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.