Enzyme replacement therapy for pancreatic insufficiency: present and future

Figures & data

Table 1 Human pancreatic enzymes involved in lipid digestion

Enzyme name	Specific substrate	References
Pancreatic lipase	Triglycerides (lipid-droplet)	^Citation10,Citation16,Citation19
Pancreatic lipase related protein 1	Unknown	^Citation11, ^Citation12
	Inhibitory effect of HPL (regulatory effect of TG digestion in the duodenum?)	^Citation9
Pancreatic lipase related protein 2	Triglycerides (milk lipid-droplet)	^Citation9
	Synergistic effect of HPL (regulatory effect of TG digestion in the duodenum?)	^Citation9
	Phospholipids	^Citation15,Citation19
	Galactolipids	^Citation13,Citation18
	Esters of vitamin A	^Citation17
Carboxyl ester lipase	Esters of lipid-soluble vitamins	^Citation14
	Esters of cholesterol	^Citation14
	Triglycerides, diglycerides, monoglycerides	^Citation14
	Phospholipids	^Citation14
	Ceramides	^Citation14
Phospholipase A2	Phospholipids	^Citation20

Abbreviations: HPL, human pancreatic lipase; TG, triglycerides.

Table 2 Baseline and postprandial activity of the main pancreatic enzymes in healthy humans^a

