Pancreatic enzyme replacement therapy in pancreatic insufficiency
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Transcript of Pancreatic enzyme replacement therapy in pancreatic insufficiency
Pancreatic enzyme
replacement therapy in
pancreatic insufficiency
Dr Rahul Singh (MS)
Physiology of the secretion of pancreatic
enzymes.
Pancreatic Exocrine Dysfunction
Pancreatic enzyme replacement therapy is currently the mainstay of treatment for nutrient malabsorption secondary to pancreatic insufficiency.
The leading cause of pancreatic insufficiency is chronic pancreatitis in adults.
In children, the most common cause of pancreatic insufficiency is cystic fibrosis.
Prevalence of exocrine pancreatic insufficiency :
Chronic pancreatitis - 30% to 40%
Cystic fibrosis - 80% to 90% * Bruno et al , Maldigestion associated with exocrine pancreatic insufficiency: implications of gastrointestinal physiology and properties of enzyme preparations for a cause-related and patient-tailored treatment. Am J Gastroenterol. 2005;90(9):1383– 1393.
Etiology
Pancreatic causes :
Chronic pancreatitis
Cystic fibrosis
Obstructions of the pancreatic duct
Shwachman-Diamond syndrome (SDS)
Nonpancreatic causes:
Celiac disease
Crohn disease
Autoimmune pancreatitis
Zollinger-Ellison syndrome
GI and pancreatic surgical procedures
Diagnosis of PED
Exocrine pancreatic insufficiency (EPI) is largely a clinical diagnosis.
A patient with a known cause of pancreatic insufficiency who presents with weight loss and fatty diarrhea is usually begun on treatment without extensive testing.
The diagnostic options include
Indirect measures 72-hour fecal fat and fecal elastase
Direct measures Secretin– cerulein or
Secretin– pancreozymin tests
Steatorrhea is classically defined as at least 7 g of fecal fat over 24 hours, in the context of a 72-hour stool test while on 100 g of fat daily
Fecal elastase testing may be used to demonstrate a lack of endogenous enzyme. 72% sensitive for severe pancreatic insufficiency and 90% specific.
Direct measurements with the secretin–cerulein or secretin–pancreozymin tests are the gold standard for accurate assessment of the exocrine function of the pancreas
* Hahn JU, Kerner W, Maisonneuve P, Lowenfels AB, Lankisch PG. Low fecal elastase 1 levels do not indicate exocrine pancreatic insufficiency in type-1 diabetes mellitus. Pancreas. 2008;36(3):274–278.
Impairment of fat digestion first . Why? Impairment of pancreatic lipase synthesis and secretion occurs
earlier;
More rapid and complete inactivation of lipase occurs in the acidic duodenum as a result of impaired bicarbonate output;
Proteolytic degradation of lipase occurs earlier during aboral transit than that of amylase and proteases;
Impairment of pancreatic bicarbonate secretion decreases duodenal pH, resulting in precipitation of glycine-conjugated bile acids and further deterioration of fat digestion; and
Extrapancreatic sources of lipase are unable to compensate for loss of pancreatic lipase activity.
Clinical presentation
Patients usually will present for evaluation when <10% of exocrine pancreatic function remains.
Steatorrhea is the leading symptom in patients with pancreatic exocrine insufficiency.
Dyspepsia, diarrhea, meteorism, and malabsorbtion of fats, proteins and carbohydrates and resulting deficiencies of fat soluble vitamins (A, D, E, K)
Pancreatic Exocrine Enzyme
Supplementation
Indications* :
Weight loss and/or steatorrhea (≥15 g/day)
Dyspepsia
Diarrhea
Meteorism
Malabsorbtion of proteins and carbohydrates
No benefit in Pain management in Chronic Pancreatitis ( meta-analysis result)
*Blumgart Hepatobiliary surgery
The main goal of the treatment of pancreatic exocrine dysfunction is to ensure that optimal amounts of lipase reach the duodenum with the delivered food.
With the currently available pancreatic enzyme supplement preparations, azotorrhea (protein malabsorption) can be eliminated (Brady et al, 1991), whereas steatorrhea usually can be reduced but not totally corrected.
Management of PED
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)
Pancreatic Enzyme Replacement
Therapy
Endpoints of treatment are normalization of gut absorption and correction of nutritional deficiencies.
The typical indications for initiating PERT are progressive weight loss and steatorrhea.
