also converts the other two zymogens into chymotrypsin and carboxypeptidase, in addition to its primary role of digesting dietary protein.

Pancreatic acinar cells also secrete a protein called trypsin inhibitor that combines with any trypsin formed accidentally in the pancreas or in pancreatic juice and blocks its enzymatic activity.

Other pancreatic enzymes include pancreatic amylase, which digests starch; pancreatic lipase, which digests fat; and ribonuclease and deoxyribonuclease, which digest RNA and DNA, respectively. Unlike the zymogens, these enzymes are not altered after secretion. They become fully active, however, only upon exposure to bile or ions in the intestinal lumen.

Regulation of Pancreatic Secretion

Three stimuli are chiefly responsible for the release of pancreatic juice and bile.

• Acetylcholine (ACh), coming from the vagus nerves and enteric neurons. ACh stimulates the pancreatic acini to secrete their enzymes even during the cephalic phase of gastric control, before food is swallowed. The enzymes remain stored in the pancreatic acini and ducts, however, in preparation for release later when chyme enters the duodenum.
• Cholecystokinin (CCK), secreted by the mucosa of the duodenum and proximal jejunum (the next segment of the small intestine), primarily in response to fats in the small intestine. CCK also stimulates the pancreatic acini to secrete enzymes, but it is named for its strongly stimulatory effect on the gallbladder. It induces contractions of the gallbladder and relaxation of the hepatopancreatic sphincter, discharging bile into the duodenum.
• Secretin, produced by the same regions of the small intestine, mainly in response to the acidity of chyme from the stomach. Secretin stimulates the ducts of both the liver and pancreas to secrete an abundant sodium bicarbonate solution. In the pancreas, this flushes the enzymes into the duodenum.

Hormones of the Pancreatic Islets

The pancreas is primarily an exocrine digestive gland. Scattered throughout the exocrine tissue, are 1 to 2 million endocrine groups of cells that are closely associated with blood vessels called pancreatic islets (islets of Langerhans). Although they are less than 2% of the pancreatic tissue, the islets of Langerhans secrete the hormone glucagon and the hormone insulin of vital importance, especially in the regulation of glycemia, the blood glucose concentration. The pancreatic islets of Langerhans include two distinct types of cells—alpha cells, which secrete the hormone glucagon, and beta cells, which secrete insulin hormone. A typical islet measures about 75 × 175 μm and contains from a few to 3,000 cells. Islets of Langerhans main cell types are alpha cells (20%), beta cells (70%), and delta cells (5%). Islets of Langerhans respond directly to blood nutrient levels associated with the cycle of eating and fasting. Their functions are as follows:

• Alpha (α) cells, or A cells, secrete glucagon between meals when the blood glucose concentration falls below 100 mg/dL (5.6 mmol/L). Glucagon exerts two primary actions on the liver: (1) glycogenolysis, the breakdown of glycogen into glucose; and (2) gluconeogenesis, the synthesis of glucose from fats and proteins. These effects lead to the release of glucose into circulation, thus raising the blood glucose level. In adipose tissue, glucagon stimulates fat catabolism and the release of free fatty acids. Glucagon is also secreted in response to rising amino acid levels in the blood after a high-protein meal. It promotes amino acid absorption and thereby provides cells with the raw material for gluconeogenesis.
• Beta (β) cells, or B cells, secrete two hormones, insulin and amylin. Insulin, “the hormone of nutrient abundance,” is secreted during and immediately following a meal when blood nutrient levels are rising. Osteocalcin, a hormone from the osteoblasts of bone, also stimulates multiplication of beta cells, insulin secretion, and insulin sensitivity of other body tissues. The principal targets of insulin are the liver, skeletal muscles, and adipose tissue. In times of plenty, insulin stimulates cells to absorb glucose, fatty acids, and amino acids and to store or metabolize them; therefore, it lowers the level of blood glucose and other nutrients. It promotes the synthesis of glycogen, fat, and protein, thereby promoting the storage of excess nutrients for later use and enhancing cellular growth and differentiation. It also antagonizes glucagon, thus suppressing the use of already-stored fuels. The brain, liver, kidneys, and red blood cells absorb and use glucose without need of insulin, but insulin does promote glycogen synthesis in the liver. Insulin insufficiency or inaction is well known as the cause of diabetes. The beta cells also secrete another hormone, amylin, simultaneously with insulin. Amylin helps to reduce spikes in blood glucose by slowing the emptying of the stomach; modulating the secretion of gastric enzymes, acid, and bile; inhibiting glucagon secretion; and stimulating the sense of satiety (having had enough to eat).
• Delta (δ) cells, or D cells, secrete somatostatin (growth hormone–inhibiting hormone) concurrently with the release of insulin by the beta cells. Somatostatin is a peptide hormone that inhibits the secretion of glucagon and insulin by the nearby alpha and beta cells. Somatostatin also work with amylin to limit the secretion of stomach acid.
• Other, minor types of pancreatic cells, about 5% of the total, are called pancreatic polypeptide (PP) and G cells. Pancreatic polypeptide (PP) cells secrete pancreatic polypeptide, a hormone that may inhibit the exocrine activity of the pancreas.

