Less common etiologies of exocrine pancreatic insufficiency

Table 1 Causes of exocrine pancreatic insufficiency

Definite association with EPI

Chronic pancreatitis

Pancreatic tumor/cancer

Cystic fibrosis

Pancreatic resection

Pancreatic hemochromatosis

Mechanisms associated with EPI not fully identified

Type 1 and 2 diabetes

Type 3c (pancreatogenic) diabetes

Gastrointestinal diseases

Celiac disease

Inflammatory bowel disease

Crohn’s disease

Ulcerative colitis

Gastrointestinal surgery

Aging

EPI: Exocrine pancreatic insufficiency.

Table 2 Factors involved with exocrine pancreatic insufficiency in different medical conditions[1,16,77,78,107,129,131,133,143,144,152-154,164]

Mechanism involved	Pancreatic cancer	Diabetes mellitus	Celiac disease	IBD	GI surgery
Normal pancreas		√	√	√	√
Abnormal pancreas	√	√	√	√
Low or absent pancreatic enzyme production	√	√	√	√	√
Lack of stimulus for pancreatic enzyme production			√	√	√
Postcibal asynchrony	√	√	√	√	√
Pancreatic or biliary tract abnormalities	√	√		√
GI malabsorption			√	√	√

EPI: Exocrine pancreatic insufficiency; GI: Gastrointestinal; IBD: Inflammatory bowel disease.

Table 3 Common signs and symptoms of exocrine pancreatic insufficiency[1,14-16,18,19,22]

Sign/symptom	Associated findings
Excessive flatulence	Abdominal bloating or distension, cramps, belching
Steatorrhea	Fatty, bulky stools; increased bowel movements
Malnutrition	Weight loss, anorexia, fatigue
Vitamin D deficiency	Deficient bone mineralization, osteomalacia, osteoporosis
Vitamin K deficiency	Coagulation abnormalities, ecchymoses, bone metabolism deficiencies
Vitamin A deficiency	Night blindness, decreased immune competence
Vitamin E deficiency	Ataxia and peripheral neuropathy
Hypocalcemia	Muscle spasms, osteomalacia, osteoporosis
Hypoalbuminemia	Nail leukonychia

Table 4 Symptoms and tests used in the diagnosis of exocrine pancreatic insufficiency[2,16,23,24]

Clinical symptoms

Steatorrhea

Diarrhea

Flatulence

Weight loss

Laboratory findings

Fecal fat > 7 g/d on a 100-g fat/d diet

Inconvenient; special high-fat diet and prolonged collection of feces

Considered gold standard

An abnormal coefficient of fat absorption is not specific for EPI

Fecal elastase-1 level ≤ 200 μg/g stool; < 100 μg/g stool = severe EPI

Simple, convenient, and widely available

Measured on a random stool sample

Liquid stools may lead to falsely low results due to dilution

Less accurate in mild stages of disease

Positive qualitative fecal fat (Sudan III) staining

Special high-fat diet

Less accurate; semi-quantitative microscopic method

Insensitive for mild disease

Fecal chymotrypsin ≤ 6 U/g stool

Less sensitive than fecal elastase for mild EPI

Fluorescein dilaurate (pancreolauryl test)

Easy to perform

Not widely available

13C-mixed triglyceride breath test

Well established

Not widely available

Imaging/endoscopy

Pancreatic duct dilatation

Main pancreatic duct calculi

Endosonographic criteria of chronic pancreatitis

Secretin-enhanced diffusion-weighted magnetic resonance cholangiopancreatography imaging

New

Not widely available

EPI: Exocrine pancreatic insufficiency.