PERT’s efficacy may be increased through the use of higher enzyme doses and enteric-coated enzymes, the administration of therapy during food, and the suppression of acid.*
* Daniel et al, Efficacy of pancreatic enzyme replacement therapy in chronic pancreatitis: systematic review and meta-analysis, Gut j .2016
PERT causes improvement in:
Coefficient of fat absorption (CFA),
Serum nutritional parameters,
GI symptoms,
Quality of life
Approved agents
The pancreatic enzyme products (PEPs) used for PERT are extracts of porcine pancreas that contain all 3 pancreatic enzymes (i.e., amylase, protease, and lipase) in varying proportions.
Lipase plays the paramount role in therapy
6 PEPs have been approved by the US Food and Drug Administration (FDA) for the treatment of maldigestion in patients whose bodies do not produce sufficient pancreatic enzymes:
Creon (Abbott Laboratories, North Chicago, IL)
Zenpep (Eurand Pharmaceuticals, Yardley, PA)
Pancreaze (Janssen Pharmaceuticals, Titusville, NJ)
Ultresa (Aptalis Pharma US, Birmingham, AL)
Viokace (Aptalis Pharma US, Birmingham, AL)
Pertzye (Digestive Care, Bethlehem, PA)
* These PEPs are not interchangeable.
Pakreoflat ( tab & Syrup)
170 mg pancreatin from porcine pancreas
6 500 FIP units lipase5 500 FIP units amylase400 FIP units protease
&
80 mg dimethicone
PEPs are administered together with meals and snacks.
PEP dosing for PERT is based on the content of lipase units
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
Dosage Recommendations*
Total daily dose reflects ~3 meals per day and 2 to 3 snacks per day, with half the mealtime dose given with a snack.
Dosing should not exceed recommended maximum dosage set forth by the Cystic Fibrosis Foundation Consensus Conferences Guidelines.
Doses of lipase >2,500 units/kg/meal, lipase >10,000 units/kg/day, or lipase >4,000 units/g fat daily should be used with caution and only with documentation of effectiveness by 3-day fecal fat measures indicating a significantly improved coefficient of fat absorption
Doses of lipase >6,000 units/kg/meal are associated with colonic stricture and should be decreased.
Pancreatic insufficiency due to conditions such as cystic fibrosis
Oral (Creon, Pancreaze, Pertzye, Ultresa, Zenpep):
Initial: Lipase 500 units/kg/meal. Dosage range: Lipase 500 to 2,500
units/kg/meal.
Maximum: Lipase ≤2,500 units/kg/meal or lipase ≤10,000
units/kg/day or lipase <4,000 units/g of fat daily
Pancreatic insufficiency due to chronic pancreatitis or pancreatectomy:
Oral:
Creon , Viokace (administer in combination with a proton pump inhibitor): :
Initial: Lipase 500 units/kg/meal with individualized dosage
titrations. Usually, half the prescribed dose for an
individualized full meal should be given with each
snack.
Maximum: Lipase ≤2,500 units/kg/meal or lipase ≤10,000
units/kg/day or lipase <4,000 units/g of fat daily
Pancreatic insufficiency (exocrine) due to pancreatic cancer (off-label dosing):
Oral:
Initial: 25,000 to 50,000 units (lipase) per meal or 1,000 units (lipase)/kg/day or 4,000 units/5 to 7 g fat at each meal; escalate dose based on relief of symptoms;
Maximum dose: 2,500 units (lipase)/kg/meal
Adverse Effects
>10%
Abdominal pain/cramping (3-18% )
Headache (3-15% )
1-10%
Dyspepsia (10%)
Cough (4-10%)
Diarrhea (0-10%)
Hyperglycemia (8%)
Pharyngolaryngeal pain (7%)
Epistaxis (7%)
Anal pruritus (7%)
Biliary tract stones (7%)
Use with caution in Pregnancy , Renal dysfunction and hepatic dysfunction
Summary
Pancreatic enzyme replacement therapy is currently the mainstay of treatment for nutrient malabsorption secondary to pancreatic insufficiency.
The leading cause of pancreatic insufficiency is chronic pancreatitis in adults.
Exocrine pancreatic insufficiency (EPI) is largely a clinical diagnosis.
Steatorrhea is the leading symptom in patients with pancreatic exocrine insufficiency.
Lipase plays the paramount role in therapy
Dosage range: Lipase 500 to 2,500 units/kg/meal with half the dose with snacks.