Any hormone that raises blood glucose concentration is called a hyperglycemic hormone. You may have noticed that glucagon is not the only hormone that does so; so do growth hormone, epinephrine, norepinephrine, cortisol, and corticosterone. Insulin is called a hypoglycemic hormone because it lowers blood glucose levels.

Glucagon raises the blood sugar concentration by stimulating the liver to break down glycogen and convert certain noncarbohydrates, such as amino acids, into  glucose. These actions raise the blood glucose concentration. Glucagon much more effectively elevates blood glucose than does epinephrine (adrenaline).

A negative feedback system regulates glucagon secretion. A low blood glucose concentration stimulates alpha cells to release glucagon. When the blood glucose concentration rises, glucagon secretion falls. This control prevents hypoglycemia when the blood glucose concentration is relatively low, such as between meals, or when glucose is used rapidly, such as during exercise.

The main effect of insulin is to lower the blood glucose level, exactly opposite that of glucagon. Insulin does this in part by promoting facilitated diffusion of glucose into cells that have insulin receptors, for use in cellular respiration. Such cells include those of adipose tissue, liver, and skeletal muscle. (Glucose uptake by active skeletal muscle does not require insulin.) Insulin also stimulates the liver to form glycogen from glucose and inhibits conversion of noncarbohydrates into glucose. In addition, insulin promotes transport of amino acids into cells, increases the rate of protein synthesis, and stimulates adipose cells to synthesize and store fat.

A negative feedback system sensitive to the blood glucose concentration regulates insulin secretion. When the blood glucose concentration is high, such as after a meal, beta cells release insulin. Insulin helps prevent too high a blood glucose concentration by promoting glycogen formation in the liver and entrance of glucose into adipose and muscle cells.

When glucose concentration falls, such as between meals or during the night, insulin secretion decreases. As insulin secretion decreases, less glucose enters adipose and resting muscle cells. Cells that lack insulin receptors and are therefore not dependent on insulin, such as nerve cells, can still take up glucose from the blood. At the same time that insulin is decreasing, glucagon secretion is increasing. Nerve cells, including those of the brain, obtain glucose by a facilitated diffusion mechanism that does not require insulin, but rather depends only on the blood glucose concentration. For this reason, nerve cells are particularly sensitive to changes in blood glucose concentration. Conditions that cause such changes—for example, oversecretion of insulin leading to decreased blood glucose—are likely to affect brain functions.

Insulin and glucagon are coordinated to maintain a relatively stable blood glucose concentration, despite great variation in the amount of carbohydrates a person eats. About 85% to 90% of people with diabetes mellitus have type 2 diabetes, in which the beta cells produce insulin but body cells lose the ability to recognize it. On the other hand, type 1 diabetes mellitus usually appears before age twenty and it is an autoimmune disease: the immune system destroys the beta cells of the pancreas.

Stages of chronic pancreatitis

Standardized reporting terminology has been suggested for chronic pancreatitis ². The most used classification is the Cambridge classification, based on the status of the main pancreatic duct and the presence of side branches abnormalities.

Cambridge classification ²:

• Grade 0. Normal.
  
  • Normal: main pancreatic duct;
  • Abnormal side branches: none
• Grade 1. Equivocal.
  • Normal: main pancreatic duct;
  • Abnormal side branches: < 3
• Grade 2. Mild chronic pancreatitis.
  • Normal: main pancreatic duct;
  • Abnormal side branches: ≥ 3
• Grade 3. Moderate chronic pancreatitis.
  • Abnormal: main pancreatic duct;
  • Abnormal side branches: > 3
• Grade 4. Severe chronic pancreatitis.
  • Abnormal: main pancreatic duct;
  • Abnormal side branches: presence of filling defect, severe dilatation, irregularity, obstruction or one (or more) large cavity

Chronic pancreatitis causes

Repeated episodes of acute pancreatitis can lead to chronic pancreatitis. Instead of the inflammation getting better as in acute pancreatitis, the inflammation continues in some more susceptible people and causing permanent damage to the pancreas. In some cases, genetics may be a factor. However, sometimes, the cause is unknown.

