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Pancreatitis

Lecture 19

Pancreas Physiology & Anatomy

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The pancreas is a narrow retroperitoneal structure, 15 cm long gland that lies posterior and inferior to the stomach on the left side of the abdominal cavity.

The pancreas extends laterally and superiorly across the abdomen from the curve of the duodenum to the spleen.

The head of the pancreas, which connects to the duodenum, is the widest and most medial region of the organ.

Extending laterally toward the left, the pancreas narrows slightly to form the body of the pancreas.

The tail of the pancreas extends from the body as a narrow, tapered region on the left side of the abdominal cavity near the spleen.

The pancreas is a glandular organ in the upper abdomen, it serves as two glands in one:

A digestive exocrine gland: excretes enzymes to break down the proteins, lipids, carbohydrates, and nucleic acids in food.

A hormone-producing endocrine gland: (Will be discussed in Diabetes Mellitus)

o The islets of Langerhans have different cells types that are responsible for the synthesis and secretion of : insulin (B cell), glucagon (A cell), and somatostatin (D cell) and amylin (amylin cell) that together modulate energy metabolism; and pancreatic polypeptide (PP cell), which is a regulator of GI function.

Both of these diverse functions are vital to the body’s survive

Endocrine Function

Pancreatic Enzymes Exocrine Function

Amylase (which digests carbohydrates): it splits molecules of Starch or Glycogen into Disaccharides.

Lipase (which digests fats); it breaks Triglycerides molecules into Fatty acids & Monoglycerides.

Protease (which digests protein) such as Trypsinogen . Proteases are the most abundant class of enzymes.

Bicarbonate is also produced in large amounts to neutralize the acid produced by the stomach.

Trypsinogen, chymotrypsinogen, proelastase, procarboxypeptidase and prophospholipase A2 are stored in the pancreas and secreted into the duodenal lumen as Inactive proenzymes forms.

If these enzymes were active in the pancreas, they would digest the pancreatic gland.

Amylase and Lipase are stored and secreted in their active forms. The active forms of these enzymes (amylase and lipase) have no effect on the pancreatic gland because it does not contain starch or triglyceride.

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Pancreatitis Overview

Pancreatitis is classified as either acute or chronic.

Acute Pancreatitis refers to an acute inflammation that resolves both clinically and histologically.

o The acute inflammatory process of the pancreas that may also involve peripancreatic tissues and/or remote organ systems (involvement of other regional tissue).

o Severe pancreatitis is characterized by the presence of organ failure (including Shock: systolic blood pressure <90 mm Hg , Pulmonary insufficiency: Pao2 ≤60 mm Hg, Renal failure: serum creatinine >2 mg/ld., Gastrointestinal bleeding: >500 mL/24 hr ) and/or

o The presence of local complications (pancreatic necrosis, abscess or pseudocyst).

Chronic Pancreatitis is characterized by histologic changes that persist even after the cause has been removed. The histologic changes in chronic pancreatitis are irreversible and tend to progress, resulting in serious loss of exocrine and endocrine pancreatic function and deterioration of pancreatic structure.

When the pancreatic fluid extravasates out of the pancreas, it collects in the anterior pararenal space and other areas. This is acute fluid collection.

If it persists for > 4 weeks, it becomes encapsulated in a wall and develops into a pseudocyst.

Pancreatic necrosis is defined as one or more areas of nonviable pancreatic parenchyma and is usually associated with peripancreatic fat necrosis.

2 types of pancreatitis

o Interstitial (80%) (edematous) mild, self-limiting (3-5 days), fluid accumulation with swelling and edema

o Necrotizing (20%) (death of tissue) hemorrhagic with cellular death and systemic complications

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Prevalence: There are >100,000 hospital admissions for pancreatitis in the U.S. per year.

Approximately 2,000 of these patients will die from severe pancreatitis.

