Chronic pancreatitis

Abstract

Chronic pancreatitis is a challenging condition for a variety of reasons: it is relatively poorly understood, difficult to diagnose, complex to manage, and is associated with significant morbidity and mortality. The aim of this article is to outline the important aspects of this fibro-inflammatory disease, highlighting the difficulties and providing guidance regarding these problems.

The GP curriculum and chronic pancreatitis

Clinical module 3.13: Digestive health lists the learning objectives required for a GP to manage digestive disorders. In particular, GPs are expected to:

Understand the epidemiology of gastrointestinal symptoms and disorders in primary care, and the evidence on the risks for cancer and other serious diseases associated with various symptoms and symptom complexes

Have a good understanding of the availability of endoscopic services for upper and lower gastrointestinal symptoms/diseases

Advise patients appropriately regarding lifestyle interventions that have an impact on gastrointestinal health, such as advice on diet and on stress reduction

Understand the range of gastrointestinal problems associated with alcohol and drug usage

Appreciate the complex issues around drug and alcohol misuse, the ways these impact on digestive disorders and the management problems they are associated with, demonstrating a non-judgmental approach to individuals with, for example, chronic gastrointestinal symptoms, drug and alcohol problems

Aetiology and pathogenesis

Chronic pancreatitis (CP) is a fibro-inflammatory disorder of the pancreas, primarily differing from acute pancreatitis in being an irreversible process. There is structural damage with associated impairment of the pancreas’ function. Although relatively uncommon, it carries a significant mortality and its incidence is increasing: one study in the United States evaluated the incidence to have increased from 2.94 in 1977–86 to 4.35 per 100 000 in 1997–2006 (Yadav, Timmons, Benson, Dierkhising, & Chari, 2011).

The main functions of the pancreas can be subcategorised as exocrine and endocrine. The exocrine pancreas affects digestion of food through exogenous release of enzymes and bicarbonate. The endocrine pancreas impacts upon metabolism and regulates blood glucose levels through release of hormones, including insulin and glucagon.

There are numerous causes of CP (Box 1), and its aetiology is likely to be multifactorial in the majority of cases. Recurrent pancreatic injury, with subsequent immune activation, leads to injury of pancreatic exocrine acinar cells. The cytokine-driven anti-inflammatory response can then result in fibrosis, through the action of pancreatic stellate cells. These are myofibroblast-like cells that can be either activated or inactivated, and in the healthily functioning pancreas are vital in tissue repair at the site of injury upon activation. There is a requirement for all three of these processes to develop CP: injury, inflammation, and an anti-inflammatory response leading to fibrosis (Whitcomb, 2014).

Box 1.

Common causes and risk factors for CP.

• Alcohol

• Idiopathic

• Smoking

• Genetic predisposition

• Cystic fibrosis

• Ductal obstruction due to tumour, stones or strictures

• Autoimmune

• Drugs

Alcohol is believed to lead to CP through direct toxicity of acinar cells. It is recognised as the commonest cause of CP, particularly in Western countries. High alcohol intake and persistence of this over a number of years leads to an increased risk, although the majority of those who are alcohol dependent do not develop CP. Most cases of CP are believed to be multifactorial, which may explain this apparent discrepancy (Freedman & Lewis, 2013). The proportion of patients in whom CP has been attributed to alcohol has likely been overestimated in the past: this figure has reduced as a greater understanding of other aetiologies has developed. The exact incidence due to alcohol remains unclear. Previously believed to account for well over 80% of cases, a recent study in the United States estimated alcohol to be implicated in only 45% (Coté et al., 2011).

The next-most-common cause, in up to 25% of cases, is idiopathic i.e. no cause is found. However, for many patients, there are believed to be factors that are unknowingly contributing e.g. surreptitious alcohol use, previous trauma not accounted for, and predisposition through genetic mutations (Keller & Layer, 2008).

