CHRONIC PANCREATITIS: NEWER INSIGHTS INTO PATHOPHYSIOLOGY AND MANAGEMENT

KUSH KUMAR BHAGATM.L.N MEDICAL COLLEGE ALLAHABAD

Chronic pancreatitis is defined as permanent and irreversible damage to the pancreas, with histologic evidence of chronic inflammation, fibrosis, and destruction of exocrine (acinar cell) and endocrine (islets of Langerhans) tissue.

DEFINITION

Autopsy reports – 0.04-5% Retrospective studies – 3-9/100,000 Prospective data

◦among alcoholics – 8.2/yr/100,000; Alcohol abuse – 2/3 of causes Mortality 3.6 X age matched control.

PREVALENCE

Incompletely understood Alcoholic chronic pancreatitis, being the most

common form, has received the most attention. No single theory explains adequately why only about

10% of heavy alcohol users develop chronic pancreatitis

In most studies, alcohol abuse accounts for two thirds of all cases of chronic pancreatitis.

PATHOPHYSIOLOGY

Alcohol is metabolized by the liver and the pancreas. In the liver the main end product of oxidative alcohol metabolism is acetaldehyde.

In the pancreas, an alternative pathway produces fatty acid ethanol esters (FAEEs).

Alcohol and its metabolites like FAEE, have direct injurious effects on pancreatic acinar cells.

Alcohol and its metabolites appear to stimulate the pancreatic stellate cell. These cells appear to be the final common pathway for fibrosis.

When activated, they assume a stellate or myofibroblastic appearance, express smooth muscle actin, and lose the lipid droplets.

This activation is necessary for the cell to begin to secrete extracellular matrix and produce fibrosis within the gland.

Activation of pancreatic stellate cells is likely occurring via at least two mechanisms in alcoholic chronic pancreatitis: directly by alcohol and its metabolites and indirectly by cytokines induced by cellular necrosis.

Chronic alcohol use acinar and ductal cell

protein rich pancreatic juice, low in volume and HCO3

formation of protein precipitates – plug calcification of ppt. – ductal stone formation

duct obstruction parenchymal damage

Pancreatic ductal stone are seen in alcoholic, tropical, hereditary and idiopathic pancreatitis.

Ductal obstruction hypothesis

The toxic-metabolic hypothesis, focuses primarily on the role of alcohol and its metabolites (or other toxins) and their ability to damage the pancreas and activate pancreatic stellate cells.

Direct injurious effect on acinar and ductal cells Increased membrane lipid peroxidation (oxidative

stress), free radical production Activation of pancreatic stellate cells (alcohol,

cytokines) – begin to secrete extracellular matrix and produce fibrosis.

Toxic metabolic hypothesis

The occurrence of repeated episodes of acute pancreatitis with cellular necrosis or apoptosis eventually leads to the development of chronic pancreatitis as the healing process replaces necrotic tissue with fibrosis.

The concept that multiple clinical or subclinical attacks of acute pancreatitis lead to chronic pancreatitis is certainly being reinforced by observations in both animal models and in humans.

Necrosis fibrosis hypothesis

Multiple mutations have been identified in several forms of chronic pancreatitis, suggesting a complex genetic background that provides the relative predisposition to develop chronic pancreatitis.

Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR), cationic trypsinogen gene (PRSS1 gene), serine protease inhibitor Kazal type 1 (SPINK1) a trypsin inhibitor have been identified.

CFTR - Cystic fibrosis is associated with abnormalities of HCO3 secretion, ductal dilatation, ppt formation, pancreatic atrophy. Seen in 50% of idiopathic CP.

Genetic forms

PRSS1 - Once trypsinogen is activated to trypsin, it becomes resistant to inactivation and activate other proenzymes leading to episodes of acute pancreatitis. The mutant trypsin activate other proenzymes and produce clinical or subclinical episodes of acute pancreatitis, ultimately leading to chronic pancreatitis in affected patients.

SPINK1 - Seen in pediatric ICP, hereditary P, TP; but not in chronic alcoholic pancreatitis. It is a trypsin inhibitor. Mutation of this gene leads to non inhibition of trypsin producing clinical or subclinical episodes of acute pancreatitis.

Etiologic factors ass. with CP: TIGAR-O

Abbreviations: DBTC, dibutylin dichloride

Alcohol is the cause of at least 70% of all cases of chronic pancreatitis

The risk of alcoholic chronic pancreatitis increases with rising alcohol use, but there is no true threshold value below which the disease does not occur.

In nearly all patients, at least 5 years (and in most patients more than 10 years) of intake is required before the development of chronic pancreatitis.

