Approach

Patients with chronic abdominal pain and/or a history of relapsing acute pancreatitis, symptoms of pancreatic exocrine insufficiency (diarrhoea, steatorrhoea, weight loss, bloating, excessive flatulence, fat-soluble vitamin deficiencies, and protein-calorie malnutrition), or pancreatogenic diabetes should be evaluated for suspected chronic pancreatitis.[60][82][83][84]​​

The initial approach should include a thorough history and physical examination.[85]

Establishing the diagnosis is challenging

Individual patient symptoms and objective diagnostics provide a probability of chronic pancreatitis, but a diagnosis usually requires a combination of features.

Diagnosing the early stages of chronic pancreatitis is problematic when pain is the only feature and imaging tests are inconclusive. These patients require prospective follow up as after a first attack of acute pancreatitis; up to 10% of patients may progress to chronic pancreatitis.[20][86]

Progression is independently predicted by four variables:[86]

  • current smoking

  • idiopathic aetiology

  • alcohol aetiology

  • necrotising pancreatitis

Three longitudinal studies reported that 26% to 50% of patients with idiopathic attacks (recurrent attacks with no aetiology identified) developed evidence of chronic pancreatitis over 18-36 months.[87][88][89]

History and clinical features

In patients with clinical features of chronic pancreatitis, a comprehensive review of all risk factors should be performed. This will identify potential underlying mechanisms, both fixed and modifiable risk factors, potential targets for therapy, and clinically relevant prognostic information.[85]

The history should include:[85]

  • previous dates and number of episodes of acute pancreatitis (outlined in TIGAR-O or M-ANNHEIM)

  • dates of onset of diabetes mellitus (if present)

  • maldigestion/malnutrition

  • weight loss

  • bone health (e.g., fractures)

  • renal disease

  • diseases in organs associated with cystic fibrosis (e.g., lung disease, sinusitis, or male infertility).

Family history should include at least third-degree relatives and include:[85]

  • pancreatitis

  • cystic fibrosis

  • diabetes mellitus

  • pancreatic cancer.

The TIGAR-O checklist provides guidance for recording alcohol use, smoking, medications, toxins, diabetes mellitus, diet, and key biomarkers including serum calcium, and triglycerides.[85]

Hallmark clinical features are:

  • Abdominal pain: occurs in more than 80% of people at time of diagnosis.[11] The pain is epigastric, dull, radiates to the back, diminishes by sitting forwards, and worsens approximately 30 minutes postprandially.

  • Jaundice: overall incidence is approximately 10%.[90] Occurs due to common bile duct compression and is usually preceded by alkaline phosphatase elevation without jaundice or other symptoms. Cancer should be excluded if this symptom is present.

  • Steatorrhoea: overall incidence ranges between 8% and 22% at time of diagnosis.[11] Steatorrhoea occurs before azotorrhoea (malabsorption of dietary protein). It is due to injury, atrophy, and loss of pancreatic exocrine tissue due to inflammation and fibrosis of the gland. Mineral oil ingestion should be excluded if this symptom is present.

  • Malnutrition: commonly develops because of fear of food (due to pain), malabsorption, poor dietary intake related to alcohol abuse, and increased resting energy expenditure in 30% to 50% of patients.[91] Approximately 10% to 15% of patients will require nutritional supplements.[91]

  • Diabetes mellitus and glucose intolerance: glucose intolerance occurs early due to insulin resistance, and diabetes mellitus occurs late due to insulinopenia. The overall prevalence of hyperglycaemia is 47%.[92] The incidence of diabetes mellitus ranges from 0% to 22% at onset of symptoms, and more than 80% after 25 years.[11][93] A prospective cohort of 500 patients identified two independent risk factors (pancreatic calcifications and distal pancreatectomy), but a larger retrospective study of over 2000 patients identified five independent risk factors that did not include calcifications (alcoholism, male sex, steatorrhoea, biliary stricture, and distal pancreatectomy).[93][94]

Additional non-specific clinical features include:

  • Weight loss: caused by fear of food (due to pain), malabsorption, poor dietary intake related to alcohol abuse, and increased resting energy expenditure. However, malignancy should be excluded.

  • Some patients with exocrine pancreatic insufficiency report bloating and/or excessive flatulence.[84]​

  • Micro-nutrient deficiencies: caused by fear of food (due to pain), malabsorption, poor dietary intake related to alcohol use, and increased resting energy expenditure. The prevalence of fat-soluble vitamin deficiencies is variable and is reported to be 14.5% for vitamin A, 24.2% for vitamin E, and as high as 53% for vitamin D.[95][96] These deficits can potentially lead to long-term health problems, including visual deficits, neurological defects, and poor bone health.

  • Low-trauma fracture and decreased bone mineral density: related to micro-nutrient deficiencies and increased systemic inflammation.[97] The prevalence of low-trauma fracture has been reported to be 4.8%, likely due to the high pooled prevalence rates for osteopenia (39.8%) and osteoporosis (23.4%).[98][99] Fracture risk is greater if alcohol is an underlying risk factor for chronic pancreatitis and the patient has cirrhosis.[100]

  • Nausea and vomiting: occurs due to the short- and long-term complications of chronic pancreatitis. It may result from pain, obstruction of the bile duct or duodenum, or altered postprandial gastric myoelectrical activity and is exacerbated by opioid analgesics.[101] However, it remains controversial whether patients with chronic pancreatitis have delayed, normal, or rapid gastric emptying.[102][103][104][105]

  • Skin nodules: pancreatic lipase may leak into the circulation and cause fat necrosis at non-pancreatic sites. This results in painful and painless skin nodules on the extremities, associated with fever and polyarthritis.[106][107] Around 5% of patients with pancreatitis develop intramedullary fat necrosis, but this does not commonly cause symptoms.[108]

  • Painful joints: occurs in at least two conditions associated with pancreatic disease: metastatic fat necrosis; immunoglobulin G4 (IgG4)-related autoimmune pancreatitis, associated with rheumatoid arthritis with or without secondary amyloidosis.[107][109]

  • Abdominal distension: occurs as a result of an enlarged pseudocyst, pancreatic cancer, pancreatic ascites due to juice leaking from a ruptured duct or pseudocyst, or duodenal fibrosis and obstruction leading to gastric distension.

