Cystic fibrosis

Pancreas

• is a glandular organ in

the digestive system and endocrine system of vertebrates. It is an endocrine gland producing several important hormones ,also a digestive organ, secreting pancreatic juice containing digestive enzymes that assist digestion and absorption of nutrients in the small intestine.

• Located in the concavity of the duodenum .

• Connected with spleen by lienorenal ligament.

• Most of pancreas located behind stomach.

• Connected with bilary system at 2nd part of duodenum .

• 1. Bile ducts: 2. Intrahepatic bile ducts, 3. Left and right hepatic ducts,

• 4. Common hepatic duct• 5. Cystic duct• 6. Common bile duct• 7. Ampulla of Vater• 8. Major duodenal papilla

9. Gallbladder,• 10–11. Right and left lobes of liver.

12.Spleen.13. Esophagus.

• 14. Stomach. • 15.Duodenum, • 16. Jejunum

17. Pancreas: 18: Accessory pancreatic duct, 19:Pancreatic duct.20–21: Right and left kidneys (silhouette).

• Under light Microscope by H&E stain appear two types of cell clusters :– Rounded large pale

cells= Islets of Langerhans .

– Dark small berry like = pancreatic acini

• Islets of Langrhans = Endocrinal part of pancreas ,contain four types of cells – Alpha: secret Glucagon rise

glucose level in blood– Beta: secret Insulin ,lowering

glucose level in blood– Gamma: or P.P cells secret

pancreatic polypeptide – Delta: secret Somatostatin

which control Alpha & Beta cells

Pancreatic acini :very similar to what is seen in salivary

glands.secretions are secreted into the lumen of

the acinus, and then accumulate in intralobular ducts that drain to the main pancreatic duct, which drains directly into the duodenum.

• Control of the exocrine function of the pancreas is via the hormones gastrin, cholecystokinin &secretin, which are hormones secreted by cells in the stomach and duodenum, in response to distension and/or food and which cause secretion of pancreatic juices.

• There are two main classes of exocrine pancreatic secretions:– Bicarbonate ions from

centroacinair cells ,stimulus Secretin ( in order to neutralize the acidic chyme that the stomach churns out.)

– Digestive Enz from basophilic cells, stimulus cholecystokinin

Pancreas & digestion.Enzymes secreted by the acini include proteolytic enzymes, amylases and lipases. The proteolytic enzymes are all secreted in an inactive form to prevent auto-digestion.Pancreatic enz are:Amylase breaks down carbohydrates (except cellulose) to di-saccharides and some tri-saccharides.Proteolytic enzymes are secreted in the inactive form to prevent auto digestion, they are converted to the active form in the small intestine. Trypsin is activated by enterokinase, secreted by the intestinal mucosa;Tripsin then activates ChymotripsinogenLipase converts fats to fatty acids and monoglyceridesPhospholipase splits fatty acids from phospholipidsCholesterol esterase hydrolises cholesterol esters

Phases of Digestion•

The Cephalic phase occurs when we think about or anticipate food. It is mediated by the vagus nerve. It causes secretion of about 20% of the enzymes, but as this secretion is not accompanied by fluid secretions, the enzymes are not flushed out and tend to remain in the ducts.

• The gastric phase occurs when food enters the stomach, and again is mediated by neural stimuli. This accounts for another 5-10%, and again in the absence of serous flow these secretions tend to remain in the ducts.

• The Intestinal phase occurs when food enters the small intestine and both serous pancreatic secretion becomes copious due to the hormone secretin.

Regulation of pancreatic Secretion

• Acetylcholine from the parasympathetic nerves of the vagus and the cholinergic nerves of the enteric nervous system.

• Cholecystokinin secreted in the duodenum and the uopper small intestine

• Secretin, also secreted in the duodenum and upper jejunum.

Exocrine Pancreatic Insufficiency

a condition characterized by deficiency of the exocrine pancreatic enzymes, resulting in the inability to digest food properly, or

maldigestion.

Signs & symptoms • Steatorrhea is the result of fat malabsorption and is characterized

by pale, bulky, and malodorous stools. • Weight loss & fatigue are common; however, patients may

compensate by increasing their caloric consumption, and as a result, weight loss from malabsorption may be masked.

• Flatulence & abdominal distention are caused by bacterial fermentation of unabsorbed food substances, which releases gaseous products such as hydrogen and methane.

• Edema may result from hypoalbuminemia caused by chronic protein malabsorption.

• Anemia resulting from malabsorption can be either microcytic (related to iron deficiency) or macrocytic (related to vitamin B-12 deficiency).