The most common causes of chronic pancreatitis are:

• heavy alcohol use
• genetic disorders of your pancreas (cystic fibrosis, hereditary pancreatitis)

Other causes of chronic pancreatitis include:

• blockage in your pancreatic duct that drain enzymes from the pancreas (tumors, gallstones)
• high levels of blood fats, called lipids (hypertriglyceridemia)
• high level of calcium in your blood (hypercalcemia)
• autoimmune diseases such as systemic lupus erythematosus (SLE), celiac disease, inflammatory bowel disease (IBD) or autoimmune pancreatitis ⁸¹, ⁸², ⁸³
• smoking or tobacco use. Cigarette smoking has been reported to be an independent risk factor for developing chronic pancreatitis ¹² and increases its rate of progression ¹³, ¹⁴.
• overactive parathyroid gland (hyperparathyroidism)
• trauma
• use of certain medicines (especially sulfonamides, thiazides, and azathioprine)
• pancreas divisum

The results of past studies that have noted a significant association of very heavy alcohol consumption and cigarette smoking with chronic pancreatitis. This study is the first to demonstrate that a significant increase in the risk of chronic pancreatitis occurs only above a threshold of ≥5 alcohol drinks per day ⁸⁴.

New studies are finding that deficiencies in certain vitamins and antioxidants may be linked to chronic pancreatitis ⁸⁵, ⁸⁶.

In many cases, doctors can’t find the cause of pancreatitis. This is called idiopathic pancreatitis.

Chronic pancreatitis prevention

Finding the cause of acute pancreatitis and treating it quickly may help prevent chronic pancreatitis. Limit the amount of alcohol you drink and quit smoking can reduce your risk of developing chronic pancreatitis.

Maintain a healthy weight or lose weight safely

Maintaining a healthy lifestyle and a healthy weight or losing weight if you’re overweight or obese can help to:

• make your pancreas work better
• lower your chance of getting gallstones, a leading cause of pancreatitis
• prevent obesity, a risk factor for pancreatitis
• prevent diabetes, a risk factor for pancreatitis

Avoid alcohol use

Alcohol use can cause acute and chronic pancreatitis. Talk with your doctor if you need help to stop drinking alcohol.

Avoid smoking

Smoking is a common risk factor for pancreatitis and the chances of getting pancreatitis are even higher in people who smoke and drink alcohol. Talk with your doctor if you need help to stop smoking.

Chronic pancreatitis signs and symptoms

The most common symptom of chronic pancreatitis is repeated episodes of severe pain in your upper abdomen, although some people have no pain at all. The pain usually develops in the middle or left side of your belly and can move along your back.

The upper abdominal pain may:

• spread to your back
• become constant and severe
• become worse after eating
• go away as your condition gets worse

The pain been described as a burning or shooting pain that comes and goes, but may last for several hours or days. Although the pain sometimes comes on after eating a meal, there’s often no trigger. Some people might feel sick and vomit. As the condition progresses, the painful episodes may become more frequent and severe. Eventually, a constant dull pain can develop in your abdomen, between episodes of severe pain. This is most common in people who continue to drink alcohol after being diagnosed with chronic pancreatitis.

Some people who stop drinking alcohol and stop smoking may find the pain is less severe.

Some people with chronic pancreatitis may not have symptoms until they have complications.

Other symptoms may include:

• diarrhea
• nausea
• oily, foul-smelling stools (steatorrhea)
• vomiting
• weight loss without trying
• jaundice (your skin or the whites of your eyes turn yellow)

Advanced chronic pancreatitis

Other symptoms develop as the damage to the pancreas progresses and it becomes unable to produce digestive juices, which help to break down food. The absence of digestive juices means it’s harder to break down fats and some proteins. This can cause your poop to become very smelly and greasy (steatorrhea), and make it difficult to flush down the toilet. The pancreas usually only loses these functions many years after the first symptoms started.

You may also experience:

• weight loss
• loss of appetite
• your skin or the whites of your eyes turn yellow (jaundice)
• symptoms of diabetes – such as feeling very thirsty, needing to pee more often than usual and feeling very tired
• ongoing nausea and sickness (vomiting).