  • Shortness of breath: due to pleural effusion, secondary to juice leaking from a ruptured duct or pseudocyst and tracking to the pleural space.

The age at presentation gives an indication about the underlying aetiology. Hereditary pancreatitis has a peak incidence at 10-14 years, juvenile idiopathic chronic pancreatitis at 19-23 years, alcohol-related chronic pancreatitis at 36-44 years, and senile idiopathic chronic pancreatitis at 56-62 years.[10][11][12]

Initial tests

Cross-sectional imaging techniques are recommended as initial tests.[85]

Computed tomography (CT) or magnetic resonance imaging (MRI)

Either CT or MRI is recommended first-line for the diagnosis of chronic pancreatitis.[85]

Endoscopic ultrasonography (EUS)

EUS should only be used if the diagnosis is in question after cross-sectional imaging is performed. It is invasive and lacks specificity.[85]

EUS affords a more detailed evaluation of the pancreatic parenchyma and ducts than abdominal ultrasound or CT, and is less invasive than endoscopic retrograde cholangiopancreatography. Risks of EUS include perforation, infection, and bleeding.[110]

Secretin-enhanced magnetic resonance cholangiopancreatography (s-MRCP)

s-MRCP is suggested when the diagnosis of chronic pancreatitis is not confirmed following cross-sectional imaging with CRT/MRI or EUS, and the clinical suspicion remains high.[85]

s-MRCP allows for better visualisation of the main and side branch pancreatic ducts by stimulating the release of bicarbonate from the pancreatic duct cells.[111]

Other tests to consider

Several additional tests may be considered when results from imaging studies are inconclusive.

Histological examination

Suggested as the gold standard to diagnose chronic pancreatitis in high-risk patients when the clinical and functional evidence of chronic pancreatitis is strong, but diagnosis is inconclusive after cross sectional imaging with CT/MRI or EUS.[85]

Genetic testing

Recommended in patients with clinical evidence of possible chronic pancreatitis in which the aetiology is unclear, especially in younger patients.[85]

Patients with idiopathic chronic pancreatitis should be evaluated for PRSS1, SPINK1, CFTR, CTRC, CASR, and CPA1 gene mutations.[85] Up to 50% of patients with idiopathic chronic pancreatitis have mutations of SPINK or the CFTR gene.​[59][60]

Pancreatic function test

An important means of diagnosing exocrine pancreatic insufficiency. Its role in establishing the diagnosis of chronic pancreatitis is complementary.[85]

Pancreatic function is measured by direct or indirect methods. Direct pancreatic function tests involve exogenous hormone stimulation of pancreatic secretion and collection and measurement of pancreatic juice enzyme or bicarbonate concentrations. Direct function tests are likely the most sensitive and specific tests for diagnosing mild to moderate pancreatic insufficiency or chronic pancreatitis.[112][113]

Indirect pancreatic function tests (e.g., measuring elastase-1 in stool) are simple and non-invasive, but inaccurate for diagnosing mild to moderate chronic pancreatitis. They are mainly used to diagnose severe disease.[114][115] Faecal elastase-1 test is the initial test for diagnosing exocrine pancreatic insufficiency.​[84]​

Tests of function and structure are complementary because comparisons of direct pancreatic function tests to ERCP or to EUS may yield discordant results.

Differential diagnosis

Pancreatic cancer and autoimmune pancreatitis should be considered and excluded as differential diagnoses in patients with older onset disease.[7]

Excluding malignancy

Ruling out malignancy is a major diagnostic problem, especially in patients with an enlarged pancreatic head. Exclusion of malignancy frequently requires some form of surgical resection to ensure a reliable histopathological examination. In 10% of patients, the diagnosis is only established by histological proof at the time of operation (even in experienced centres).[116][117]

Additional investigations to distinguish between autoimmune pancreatitis and pancreatic cancer include serological testing (antinuclear antibody, IgG4 level), ampullary biopsy to detect IgG4-positive plasma cells, and a 2-week trial of corticosteroids, but these decisions should be made by specialists and require short-term follow-up.[116][117]

Pancreatic cancer should be considered in patients with a first attack of acute pancreatitis within the first year of diagnosis or in patients with a new diagnosis of chronic pancreatitis, particularly in those aged 40 years or older. One retrospective study reported that among patients with pancreatic cancer, approximately 5% were initially misdiagnosed with a new diagnosis of chronic pancreatitis and 11% with first-attack acute pancreatitis.[118][119]

Venepuncture and phlebotomy animated demonstration
Venepuncture and phlebotomy animated demonstration

How to take a venous blood sample from the antecubital fossa using a vacuum needle.

Diagnostic criteria

Several diagnostic criteria have been proposed, but none are universally accepted. They include:[5][6][10][11][121][122][123]

  • Cambridge classification for chronic pancreatitis

  • Ammann's criteria (Zurich workshop)

  • Mayo Clinic multicomponent diagnostic scoring system for chronic pancreatitis

  • M-ANNHEIM criteria (modified from Ammann)

  • Japanese Pancreas Society guidelines.

Commonly, patient follow-up is required to confirm suspicions of mild to moderate chronic pancreatitis. More information about the different criteria can be found in the Diagnostic Criteria section of this topic.

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