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Etiology of Chronic Pancreatitis

TIGAR-O → toxic, idiopathic, genetic, autoimmune, recurrent, and obstructive.

MANNHEIM → (multiple) alcohol, nicotine, nutritional, hereditary, efferent duct, immunologic, and

The best known hypotheses about the pathogenesis of CP include necrosis- fibrosis, toxic-metabolic
causes, oxidative stress, plug and stone formation with duct obstruction, primary duct obstruction,
and the sentinel acute pancreatitis event (SAPE).

Two-hit hypothesis explains the process best.

The pancreatic stellate cells are the major mediators of formation of the dense, fibrotic extracellular
matrix around the acinar cells and pancreatic duct and ductules.

A computed tomography (CT) scan of the pancreas is usually the initial imaging modality of choice.

In early stages of CP, both endoscopic retrograde pancreatography (ERP) and EUS are methods with
reliable diagnostic accuracy, although several studies have shown superiority of EUS over ERP for the
diagnosis of CP in its early stages.

In the absence of EUS, the combination of ERP and CT provides the most reliable morphologic

The most common pancreatic function tests do not detect mild to moderate exocrine pancreatic
insufficiency with adequate accuracy, and therefore functional investigation techniques of the
pancreas play only a complementary role in the routine clinical evaluation of CP.

Etiology of Chronic Pancreatitis

The most common etiologies of chronic pancreatitis (CP) in adults in Western societies are long-term
alcohol abuse, which accounts for 50% to 60% of cases, followed by smoking (25%- 30%).

Two current classification systems are used: TIGAR-O and MANNHEIM

Toxic and Metabolic (A, N = Alcohol and Nicotine in MANNHEIM)

CP develops in only 5% to 10% of patients with alcoholism.

Most patients (60%-90%) with CP have 10 to 15 years of heavy alcohol consumption, but some
individuals have ingested less alcohol during a shorter period and still experience CP. This is
especially true for patients who began to drink alcohol during puberty.

The critical threshold of daily alcohol intake has been estimated to be approximately 40 g daily for
women and 80 g daily for men (4-5 drinks a day).

In alcohol-induced pancreatitis, necrosis and pseudocyst formation are more common.

Smoking increases the risk of CP in a dose-dependent manner, and the risk for CP in individuals
smoking less than 1 pack of cigarettes per day is 2.4, increasing to 3.3 in individuals who smoke
more than 1 pack/day.

Smoking cessation reduces the risk ratio estimate for CP by approximately 50%.

Smoking is an independent risk factor for acute pancreatitis and augmented the effect of alcohol on
the risk, age of onset, and recurrence of pancreatitis.
Tobacco induces oxidative stress and alters the secretion and composition of pancreatic juice,
resulting in decreased juice and bicarbonate secretion and inflammation.

Uridine 5′-diphosphate (UDP) glucuronosyltransferase (UGT1A7) genes. These proteins are vital
biochemical factors for detoxification and cell defense. The incidence of this mutation was much
more common in patients with CP and tobacco abuse, but not in patients with nonalcoholic CP.

Idiopathic (I = Idiopathic in MANNHEIM)

30% of patients with CP have no known risk factors; therefore this type of CP is called idiopathic.

Mutations of the serine protease inhibitor Kazal type 1 (SPINK1 gene) in up to 25% of patients with
“idiopathic” CP.

Based on the bimodal age of onset of the clinical symptoms, idiopathic pancreatitis is separated into
two distinct entities:

 Early idiopathic CP
o First 2 decades of life,
o Abdominal pain the predominant clinical feature
o Pancreatic calcifications and exocrine and endocrine pancreatic insufficiency are rare
at the first diagnosis.
 Late- onset idiopathic CP
o Fifth decade of life
o Painless course
o Significant exocrine and endocrine pancreatic insufficiency and pancreatic

Histologically ꟷ T-lymphocyte infiltration, ductal obstruction, acinar atrophy, and fibrosis, raising the
possibility of autoimmune etiology.

Rather than mutations in trypsinogens, variants in SPINK1, cathepsin B, chymotrypsin C (CTRC),

cystic fibrosis transmembrane regulator (CFTR), and carboxypeptidase A1 predict the risk for tropical
calcific pancreatitis (TCP).

TCP is the most common form of CP in certain parts of the world, including India , sub-Saharan
Africa, and Brazil, where it is also affects children and adolescents.

TCP is characterized by ꟷ severe recurrent and chronic abdominal pain and extensive pancreatic
calcifications and fibrocalculous pancreatic diabetes, with significant pancreatic endocrine

TCP is now seen in relatively older people with less severe symptoms.

The role of malnutrition and cassava toxicity in its pathogenesis has been completely disproved in
case-control and animal studies.

