Chronic pancreatitis

See also the separate Acute Pancreatitis article.

What is chronic pancreatitis?

Chronic pancreatitis is the result of chronic inflammation of the pancreas which results in irreversible damage. Chronic pancreatitis is associated with severe abdominal pain and endocrine or exocrine dysfunction. It is a difficult illness to diagnose and manage, making it a challenge for all involved.

It is unclear if acute and chronic pancreatitis are related, although the damage to the pancreas in acute pancreatitis is reversible. At present there is no method to detect early chronic pancreatitis and calcification of the pancreas may not develop until 5-10 years after initial symptoms.

Epidemiology¹

• The UK prevalence is estimated as 3/100,000.

• The prevalence of chronic pancreatitis in the UK is rising in parallel with other alcohol-related diseases.

• One study reported a male:female ratio of approximately 4:1 and an average patient age of 40.

Chronic pancreatitis pathophysiology

The underlying mechanism of chronic pancreatitis is unclear. There have been many theories.

• The most common thought is that there is obstruction or reduction of bicarbonate excretion. This in turn leads to activation of pancreatic enzymes, which leads to pancreatic tissue necrosis with eventual fibrosis. Abnormalities of bicarbonate excretion can be the result of functional defects at the level of the cellular wall, as in cystic fibrosis, or mechanical, such as trauma.

• Epigenetic (= heritable variations in gene expression) deregulation is known to be associated with the progression of both acute and chronic pancreatitis² .

• Alcohol causes proteins to precipitate in the ductular structure of the pancreas. This leads to local pancreatic dilatation and fibrosis. However, this is not seen in patients with recurrent attacks of acute pancreatitis associated with alcohol use³ .

• There may be direct toxic effects of alcohol on the pancreas. However, it has been noted that patients who drink 'normal' amounts of alcohol can also develop chronic pancreatitis, ie a dose-response relationship does not exist. It may be that there is excessive free radical formation which leads to pancreatic damage. Studies suggest that oxidative stress plays an important role in the pathogenesis of chronic pancreatitis. This may lead to innovative treatments⁴ .

Whatever the cause, the end result is pancreatic fibrosis which can take several years to develop.

Large duct pancreatitis versus small duct pancreatitis³

It is thought that there are two pathological subtypes of chronic pancreatitis: large duct pancreatitis and small duct pancreatitis. These two entities may represent two ends of the same spectrum but they have different pathological and radiological features and the management varies. They are usually applied to all causes of chronic pancreatitis.

Large duct pancreatitis is characterised by dilatation and dysfunction of the large ducts and is easily seen on imaging. Chronic pancreatitis tends to occur more in men and there is also diffuse pancreatic calcification. Steatorrhoea is common and replacement of pancreatic enzymes does not reduce pain; patients usually require surgery to alleviate symptoms.

On the other hand, small duct pancreatitis occurs more in women and is not associated with pancreatic calcification. Imaging is usually normal, making it difficult to diagnose and, therefore, a high index of suspicion is needed. Steatorrhoea is a rare feature and patients respond to replacement of pancreatic enzymes.

Some specific types of chronic pancreatitis

Hereditary pancreatitis⁵

• Rare and similar to chronic pancreatitis.

• Most cases are thought to result from genetic mutation-induced changes in human cationic trypsinogen (PRSS1) which lead to increased auto-activation by altering chymotrypsin C (CTRC)-dependent trypsinogen activation and degradation.

• It presents at a younger age with epigastric pain.

• Exocrine and endocrine dysfunction are also present and there is a high incidence of pancreatic carcinoma (10% at age 50, 18.7% at age 60, 53.5% at age 75)⁶ .

Tropical chronic pancreatitis⁷

• This was first described in the 1960s.

• Tropical chronic pancreatitis is seen in developing countries with a tropical climate and affects patients at a younger age.

• It has similar presentation to alcoholic chronic pancreatitis.

• Tropical chronic pancreatitis is associated with large intraductal calculi and development of insulin-requiring diabetes mellitus, although ketosis is rare.

• Once diabetes mellitus has developed, it is often called fibrocalculous pancreatic diabetes.

• Tropical chronic pancreatitis affects 10-15 per 100,000 population in Western countries but is much higher in Japan - 45 per 100,000⁸ .

• One study reported a prevalence of 0.36% (1:276) of all self-reported diabetes and 0.019% (1:5,200) of the general population in Chennai in South India⁹ .