Acute Pancreatitis Causes

Gallstones: 45%

Alcohol abuse: 35% Idiopathic: 10%

Other 10%

Drugs: azathiprine, thiazide, valproate, sulfasalazine, bactrim, pentamidine, tetracycline

Blunt and penetrating Trauma

Postoperative (particularly of stomach and biliary tract and after coronary artery bypass grafting), ERCP.

Hyperlipidemia (hypertriglyceridemia), Hypercalcemia & Hyperparathyroidism

Infectious agents: mumps, Coxsackie B, CMV, Candida, HIV, salmonella, shigella, E. coli, legionella, leptospira

Ductal obstruction , Structural abnormalities of the pancreatic duct (eg, stricture, cancer, pancreas divisum) & Structural abnormalities of the common bile duct and ampullary region (eg, choledochal cyst, sphincter of Oddi stenosis),

Hereditary, Vascular disease (especially severe hypotension) & Renal transplantation.

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Pancreatitis Pathophysiology

Normally, the pancreatic enzymes are stored in an inactive precursor form intracellularly (within the acinar cell).

In acute pancreatitis, pancreatic proenzymes are exposed to the lysosomal enzymes such as Cathepsin B (an enzymatic protein belonging to the peptidase “or protease” families), which activate trypsinogen to trypsin.

This initiates premature activation of other pancreatic enzymes and autodigestion.

The activated enzymes enter the systemic circulation and cause widespread systemic toxicity.

Recent evidence focuses on the role played by leukocytes and their products such as cytokines, enzymes and nitric oxide in the mediation of systemic and local inflammation.

Acute Pancreatitis signs and symptoms

Typical symptoms of acute pancreatitis are :

o Epigastric pain (95%) usually radiating to the back,

o Nausea and vomiting (80%).

o Symptoms persist for several hours without relief.

Physical examination reveals

o Epigastric tenderness,

o Guarding and reduced bowel sounds due to ileus.

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Ecchymosis in the flanks (Grey Turner sign : reddish-purple or greenish-brown color to the flank area (the area between the ribs and the hip bone) or

in the periumbilical region (Cullen's sign :bluish color around the navel) reflecting the extravasation of hemorrhagic pancreatic exudate to these areas.

Rarely: Nodules of subcutaneous fat necrosis may be found on the extremities.

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Laboratory Diagnosis (Pancreatic Enzymes)

Diagnosis of acute pancreatitis relies on at least a three-fold elevation of amylase or lipase in the blood.

Serum Amylase (30-180 IU/L)

It rises within 6 to 12 hours of onset (half-life, 10 hours).

The serum amylase is usually increased on the first day of symptoms, and it remains elevated for three to five days in uncomplicated attacks.

Sensitivity is greater than 85%, the serum amylase may be normal or minimally elevated in fatal pancreatitis, during a mild attack or an attack superimposed on chronic pancreatitis, or during recovery from acute pancreatitis also in hypertriglyceridemia-associated pancreatitis.

Hyperamylasemia is not specific for pancreatitis because it occurs in: intestinal ischemia, renal insufficiency, small bowel obstruction, parotitis & macroamylasemia (is a benign condition caused by circulating macroamylase complexes of pancreatic or salivary amylase bound to plasma proteins, which cannot be cleared by the renal glomeruli).

Serum Lipase (0-160 IU/L)

The sensitivity of serum lipase is similar to that of serum amylase and is between 85% and 100%.

Lipase may have greater specificity for pancreatitis than amylase.

Serum lipase always is elevated on the first day of illness and remains elevated longer than does the serum amylase.

Secretin-pancreozymin (CCK) test

Secretin leads to increased output of pancreatic juice and HCO3; CCK leads to increased output of pancreatic enzymes.

Sensitive enough to detect occult disease; involves duodenal intubation and fluoroscopy only role in acute on chronic pancreatitis.

Other blood test

White blood cell count -Increased

Monitor daily : Hematocrit->44 show poor prognosis, Serum Creatinine and serum electrolytes

Other laboratory features include hyperglycemia, hypocalcemia, hyperbilirubinemia and mild elevations in serum alanine aminotransferase (ALT) and alkaline phosphatase.