Chronic pancreatitis complications

Chronic pancreatitis complications may include:

• Ascites
• Blockage (obstruction) of the small intestine or bile ducts
• Blood clot in the vein of the spleen
• Fluid collections in the pancreas (pancreatic pseudocysts) that may become infected
• Diabetes
• Poor absorption of fat, nutrients, and vitamins (most often the fat-soluble vitamins, A, D, E, or K)
• Iron deficiency anemia
• Vitamin B12 deficiency

Gastroparesis

The frequency of gastroparesis in adult patients with chronic pancreatitis is ~3.6% ⁸⁷. Gastroparesis is frequently seen in patients with small duct chronic pancreatitis and can present with similar symptoms as seen in acute pancreatitis. Gastroparesis may also cause confusion in diagnosis, and affect the efficacy of pancreatic enzyme replacement therapy, complicating both evaluation and treatment of chronic pancreatitis ⁸⁸. As per 1 publication, patients with abdominal pain who do not respond to pancreatic enzyme replacement therapy or express early satiety should be evaluated for gastroparesis ⁸⁸. Treatment of gastroparesis is challenging in patients with chronic pancreatitis. Management for mild cases includes dietary modifications, such as small and frequent meals and prokinetic agents such as erythromycin and metoclopramide. Severe gastroparesis may require intrapyloric botulinum toxin injections, gastrostomy feeding tube placement, or implantation of gastric electrical stimulator ⁸⁷.

Small Intestinal Bacterial Overgrowth (SIBO)

Small intestinal bacterial overgrowth (SIBO) is defined as excessive bacteria in the small intestine. Exocrine pancreatic insufficiency, impaired motility secondary to inflammation/narcotic use, and/or proton pump inhibitors (PPIs) can predispose patients with chronic pancreatitis to SIBO ⁸⁹. Various adult studies have shown of the prevalence of SIBO in chronic pancreatitis patients to be between 22% and 67% ⁹⁰. The presentation of SIBO may mimic exocrine pancreatic insufficiency or constipation and includes abdominal pain, bloating, diarrhea, steatorrhea, weight loss, weakness, neuropathy, and excessive flatulence ⁹¹. Small intestinal bacterial overgrowth (SIBO) should be considered in patients with chronic pancreatitis and suggestive symptoms not responsive to other therapy ⁸⁹.

Pancreatic cancer

Meta-analysis reveals a relative risk of 13.3 for the development of pancreatic cancer among adults with chronic pancreatitis ⁹², ⁹³, ⁹⁴. The risk for the development of pancreatic cancer among children with chronic pancreatitis is not yet known. Genetic etiologies account for the most common cause of chronic pancreatitis among children. These are associated with a lifetime risk as high as 40% to 50% for the development of pancreatic cancer among adults, although genetic predisposition may be confounded by smoking, drinking, and other factors ⁸⁷, ⁹⁵. More recent analysis controlling for smoking exposure showed relative risk for the development of pancreatic cancer to be ~7% with those patients with hereditary pancreatitis with a PRSS1 mutation ⁶⁰, whereas certain cystic fibrosis transmembrane conductance regulator (CFTR) mutations were associated with a more modest risk and SPINK1 mutations showing no increased association ⁹⁶. Cigarette smoking, alcohol, and diabetes mellitus may further increase the risk for the development of pancreatic cancer in chronic pancreatitis ⁹⁷, ⁸⁷.

Whether chronic/recurrent inflammation or the genetic mutations alone account for the increased risk of pancreatic cancer is unknown. No reliable screening tests or screening recommendations have been developed to distinguish sub-groups of patients with chronic pancreatitis who are at risk for developing pancreatic cancer or whether age of diagnosis impacts future risk. Recently, the intestinal microbiota or more precisely, the mycobiota have been implicated in the pathogenesis of pancreatic cancer ⁹⁸. Future studies are critical to determine the impact of hereditary pancreatitis among children on long-term pancreatic cancer risk especially as it pertains to earlier surgical intervention to potentially decrease this risk.