• The aetiology of tropical pancreatitis is not clearly understood but may relate to malnourishment and dietary toxins - eg, in cassava.

• Tropical pancreatitis is associated with SPINK1 and/or CFTR gene mutations in approximately 50% of patients¹⁰ .

• There is an increased risk of developing pancreatic carcinoma¹¹ .

Autoimmune chronic pancreatitis^{12 13}

• This is chronic pancreatic inflammation which results from an autoimmune process.

• There is a high prevalence in Japan.

• It is recognised that there are two types of the condition. Type 1 autoimmune chronic pancreatitis (AICP) is more common in Eastern countries whilst type 2 is more common in the Western world. Recent advances in histopathology have identified that type 2 is a distinct entity and should now more appropriately be called idiopathic duct-centric chronic pancreatitis (IDCP).

• The presentation of both types is very similar to other forms of chronic pancreatitis.

• There are elevated levels of serum gammaglobulins and immunoglobulin G (IgG) levels in AICP. In fact, AICP can be considered the pancreatic manifestation of immunoglobulin G4-related disease (IgG4-RD). Autoantibodies may also be increased - eg, antinuclear antibody and rheumatoid factor. In fact, a whole host of antibodies have been found - eg, antibodies to carbonic anhydrase, lactoferrin, heat-shock protein 10, amylase alpha and plasminogen-binding protein. However, none has been found which is specific to AICP¹⁴ .

• AICP and IDCP are both steroid-responsive¹⁵ . However, recurrence is common in AICP but rare in IDCP. Maintenance therapy with either an immunomodulator (eg, azathioprine, 6-mercaptopurine, or mycophenolate mofetil) or rituximab is therefore often necessary in patients with AICP.

• Both types usually have an excellent long-term survival rate. However, there may be an association with pancreatic carcinoma - further research is needed¹⁶ . One long-term study of patients with autoimmune chronic pancreatitis found that the incidence rate of developing pancreatic cancer ranged from 0% to 4.8%¹⁷ .

Predisposing factors

One study reported that in the Western world 60-70% of patients with chronic pancreatitis have a 6- to 12-year history of alcohol abuse¹⁸ .

Smoking is an independent risk factor¹⁸ .

There has also been research into the role of genetic abnormalities in chronic pancreatitis. Genetic variation in the gamma-glutamyltransferase 1 (GGT1), CFTR and SPINK1 genes is associated with chronic pancreatitis^{19 20} . Chronic pancreatitis is emerging as a multifactorial condition which is the result of a complex interplay between genetically induced metabolic changes at the level of the pancreatic cell²¹ .

Other causes of chronic pancreatitis

There are many other causes of chronic pancreatitis and they are similar to those for acute pancreatitis:

• Biliary tract disease.

• Iatrogenic - eg, endoscopic retrograde cholangiopancreatography (ERCP).

• Metabolic disorders - eg, hypertriglyceridaemia, hypercalcaemia.

• Trauma.

• Congenital disorders - eg, cystic fibrosis.

• Drugs - eg, azathioprine, sulphonamides, loop diuretics.

• Idiopathic - thought to be early- and late-onset subgroups.

• Abdominal radiotherapy.

Chronic pancreatitis presentation

Chronic pancreatitis may present with episodes of exacerbation with intervening remission or continuous pain in patients.

• Abdominal pain. Classically, epigastric pain radiating into the back. The pathogenesis of this pain is not understood but pancreatic duct obstruction from one of the complications of chronic pancreatitis may be one cause¹⁸ . Usually the pain is very severe, which often requires opiates in the acute setting. In some cases pain may not be the major feature.

• Nausea and vomiting.

• Decreased appetite.

• Exocrine dysfunction. Malabsorption with weight loss, diarrhoea, steatorrhoea (pale, loose, offensive stools which are difficult to flush) and protein deficiency.

• Endocrine dysfunction. Diabetes mellitus and its associated morbidity and mortality.

Examination can be largely unremarkable apart from tenderness in the abdomen.

Differential diagnosis

Of abdominal pain:

• Acute cholecystitis.

• Peptic ulcer disease.

• Acute hepatitis.

• Abdominal aortic aneurysm.

• Pyelonephritis.

• Acute pancreatitis.

• Non-abdominal causes - eg, myocardial infarction and pneumonia.

Of pancreatic calcification on abdominal imaging:

• Severe protein malnutrition.

• Hereditary pancreatitis.

• Hyperparathyroidism.