“Classic” tropical pancreatitis may indeed be idiopathic or hereditary.

TCP ꟷ mutations in the SPINK1 gene. The SPINK1 pancreatic secretory trypsin inhibitory (PSTI) gene
is responsible for the encoding of SPINK1.

PSTI has the main function of inhibiting activated trypsin.

SPINK1 is the major intrapancreatic “deactivator” of activated trypsinogen.

The strong association between CFTR mutations and idiopathic CP.

One third of all patients with idiopathic CP have CFTR mutations.

Genetic (H = Hereditary in MANNHEIM)
 Cationic trypsinogen (PRSS1),
 Anionic trypsinogen (PRSS2),
 Calcium-sensing receptor (CASR), and

SPINK1-N34S gene mutation, which is also closely associated with tropical (50%), alcoholic (6%), or
idiopathic (20%) CP.

Associated with trypsinogen gene mutations, HP is an autosomal dominant disease that carries an
80% penetrance.

HP is characterized by recurrent episodes of acute pancreatitis or familial aggregation of CP, but most
patients with this genetic mutation are asymptomatic.

The progression of CP is faster in patients with SPINK-N34S mutation than in patients with PRSS1

Patients with HP have a more than 50-fold increased risk of pancreatic ductal cancer compared with
the general population.

Currently it is only advised to evaluate for mutations in patients with HP.

HP, which typically present in a bimodal pattern of childhood and adulthood.

Autoimmune (I = Immunologic in MANNHEIM)

Its morphologic hallmarks are ꟷ
Periductal infiltration by lymphocytes and plasma cells and granulocytic epithelial lesions, with
consequent destruction of the duct epithelium and venulitis

Based on etiology, serum markers, histology, and systemic involvement, AIP is classified into two
distinct subtypes:

 Type 1, related to IgG4 (lymphoplasmacytic sclerosing pancreatitis), and

 Type 2, related to a granulocytic epithelial lesion (idiopathic duct-centric chronic pancreatitis)

The pathogenesis of AIP involves both a cellular (CD4 and CD8 T cells) and a humoral
immunemediated attack on the ductal cells.

Unlike type 2 AIP, type 1 AIP is characteristically associated with increasing levels of serum
immunoglobulin G4 (IgG4) and positive serum autoantibodies, abundant infiltration of IgG4- positive
plasmocytes, frequent extrapancreatic lesions, and clinical recurrence.

AIP, especially type 1, is often associated with other autoimmune diseases, such as Sjögren’s
syndrome, primary sclerosing cholangitis, and inflammatory bowel disease.

More than one third of patients with AIP do not have other extrapancreatic autoimmune disorders.

AIP is clinically characterized by minimal abdominal pain and diffuse enlargement of the pancreas
without calcifications or pseudocysts, and it most frequently involves the head of the pancreas and
the distal bile duct.

On occasion, masses have been described as inflammatory myofibroblastic tumors.

The presentation and imaging findings of AIP sometimes resemble those of pancreatic malignancy.
Hypergammaglobulinemia and autoantibodies, such as antinuclear and anti– smooth muscle

Recurrent and Severe Acute Pancreatitis

Obstructive (E = Efferent Duct Factors in MANNHEIM)

The most common etiologies causing CP as a result of obstruction of the pancreatic duct include ꟷ

Scars of the pancreatic duct, tumors of the ampulla of Vater, mucinous duct ectasia, tumors of head
of the pancreas, and trauma.

Obstruction of the main pancreatic duct produces changes of CP within weeks in several animal

Miscellaneous (M = Miscellaneous in MANNHEIM)

The TIGARO system does not contain a letter for miscellaneous forms of chronic pancreatitis, such as
primary hypercalcemia, hyperlipidemia, or hyperthyroidism. These etiologic factors are summarized
under the second “M” of MANNHEIM.

Tropical calcific pancreatitis is included here in the MANNHEIM classification, whereas TCP is
considered “idiopathic” in the TIGARO classification.

Pathogenesis of Chronic Pancreatitis

Six major established theories.

1. Necrosis-Fibrosis Hypothesis
Several distinct episodes of acute pancreatitis at different times, which then lead to necrosis and

One important aspect that partially contradicts this hypothesis, however, is that the type of fibrosis
following acute attacks of pancreatitis involves short-lived collagen type III and procollagen type IV,
not the long-lasting collagen types I and IV.

2. Protein-Plug (Stone/Ductal Obstruction) Hypothesis

Increased lithogenicity of pancreatic fluid → eosinophilic proteinaceous aggregates that precipitate
and obstruct the pancreatic ductules.

These plugs then become rich in calcium and precipitate in the ductules because of deficiency of
lithostatin (“lithostathine”) or pancreatic stone protein (PSP).