A bilirubin >two and half times the normal and a serum ALT > twice the normal are suggestive of gallstone pancreatitis.

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MCV- Alcoholic patients tend to have a higher MCV.

Serum triglyceride levels- increase in acute pancreatitis, but also with alcohol use, uncontrolled diabetes mellitus, or defective triglyceride metabolism

Acute Pancreatitis Diagnosis

AP established by the presence of 2 of the 3 following criteria:

Abdominal pain consistent with the disease

Serum amylase and / or lipase greater than three times the upper limit of normal

Characteristic findings from abdominal imaging

Ultrasound –Most useful initial test for common bile duct dilation and gallstones

Contrast CT Scan

o Not necessary for diagnosis of acute pancreatitis

o May help identify etiology in rare instances (tumor)

o Useful to assess complications-fluid collections or pancreatic necrosis

ERCP’s are done frequently for both diagnostic and treatment reasons, especially with gall stones as the responsible cause can create additional problems with manipulation and trauma

Acute Pancreatitis Treatment

1) Goals of treatment include:

Supportive care,

Limitation of systemic complications and

Prevention of pancreatic necrosis or abscess formation.

2) Treatment of acute interstitial pancreatitis:

Is supportive with intravenous fluids and

Adequate analgesia.

3) A nasogastric tube is needed only for vomiting or for gastric decompression in ileus.

4) Refeeding is instituted once the pain subsides and the patient is hungry.

5) Treatment of severe pancreatitis requires:

Aggressive fluid resuscitation,

Appropriate respiratory care,

Cardiovascular support including maintenance of Hematocrit around 30 (for adequate microperfusion of the pancreas)

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Pain relief. (Morphine ,Hydromorphone-Dilaudid®-& Fentanyl)

6) Nutritional support with parenteral nutrition may be necessary.

7) Endoscopic sphincterotomy within 72 hours was shown to reduce morbidity—but not mortality—of severe gallstone pancreatitis in the elderly.

8) Use of antibiotics: In acute pancreatitis, antibiotics are used for two major indications.

The Prophylactic use of antibiotics may reduce the number of pancreatic infections and non-pancreatic infections (UTI), but are usually reserved for those with severe disease.

Antibiotics are used Therapeutically for the treatment of cholangitis or other infections( Infected Necrosis, Pancreatic Abscess, Infected Pseudocyst)

9) If there is no improvement in the first 7-14 days, then pancreatic necrosis is suspected.

– If necrosis is seen, a CT-guided percutaneous aspiration should be performed and sent for gram stain and culture to rule out infection.

10) If infection is documented, then surgical debridement should be performed.

11) In the absence of infection, choices include medical therapy or debridement of sterile necrosis.

12) Severe pancreatitis may also be complicated by pseudocyst or pancreatic abscess formation.

– Pseudocysts occur in approximately 20% of cases and should be drained only if causing symptoms.

– Pancreatic abscesses are collections of pus that usually occur 4 to 6 weeks after the onset of acute pancreatitis. Treatment options include surgical drainage and percutaneous catheter drainage, which are equally effective.

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AST, aspartate aminotransferase; BUN, blood urea nitrogen; LDH, lactate dehydrogenase; Pao2, partial pressure of arterial carbon dioxide; WBC, white blood cell.

Sequestration :Loss of blood or of its fluid content into spaces within the body so that it is withdrawn from the circulating volume, resulting in hemodynamic impairment,

hypovolemia, hypotension, and reduced venous return to the heart. The table lists 11 signs that Ranson and colleagues identified as early prognostic criteria

that predict the severity of outcome in acute pancreatitis.

These signs are obtained during the first 48 hours of acute pancreatitis.

Mortality increases with an increase in the number of abnormal values in the list of Ranson’s early prognostic criteria.

Most of the patients who develop a severe disease outcome have 3-5 abnormal Ranson early prognostic criteria.

5% mortality risk with <2 signs

15-20% mortality risk with 3-4 signs

40% mortality risk with 5-6 signs

99% mortality risk with >7 signs

Chronic pancreatitis Overview

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.