Investigations and diagnosis^{17 22}

Early diagnosis is difficult, as no biochemical markers exist and abdominal radiology may show normal pancreatic appearances. Investigation may reveal aetiology or complications.

• Blood tests: FBC, U&E, creatinine, LFTs, calcium, amylase (usually normal), glucose, HBa1C.

• Secretin stimulation test: a positive result occurs if 60% or more pancreatic exocrine function is damaged. The use of endoscopic techniques has made what was once a lengthy and invasive procedure more accessible. Secretin stimulation is most often used in combination with imaging modalities (see below).

• Serum nutritional markers are being evaluated as potential diagnostic factors. Low levels of magnesium, haemoglobin, albumin, prealbumin and retinol binding protein and a high level of HbA1c are characteristic of chronic pancreatitis²³ .

• Serum trypsinogen and urinary D-xylose or faecal elastase if malabsorption is present.

• Tests to assess pancreatic function include aspiration of duodenal fluid to determine the output of amylase, pancreatic bicarbonate, and lipase. The pancreatic duct can also be cannulated during ERCP and the pancreatic juice can be assessed for the same parameters²⁴ .

• Imaging - a suggested algorithm recommends:

  • CT scanning to detect typical calcification, atrophy or duct dilatation.

  • Secretin-enhanced MRI or magnetic retrograde cholangiopancreatography (MRCP).

  • Endoscopic ultrasound (EUS) with quantification of parenchymal and ductal criteria. EUS is a newer technique. It involves passing a probe down the oesophagus and stomach and visualising the pancreas. Features like irregular duct walls, duct dilatation and cysts can be detected. However, there are varying rates of sensitivity and specificity and the diagnostic criteria need to be more closely defined, particularly in early and intermediate cases¹⁰ .

• Pancreatic biopsy - this usually shows chronic inflammation and irregularly placed fibrosis. However, pancreatic biopsy is associated with a significant risk and is therefore rarely performed.

Management principles

• Pain and malabsorption need to be managed.

• Patients may also need assessment and counselling regarding alcohol intake and illicit drug use - eg, CAGE questionnaire.

• Look for the presence of psychiatric conditions - eg, depression.

• History - symptoms of abdominal pain, diarrhoea, weight loss. Look for red flags such as bowel change which may indicate neoplastic disease.

• Alcohol intake, smoking status, family history.

• Examination - mostly to rule out other causes of abdominal pain - eg, cholecystitis.

• Investigations - abdominal ultrasound, baseline blood tests including liver function to look for biliary tract obstruction and refer on for possible secretin test and MRCP or CT scan.

• Management - if there is severe pain, the patient may need to be referred urgently for assessment. If there is mild-to-moderate pain, consider whether the patient can manage at home with simple analgesia, and refer as an outpatient to gastroenterologists.

Supportive measures

• Lifestyle advice regarding alcohol intake, smoking cessation, dietary advice - high in protein and low in carbohydrate.

• If there is opiate dependence then this may need to be reviewed and managed.

• Advise abstinence from alcohol.

Pain relief¹⁸

• Pain relief commonly requires opiates and there is a risk of opiate dependency. Simple analgesics should be used initially - eg, paracetamol and non-steroidal anti-inflammatory drugs (NSAIDs), provided there are no contra-indications.

• Opiates may also lead to gastroparesis.

• ERCP may help to reduce pain by dilating strictures of the pancreatic ducts. Stenting is appropriate for single benign strictures but the stent may require changing every three months. The stricture often recurs if the stent is removed completely.

• Coeliac plexus block via a gastric approach under EUS guidance has a technically high success rate with low complications. Unfortunately, its effects wear off eventually (only 10% of patients experience long-term pain relief after 24 weeks) so it is reserved as a temporary measure or where no other option is available.

It is important to make sure that there is not another cause for the pain - eg, pseudo-cyst, duct obstruction or dysmotility.

Some of these procedures may result in acute pancreatitis and other complications.

Patients who remain in pain despite the above measures may need to be referred for a surgical opinion (see 'Surgical management', below) and if there is likely to be a delay or they are unsuitable for surgery, they should be referred to local pain clinics.

Malabsorption

Malabsorption is treated by replacing pancreatic enzymes. Diarrhoea can improve but does not usually resolve completely. Lipase is the treatment of choice but it is degraded in the stomach so that high doses have to be given. The results of using enteric coated forms has thus far been disappointing.