	Activity (Units)^b	Collection condition	Method of measurement	Age, number, references
Full-term infants
Lipase	1061 ± 101	CCK + secretin	Olive oil emulsion, pH 9, 25°C^m	7 mo, n = 18, Palasciano^Citation41
	982 (49–978)	CCK + secretin	Olive oil emulsion, pH 9.1, 37°C^m	At birth, n = 8, Zoppi^Citation23
	20/50/600	Baseline	Olive oil emulsion, pH 8	1 d/1 mo/2 yr, n = 15, Lebenthal^Citation22
	20/50/1400	CCK	Olive oil emulsion, pH 8	1 d/1 mo/2 yr, n = 15, Lebenthal^Citation22
	1071 ± 143	CCK + secretin	Olive oil emulsion, pH 9.1, 37°C^m	10–144 mo, n = 7, Moreau^Citation40
Phospholipase	16.7 ± 1.9	CCK + secretin	Egg-yolk lipoprotein, pH 8, 40°C	7 mo, n = 18, Palasciano^Citation41
Trypsin	451 (27–1328) μg	CCK + secretin	BAEE, pH 8, 25°C^n	At birth, n = 8, Zoppi^Citation23
	180/325/180	Baseline	BAPNA, pH 8.2, 25°C^o	1 d/1 mo/2 yr, n = 15, Lebenthal^Citation22
	170/280/400	CCK	BAPNA, pH 8.2, 25°C^o	1 d/1 mo/2 yr, n = 15, Lebenthal^Citation22
Chymotrypsin	93 ± 9	CCK + secretin	ATEE, pH 7.9, 25°C	7 mo, n = 18, Palasciano^Citation41
	5–7.5–12.5	Baseline	BTEE, pH 7.2–8.0, 30°C	1 d/1 mo/2 yr, n = 15, Lebenthal^Citation22
	7–9–25	CCK	BTEE, pH 7.2–8.0, 30°C	1 d/1 mo/2 yr, n = 15, Lebenthal^Citation22
Amylase	22 (2–37)	CCK + secretin	Starch, pH 6.9, 25°C	At birth, n = 8, Zoppi^Citation23
	0	Baseline or CCK	Starch	1 d/1 mo, n = 15, Lebenthal^Citation22
	225	Baseline	Starch	2 yr, n = 15, Lebenthal^Citation22
	300	CCK	Starch	2 yr, n = 15, Lebenthal^Citation22
Adults
Lipase	1454 ± 95	CCK + secretin	Olive oil emulsion, pH 9, 25°C^m	42–46 yr, n = 38, Palasciano^Citation41
	839 ± 429	Baseline	Olive oil emulsion, pH 9, 25°C^m	20–55 yr, n = 7, Mott^Citation43
	74–1674	Test meal^c	Olive oil emulsion, pH 9.1, 37°C^m	nd, n = 15, Braganza^Citation7
	84–1127	Baseline	Tributyrin, pH 8, 25°C	22–36 yr, n = 7, Fredrikzon^Citation24
	750–1125	Test meal^d	Tributyrin, pH 8, 25°C	22–36 yr, n = 7, Fredrikzon^Citation24
	1200 ± 459	CCK + cerulein (PPJ)*	Olive oil emulsion, pH 9, 25°C^m	29–58 yr, n = 7, Escourrou^Citation8
	977 ± 282	CCK + cerulein	Olive oil emulsion, pH 9, 25°C^m	29–58 yr, n = 7, Escourrou^Citation8
	1969 ± 241	Test meal^e	Olive oil emulsion, pH 9, 25°C^m	20–28 yr, n = 26, Bozkurt^Citation44
	1020 ± 128	CCK + secretin	Olive oil emulsion, pH 9.1, 37°C^m	25–71 yr, n = 15, Moreau^Citation40
	200–2400	Test meal^f	Tributyrin, pH 8.0, 37°C	22–42 yr, n = 15, Carrière^Citation34
	600–1400	Test meal^g	Triolein emulsion, pH 9.0, 37°C^p	19–24 yr, n = 7, Armand^Citation29
	200–1000	Test meal^h	Tributyrin, pH 7.5, 27°C	38–58 yr, n = 18, Yago^Citation36
	772,000 ± 200,000/240 min	Test meal^i	Olive oil emulsion, pH 8.8, 30°C^q	22–40 yr, n = 6, Schwizer^Citation31
	1105 ± 360	Baseline	Triolein emulsion, pH 9, 25°C	22–26 yr, n = 14, Keller^Citation39
	4740 ± 800	Test meal^j	Triolein emulsion, pH 9, 25°C	22–26 yr, n = 14, Keller^Citation39
	1500–4000	Test meal^k	Tributyrin, pH 8.0, 37°C	22–26 yr, n = 8, Armand^Citation30
	2000–7000	Test meal^l	Tributyrin, pH 8.0, 37°C	21–25 yr, n = 6, Carrière^Citation35
CEL	3.9–29.5	Baseline	p-nitrophenyl acetate, pH 7.4	22–36 yr, n = 7, Fredrikzon^Citation24
	10–15	Test meal^d	p-nitrophenyl acetate, pH 7.4	22–36 yr, n = 7, Fredrikzon^Citation24
Phospholipase	24.44 ± 1.53	CCK + secretin	Egg-yolk lipoprotein, pH 8, 40°C	42–46 yr, n = 38, Palasciano^Citation41
Trypsin	13–138	Test meal^c	TAME, pH 7.7, 37°C	nd, n = 15, Braganza^Citation7
	25–50	Test meal^h	BAEE, pH 7.9, 27°C	38–58 yr, n = 18, Yago^Citation36
Chymotrypsin	147 ± 11	CCK + secretin	ATEE, pH 7.9, 25°C	42–46 yr, n = 38, Palasciano 1979^Citation41
	65 ± 17	Baseline	ATEE, pH 7.9, 25°C	20–55 yr, n = 7, Mott^Citation43
	113 ± 56	CCK + cerulein (PPJ)*	ATEE, pH 7.9, 25°C	29–58 yr, n = 7, Escourrou^Citation8
	109 ± 30	CCK + cerulein	ATEE, pH 7.9, 25°C	29–58 yr, n = 7, Escourrou^Citation8
	30–100	Test meal^l	ATEE, pH 7.5, 37°C	21–25 yr, n = 6, Carrière^Citation35
	50–75	Test meal^h	ATEE, pH 7.9, 27°C	38–58 yr, n = 18, Yago^Citation36
Amylase	31–840	Test meal^c	Starch, pH 7, 30°C	nd, n = 15, Braganza^Citation7
	161 ± 68	CCK + cerulein (PPJ)*	Starch	29–58 yr, n = 7, Escourrou^Citation8
	143 ± 36	CCK + cerulein	Starch	29–58 yr, n = 7, Escourrou^Citation8
	1.5–4.2	Test meal^h	Starch, pH 6.9	38–58 yr, n = 18, Yago^Citation36
	2.5–16	Test meal^l	Starch, pH 6.9, 30°C	21–25 yr, n = 6, Carrière^Citation35