• Bleeding disorders are usually a consequence of vitamin K malabsorption and subsequent hypoprothrombinemia. Ecchymosis usually is the manifesting symptom, though melena and hematuria may occur on occasion.

• Metabolic bone disease caused by vitamin D deficiency can result in osteopenia or osteomalacia. In severe cases, bone pain and pathologic fractures occur with low calcium levels leading to secondary hyperparathyroidism.

• Neurologic manifestations can result from electrolyte disturbances (eg, hypocalcemia and hypomagnesemia) and can lead to tetany. Malabsorption of certain vitamins can cause generalized motor weakness (pantothenic acid and vitamin D), peripheral neuropathy (thiamine), loss of a sense of vibration and position (cobalamin), night blindness (vitamin A), or seizures (biotin).

Diagnosis

A complete laboratory evaluation is required not only to diagnose exocrine pancreatic insufficiency (EPI) but

also to determine the extent of the malabsorption and assess manifestations of the underlying disease,

if present.

Etiology

Chronic pancreatitis

Cystic fibrosis

Obstruction of pancreatic

duct

Shwachman-Diamond syndrome

Pancreatic

Celiac disease

Crohn disease

Zollinger-Ellison

syndrome

Autoimmune

pancreatitis

Non-pancreatic

Chronic pancreatitis

• a continuing, chronic, inflammatory process of the pancreas, characterized by irreversible morphologic changes. This chronic inflammation can lead to chronic abdominal pain and/or impairment of endocrine and exocrine function of the pancreas.

(ERCP) shows advanced chronic pancreatitis. The pancreatogram has

blunting of the lateral branches, dilation of the main pancreatic duct,

and filling defects consistent with pancreatolithiasis. The

cholangiogram also shows a stenosis of the distal bile duct and a

dilated biliary tree.

• Alcohol is the most common etiology (60-70%), approximately 20-30% of cases are idiopathic (Oxidative stress - Eg, idiopathic pancreatitis) and 10% of cases are due to rare diseases(autoimmune chronic pancreatitis are associated with primary biliary cirrhosis, primary sclerosing cholangitis, and Sjögren syndrome.)

Treatment

Diet

surgical

Behavioral modification

Pharmacological

•Alleviation of Abdominal Pain•Restoration of Digestion and

AbsorptionPharmacological

•Pancreatic duct drainage•Pancreatic resection•Total pancreatectomy and islet

autotransplantationSurgical Therapy

Cystic fibrosis

• Cystic fibrosis is the most common lethal inherited disease in white persons, autosomal recessive disorder, and most carriers of the gene are asymptomatic.

• Cystic fibrosis is a disease of exocrine gland function that involves multiple organ systems but chiefly results in chronic respiratory infections, pancreatic enzyme insufficiency, and associated complications in untreated patients . Pulmonary involvement occurs in 90% of patients surviving the neonatal period. End-stage lung disease is the principal cause of death.

• Cystic fibrosis is caused by defects in the cystic fibrosis gene, which codes for a protein transmembrane conductance regulator (CFTR) that functions as a chloride channel and is regulated by cyclic adenosine monophosphate (cAMP).

• Defective CFTR results in decreased secretion of chloride and increased reabsorption of sodium and water across epithelial cells. The resultant reduced height of epithelial lining fluid and decreased hydration of mucus results in mucus that is stickier to bacteria, which promotes infection and inflammation. Secretions in the respiratory tract, pancreas, GI tract, sweat glands, and other exocrine tissues have increased viscosity, which makes them difficult to clear..

Pansinusitis

• Most

co

mmon

cause

of

death

Lung disease

• Meconi

um

il

eus

Intestinal disease

Pancreatic disease

Liver disease

Worldwide, the median survival age in patients with cystic fibrosis varies from country to country; it is highest in the United States. Median survival age is 36.9 years, but progress in medical and surgical treatment options have improved the prognosis over the last few decades. An individual with cystic fibrosis born in the United States today is expected to survive longer than 40 years. The median survival age is higher in males than in females.

Treatment • The primary goals of CF treatment include the following:

– Maintaining lung function as near to normal as possible by controlling respiratory infection and clearing airways of mucus

– Administering nutritional therapy (ie, enzyme supplements, multivitamin and mineral supplements) to maintain adequate growth

– Managing complications• Mild acute pulmonary exacerbations of cystic fibrosis can be treated successfully at home

with the following measures:– Increasing the frequency of airway clearance– Inhaled bronchodilator treatment– Chest physical therapy and postural drainage– Increasing the dose of the mucolytic agent dornase alfa (Pulmozyme)– Use of oral antibiotics (eg, oral fluoroquinolones)