Pancreatic or peripancreatic fluid collections

Pancreatic fluid collections include acute fluid collections. Acute fluid collections are those <4 weeks old and divided into acute peri-pancreatic fluid collections and acute necrotic fluid collections. More mature fluid collections >4 weeks old are divided into walled off necrosis and pancreatic pseudocysts. Pancreatic pseudocysts are typically a consequence of acute pancreatitis, pancreatic trauma, and/or chronic pancreatitis ⁹⁹. Among adults, the prevalence of pseudocysts in chronic pancreatitis have been reported to be between 10% and 40%, though this is likely overestimated because of previous inclusion of acute fluid collections and walled off necrosis within the definition of pancreatic pseudocysts ¹⁰⁰. Although usually asymptomatic, mass effect from pancreatic pseudocysts can cause abdominal pain, early satiety, nausea, vomiting, jaundice, weight loss; secondary complications, such as gastric outlet obstruction, biliary obstruction, infection, or vascular complications, such as splenic vein thrombosis or intra-cystic hemorrhage can also present with pain ¹⁰¹. Asymptomatic pseudocysts are usually managed conservatively with observation, and pain control ¹⁰². Drainage, however, should be considered when fluid collection becomes clinically symptomatic (uncontrolled nausea/vomiting or pain), infected, causes obstructive complications (blood vessels, common bile duct, gastric outlet obstruction), bleeding, or fistula formation. Even when asymptomatic, endoscopic drainage has been proposed if the pseudocyst measures >5 cm in diameter without spontaneous regression ¹⁰³. Previously walled off necrosis was felt to require definite intervention via surgery or advanced endoscopic techniques but recently care has evolved and many of these collections may also be managed conservatively if the patient remains clinically stable during the course ¹⁰⁴.

Pancreatic duct disease

Pancreatic duct abnormalities are most often characterized by strictures and intraductal stone formation ¹⁰⁵. For some patients, ductal obstruction may cause increased pressure resulting in ductal dilation, and is the assumed cause of pain. Endoscopic therapy is often offered for decompression of these strictures and removal of pancreatic duct stones when this is believed to be the cause of pain or for recurrent pancreatitis episodes ⁵³, ¹⁰⁶.

Vascular complications

Splenic vein thrombosis is a reported complication in about 10% to 20% of adult patients with chronic pancreatitis and is often related to the presence of a pancreatic pseudocyst or severe acute pancreatitis, in general ¹⁰⁷. Most patients with splenic vein thrombosis are asymptomatic but they may develop varices, which are at high risk of gastrointestinal bleeding ¹⁰⁸. Less commonly, deep vein thrombosis and pulmonary embolism have been reported, although are more typical in acute pancreatitis. Management is usually conservative. The use of anticoagulation is not well studied in chronic pancreatitis though no significant difference has been demonstrated in acute pancreatitis patients with regard to recanalization rate ¹⁰⁹.

Chronic pancreatitis diagnosis

To diagnose pancreatitis and find its causes, doctors use:

• Your medical history. Your doctor will ask:
  • about your symptoms
  • if you have a history of health conditions or concerns that make you more likely to get pancreatitis—including medicines you are taking
  • if you have a personal or family medical history of pancreatitis or gallstones
• A physical exam. During a physical exam, your doctor will:
  • examine your body
  • check your abdomen for pain, swelling, or tenderness
• Lab and imaging tests

Tests and procedures used to diagnose pancreatitis include:

• Blood tests to look for elevated levels of pancreatic enzymes, along with white blood cells, kidney function and liver enzymes
• Abdominal ultrasound to look for gallstones and pancreas inflammation
• Computerized tomography (CT) scan of your abdomen to look for gallstones and assess the extent of pancreas inflammation
• Magnetic resonance imaging (MRI) of your abdomen to look for abnormalities in the gallbladder, pancreas and ducts
• Endoscopic ultrasound to look for inflammation and blockages in the pancreatic duct or bile duct
• Stool tests in chronic pancreatitis to measure levels of fat that could suggest your digestive system isn’t absorbing nutrients adequately
• Biopsy.

Your doctor may recommend other tests, depending on your particular situation.

Lab tests

Lab tests to help diagnose pancreatitis include the following:

• Blood tests. Your physician may take a blood sample from you and send the sample to a lab to test for:
  • high amylase and lipase levels—digestive enzymes made in your pancreas
  • high blood glucose, also called blood sugar
  • high levels of blood fats, called lipids
  • signs of infection or inflammation of the bile ducts, pancreas, gallbladder, or liver
  • pancreatic cancer
• Stool tests. Your doctor may test a stool sample to find out if a person has fat malabsorption. At present, measurement of fecal elastase is the most popular test to evaluate pancreatic exocrine insufficiency. Low levels of fecal elastase (<200 µg/g stool, although even lower levels are more specific) or serum trypsin (<20 ng/mL) are usually observed in patients with pancreatic exocrine insufficiency ¹¹⁰.

