Pancreatic Exocrine Insufficiency in Type 1 & Type 2 Diabetes Mellitus

CME INDIA Presentation by Dr. Mohsin Aslam, Consultant Physician & Clinical Endocrinologist, Asian Institute of Gastroenterology, Hyderabad.

Based on the presentation at RSSDI-Jharkhand annual conference 2022, Ranchi on 27th August.

Introduction

• Pancreas – doubled-entity organ.
• Both exocrine and an endocrine component, reciprocally interacting and closely cooperating for the digestion, absorption, and metabolism of oral nutrients.
• Disorders of the exocrine pancreas also affect the endocrine system and vice versa.
• Patients with chronic pancreatitis develop diabetes (type IIIc), caused by destruction and fibrotic injury of islet cells.
• Less is known on the influence of diabetes on pancreatic exocrine function.

PEI (Pancreatic Exocrine Insufficiency)

• Digestion – major pancreatic enzymes lipase, amylase and proteases.
• Reduced secretion of these enzymes from the pancreas, rapid destruction or inadequate contact between food and pancreatic enzymes within the intestine results in nutrient maldigestion – pancreatic exocrine insufficiency (PEI).

Etiology of Pancreatic Exocrine Insufficiency

Clinical Consequences of Pancreatic Exocrine Insufficiency

• Main – fat maldigestion and malabsorption, resulting in steatorrhea (frothy, foul- smelling and buoyant stools).
• Non- specific symptoms:
  • Abdominal pain.
  • Flatulence.
  • Loose bowel movements.
  • Weight loss in adults, or lack of weight gain in children.

Prevalence of Pancreatic Exocrine Insufficiency In Diabetes Mellitus

Pathophysiology for development of pancreatic exocrine insufficiency in diabetes mellitus

Risk factors for pancreatic exocrine insufficiency in diabetes

Diagnosis of pancreatic exocrine insufficiency in diabetes

• More commonly – loose bowel movements, abdominal discomfort and flatulence.
• Diabetic patients – symptoms of fatigue and difficulty controlling blood glucose levels.
• Many causes of diarrhea in diabetic patients – small bowel bacterial overgrowth and diabetic dysautonomia.
• PEI should be suspected in patients with long standing type I and type II Diabetes.
• Other causes – gastroparesis, celiac disease, and side effects of blood glucose lowering medications should be excluded before considering PEI.

Fecal Elastase-1 Assay

• Currently the most commonly used test for detecting PEI.
• Values > 200 µg/g are within normal limits, whereas values <100 µg/g indicate significant exocrine insufficiency.
• 1 in 3 patients with DM had impaired exocrine function – by fecal elastase-1 testing.
• Steatorrhea can be detected in 60% of patients with DM and reduced fecal elastase-1.
• Conducted in a few laboratories across India.
• Advantage:
  • In contrast to other non-invasive tests, such as chymotrypsin, elastase-1 is stable and unaffected by exogenous pancreatic enzyme substitution.
  • Patient need not stop taking pancreatic enzymes before conducting the test.
• In the presence of diarrheal disease it might be falsely low.

¹³C–Mixed Triglyceride Breath Test

• Most recent test for PEI.
• Fairly accurate.
• Advantage:
  • It could also be used to monitor the effect of pancreatic enzyme therapy on fat digestion.
  • Simpler than the standard fecal fat test to assess therapy in patients with PEI.
• Not widely available.

Management of pancreatic exocrine insufficiency in diabetes

• The mainstay of treatment of PEI in diabetes is pancreatic enzyme replacement therapy (PERT).
• Scant data or guidelines on PERT in patients with diabetes.
• Treatment – based on literature pertaining to treatment of PERT in chronic pancreatitis.
• Recent recommendations support the use of PERT in patients with diabetes and PEI.

Pancreatic Enzyme Replacement Therapy

• Lowest recommended dose of PERT is 25,000-40,000 units of lipase per meal, then titrated upwards according to clinical response.
• Maximum recommended dose of PERT in adults is 75,000-80,000 units of lipase with each meal.
• Optimal action could be achieved by taking the preparation along with or immediately after food intake.
• Enzyme replacement therapy – impact on glucose metabolism.
• In diabetic patients with exocrine insufficiency – reduce insulin requirement and contribute to improved control of glucose metabolism.
• A study with a high patient number – pancreatin therapy in diabetic subjects with reduced elastase 1 levels: HbA1c could be lowered and insulin doses could be reduced.
• Impaired GLP-1 secretion can by normalized by pancreatic enzyme supplementation resulting in better glycemic control.
• Besides helping to control symptoms of steatorrhea, it also seems capable of preventing qualitative malnutrition and metabolic complications.
• Adequate oral pancreatic enzyme replacement therefore seems very important in diabetes mellitus.