Only 3% to 15% of heavy drinkers ultimately develop chronic pancreatitis, suggesting an important cofactor for development of chronic pancreatitis which include genetic polymorphisms and tobacco.

Tropical pancreatitis is one of the most common forms of chronic pancreatitis in certain areas of southwest India.

Tropical pancreatitis is generally a disease of youth and early adulthood, with a mean age at onset of 24 years.

Tropical pancreatitis accounts for about 70% of all cases of chronic pancreatitis in southern India, whereas alcohol is a more dominant cause in the north.

The disease classically manifests as abdominal pain, severe malnutrition, and exocrine or endocrine insufficiency.

TROPICAL PANCREATITIS

One striking feature is the propensity to diabetes, and endocrine insufficiency appears to be an inevitable consequence of tropical chronic pancreatitis (often classified as a specific cause of diabetes called fibrocalculous pancreatic diabetes).

Pancreatic calculi develop in more than 90% of patients.

The pathology is characterized by large intraductal calculi, marked dilation of the main pancreatic duct, and gland atrophy.

The pathophysiology of tropical pancreatitis is unknown, a number of genetic mutations have been identified, with mutations in the SPINK1 and chymotrypsinogen genes being most common.

Environmental triggers for the disease that have been proposed include protein-calorie malnutrition, deficiencies of trace elements and micronutrients coupled with oxidative stress, cyanogenic glycosides present in cassava (tapioca—a main dietary component).

AUTOIMMUNE PANCREATITIS

Clinical features of auto immune pancreatitis

Idiopathic pancreatitis accounts for 10% to 30% of all cases of chronic pancreatitis.

Two forms, an early-onset type that manifests in the late second or third decade of life and a late-onset form that appears in the sixth or seventh decade of life.

IDIOPATHIC CHRONIC PANCREATITIS

ABDOMINAL PAIN Abdominal pain is the most common symptom. Pain is most commonly described as being felt in the

epigastrium, often with radiation to the back. Pain is typically deep, boring and penetrating and is

often associated with nausea and vomiting. Pain may be relieved by sitting forward or leaning

forward, by assuming the knee-chest position on one side, or by squatting and clasping the knees to the chest.

CLINICAL FEATURES

Severe pain decreases appetite and limits food consumption, contributing to weight loss and malnutrition.

Intractable pain is the most common reason for hospitalization and for surgery in patients with chronic pancreatitis.

STEATORRHEA The human pancreas has substantial exocrine

reserve. Steatorrhea does not occur until pancreatic lipase secretion is reduced to less than 10% of the maximum output.

Steatorrhea is therefore a feature of far-advanced chronic pancreatitis, in which most of the acinar cells have been injured or destroyed.

Affected patients may present with diarrhea and weight loss. Some patients may note bulky foul-smelling stools.

With very long follow-up, approximately 50% to 80% of patients with chronic pancreatitis eventually have exocrine insufficiency.

Deficiencies of fat-soluble vitamins may develop in patients with chronic pancreatitis and steatorrhea.

Significant vitamin D deficiency and osteopenia and osteoporosis occur in patients with chronic pancreatitis.

DIABETES MELLITUS Like exocrine insufficiency, endocrine insufficiency is

a consequence of long-standing chronic pancreatitis and is especially common after pancreatic resection and in tropical (fibrocalcific) pancreatitis.

Islet cells appear to be relatively resistant to destruction in chronic pancreatitis.

About half of patients with chronic pancreatitis who develop diabetes will require insulin.

Unlike type 1 diabetes, insulin-producing beta cells and glucagon-producing alpha cells are injured.

This combination increases the risk of prolonged and severe hypoglycemia with overvigorous insulin treatment, owing to the lack of a compensatory release of glucagon

Ultimately, 40% to 80% of patients with chronic pancreatitis have diabetes after long follow-up.

Examination: During an attack, patients may assume a

characteristic position in an attempt to relieve their abdominal pain (leaning forward).

Occasionally, a tender fullness or mass may be palpated in the epigastrium, suggesting the presence of a pseudocyst or an inflammatory mass in the abdomen.

Patients with advanced disease (ie, patients with steatorrhea) exhibit decreased subcutaneous fat, temporal wasting, sunken supraclavicular fossa, and other physical signs of malnutrition.

Jaundice may be seen in the presence of coexistent alcoholic liver disease or bile duct compression within the head of the pancreas.

A palpable spleen may also rarely be found in patients with thrombosis of the splenic vein as a consequence of chronic pancreatitis or in patients with portal hypertension due to coexistent chronic liver disease.

The diagnostic tests are usually separated into those that are designed to detect abnormalities of pancreatic function and those that detect abnormalities of pancreatic structure.