An association between cigarette smoking and CP is well-established, with the risk of disease again being related to both quantity and duration of smoking. As well as being implicated in the pathogenesis of pancreatic calcification, smoking can inhibit the pancreas’ ability to secrete bicarbonate and water, leading to digestive enzymes becoming prematurely activated, prior to entering the intestine (Coté et al., 2011).

Rarer causes include ductal obstruction through pancreatic stones, tumours and even trauma-associated strictures. The effects of these may fail to resolve upon relieving the obstruction (Owyang & Levitt, 1991).

Cystic fibrosis may lead to CP. Although pancreatic insufficiency is very common in those with cystic fibrosis, it is actually those with a less severe genotype and a sufficiently functioning pancreas who may develop CP. In idiopathic CP, the prevalence of the cystic fibrosis transmembrane conductance regulator (CFTR) carrier genes is higher than the general population. The pathophysiology behind these is incompletely understood (Sabharwal & Borowitz, 2015).

An unfortunate number of patients are affected by hereditary CP, which follows an autosomal dominant pattern with high penetrance, although a recessive pattern is less commonly seen. It is a rare condition, with a prevalence of 3 per 1 000 000. This commonly presents in early childhood, with the vast majority of cases diagnosed before reaching 20 years in age. Although it is managed in the same way as other forms of CP, there are significantly increased risks of complications, such as cancerous transformation in 40% by the age of 70 years (Rebours, Levy, & Ruszniewski, 2011).

Signs and symptoms

Abdominal pain

The clinical features of CP are outlined in Box 2. The predominant symptom is abdominal pain, although its presence and nature is extremely variable and it can even be absent. Typically, this is epigastric and described as ‘deep’ in nature, radiating to the back with some relief gained by leaning forward. It can be severe, with opiates commonly required to provide adequate analgesia. A postprandial peak has been reported, roughly 30 minutes after meals. The pain may be associated with nausea and vomiting (Freedman, 2014).

Box 2.

Clinical features of CP.

• Deep epigastric abdominal pain, occurring intermittently and recurrently

• Steatorrhoea, abdominal bloating and excessive flatulence

• Fatigue

• Malabsorption with hypoalbuminaemic oedema

• Impaired glucose tolerance

• Unremarkable clinical examination which is relatively disproportionate to the level of pain

• Features of chronic liver disease may be present

The spectrum of pain is wide. Two major distinct groups are recognised (Ammann, 1999):

Intermittent exacerbations of pain for up to a week, with prolonged pain-free periods

Daily pain, or regular episodes for a longer duration.

Clinical examination is often relatively unremarkable, in contrast with severe symptoms, although epigastric tenderness is recognised. Indirect physical manifestations of associated pathology may be elicited e.g. signs of chronic liver disease due to alcohol excess, finger clubbing associated with cystic fibrosis, and occasionally palpable pancreatic pseudo-cysts (Freedman, 2014).

Pancreatic insufficiency

Pancreatic insufficiency is common, and may be the presenting feature. Insufficiency takes the form of exocrine dysfunction, endocrine dysfunction, or both.

Exocrine dysfunction consists of a deficiency of three major classes of enzymes: amylase, protease and lipase. The roles of these go beyond the scope of this article, but ultimately their deficiencies cause maldigestion and malabsorption. Unlike carbohydrate and protein digestion, the vast majority of fat digestion occurs through pancreatic lipase, and therefore fat malabsorption is most profound. Steatorrhoea, malodourous pale stool, is the presence of this fat within the faeces. Weight loss and fatigue subsequently occur. Fat-soluble vitamins (A, D, E and K) can consequently be low. Bleeding and mineral bone disease may then be seen, but are rare (Al-Kaade, 2014).

Less commonly, bacterial fermentation of unabsorbed food substances can lead to excessive flatulence and abdominal distension. This can be both uncomfortable and embarrassing for those affected. Other effects of malabsorption include oedema due to hypoproteinaemia and electrolyte imbalances, most notably hypomagnesaemia and hypocalcaemia (DiMagno, Go, & Summerskill, 1973).