Biopsy

Sometimes the symptoms of chronic pancreatitis can be very similar to pancreatic cancer. You may need a biopsy, where a small sample of cells is taken from the pancreas and sent to a laboratory to be checked, to rule this out.

Imaging tests

Your doctor also use imaging tests to diagnose pancreatitis. A technician performs most tests in an outpatient center, a hospital, or a doctor’s office. You don’t need anesthesia, a medicine to keep you calm, for most of these tests.

• Ultrasound. Ultrasound uses a device called a transducer, which bounces safe, painless sound waves off your organs to create a picture of their structure. Ultrasound can find gallstones.
• Computed tomography (CT) scan. CT scans create pictures of your pancreas, gallbladder, and bile ducts. CT scans can show pancreatitis or pancreatic cancer. CT features of chronic pancreatitis include dilatation of the main pancreatic duct, pancreatic calcification, changes in pancreatic size (i.e. atrophy), shape, and contour and pancreatic pseudocysts.
• Magnetic resonance cholangiopancreatography (MRCP). MRCP uses a magnetic resonance imaging (MRI) machine, which creates pictures of your organs and soft tissues without x-rays. Your doctor or a specialist may use MRCP to look at your pancreas, gallbladder, and bile ducts for causes of pancreatitis.
• Endoscopic ultrasound (EUS). Your doctor inserts an endoscope—a thin, flexible tube—down your throat, through your stomach, and into your small intestine. The doctor turns on an ultrasound attachment to create pictures of your pancreas and bile ducts. Your doctor may send you to a gastroenterologist to perform this test.
• Pancreatic Function Test (PFT). Your doctor may use this test to measure how your pancreas responds to secretin, a hormone made by the small intestine. This test is done only at some centers in the United States.

Cross-sectional imaging is the most commonly used method to establish a diagnosis of acute pancreatitis and chronic pancreatitis. Among cross-sectional imaging studies, CT is readily available and performed often in the setting of acute pancreatitis. It is widely acknowledged that MRI with MR cholangiopancreatography (MRCP) is more sensitive than is CT for detection of ductal and subtle parenchymal changes, especially during early stages of chronic pancreatitis ¹¹¹. However, the two modalities are complementary because CT is the modality of choice for evaluation of parenchymal and ductal calcifications.

Both the size and number of pancreatic calcifications should be graded because the degree of calcification in chronic pancreatitis may parallel the course of the disease ¹¹². Coarse pancreatic calcifications are accepted as a definite sign of chronic pancreatitis ¹¹³, ¹¹⁴. Senescent pancreatic parenchymal calcifications are usually 1–3 mm and may not always imply chronic pancreatitis. Senescent calcifications are seen in peripheral ducts and lack association with clinical signs and symptoms of chronic pancreatitis, hypercalcemia, or alcoholism ¹¹⁵. Innumerable punctate calcifications, on the other hand, strongly suggest chronic pancreatitis. Calcification seen in chronic pancreatitis has rarely been scored and/or graded. Selection of seven as the number of coarse calcifications to discriminate more severe from less severe chronic pancreatitis is somewhat arbitrary but provides distinction. A cutoff of 50 punctate calcifications was chosen as a surrogate for innumerable calcifications ².

Currently, no standardized reporting system for CT, MRI, or MR cholangiopancreatography (MRCP) is universally used. The Cambridge classification ¹¹⁶, which was developed for endoscopic retrograde cholangiopancreatography, has been suggested for translational use in CT and MRI or MR cholangiopancreatography interpretation by recent guidelines of the American Pancreatic Association ¹¹⁷. Although useful, the Cambridge classification only acknowledges ductal changes ¹¹⁸. Hence, the contribution of parenchymal observations is not captured.

Cambridge classification

• Grade 0. Normal.
  