• Medications used to treat patients with cystic fibrosis may include the following:– Pancreatic enzyme supplements– Multivitamins (including fat-soluble vitamins)– Mucolytics– Nebulized, inhaled, oral, or intravenous antibiotics– Bronchodilators– Anti-inflammatory agents– Agents to treat associated conditions or complications (eg, insulin, bisphosphonates)– Agents devised to potentially reverse the abnormalities in chloride transport

Treatment • Management approaches to exocrine pancreatic insufficiency

include the following:– Lifestyle modifications (eg, avoidance of fatty foods, limitation of

alcohol intake, cessation of smoking, and consumption of a well-balanced diet)

– Vitamin supplementation (primarily the fat-soluble vitamins A, D, E, and K)

– Pancreatic enzyme replacement therapy (PERT), which is the therapeutic mainstay

• Long-term monitoring of patients with EPI should focus on the following 2 issues:– Correction of nutritional deficiencies– Treatment of causative diseases (when possible); such treatment

will vary according to the specific disease present

PERT• The goal of supplemental enzyme therapy in EPI is to minimize

nutrient malabsorption, especially of lipids, and to do this it is important to achieve an adequate concentration of active pancreatic enzymes in the duodenum at the same time that food is delivered

• The pancreatic enzyme products , contain all 3 pancreatic enzymes (ie, amylase, protease, and lipase) in varying proportions. However, it is lipase that plays the paramount role in therapy.

• The pancreatic lipase replacement dose should be adjusted on the basis of body weight, clinical symptoms, and stool fat content. Several days should be allowed between dose adjustments.

picture Company Pancreatic Enzyme Product

Lipase Content, units

Abbott Laboratories

pancrelipase

3000 1203 Creon

6000 Creon 1206

12000 Creon 1212

24000 Creon 1224

Eurand Pharmaceuticals

pancrelipase

3000 Zenpep EURAND 3



15000 Zanpep EURAND 15



picture Company Pancreatic Enzyme Product

Lipase Content, units

Janssen Pharmaceuticals

pancrelipase

4200 Pancreaze MT 4

10500 Pancreaze MT 10



Aptalis Pharma US

13800 Ultresa 13800UL



Aptalis Pharma US

10440 Viokace 9111

20880 Viokace 9116

Digestive Care 8000 Pertzye 8

16000 Pertzye 16

N.B

•With the exception of Viokace, all PEPs have enteric coatings and are used to treat EPI due to cystic fibrosis or other conditions. Viokace is used in combination with a proton pump inhibitor to treat pancreatic insufficiency due to chronic pancreatitis or pancreatectomy.

• The PEPs are not interchangeable. When a patient is switched to a new PEP, the dose must be started at a similar amount of lipase units and then titrated according to patient response. It may take 1-2 weeks for the patient to adjust to new PEP dose, which can vary.

• Because exogenous pancreatic enzymes should exert their action on the ingested meal and because gastric emptying of nutrients should occur in parallel with pancreatic enzymes reaching the duodenum, PEPs are administered together with meals and snacks. When a sufficient enzyme concentration is delivered into the duodenal lumen simultaneously with a meal, fat absorption is enhanced.

• The composition and various formulations of pancreatin and pancrelipase affect their use and ability to deliver appropriate amounts of active enzyme to the duodenum. Pancreatin, a crude mixture, is derived from swine or ox pancreas, and each milligram contains no less than 2 USP (United States Pharmacopeia) units of lipase and 25 USP units of amylase and protease activity. Pancrelipase is obtained from swine pancreas and is a more concentrated and purified enzyme preparation. Each milligram contains no less than 24 USP units of lipase and 100 USP units of amylase and protease activity. Because of its higher enzyme content, pancrelipase formulations are favored over pancreatin preparations

Calculate the dose

• Dosing for pancreatic insufficiency is as follows:– Initial oral lipase dose, 500 units/kg/meal– Lipase dose range, 500-2500 units/kg/meal– Maximum lipase dosage, 10,000 units/kg/day or 4000 units

per gram of fat daily• Dosing for pancreatic insufficiency due to chronic

pancreatitis or pancreatectomy is as follows:– Oral lipase dose, 72,000 units/meal with consumption of at

least 100 g of fat daily– Alternatively, lower initial lipase doses (500 units/kg/meal)

with individualized dose titration may be considered

Safety and side effects

• The most commonly reported side effects for recently approved enzymes are

• headache (6%)• dizziness (6%)• abdominal pain (9%)• flatulence

• Historically, hyperuricemia, and hyperuricosuria, which leads to dysuria and uric acid crystaluria, have been reported in cystic fibrosis patients with older formulations. Folic acid deficiency has been associated with use of pancreatin extracts

Health & Medicine

Cystic fibrosis