Pancreatic enzymes

Replacement of pancreatic enzymes can help malabsorption and also reduce pain - eg, Creon®. It is thought that the pancreatic enzymes provide negative feedback on pancreatic exocrine function. Randomised trials have shown this method to be effective in 30% of patients, especially patients with small duct disease¹⁸ .

Cholecystokinin (CCK) also stimulates the pancreas and is released from the small intestine by CCK-releasing peptide. The CCK-releasing peptide is broken down by proteases. Pancreatic enzymes which reach the small intestine can break down the CCK-releasing peptide, thereby halting pancreatic stimulation.

Pancreatic enzymes are administered orally and are degraded by stomach fluid reducing the bioavailability. Acid-suppressing medications can be administered at the same time with varying results.

Pancreatic enzymes are usually given as a trial for one month and, if they are effective, they are continued for six months and are then withdrawn. 50% of patients will have long-term resolution of pain³ . However, if patients fail to respond then they should be considered for surgical procedures.

Octreotide

Octreotide is a somatostatin analogue and inhibits pancreatic enzyme secretion and CCK levels. It has been used with varying success rates - but this is limited by the subcutaneous route of administration³ .

Surgical management¹⁸

• EUS is increasingly being used to facilitate the surgical management of complications - eg, pseudo-cyst decompression.

• Pancreatic duct stones may pass spontaneously, may dislodge with ERCP or may require endoscopic shock-wave lithotripsy or laser lithotripsy.

• Surgical decompression of duct dilatation can be performed if this cannot be achieved by ERCP alone. Furthermore, if duct dilatation is large (eg, more than 6 mm), a lateral pancreaticojejunostomy can be performed. Surgical drainage has proved superior to endoscopic techniques for patients with dilated ducts and chronic severe pain (1.5 years or more) unresponsive to opiates²⁰ .

• Local surgical resection may also relieve pain in selected cases²⁵ .

• Most children and young adults with hereditary pancreatitis can be managed with endoscopic therapy but more invasive surgery is sometimes required²⁶ .

Pancreatic resection²⁷

• Pancreatoduodenectomy has been used in chronic pancreatitis and pancreatic cancer.

• Other forms of surgery used include Beger's procedure (duodenal preserving resection of the pancreatic head) and Frey's procedure (extended lateral pancreaticojejunostomy). One study suggested that duodenal preserving resection results in a shorter hospital stay than pancreatoduodenectomy but the evidence was low-quality and larger studies are needed²⁸ .

• Radical surgery is used for relief of intractable pain not responding to other methods.

• This procedure has been shown to be effective in providing long-term pain relief in patients.

• Recurrence of pain can occur and is often related to alcohol use.

• However, patients will require pancreatic enzyme supplementation, as they lose a large majority of exocrine function.

• A meta-analysis reported that pancreaticoduodenectomy and duodenum-preserving pancreatic head resection were equally effective with regard to pain relief and preservation of pancreatic function. However, at long-term follow-up, duodenum-preserving procedures resulted in a better quality of life and improved long-term outcome in several measures including weight gain, diarrhoea and fatigue.

• Combining surgery with pancreatic enzyme replacement not only provides pain relief but is also associated with weight gain.

• One study reported that the prevalence of pancreatic carcinoma was lower in patients who had pancreatic surgery²⁹ .

Newer management strategies

• Pancreatectomy, followed by autologous islet cell transplantation, has been used in chronic pancreatitis. As islet cells are replaced there is no, or less, endocrine dysfunction. The autologous cells are infused into the portal vein. It is a lengthy operation and is associated with major complications³⁰ . However, it is associated with reduced pain scores and a reduction in insulin requirements^{3 31} .

• Radiofrequency treatment and spinal cord stimulation are being evaluated as potential pain management options³ .

Chronic pancreatitis complications

• Cobalamin deficiency.

• Diabetes mellitus - usually brittle and associated with complications.

• Pericardial, peritoneal or pleural effusions.

• Pseudo-cyst - localised collections of pancreatic fluid which require drainage and bowel rest¹⁸ .

• Gastrointestinal tract haemorrhage - eg, from a pseudo-cyst invading the duodenum.

• Pancreatic carcinoma - it is postulated that chronic inflammation leads to adenocarcinoma change in pancreatic tissue³² .

Chronic pancreatitis prognosis²⁴

Chronic pancreatitis is associated with increased mortality and morbidity.

Poor prognosis is associated with smoking, continued alcohol intake and the development of end-stage liver disease. At 10 years, there is a survival of 70%, which drops to 45% at 20 years.