Chronic Pancreatitis

Chronic pancreatitis is the result of chronic inflammation of the pancreas which results in irreversible damage to the pancreas. It 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.

• Annual incidence in the UK is 1 per 100,000 with a prevalence of 3 per 100,000¹
• Affects males more than females (4:1) and average age at onset is 40 years.

Aetiology

The underlying aetiology of chronic pancreatitis is unclear. There have been many theories including:

• The commonest 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.
• 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 use.
• 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 i.e. a dose-response relationship does not exist. It may be that there is excessive free radical formation which leads to pancreatic damage. Some trials have looked at the role of antioxidants e.g. selenium and methionine and pain relief with promising results.²

What ever the cause the end result is pancreatic fibrosis which can take several years to develop.

Large duct pancreatitis vs. Small duct pancreatitis

It is thought that there are two pathological subtypes of chronic pancreatitis: Large duct pancreatitis and Small duct pancreatitis.² 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. It 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 and patients usually require surgery to alleviate symptoms.²

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.²

Some specific types of chronic pancreatitis

Hereditary pancreatitis

• Rare and similar to chronic pancreatitis
• Results from autosomal dominant transmission of impaired trypsinogen gene
• Presents at a younger age with epigastric pain
• Exocrine and endocrine dysfunction are also present and there is a high incidence of pancreatic carcinoma (40% lifetime risk).³

• First described in the 1960's
• Seen in developing countries with a tropical climate and affects patients at a younger age
• Similar presentation as alcoholic chronic pancreatitis
• It is associated with large intraductal calculi and development of insulin requiring diabetes mellitus (although ketosis is rare)⁴
• Once DM has developed it is often called fibrocalculous pancreatic diabetes
• Affects 10-15 per 100,000 population in western countries but much higher in Japan - 45 per 100,000⁴
• The aetiology of tropical pancreatitis is not clearly understood but may relate to malnourishment and dietary toxins e.g. in cassava⁴
• There is an increased risk of developing pancreatic carcinoma in tropical pancreatitis.

• This is chronic pancreatic inflammation which results from an autoimmune process
• There is a high prevalence in Japan
• The presentation is very similar to other forms of chronic pancreatitis
• There are elevated levels of serum gammaglobulins and IgG levels
• Autoantibodies may also be increased e.g. antinuclear antibody and rheumatoid factor⁵
• Autoimmune chronic pancreatitis is steroid responsive and reversible.⁵

It has intrigued researchers that only a small number of chronic alcoholics develop chronic pancreatitis. It is thought that this subgroup of chronic alcohol users may have predisposing factors e.g. dietary constituents, smoking and a genetic predisposition.⁶

Even so there is probably a correlation between quantity and duration of alcohol use.

There has also been research into the role of genetic abnormalities in chronic pancreatitis. This includes abnormalities of the cholecystokinin peptide (CCK) gene or over expression of interleukins. Hereditary pancreatitis is associated with abnormalities of the trypsinogen gene and mutations in the secretory trypsin inhibitor gene.^7,8

There are many causes and they are similar as for acute pancreatitis:

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

1. Abdominal pain - classically epigastric pain radiating in to the back. The pathogenesis of this pain is not understood. Usually the pain is very severe which often requires opiates in the acute setting. In some cases pain may not be the major feature.
2. Nausea and vomiting
3. Decreased appetite
4. Exocrine dysfunction - malabsorption with weight loss, diarrhoea, steatorrhoea (pale, loose, offensive stools that are difficult to flush) and protein deficiency
5. Endocrine dysfunction - diabetes mellitus (DM) and its associated morbidity and mortality.

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

Of abdominal pain:

• Acute cholecystitis
• Peptic ulcer disease
• Acute hepatitis
• Abdominal aortic aneurysm
• Pyelonephritis
• Acute pancreatitis
• Non-abdominal causes e.g. ischaemic heart disease and pneumonia.

Of pancreatic calcification on abdominal imaging:

• Severe protein malnutrition
• Hereditary pancreatitis
• Hyperparathyroidism.

Early diagnosis is difficult as no biochemical markers exist and abdominal radiology may show normal pancreatic appearances.