Endocrine dysfunction manifests as glucose intolerance, although diabetes mellitus itself is generally only found in late disease and usually requires treatment with insulin. Unlike type-1 or type-2 diabetes, however, the risk of hypoglycaemia is amplified by impairment in the ability to form glucagon by alpha cells. This hypoglycaemia can occur sporadically or through iatrogenic overly aggressive insulin use (Angelopoulos et al., 2005).

Differential diagnoses

The variable nature and severity with which CP presents means it should be suspected in those with upper abdominal pain. However, the differential diagnoses to be considered in primary care are wide. Common causes of epigastric pain include biliary colic and peptic ulcer disease. Acute pancreatitis is an important differential, as it has significant mortality and morbidity. Pancreatic cancer is clearly a diagnosis that needs to be excluded if suspected.

Investigation

Primary care

The diagnosis of CP, particularly in its early stages, is challenging. In a primary care setting, the possibility of CP should be suspected in those who have persistent or recurring abdominal pain of unknown aetiology. Clinical suspicion should be higher in those with lifestyle factors predisposing them to higher risk, most notably excessive alcohol intake.

The GP will often have to exclude more common causes of epigastric pain before the rarer CP is considered. The relevant investigations clearly depend upon the presenting symptoms e.g. ultrasound scan of the abdomen for gallstones, endoscopy for peptic ulcer disease, or urgent computerised tomography (CT) scan of the abdomen for pancreatic malignancy. There is a limited role for blood tests, as unlike acute pancreatitis, biochemical markers can be entirely normal, including amylase and liver function tests. If acute pancreatitis is suspected, however, same-day inpatient investigation is required, with admission if confirmed.

Diagnosis of CP itself is made in secondary care, and all patients should be referred to a specialist gastroenterologist or hepatobiliary surgeon, where further imaging modalities are available (National Institute for Health and Care Excellence (NICE), 2010).

Secondary care

A clinic appointment should be offered within 4 weeks of referral from primary care. The primary modality of investigation is imaging. In advanced stages of the disease, cross-sectional imaging e.g. CT scanning is generally sufficient to establish a diagnosis. The caveat to this is that appearances can occasionally be similar to that of pancreatic malignancy (British Society of Gastroenterology, 2009).

Earlier in the disease process, either conventional ultrasound or endoscopic ultrasound (EUS) has been shown to be effective at yielding a diagnosis through visualisation of both parenchymal and ductal changes. This includes parenchymal fibrosis, pancreatic cysts, duct calculi, duct dilatation and duct strictures (Gupte & Forsmark, 2014). Being more readily available, cheaper and non-invasive, conventional ultrasound is still more widely used over an endoscopic approach. Endoscopic retrograde cholangiopancreatography is another modality commonly used to investigate suspected CP.

There is no single classification method used that is universally accepted as the gold standard for CP diagnosis, however, the recently developed Rosemont classification is able to define the radiological findings of EUS into major and minor categories, and therefore provide diagnoses in a standardised manner. In the Rosemont criteria outlined below in Tables 1 and 2, the number of major or minor features are used to class patients as being ‘consistent with CP’, ‘suggestive of CP’, ‘indeterminate for CP’ or ‘normal’ (Yamabe et al., 2013).

Table 1.

EUS criteria for diagnosis of CP in the main pancreatic duct (MPD).

Rosemont criteria	Parenchymal criteria	Duct criteria
Major A	Hyperechoic foci (more than 2 mm with shadowing)	MPD calculi (echogenic structures within the MPD)
Major B	Lobularity
Minor	• Cysts • Hyperechoic strands (more than 3 mm) • Hyperechoic foci (more than 2 mm without shadowing)	• Irregular MPD contour • Dilated side branch • Hyperechoic MPD wall • Dilated duct (more than 3.5 mm in body or 1.5 mm in tail)

Reproduced from Yamabe et al. (2013)

Table 2.