Characteristics of Ideal Pancreatic Enzyme Preparation

• For optimal digestive action.
  • A pancreatic enzyme preparation should survive the gastric acidic milieu.
  • Get released into the duodenum along with chyme.
  • Contain the correct dose of lipase.
  • Use of enteric-coated technology to protect them from gastric acid mediated degradation.
• The HP55 coating dissolves at a pH >5.5 to release the lipase, amylase and protease in the duodenum.

Pancreatic Enzyme Replacement Therapy

• Lipase is the most vulnerable among the supplemented pancreatic enzyme, with survival of as low as 1% of the enzyme during intestinal transit in the absence of substrate, i.e. fat in the diet.
• Therefore, a high concentration of lipase in the pancreatic enzyme supplement is mandatory to achieve the optimal dose.
• The pancreas has a huge reserve of enzymes, and it has been shown that only 10% of the total daily lipase output (which is 6,00,000U) is required for fat digestion.
• Therefore, the daily dose of at least 20,000U per meal of lipase is mandatory for fat digestion.

Ideal Pancreatic Enzyme Preparation

• An ideal pancreatic enzyme supplement preparation should:
  • Be an enteric-coated mini-microsphere.
  • With at least 20,000U of lipase.
  • Optimal action could be achieved by taking the preparation along with or immediately after food intake.
• For Indian patient’s intake, along with food provides the best compliance.

Pancreatic Enzyme Replacement Therapy

• Since the initial response of PEI to PERT could be erratic, supplementation should usually be started with a higher dose of 25000 to 40000U of lipase with each major meal, which could then be titrated up or down based on patient’s response.
• Factors such as the size of the patient, size of the meals and nutrition status could also aid in determining the starting and maintenance doses of PERT.

Adverse Effects of Pancreatic Enzyme Replacement Therapy

• PERT is regarded as well-tolerated with few side effects.
• Supplemental enzymes act within the lumen of the intestine – this is considered an intraluminal and not a systemic therapy.
• Most common side effects of pancreatin preparations are:
  • Abdominal pain.
  • Nausea.
  • Vomiting.
  • Constipation.
  • Diarrhoea.

CME INDIA Quick Take-Aways

• Patients with diabetes mellitus have an increased risk of developing PEI due to pancreatic acinar atrophy.
• Symptoms of PEI do not manifest until duodenal lipase levels fall below 5-10% of normal postprandial levels.
• Clinical consequence of PEI is fat maldigestion, resulting in steatorrhea and weight loss.
• Upon clinical suspicion, a pancreatic function test should be performed for identifying subclinical PEI.
• Pancreatic enzyme replacement therapy is the main pharmacological treatment for PEI.
• Pancreatic enzymes are most effective when given with meal, rather than before or after it.

References:

1. Piciucchi M, Capurso G, Archibugi L, Delle Fave MM, Capasso M, Delle Fave G. Exocrine pancreatic insufficiency in diabetic patients: prevalence, mechanisms, and treatment. International journal of endocrinology. 2015 Mar 29;2015.
2. Talukdar R, Reddy DN. Pancreatic Exocrine Insufficiency in Type 1 and 2 Diabetes: Therapeutic Implications. The Journal of the Association of Physicians of India. 2017 Sep 1;65(9):64-70.
3. Andriulli A, Ippolito AM, Festa V, et al. Exocrine pancreatic insufficiency as assessed by fecal elastase-1 levels in diabetic patients: An estimate of prevalence in prospective studies. J Diabetes Metab 2014; 5:379.
4. Exp Diabetes Res. 2011; 2011: 761950.
5. Sikkens EC, Cahen DL, Koch AD, Braat H, Poley JW, Kuipers EJ, Bruno MJ. The prevalence of fat-soluble vitamin deficiencies and a decreased bone mass in patients with chronic pancreatitis. Pancreatology 2013; 13: 238-242.
6. JAPI: 2017:  Volume 65: http://www.japi.org/september_2017/11_ra_pancreatic_exocrine_insufficiency_n_type_1_and.html

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