Aetiology

Worldwide, the major causes of chronic pancreatitis are alcohol (70% to 80%), followed by idiopathic chronic pancreatitis, many which have a genetic predisposition.[22][23]​​ Single and multicentre US studies report the frequency of chronic pancreatitis associated with alcohol as 51% or lower.[16][24][25]

Autopsy studies show that chronic pancreatitis is 45-50 times more common in people with alcohol-use disorder.[26] It is not clear whether there is a continuous spectrum of individual thresholds for alcohol toxicity or an absolute threshold, because the available data are conflicting.[27] Observations from one meta-analysis support a linear relationship between dose of alcohol and risk of pancreatitis in men, but a non-linear (J-shaped) relationship in women, the latter possibly due to the inclusion of former drinkers in the control group.[28] One study found that the logarithm of mean daily alcohol consumption correlates linearly with the risk of developing chronic pancreatitis.[29] Most patients report alcohol consumption over 150 g per day for years, but the risk of chronic pancreatitis is increased with consumption of only 25 g per day or more (around 2 drinks).[29][30] In contrast, one large multi-centre study reported that only heavy alcohol consumption (5 or more drinks daily) increases the risk of chronic pancreatitis significantly.[25] However, few patients with chronic alcohol dependence develop chronic pancreatitis (no more than 10% but likely <3%) and total alcohol consumption in heavy drinkers is no greater among those who develop chronic pancreatitis than in those who do not.[29][31][32][33][34][35][36]​ This suggests that co-factors are necessary to sufficiently lower the threshold for alcohol to induce chronic pancreatitis.[27][37]​ These include cigarette smoking, high fat/protein diet, genetic predisposition (e.g., uridine 5'-diphospho-glucuronosyltransferase gene polymorphisms), and possibly coxsackievirus infections.[29]​​[38][39][40][41]​ Regardless of the causative factor, patients with chronic pancreatitis are predisposed to pancreatic cancer.[23]

Pathophysiology

The triggers, thresholds, immunological response, and cellular mechanisms of chronic pancreatitis are unclear. Theories to explain the pathogenesis of chronic pancreatitis include: oxidative stress, toxic-metabolic factors, ductal obstruction, and necrosis-fibrosis.[42]

The primary duct hypothesis suggests that the first insult begins in pancreatic ducts as a primary autoimmune or inflammatory reaction, whereas the sentinel acute pancreatitis event hypothesis suggests that the first insult occurs in acinar cells, triggering sequestration of inflammatory cells and secretion of cytokines.[3]

Removal of the inciting factor(s) results in healing, but with persistent cytokine secretion, fibrogenic pancreatic stellate cells secrete collagen facilitating fibrosis and chronic pancreatitis. The window of opportunity to influence the natural history of chronic pancreatitis is unclear, because removal of major risk factors such as alcohol does not result in reversal.[43][44][45][46]

The mechanisms of pain in chronic pancreatitis are unclear but are likely to be multi-factorial, including pancreatic inflammation, fibrosis-related increases in intra-pancreatic pressure and ischaemia, neural sources of pain (nerve sheath inflammation, fibrotic encasement of sensory nerves, and neuropathy), and extra-pancreatic causes (e.g., common bile duct stenosis, duodenal stenosis, and pancreatic pseudocysts).[47]

Classification

Sarles classification[2]

Sarles classified chronic pancreatitis into three major groups:

  • Obstructive pancreatitis

  • Inflammatory pancreatitis

  • Lithogenic or calcifying chronic pancreatitis.

TIGAR-O[3][4]

The TIGAR-O aetiological classification of chronic pancreatitis incorporates insights into genetic, environmental, immunological, and pathobiological risk factors associated with chronic pancreatitis. The TIGAR-O aetiological classification consists of six groups:

1. Toxic-metabolic

  • Alcoholic

  • Tobacco smoking

  • Hypercalcaemia

  • Hyperlipidaemia

  • Chronic kidney disease

  • Medicines: phenacetin abuse (weak association)

  • Toxins: organotin compounds, for example, di-N-butyltin dichloride (DBTC)

2. Idiopathic

  • Early onset

  • Late onset

  • Tropical

3. Genetic

  • Hereditary pancreatitis: cationic trypsinogen mutations

  • Cystic fibrosis transmembrane conductance regulator (CFTR) mutations

  • Serine protease inhibitor Kazal type 1 (SPINK1) mutations

  • Chymotrypsinogen C (CTRC) mutations

  • Calcium-sensing receptor (CaSR, CSR) mutations

  • Claudin-2 (CLDN2) mutations

  • Carboxypeptidase A1 (CPA1)