Classification of patients based upon criteria from Table 1.

Rosemont criteria	Consistent with CP	Suggestive of CP	Indeterminate for CP	Normal
A	1 major A and at least 3 minor	1 major A and less than 3 minor	3 to 4 minor, no major	Less than 3 minor, no major
B	1 major A and major B	1 major B and at least 3 minor	Major B and less than 3 minor
C	2 major A	At least 5 minor, no major

Reproduced from Yamabe et al. (2013).

Pancreatic function tests, predominantly through measurement of secretin, are also useful in investigation, particularly when imaging is inconclusive. This can be tested directly through endoscopic placement of a catheter or collecting tube, the drawback to this being the fact it is both expensive and technically challenging, thus limiting its availability. More widely-used is faecal elastase testing, which measures the enzyme in the stool to assess pancreatic insufficiency. This is a simple test and inexpensive, yet has a relatively low sensitivity. A variant on this investigation is the faecal fat test, although this is more widely used in assessment of response to treatment with pancreatic enzyme replacement therapy, and less so specifically for insufficiency assessment. Following a period of high fat ingestion the fat levels within the stool are measured over a period of 24–72 hours (Gupte & Forsmark, 2014).

Management

Management of CP is multifaceted and complex. It involves treating the effects of the disease process, namely the pain, endocrine and exocrine dysfunction, and dealing with the complications. On top of this, emphasis is placed upon challenging what are frequently lifelong behaviours, such as excess alcohol consumption, to alter the disease process where possible.

Given its complex nature, secondary care input is required for large aspects of the management. A patient will conceivably be under the care of a gastroenterologist, an endocrinologist or diabetologist, an anaesthetist with an interest in pain management, and possibly a hepatobiliary surgeon. A major role of the GP is to coordinate these varying specialties. This may be complicated by the fact this demographic of patients may lead chaotic lifestyles or be reluctant to engage with medical professionals, leading to a failure to attend appointments. GPs are commonly the first port of call for many when suffering from recurrence of symptoms or potentially developing complications.

Lifestyle advice

Simple measures can both limit symptoms, such as pain, and reduce disease progression. Cessation of stimulating factors, particularly alcohol intake, is vital. Regardless of the suspected underlying cause, complete abstinence from alcohol and smoking is advised. Frequent, smaller meals can reduce the postprandial pain experienced by many (Maisonneuve et al., 2005). Overt diabetes mellitus from endocrine dysfunction is rare, but impaired glucose tolerance does occur and should be tested for on a regular basis, although there are no guidelines indicating specifically what interval is appropriate.

Pain management

Arguably, the most complex aspect of CP is pain management. The pain is often multifactorial, and although there are numerous approaches available, it can be difficult to control. Pain can be caused by pancreatic hyper-stimulation, inflammation, ductal obstruction, or even be of neuropathic origin. Complicating this is the fact that pain is often disproportionate to imaging findings. Unfortunately, given the nature of the aetiology, substance abuse is relatively more frequent in this demographic of patients, leading to challenges when considering prescription of high-dose opiates (Westlund High & McIlwrath, 2013).

The principles for pain management follow those used for most chronic pain conditions, in that the lowest dose of weakest analgesics should be used where possible. This can be titrated up or have other therapies added if this is inadequate. Therefore, weak analgesics such as paracetamol and non-steroidal anti-inflammatory drugs (NSAIDs) are recommended initially before consideration of opiates. Caution with the use of NSAIDs should be noted, however, with high-dose use being linked to worsening of pancreatic fibrosis and subsequently, of associated pain (Zhang et al., 2010).

Opioids are required by many patients, particularly in those with advanced disease. Although short-acting opioids may be required during exacerbations, between these episodes, they should be reverted to slow-release preparations and the dose reduced where possible. Adjunct treatment with tricyclic antidepressants and selective serotonin reuptake inhibitors has been shown to increase efficacy (Freedman, 2015; Westlund High & McIlwrath, 2013).