Another protein believed to induce pancreatic plug formation is glycoprotein 2 (GP-2)

3. Oxidative Stress Theory

Dysregulation and overactivity of the hepatic mixed-function oxidases.

Exposure of xenobiotics that induce the cytochrome P-450 enzymatic system and deplete glutathione
Alcohol may also contribute to oxidative stress as a result of the depletion of scavengers such as
selenium, vitamins E and C, and riboflavin.

4. Toxic-Metabolic Theory
Alcohol and its toxic metabolites cause accumulation of intracellular lipids and fatty acid ethyl esters,
which damage the acinar cell.

The alterations of intracellular lipid metabolism lead to fatty degeneration, apoptosis, and scarring of
the pancreatic parenchyma with impairment of the pancreatic microcirculation.

5. Primary Duct Hypothesis

Outflow obstructio, likely the result of duct inflammation, destruction, and fibrosis, probably caused
by an immunologic attack to a specific genetic, structural, or acquired antigen of the periductular

CP is an autoimmune or “duct- destroying” disease, analogous to primary sclerosing cholangitis


6. Sentinel Acute Pancreatitis Event Hypothesis

The SAPE is an effort to link previous hypotheses and provide a “final common pathway” for the
many etiologies of pancreatitis.

Sustained Intraacinar Nuclear Factor-κB Activation

Recent advances have challenged the trypsin-centered understanding of pancreatitis etiology.

Nuclear factor (NF)-κB activation occurs very early in the process of pancreatitis, independent of
trypsinogen activation.

Diagnosis of Chronic Pancreatitis

Chronic pancreatitis is defined as a continuing inflammatory disease of the pancreas characterized by

irreversible morphologic changes that typically cause abdominal pain and/or permanent impairment
of pancreatic function.

For many years, the gold standard for diagnosing CP has been ERCP, but now EUS has largely
supplanted ERCP as the imaging method of choice.

90% of exocrine function must be lost before steatorrhea develops.

Symptoms of bloating discomfort, abdominal pain, or a change in bowel habits when 60% to 90% of
pancreatic function is lost.

The disease course can be classified in three distinct stages ꟷ

Stage A is the early stage, characterized by recurrent acute attacks, with no or only mild impairment
of pancreatic function.

Stage B (moderate) comes later in the disease course, when complications are seen— pseudocysts,
cholestasis, and segmental portal hypertension— along with increasing intensity of pain, more
frequent acute painful attacks, and significantly impaired pancreatic function.

Stage C (advanced) represents end-stage disease, characterized by less frequent episodes and less
intense pain but with marked impairment of endocrine and exocrine pancreatic function (“burnout”).

Four scoring systems are widely used for aiding in the diagnosis of CP: the Lüneburg, Mayo Clinic,
Milwaukee, and Rosemont criteria or scores.

The Lüneburg score appears to provide a more complete evaluation than the Mayo Clinic score,
because it includes more aspects, such as ultrasound, EUS, CT, and indirect pancreatic function tests.

The Rosemont criteria are mainly based on EUS findings

Plain Abdominal Radiography

Focal or diffuse pancreatic calcification, seen in 30% to 40% of cases, makes the diagnosis of
advanced CP almost certain and in most cases obviates the need for additional testing.

Transabdominal Ultrasonography
If US detects changes of CP, diagnosis is certain (high specificity), but if the pancreas is not
completely visualized or appears normal, further examinations are necessary.

Diagnostic criteria for CP by transabdominal US are ꟷ

(1) Irregular contour (lobulation),
(2) Pancreatic duct dilation and irregularity of the main pancreatic duct,
(3) Loss or reduction of pancreatic parenchyma echogenicity (echo-poor or echo-rich areas),
(4) Cysts or cavities, and
(5) Pancreatic calcifications

Transabdominal US is useful as an initial imaging test but only helpful in patients with advanced
disease and those with complications such as pseudocyts.

Computed Tomography
The CT findings of CP include main pancreatic duct and secondary ductule dilation, intraductal
calcifications, gland atrophy, and cystic lesions.

CT is as specific as US but is more sensitive (80%).

CT is the most sensitive method to detect calculi. Importantly, calculi should be evaluated during the
noncontrast phase.

Dilation of the main pancreatic duct is visualized with high sensitivity, whereas side branches are only
detectable in advanced stages of the disease.

Discrete changes of the early stages of CP can be easily missed.

Endoscopic Retrograde Pancreatography

Endoscopic retrograde pancreatography (ERP) is the gold standard among all imaging methods for
diagnosis and staging of CP, because it has 90% sensitivity and 100% specificity

Currently, ERP is mainly used as a therapeutic tool in patients with CP.

Changes of early CP may not be seen on ERP.