DIAGNOSIS

Abnormalities of pancreatic structure or function may take years or even decades to develop, or may not develop at all.

All available diagnostic tests are most accurate in far-advanced disease, when obvious functional or structural abnormalities have developed.

Conversely, all diagnostic tests are less accurate in less advanced or early chronic pancreatitis.

Functional abnormalities in chronic pancreatitis include exocrine insufficiency (maldigestion and steatorrhea), and endocrine insufficiency (diabetes mellitus).

Structural abnormalities that can be diagnostic include changes within the main pancreatic duct (dilation, strictures, irregularity, pancreatic ductal stones) or pancreatic parenchyma (lobularity of the gland, alterations in echogenicity, cysts, enlargement or atrophy, and others).

Tests of pancreatic function can be divided into those that directly measure pancreatic function by measuring the output of enzymes or bicarbonate from the pancreas and those that measure the released enzymes indirectly (through its action on a substrate or its level in blood or stool)

Direct Tests includes Direct hormonal stimulation by secretin or

cholecystokinin or both using oroduodenal tube, Using endoscopy or Magnetic resonance cholangiopancreatography with secretin stimulation

TESTS OF PANCREATIC FUNCTION

Indirect Tests Serum trypsinogen can be measured in blood and

provides a rough estimation of pancreatic function. Very low levels of serum trypsinogen (<20 ng/mL) can be seen in patients with advanced chronic pancreatitis.

Low concentrations of chymotrypsin or elastase in stool can reflect inadequate delivery of these pancreatic enzymes to the duodenum. Both can be measured on random samples of stool.

Faecal Fat Excretion : Maldigestion of fat occurs after 90% of pancreatic lipase secretary capacity is lost.

Abdominal x-ray: The finding of diffuse (but not focal) pancreatic calcifications on plain abdominal films is quite specific for chronic pancreatitis.

Focal calcifications may be seen in cystic and islet cell tumours of the pancreas, and in peripancreatic vascular calcifications.

Pancreatic calcifications are observed in approximately 30% of cases.

TESTS OF PANCREATIC STRUCTURE

ABDOMINAL ULTRASOUND: Ultrasonographic findings indicative of chronic pancreatitis include dilation of the pancreatic duct, pancreatic ductal stones, gland atrophy or enlargement, irregular gland margins, pseudocysts, and changes in the parenchymal echo texture.

COMPUTED TOMOGRAPHY SCAN: Pseudocysts, calcifications and pancreatic duct dilatation can be observed in chronic pancreatitis.

In this CT scan there is evidence of multiple calcifications and stones in the parenchyma and dilated pancreatic duct.

In this CT scan of abdomen there is evidence of markedly dilated pancreatic duct with calcification

MAGNETIC RESONANCE CHOLANGIO PANCREATOGRAPHY (MRCP)

Noninvasive It can assess both pancreatic parenchyma and ducts

at the same time. It can detect pancreatic duct dilatation, ductal

narrowing and filling defects.

Chronic pancreatitis on MRCP; dilated duct with filling defects suggestive of pancreatic ductal calculi

ERCP: Provides the most accurate visualization of the

pancreatic ductal system and has been regarded as the gold standard for diagnosing chronic pancreatitis.

Findings include characteristic “chain of lakes” beading of the main pancreatic duct, and intraductal filling defects.

ENDOSCOPIC ULTRASOUND (EUS): To diagnose chronic pancreatitis requires the presence of at least 5 criteria of the followings:

Treatment consists of managing:

1. ABDOMINAL PAIN 2. STEATORRHEA 3. DIABETES MELLITUS

TREATMENT

ABDOMINAL PAIN Pain is the most common and most debilitating

symptom. The initial evaluation of pain should focus on

identifying associated conditions for which specific therapy exists.

These conditions can include pancreatic pseudocyst, duodenal compression, superimposed pancreatic carcinoma and gastroparesis.

VARIOUS MODALITIES OF TREATMENT OF ABDOMINAL PAIN

MEDICAL TREATMENT 1. Analgesics2. Cessation of Alcohol and Tobacco 3. Antioxidants4. Pancreatic Enzyme Therapy5. Octreotide ENDOSCOPIC THERAPY1. Pancreatic Duct Sphincterotomy 2. Stent Placement3. Pancreatic Duct Stone Removal 4. Combined Endoscopic Therapy

SURGICAL THERAPY Drainage procedure: -1. Lateral pancreaticojejunostomy (Puestow operation) Resective procedures : 1. Whipple’s procedure 2. Distal pancreatectomy3. Total pancreatectomy

Analgesics: The majority of patients with chronic pancreatitis require some form of analgesia. Some patients’ pain may be managed with acetaminophen or aspirin, but most require more potent narcotic agents.