  • Fucosyltransferase 2 (FUT2) non-secretor status

  • ABO blood group type B

4. Autoimmune

  • Type 1 autoimmune pancreatitis (associates with other IgG4 related disorders)

  • Type 2 autoimmune pancreatitis (may associate with inflammatory bowel disease)

5. Recurrent and severe acute pancreatitis

  • Post-necrotic (severe acute pancreatitis)

  • Recurrent acute pancreatitis

  • Vascular diseases/ischaemia

  • Post-irradiation

6. Obstructive

  • Pancreas divisum (controversial)

  • Sphincter of Oddi disorders (controversial)

  • Duct obstruction (e.g., solid tumour, intra-ductal papillary mucinous neoplasm)

  • Peri-ampullary duodenal wall cysts

  • Post-traumatic pancreatic duct scars.

The Cambridge classification for chronic pancreatitis[5]

The Cambridge classification of endoscopic retrograde cholangiopancreatography (ERCP) (and ultrasound [US] or computed tomography [CT] imaging) grades the severity of pancreatic structural changes based on abnormalities of the main duct and side branches.

Score 1 (Cambridge class 0)

  • Severity: normal

  • Good quality ERCP/US or CT visualising whole gland without abnormal signs.

Score 2 (Cambridge class 0)

  • Severity: equivocal

  • ERCP: <3 abnormal branches

  • US/CT: abnormal sign: main pancreatic duct 2-4 mm diameter, gland 1 to 2 x normal.

Score 3 (Cambridge class I)

  • Severity: mild

  • ERCP: 3 or more abnormal branches

  • US/CT: 2+ abnormal signs: cavities <10 mm, duct irregularity, focal acute necrosis, parenchymal heterogeneity, increased echogenicity of duct wall, contour irregularity of head/body.

Score 4 (Cambridge class II)

  • Severity: moderate

  • ERCP: >3 side branches plus abnormal main duct

  • US/CT: as score 3.

Score 5 (Cambridge class III)

  • Severity: severe

  • ERCP: all of above, plus one or more of: large cavity >10 mm, intraductal filling defects, duct obstruction (stricture), duct dilation or irregularity

  • US/CT: all of above, plus one or more of: large cavity >10 mm, intraductal filling defects, duct obstruction (stricture), duct dilation or irregularity, calculi/pancreatic calcification, contiguous organ invasion.

M-ANNHEIM classification[6]

The diagnosis usually requires a typical history of chronic pancreatitis (recurrent pancreatitis or abdominal pain). Individuals may be categorised by aetiology, clinical stage, disease severity, and the probability of having chronic pancreatitis.

M-ANNHEIM pancreatic imaging criteria for ultrasound, CT, MRI/MRCP, and endoscopic ultrasonography (EUS), based on imaging features as defined by the Cambridge classification, includes normal, equivocal, mild, moderate, and marked changes.

Definite chronic pancreatitis

Established by one or more of the following additional criteria:

  • pancreatic calcifications

  • moderate or marked ductal lesions (according to the Cambridge classification)

  • marked and persistent exocrine insufficiency defined as pancreatic steatorrhoea markedly reduced by enzyme supplementation

  • typical histology of an adequate histological specimen.

Probable chronic pancreatitis

Established by one or more of the following additional criteria:

  • mild ductal alterations (according to the Cambridge classification)

  • recurrent or persistent pseudocysts

  • pathological test of pancreatic exocrine function (such as faecal elastase-1 test, secretin test, secretin–pancreozymin test)

  • endocrine insufficiency (i.e., abnormal glucose tolerance test).

Borderline chronic pancreatitis

Established as a first episode of acute pancreatitis with or without:

  • a family history of pancreatic disease (i.e., other family members with acute pancreatitis or pancreatic cancer)

  • the presence of M-ANNHEIM risk factors.

Pancreatitis associated with alcohol consumption

Requires in addition to the above-mentioned criteria for definite, probable, or borderline chronic pancreatitis one of the following features:

  • history of excessive alcohol intake (>80 g/day for some years in men, smaller amounts in women), or

  • history of increased alcohol intake (20-80 g/day for some years), or

  • history of moderate alcohol intake (<20 g/day for some years).

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