Table 5 Pancreatic enzyme replacement therapy clinical trials

Study	Study design, duration (when given), and number of patients	Disease	Results	Adverse effects
Bruno et al[66]	DBRPC, 8 wk, 24 adults (21 analyzed)	Pancreatic cancer	The mean absolute difference for PERT vs placebo in percentage change in body weight was 4.9% (P = 0.02); other outcomes were numerically improved with PERT vs placebo [fat absorption coefficient, 12% increase vs 8% decrease (P = 0.13); stool frequency, decrease of 1/d vs increase of 2/d (P = 0.07)]	No treatment-related AEs
Woo et al[70]	DBRPC, 8 wk, 67 adults	Pancreatic cancer	The mean change in body weight at 8 wk was similar with PERT vs placebo (-1.49% vs -2.99%; P = 0.381), but the mean change in nutritional status was superior with PERT vs placebo in the subset of patients with cancer of the pancreatic head (PG-SGA score, -42.65% vs 32.93%; P = 0.039)	Three patients died [PERT group, 2/34 (6%); placebo group, 1/33 (3%)]
				There were no PERT-related serious AEs
Perez et al[60]	Open-label, 12 adults	Pancreatic cancer	Most patients with moderate to severe fat (6/7) or protein (3/3) malabsorption improved, but no patients with mild fat or protein (0/8) malabsorption improved	No descriptions regarding TEAEs
Ewald et al[49]	DBRPC, 16 wk, 80 adults	Type 1 diabetes	No significant change in HbA1c, fasting glucose, or postprandial glucose; increase in mean vitamin D from baseline to week 16 (PERT, from 54.1 to 59.4 nmol/L; placebo, 60.2 to 62.7 nmol/L)	TEAEs occurred in 33 patients (84.6%) in PERT group and in 35 (85.4%) in PBO group; most frequent AEs were headache, infection, pain, diarrhea, and dyspepsia
Carroccio et al[150]	DBRPC, 2 mo, 40 children	Celiac disease	Significant mean ± SD weight gain in first 30 d (1131 ± 461 g with PERT vs 732 ± 399 g with placebo; P < 0.006), not significant at 60 d	No undesired side effects were reported
Evans et al[141]	Open-label, up to 4 yr, 20 adults	Celiac disease	Significant increase in fecal elastase from median of 90 μg/g to 365 μg/g (P < 0.0001) and improvement in chronic diarrhea with reduction in median stool frequency from 4/d to 1/d (P ≤ 0.0001), but no weight increase (P = 0.3)	No descriptions regarding TEAEs
Leeds et al[135]	Open-label, up to 2 yr, 20 adults	Celiac disease	Significant improvement in chronic diarrhea with reduction in median stool frequency from 4/d to 1/d (P ≤ 0.0001), but no weight increase (P = 0.3)	No descriptions regarding TEAEs
Huddy et al[181]	Open-label, 10 adults	Esophagectomy	Improvement in diarrhea and steatorrhea (9/10), increased weight (7/10)	Nausea in 1 patient
Armbrecht et al[183]	DBRPC crossover trial, 2 wk (plus 1-wk washout), 15 adults	Total gastrectomy	Improved stool consistency (score, 7.6 with PERT vs 9.3 with placebo; P < 0.05), but not the number of bowel movements or abdominal symptoms	No descriptions regarding TEAEs
Hillman et al[166]	Open-label, 6 mo, 30 adults	Partial gastrectomy	Mean ± SE weight gain of 6.73 ± 0.77 (P < 0.001), mean ± SE decrease in steatorrhea of 49.7% ± 7.7% (P < 0.001)	No descriptions regarding TEAEs
Brägelmann et al[184]	DBRPC, 14 d, 52 adults	Total gastrectomy	Improvement of overall well-being (15/23 with PERT vs 6/24 with placebo; P = 0.006), but no improvement of specific symptom	No descriptions regarding TEAEs

AE: Adverse event; DBRPC: Double-blind, randomized, placebo-controlled; GIP: Gastric inhibitory polypeptide; GLP-1: Glucagon-like peptide-1; HbA_1c: Glycated hemoglobin A_1c; PBO: Placebo; PERT: Pancreatic enzyme replacement therapy; PG-SGA: Patient-generated subjective global assessment; TEAE: Treatment-emergent AE.