Cessation of Alcohol and Tobacco: Cessation of alcohol consumption and tobacco smoking are important. In early-stage pain relief can occur after abstinence from alcohol, but, in advanced stages, abstinence does not always lead to symptomatic improvement.

Pancreatic Enzyme Therapy: The use of pancreatic enzymes to reduce pain is based on the ability of these agents to reduce pancreatic secretion.

Antioxidants: Patients with chronic pancreatitis have evidence of oxidant stress and reduced antioxidant capacity.

Oxidant stress is a strong activator of pancreatic stellate cells. There are now several small randomized trials of a mixture of antioxidants (selenium, beta-carotene, vitamin C, vitamin E) that indicate that this therapy reduces the pain of chronic pancreatitis.

Octreotide: Octreotide decreases pancreatic secretion and reduces circulating CCK levels. This agent therefore might reduce pain via the same mechanisms invoked for the use of enzymes for pain.

Endoscopic treatment: Papillary stenosis: In appropriately selected patients, a

pancreatic duct sphincterotomy will facilitate drainage, reduce ductal pressures, and may help alleviate pain.

Pancreatic duct strictures: performing a pancreatic sphincterotomy, dilating the stricture, and placing a stent.

Pancreatic duct stones: Requires a pancreatic duct sphincterotomy and stricture dilation to enable their extraction.

Surgical treatment:

I-Pancreatic duct drainage: In patients with a dilated pancreatic duct, pancreaticojejunostomy is indicated.

II-Pancreatic resection: If the disease is limited to the head of the pancreas, a Whipple operation (pancreaticoduodenectomy) can produce good results.

In patients with intractable pain and diffuse disease with nondilated ducts, a subtotal or total pancreatectomy can be offered.

III-Total pancreatectomy and islet autotransplantation:

In selected patients, the long-term morbidity caused by diabetes following total pancreatectomy can be avoided.

This involves harvesting the islets from the resected pancreas and injecting them into the portal system, which then lodges them in the liver.

IV- Drainage of pseudocyst:

The indications include rapid enlargement, compression of surrounding structures (duodenal, biliary obstruction or vascular occlusion), pain, or signs of infection and abscess formation, suspected malignancy, hemorrhage and intraperitoneal rupture.

Abdominal pain – R/o ddx – US (no mass) –

3-4wk pancreatic enzyme – (4-8tablets at meals and at bed time) –

minimal change CP pt get relief of pain – if not, ERCP/EUS –

pseudocyst, obstruction, dilated duct – surgery, octreotide –

If No response subtotal pancreatic resection

STEATORRHEA

Fat maldigestion is the principal clinical problem. It has been estimated that 30,000 IU of lipase delivered to the intestine with each meal should be sufficient to eliminate steatorrhea.

This corresponds to approximately 10% of the normal pancreatic output of lipase.

The goal of managing steatorrhea is to administer 30,000 IU of lipase in the prandial and postprandial portions of each meal.

If non–enteric-coated preparations are chosen, concomitant suppression of gastric acid with a histamine-2 (H2) receptor antagonist or proton pump inhibitor is necessary

There are several explanations for failure of enzyme therapy for steatorrhea.

The most common is inadequate dose, generally due to patient noncompliance with the number of pills that must be taken.

DIABETES MELLITUS

Diabetes mellitus is an independent predictor of mortality in patients with chronic pancreatitis.

Ketoacidosis is distinctly unusual. Insulin is often needed and patients with chronic

pancreatitis tend to have lower insulin requirements than patients with type 1 diabetes mellitus.

Overvigorous attempts at tight control of blood glucose value are often associated with disastrous complications of treatment-induced hypoglycemia.

DM – but end organ damages of DM and DKA are rare

Non DM retinopathy (peripheral) due to Vit A and Zn defc.

Pleural, peritoneal and pericardial effusions with high amylase

GI bleeding – PUD, gastritis, pseudocyst, varies (SV thrombosis)

Cholestasis, icterus, cholangitis, biliary cirrhosis Fistula – internal or external Subcutaneous fat necrosis – tender red nodules on

the shins Pseudocyst Pancreatic carcinoma – 4% life time risk Narcotic addiction

COMPLICATIONS

Prognosis: The prognostic factors associated with chronic

pancreatitis are age at diagnosis, smoking, continued use of alcohol, and the presence of liver cirrhosis.

The overall survival rate is 70% at 10 years and 45% at 20 years.

The risk of developing pancreatic cancer is approximately 4% at 20 years.

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