Prevalence:

The true prevalence of the disease is not known; it is estimated to range from 0.04% to 5% of the general population.

In developed countries, 60% to 70% of chronic pancreatitis is due to alcohol abuse.

It is most frequent in men, with a peak incidence between 35 to 45 years of age.

Tropical pancreatitis also called Fibrocalculous pancreatitis, on the other hand, occurs in young children in areas of Africa and Asia.

Idiopathic pancreatitis, which accounts for 30% of cases of chronic pancreatitis, occurs in two distinct subgroups of patients—a younger group 15-30 years of age and an older group 50-70 years of age.

Chronic pancreatitis Pathophysiology

The underlying pathophysiology of chronic pancreatitis involves basal hypersecretion of pancreatic proteins with a concomitant decrease of protease inhibitors.

This changes the pancreatic juice biochemical composition and leads to protein plugging and pancreatic stone formation.

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Blockage of small ducts results in:

o Premature activation of pancreatic enzymes with development of acute pancreatitis. This leads to permanent damage of the gland over time.

One of the more popular hypotheses is that chronic pancreatitis and especially the fibrotic response arises from the summation episodes of acute pancreatitis.

Chronic pancreatitis Etiology

The most common cause is alcohol consumption

Alcohol abuse: 70%

Idiopathic: 20%

Other 10%

Tropical pancreatitis

Hereditary pancreatitis

Hyperparathyroidism

Cystic fibrosis & Pancreas divisum

Pancreas divisum is a congenital anomaly in the anatomy of the ducts of the pancreas in which a single pancreatic duct is not formed, but rather remains as two distinct dorsal and ventral ducts.

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Cystic fibrosis

Cystic fibrosis is a genetic disorder that affects function of exocrine glands throughout the body.

Caused by a defect in the CFTR gene that provides instructions for making a cell membrane–associated protein called the cystic fibrosis transmembrane conductance regulator (CFTR). This protein is embedded in lipid membrane of epithelial cells, sweat glands, pancreas and lungs.

Lack of this protein results in production of overly thick mucus that cannot be cleared from the respiratory passages and accumulates to form mucous plugs.

In this subset of patients (Chronic pancreatitis), there is no evidence of cystic fibrosis lung disease.

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Chronic pancreatitis signs and symptoms

After a subclinical phase, recurrent attacks of pain are noted and symptoms of exocrine and endocrine deficiency appear.

Patients commonly present with abdominal pain and weight loss.

Abdominal pain may be due to:

o May involve pancreatic inflammation,

o Increased intrapancreatic pressure,

o Neuroinflammation or

o Extrapancreatic causes such as obstruction of the common bile duct or duodenum.

Weight loss during the initial course of the disease is due to:

o Decreased caloric intake for fear of precipitating abdominal pain.

o Later, as the gland is progressively destroyed, patients develop fat malabsorption.

o Diabetes develops when more than 80% of the gland has been destroyed.

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The physical examination may reveal epigastric tenderness during acute exacerbations. Otherwise, it may be entirely normal in mild chronic pancreatitis.

In advanced cases, there may be an abdominal mass from a pseudocyst or pancreatic cancer or splenomegaly from splenic vein thrombosis.

Chronic pancreatitis Clinical Features

1) 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. 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.

2) Steatorrhea Steatorrhea is not a really a condition but a symptom in which fecal matter is frothy,

foul-smelling and floats because of a high fat content. 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.

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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.

3) 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.

Chronic pancreatitis Diagnosis

Is based on history and confirmed by laboratory and imaging studies.

Serum amylase and lipase may be normal or slightly elevated.

In 5% to 10% of the patients with chronic pancreatitis, compression of the distal common bile duct leads to elevation of serum bilirubin and alkaline phosphatase.

Fat malabsorption leads to elevated fecal fat excretion (Steatorrhea), more than 7 gm/day.

The appearance of pancreatic calcifications on X-ray, ultrasound or CT scan is diagnostic of chronic pancreatitis.