Pancreatic enzyme supplementation

Pancreatic enzyme replacement, or supplementation, is generally required regularly and lifelong. This has been shown in numerous studies to lead to both an increment in weight and a reduction in faecal fat. As a result, steatorrhoea is commonly improved. Anecdotally, enzyme replacement has been found to improve pain associated with CP; however, NICE guidance suggests the evidence is insufficient in showing a significant improvement. Pancreatic enzyme replacement is therefore only recommended in those with steatorrhoea or nutritional deficiencies (NICE, 2010).

As pancreatic function is difficult to quantify, the dosage of pancreatic enzymes, such as Creon, is based upon improvement of symptoms, such as steatorrhoea, or achievement of relevant nutritional targets set for the patient. Factors such as the content, specifically fat quantity, of meals and the speed at which this is eaten dictates the dose and timing of supplementation; the dose may be taken solely at the beginning of the meal or split into divided doses. Response and titration of the supplements can then be based upon degree of improvement in symptoms or weight. The supplements themselves are often non-enteric coated, and therefore require co-administration of a proton pump inhibitor to prevent intragastric enzyme denaturing (Freedman, 2015).

Diabetes management

Glucagon-secreting alpha cells of the pancreas are also affected, leading to an increased incidence in hypoglycaemic episodes. Despite insulin therapy being the mainstay of treatment of CP-induced diabetes, a trial of oral hypoglycaemic agents is advised initially. Concurrent administration of pancreatic enzyme replacement therapy to maintain optimum nutritional status is advised, as well as input from endocrinology services in secondary care (Andersen et al., 2013).

Surgical management

In some cases where lifestyle interventions and pharmacological therapy are inadequate, procedures including endoscopy and surgery can be offered in secondary care. Both endoscopy and surgery have multiple indications, including removal of pancreatic stones, dilatation of strictures, and stent insertion and drainage of pseudo-cysts. The main aim of these is to improve symptomatology, most notably pain. Particularly when complications are absent, endoscopy is preferred as the first-line option over surgical procedures, as recovery time and associated mortality is generally lower (Dumonceau et al., 2012).

Complications

Several complications can develop as a result of CP. The most common of these are pancreatic pseudo-cysts, whereby pathological disruption of the pancreatic duct leads to a walled-off collection of usually enzyme-rich fluid. There can be multiple occurrences and they are predominantly asymptomatic. Pseudo-cysts can cause abdominal pain (depending on their location), infection in the form of abscesses, or may rupture or leak (Jani, Bani Hani, Schulick, Hruban & Cunningham, 2011).

Other complications include obstruction of the common bile duct or duodenum: this can be due to a pseudo-cyst itself or as a result of fibrosis within the pancreatic head. Abdominal pain, reduced appetite and obstructive jaundice are usually seen. Less commonly, ascites may form as a result of fistula formation into the abdomen, or pleural effusion due to fistulation through the diaphragm (Freedman, 2013).

CP is an established risk factor for pancreatic cancer. Hereditary pancreatitis carries a significantly higher risk of cancerous transformation; however, in the majority of cases the risk is relatively low at 5% 20 years from diagnosis (Raimondi, Lowenfels, Morselli-Labate, Maisonneuve, & Pezzilli, 2010).

Prognosis

Prognosis is worse in those older at time of diagnosis, smokers, continued alcohol ingestion, liver cirrhosis, and those who develop complications. Overall, the 10-year survival is 70% and 20-year survival 45% (Huffman, 2015).

Key points

There are many causes of CP, with alcohol being the most common; the cause is often multifactorial

The predominant symptom of CP is abdominal pain, which is variable in intensity and often difficult to control

There are no biological markers of CP; imaging or direct endoscopic visualisation is required for diagnosis

Management of CP takes the form of lifestyle alterations, analgesia, and enzyme supplementation

Endoscopic and surgical intervention may be required to manage complications of CP or for refractory pain

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