• Bloods: FBC, U & E Cr, LFT'S, Calcium, Amylase (usually normal), glucose, HBa1C
• Secretin stimulation test: a positive result occurs if 60% or more pancreatic exocrine function is damaged. However, it is not routinely used as it is invasive and a lengthy procedure⁹
• Serum trypsinogen and urinary d-xylose or faecal elastase if malabsorption is present
• Imaging: classically there is pancreatic calcification, however some may have a normal pancreatic appearances on ultrasonography. First line is ultrasonography but CT and ERCP (endoscopic retrograde cholangiopancreatography) may also be required. In severe cases a plain AXR may show pancreatic calcification.
• Magnetic retrograde cholangiopancreatography (MRCP) may also be used. This is similar to ERCP but involves MRI scanning and not an endoscope. However, it only provides images and not a method to deal with identified problems e.g. strictures. Therefore, patients may need to go on to have ERCP.
• 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.
• Endoscopic ultrasound (EUS) - this 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.⁹

Management Principles

• Need to manage pain and malabsorption
• Patients may also need assessment and counselling regarding alcohol intake and illicit drug use e.g. CAGE questionnaire
• Look for the presence of psychiatric conditions e.g. depression
• History - symptoms of abdominal pain, diarrhoea, weight loss. Look for red flags such as, bowel change which may indicate neoplastic disease
• Alcohol intake, family history
• Examination - mostly to rule out other causes of abdominal pain e.g. cholecystitis
• Investigations - abdominal ultrasound, baseline bloods including liver function to look for biliary tract obstruction, refer on for possible secretin test and ERCP or CT scan
• Management - if severe pain may need to be urgently referred for assessment. If mild to moderate pain consider if patient can manage at home with simple analgesia then refer as an out-patient to gastroenterologists.

Supportive measures

• Lifestyle advice regarding alcohol intake, 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 relief

• The underlying cause of the pain is unclear
• Pain relief commonly requires opiates and there is a risk of opiate dependency. Simple analgesics should be used initially e.g. paracetamol and NSAIDs provided there are no contraindications.
• Opiates may also lead to gastroparesis
• ERCP may help reduce pain by dilating strictures of the pancreatic ducts
• Nerve blocks have also been used e.g. coeliac ganglionectomy or translumbar injection of local anaesthesia. Nerve blocks can also be given via EUS or CT - but this is invasive and only provides temporary relief.

It is important to make sure that there is not another cause for the pain e.g. pseudocyst, 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 below) and if there is likely to be a delay or they are unsuitable for surgery then 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 e.g. Creon^®. It is thought that the pancreatic enzymes provide negative feedback on pancreatic exocrine function. Randomized trials have shown this method to be effective in more than 50% of patients especially patients with small duct disease.²

Furthermore, 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 that reach the small intestine can break down the CCK releasing peptide thereby halting pancreatic stimulation.

However, 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 then they are withdrawn. 50% of patients will have long-term resolution of pain.² However, if patients fail to respond then they should be considered for surgical procedures. One draw back of pancreatic enzymes is that it requires the taking of eight capsules at mealtimes and bedtime which may be difficult for some patients.

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 administration.²

CCK antagonists

Proglumide is a CCK receptor antagonist that enhances the response to opiates. It may also provide an analgesic effect on it's own. Its role in chronic pancreatitis is currently under evaluation.¹⁰

Surgical management

• Surgery may be required for the management of complications e.g. pseudocyst decompression
• Thoracoscopic bilateral splanchinectomy involves transecting pancreatic pain sensing nerve fibres. This procedure has been used in both pancreatic and adrenal carcinoma with good effect. The effectiveness in chronic pancreatitis requires further research.
• Surgical decompression of duct dilatation can be performed if this can not be achieved by ERCP alone. Furthermore, if duct dilatation is large e.g. more than 6 mm a lateral pancreaticojejunostomy can be performed.

Pancreatic resection

• Pancreatoduodenectomy has been used in chronic pancreatitis and pancreatic cancer
• Other forms of surgery used include Beger procedure (duodenal preserving resection of the pancreatic head) and Frey's procedure (extended lateral pancreaticojejunostomy)
• Radical surgery such as these 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 patients¹¹
• 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.
• Combining surgery with pancreatic enzyme replacement not only provides pain relief but is also associated with weight gain.¹¹

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 dysfunction¹²
• However, this a lengthy operation and is associated with major complications
• The autologous cells are infused into the portal vein and this has been associated with reduced pain scores and a reduction in insulin requirements.^2,12

Chronic pancreatitis is associated with increased mortality and morbidity - one third of patients will die in 10 years.

Furthermore, for those who continue to drink this risk is further increased.