They are found in about 25% to 60% of cases of chronic alcoholic pancreatitis and 35% to 80% of pancreatitis due to other causes.

In addition, CT scan may show focal pancreatic enlargement, atrophy, pancreatic ductal dilatation or pseudocysts.

ERCP is the most sensitive and specific imaging study for the diagnosis of chronic pancreatitis. (It should be undertaken only if other non-invasive studies are inconclusive).

Other imaging studies such as MRCP and endoscopic ultrasound (EUS) are equally sensitive.

If the imaging studies are not informative, then pancreatic function tests such as secretin or cholecystokinin (CCK) stimulation tests can be performed.

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Chronic pancreatitis complications

The most common complications seen in chronic pancreatitis are:

Pseudocysts,

Ascites,

Splenic vein thrombosis.

1) Pancreatic pseudocysts occur in 25% of patients: can cause:

Abdominal pain; can cause Nausea and vomiting by obstructing the stomach or duodenum

Jaundice by obstructing the common bile duct.

In about 10% of cases, pseudocysts are associated with pseudoaneurysms, which can cause life-threatening bleeding.

Asymptomatic pseudocysts can be observed.

Symptomatic pseudocysts need to be drained by surgical, endoscopic or radiological means.

2) Pancreatic ascites:

Is diagnosed by high amylase levels in the ascitic fluid. This is most likely due to duct disruption and may respond to total parenteral nutrition, pancreatic stent placement and octreotide injections. If not responding, then surgery may be indicated.

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3) Splenic vein thrombosis:

Occurs in about 2% to 4% of patients. This leads to isolated gastric varices with resulting gastrointestinal hemorrhage. The diagnosis is confirmed by mesenteric angiography. In the event of hemorrhage, splenectomy is curative.

4) Other complications:

Include pancreatic cancer, common bile duct obstruction, duodenal obstruction and pancreatic fistula formation.

Chronic pancreatitis Outcomes

The treatment of pain in chronic pancreatitis is unsatisfactory.

Most patients continue to experience pain.

Pancreatic surgery leads to relief of pain for a variable period of time.

Chronic alcoholic pancreatitis is associated with a mortality rate that approaches 50% in 20 to 25 years. Of these, 15% to 20% of the deaths are directly related to pancreatitis. The rest are due to smoking, alcohol or trauma.

Pancreatic cancer develops in 4% of the patients within 20 years of diagnosis of chronic pancreatitis.

The prognosis for tropical pancreatitis and idiopathic pancreatitis is generally more favorable than for alcoholic pancreatitis.

Pancreatic Exocrine Cancer

75% of pancreatic cancers involve the head of the pancreas, 25% involve the body and tail of pancreas, so jaundice d/t blocking of the ampulla of vater may be the earliest sign

90% die within first year of Diagnosis. 4th leading cause of cancer death both genders Incidence in men is 20% higher than in women Incidence in blacks is 40-50% higher than in whites; men d/t smoking and diabetes,

women d/t obesity Survival – 24% of patients with CA pancreas survive at least one year after diagnosis

(5% five years after diagnosis). 20% long term survival with localized disease. Primary prevention is key, especially smoking cessation. Secondary and tertiary prevention is difficult d/t poor outcome.

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Risk factors:

Smoking/Alcohol.

diets high in fat, beef, pork & processed meats

diabetes

chemical exposure

chronic pancreatitis

Complications:

abdominal pain,

anorexia, nausea,

jaundice, diarrhea

Metastasis by time of diagnosis

Diagnosis: 

tumor markers- CA19-9, CEA (markers do not rise high enough to detect until cancer is far advanced)

CT with biopsy, ERCP with biopsy

Staging by TNM (Tumor, nodes, mets)

Treatment:

Some treatment protocols are showing promise. Surgical resection possible in only 5-15% and may be followed by chemo and radiation Chemo and radiation for inoperable, locally advanced disease (chemo improves survival

slightly) Chemo and supportive care for patients with metastasis

5-FU

Gemcitabine (Gemzar) better results

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