“Chain of lakes” appearance of the main pancreatic duct with intermittent points of obstruction in a
dilated pancreatic duct.

In some cases, typical changes of CP detected by ERP are not pathognomonic for CP: in patients
examined early after AP, ductal changes might be reversible; in patients older than 65 years, these
changes can be obvious without having CP.

A dominant stricture, as opposed to ductular ectasia with multiple stenosis, irregular branching ducts,
and intraductal calculi, is highly suggestive of pancreatic cancer rather than CP.

Endoscopic Ultrasonography
EUS has a high sensitivity but poor specificity for diagnosing CP, but care must be taken before
basing a diagnosis of CP only on EUS criteria.
Indeed, many EUS features of CP are not necessarily pathologic and may occur as normal aging, as a
normal variant, or from nonpathologic asymptomatic fibrosis in the absence of endocrine or exocrine

Milwaukee criteria

Were further refined with the Rosemont classification.

Parenchymal Ductal
 Hyperechoic foci with shadowing
A  Calculi in the main pancreatic duct
Major  Well-circumscribed lobularity
B  Lobularity with honeycombing
 Dilated ducts (body ≥3.5 mm and tail ≥1.5
 Cysts,
 Stranding,
 Irregular main pancreatic duct contour,
Minor  Nonshadowing hyperechoic foci,
 Dilated side branches (≥1 mm),
 Lobularity with noncontiguous
 Hyperechoic duct margin.

The diagnosis of CP based on the Rosemont classification is consistent if one of the following is
 Two major A features.
 One major A feature and one major B feature, and
 One major A feature and three or more minor features,

All other combinations of features are categorized as suggestive, indeterminate, or normal.

Relatively poor interobserver agreement for EUS.

Magnetic Resonance Imaging and Cholangiopancreatography

Use of MRI/MRCP is more sensitive for the diagnosis of CP than either CT or US.

Secretin-stimulated MRI/MRCP ꟷ

Intravenous (IV) secretin should lead to an increase in the pancreatic duct diameter of more than 1
mm, with recovery of its size after 10 minutes (“pancreatic duct compliance”).

MRCP with IV secretin can also be used to evaluate the exocrine function of the pancreas.
By using a multislice, fast T2-weighted sequence, it is possible to estimate the amount of fluid
secreted by the pancreas before and after stimulation.

MRI is especially useful to detect early parenchymal changes suggestive of CP, such as abnormal
decreased signal intensity on fat-suppressed T1-weighted images and delayed or limited
enhancement after gadolinium administration.

The major disadvantage of MRCP is that changes in side branches are not visualized with the same
accuracy as in ERP.

Tests of Exocrine Pancreatic Function

These tests have low specificity (70%).

High sensitivity only in advanced stages of CP.

Direct pancreatic function tests may be limited by, among other factors, false-positive results for at
least several months after a bout of acute pancreatitis and false-negative results in some patients
who have early CP

Any clinical manifestation of exocrine pancreatic insufficiency occurs late in the course of disease,
after approximately 90% of the exocrine parenchyma has been destroyed

The majority of these pancreatic function tests are only able to diagnose CP when approximately
70% to 80% of the pancreatic function has been lost.

Invasive (Direct) Pancreatic Function Tests

One of the most sensitive tests to detect exocrine insufficiency is invasive and requires duodenal
intubation and aspiration of duodenal juice after pancreatic stimulation.

The secretin stimulation test is sensitive for the detection of functional impairment in all stages of CP.

Even though this test has some limitations, it is considered the gold standard in the evaluation of
exocrine pancreatic function because of its acceptable sensitivity and specificity (75%-95%).

Measures the volume of secretion and the concentration of output of bicarbonate and pancreatic
enzymes (by 60-minute continuous duodenal fluid aspiration) in response to IV secretin.

Bicarbonate levels less than 50 mEq/L are consistent with CP; levels of 50 to 75 mEq/L are normal.

False- positive results may be seen in the setting of diabetes mellitus, Billroth II gastrectomy, celiac
sprue, and cirrhosis.

Although these tests have shown a good correlation with the fibrosis scores detected by EUS, their
use is limited to a few specialized centers worldwide.

Noninvasive (Indirect) Pancreatic Function Tests

Presently, evaluation of stool fat plays no significant further role in the diagnosis of CP.

Stool tests for the quantification of fat (with subsequent correction after pancreatic enzyme
replacement), fecal chymotrypsin, and fecal elastase 1 (FE-1)

Fecal chymotrypsin may be useful in detecting compliance with exogenous pancreatic enzyme

The best accuracy of all stool tests is obtained by measurement of FE-1.

The commercial test measures only human elastase. This is an advantage in patients receiving
therapeutic oral enzyme supplementation.