  • Normal: main pancreatic duct;
  • Abnormal side branches: none
• Grade 1. Equivocal.
  • Normal: main pancreatic duct;
  • Abnormal side branches: < 3
• Grade 2. Mild chronic pancreatitis.
  • Normal: main pancreatic duct;
  • Abnormal side branches: ≥ 3
• Grade 3. Moderate chronic pancreatitis.
  • Abnormal: main pancreatic duct;
  • Abnormal side branches: > 3
• Grade 4. Severe chronic pancreatitis.
  • Abnormal: main pancreatic duct;
  • Abnormal side branches: presence of filling defect, severe dilatation, irregularity, obstruction or one (or more) large cavity

Chronic pancreatitis differential diagnosis

chronic pancreatitis differential diagnoses may include ¹¹⁹:

• Ampullary carcinoma
• Cholangitis
• Acute cholecystitis
• Chronic gastritis
• Community-Acquired Pneumonia (CAP)
• Crohn disease
• Intestinal perforation
• Mesenteric artery ischemia
• Myocardial infarction
• Pancreatic cancer
• Peptic ulcer disease

Chronic pancreatitis treatment

In chronic pancreatitis, the pancreas is permanently damaged, but treatment can help control the condition and manage any symptoms. Treatment for chronic pancreatitis may help relieve pain, improve how well the pancreas works, and manage complications.

Depending on your situation, your doctor may prescribe or provide the following additional treatments:

• Pain management. Chronic pancreatitis can cause persistent abdominal pain. Your doctor will evaluate you for causes of chronic pancreatitis and may recommend medications to control your pain. If necessary, you may be referred to a pain specialist. Severe pain may be relieved with options such as endoscopic ultrasound or injections to block nerves that send pain signals from the pancreas to the brain.
• Enzymes to improve digestion. In chronic pancreatitis leading to diarrhea or weight loss, pancreatic enzyme supplements can help your body break down and process the nutrients in the foods you eat. Pancreatic enzymes are taken with each meal.
• Changes to your diet. Your doctor may refer you to a dietitian who can help you plan low-fat meals that are high in nutrients.
• Medicines and vitamins. Long-term fat malabsorption may also lead to fat-soluble vitamin (A, D, E, and K) deficiencies ¹²⁰ as well as deficiencies in calcium, magnesium, zinc, thiamine, and folic acid ¹²¹.  Your doctor may give you vitamins A, D, E, and K if you have malabsorption. He or she may also give you vitamin B-12 shots if you need them.
• Treatment for diabetes. Chronic pancreatitis may cause diabetes. If you get diabetes, your doctor and health care team will work with you to create an eating plan and a routine of medicine, blood glucose monitoring, and regular checkups.
• Surgery. Your doctor may recommend surgery to relieve pressure or blockage in your pancreatic duct, or to remove a damaged or infected part of your pancreas. Surgery is done in a hospital, where you may have to stay a few days. In patients who do not get better with other treatments, surgeons may perform surgery to remove your whole pancreas, followed by islet auto-transplantation. Islets of Langerhans are groups of cells in your pancreas that make hormones, including insulin. After removing your pancreas, doctors will take islets from your pancreas and transplant them into your liver. The islets will begin to make hormones and release them into your bloodstream.
• Procedures. Your doctor may suggest a nerve block, which is a shot of numbing medicine through your skin and directly into nerves that carry the pain message from your pancreas. If you have stones blocking your pancreatic duct, your doctor may use a procedure to break up and remove the stones.

Living with chronic pain can cause mental as well as physical strain. See your doctor if you’re experiencing stress, anxiety or depression caused by chronic pancreatitis.

Some people with chronic pancreatitis will eventually develop a type of diabetes known as type 3c diabetes ¹²². This occurs when the pancreas can no longer produce insulin because it’s become so damaged. There are currently no universally accepted diagnostic criteria for type 3c diabetes ¹²². Conceptually, the diagnosis can be made in patients who meet the three following criteria: those who fulfil the diagnostic criteria for diabetes, those who have a disease of the exocrine pancreas, and those whose diabetes is reasonably certain to be secondary to their exocrine pancreatic disease ¹²².

People with chronic pancreatitis can sometimes develop sacs of fluid on the surface of their pancreas (pancreatic pseudocysts). These can cause bloating, indigestion and dull tummy pain. These cysts often disappear on their own. But sometimes they need to be drained using a technique called endoscopic ultrasound drainage, or endoscopic transpapillary drainage.

Chronic pancreatitis increases your risk of pancreatic cancer, although the chance is still small.

Pain relief

Pain relief is an important part of the treatment of chronic pancreatitis.

Mild painkillers

In most cases, the first painkillers used are paracetamol, or anti-inflammatories such as ibuprofen.

But taking anti-inflammatory painkillers on a long-term basis can increase your risk of developing stomach ulcers, so you may be prescribed a proton pump inhibitor (PPI) to protect against this.

Stronger painkillers

If paracetamol or anti-inflammatories don’t control the pain, you may need an opiate-based painkiller, such as codeine or tramadol. Side effects include constipation, nausea, vomiting and drowsiness.

Constipation can be particularly difficult to manage, so you may be prescribed a laxative to help relieve this. See the page on constipation for more information.

If you feel drowsy after taking an opiate-based painkiller, avoid driving and using heavy tools or machines.

Severe pain

If your pain is severe, you may be referred to a specialist (a gastroenterologist or pancreatico-biliary surgeon) or pain center for further assessment.

You may be offered surgery to help relieve the pain or treat any complications.

In some cases, additional medicine – called amitriptyline, gabapentin or pregabalin – may be recommended to help relieve the pain. Tricyclic antidepressants (TCA), serotonin-norepinephrine reuptake inhibitors (SNRI), and anticonvulsants have been long established through a multitude of studies as effective agents in treating chronic neuropathic pain ¹²³. These medications provide pain relief by modulating central pain signaling, thus reducing central sensitization. Tricyclic antidepressants (TCAs) include amitriptyline and nortriptyline. Both are equally effective; however, nortriptyline is associated with fewer side effects ¹²⁴. Serotonin-norepinephrine reuptake inhibitors (SNRIs) include duloxetine and anticonvulsants, such as gabapentin and pregabalin. Ketamine has been used to treat both acute and chronic pain of numerous types in patients of all ages, and there is modest evidence to support its use in inpatient pancreatitis care ¹²⁵.

If this isn’t effective, severe pain can sometimes be relieved for a few weeks or months using an injection called a nerve block. This blocks the pain signals from the pancreas. Celiac plexus blockade has been used in adults for chronic pancreatitis for decades. Overall results have been mixed and largely short-term, based on moderate levels of data ¹²⁶, ¹²⁷.

Severe episodes

If the inflammation of your pancreas suddenly gets worse, you may need a short stay in hospital for treatment. This might involve having fluids delivered directly into a vein and oxygen through tubes into your nose.

Surgery

Surgery can be used to treat severe pain in people with chronic pancreatitis.

Endoscopic surgery

Patients with gallstones in the opening of their pancreas (the pancreatic duct) may benefit from endoscopic surgery and a treatment called lithotripsy. Lithotripsy involves using shock waves to break the stones into smaller pieces. An endoscope is then used to access the pancreatic duct so the pieces can be removed. This treatment may improve pain to some extent, but the benefit may not be permanent.

Pancreas resection

In cases where specific parts of the pancreas are inflamed and causing severe pain, they can be surgically removed. This is called a pancreas resection and may also be offered if endoscopic treatment doesn’t work.

The exact technique used for pancreas resection depends on which parts need to be removed. Speak with your surgical team about the benefits and risks of the procedure before deciding to go ahead with it.

Total pancreatectomy

In the most serious cases of chronic pancreatitis, where the pancreas has been extensively damaged, it may be necessary to remove the entire pancreas (total pancreatectomy). This can be very effective in treating pain, but you wont be able to produce the insulin that’s needed by your body any more. To overcome this problem, a technique called autologous pancreatic islet cell transplantation is sometimes used. During autologous pancreatic islet cell transplantation, the islet cells (Islets of Langerhans) responsible for producing hormones including insulin are removed from your pancreas before your pancreas is surgically removed. The islet cells are then mixed with a special solution and injected into your liver.

If autologous pancreatic islet cell transplantation is successful, the islet cells remain in your liver and begin to produce make hormones (e.g., insulin) and release them into your bloodstream.

In the short term, autologous pancreatic islet cell transplantation appears to be effective, but you may need additional insulin treatment in the long term.

On-going tests and checks

If you’ve been diagnosed with chronic pancreatitis, you should be offered:

• annual checks (every 6 months in under-16s) to make sure your diet is giving you the nutrients you need
• a bone density assessment every 2 years – problems with digesting foods may affect your bone health
• a blood test for diabetes every 6 months
• an annual check for pancreatic cancer if the cause of chronic pancreatitis is hereditary

Chronic pancreatitis prognosis

The prognostic factors associated with chronic pancreatitis are age at diagnosis, smoking, continued use of alcohol, and the presence of liver cirrhosis. Chronic pancreatitis is associated with poor prognosis in patients who continued to use alcohol, smoke and the presence of end-stage liver disease ⁴. At 10 years, there is a survival of 70%, which drops to 45% at 20 years ⁴. Pancreatic pseudocyst formation, mechanical obstruction of the bile duct and duodenum are major complications. Addition complications include diabetes (30% of patients), development of gastric varices and pseudoaneurysm formation.

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