Notes:

a The majority of the samples were duodenal aspirates except for * which were pure pancreatic juice (PPJ);

b Units are expressed per mL of fluid except otherwise indicated. 1 IU of lipase activity corresponds to 1 μmole free fatty acid released/min; 1 U of phospholipase activity corresponds to 1 NaOH μequivalent liberated/min; 1 IU of CEL activity corresponds to 1 μmol p-nitrophenol produced/minute; 1 IU of amylase activity corresponds to 1 μmole of maltose equivalent released/min; 1 IU of trypsin activity corresponds to 1 μmole of substrate hydrolyzed/min or ⁿ1 U corresponds to 1 μg/ml or ^o1 U corresponds to 1 nanomol of p-nitroaniline produced/min; 1 IU of chymotrypsin activity corresponds to 1 μmole of substrate hydrolyzed/min; For lipase activity measurement the authors used also different concentration and type of bile salts that was not reported in the “Method of measurement”. Test meals:

c Lundh Borgström test meal (500 mL, 5% proteins [P], 6% lipids [L], 15% carbohydrates [C]);

d Test meal (450–850 mL of cow milk plus cream for a lipid load of 1 g/kg body weight);

e Lundh test meal (300 mL, 5% P, 6% L, 15% C);

f Formula Shak Iso (500 mL, 14 g P, 12.5 g L, 52 g C);

g Liquid meal (400 mL, 1 egg, 1 egg white, 70 g olive oil, 70 g sucrose);

h Liquid meal (200 mL, 8.5 g P, 7 g L, 26.5 g C);

i Formula 10% Intralipid (500 mL, 550 kcal);

j Formula (300 mL, 11 g P, 10 g L, 41 g C);

k Formula (500 mL, 34 g P, 50 g L, 50 g C);

l Mixed solid/liquid meal (700 mL, 80 g string beans, 90 g beef meat, 70 g fried potatoes, 10 g butter, 15 mL olive oil); Substrate:

m Olive oil emulsion stabilized by Arabic gum;

p Triolein emulsion stabilized by Arabic gum;

q Olive oil emulsion stabilized by acacia gum.

Abbreviations: ATEE, N-acetyl-L-tyrosine ethyl ester; BAEE, N-benzoyl-L-arginine ethyl ester; BAPNA, benzoyl-DL-arginine-p-nitroaniline; BTEE, N-benzoyl-DL-tyrosine ethyl acetate ester; CEL, carboxyl ester lipase; CCK, cholecystokinin; TAME, p-toluene sulfonyl-L-arginine methyl ester; PPJ, pure pancreatic juice.

Table 3 Postprandial output expressed as amount of the main pancreatic enzymes in the duodenal lumen in healthy adult humans^a

	Output^b	Collection condition	Method of measurement	Age, number, references
Lipase	54.9 ± 10.7^Table Footnotec,Table Footnoted	Liquid test meal^h	Tributyrin, pH 8.0, 37°C	22–42 yr, n = 15, Carrière^Citation34
	88.2 ± 25^Table Footnotec,Table Footnoted	Liquid test meal^h	Tributyrin, pH 8.0, 37°C	22–42 yr, n = 15, Carrière^Citation34
	245 ± 22^Table Footnotec,Table Footnotee	Liquid test meal^i	Triolein emulsion, pH 8.0	23–30 yr, n = 6, Borovicka^Citation33
	442 ± 87^Table Footnoted,Table Footnotef	Liquid test meal^j	Enzyme immunoassay	22–40 yr, n = 6, Schwizer^Citation31
	253 ± 95^g	Liquid test meal^k	ELISA	20–50 yr, n = 3, Carrière^Citation38
	203 ± 96^g	Liquid/solid test meal^l	ELISA	20–50 yr, n = 7, Carrière^Citation38
	416 ± 142^Table Footnotec,Table Footnotee	Liquid/solid test meal^m	Tributyrin, pH 8.0	21–25 yr, n = 6, Carrière^Citation35
Chymotrypsin	133 ± 50^Table Footnotec,Table Footnotee	Liquid/solid test meal^m	ATEE, pH 7.5, 37°C	21–25 yr, n = 6, Carrière^Citation35
Amylase	167 ± 133^Table Footnotec,Table Footnotee	Liquid/solid test meal^m	Starch, pH 6.9, 30°C	21–25 yr, n = 6, Carrière^Citation35

Notes:

a Samples are duodenal aspirates;

b Output is expressed as total mg of proteins measured by immunoassay or specific ELISA test or

c estimated using the known specific activity of enzymes (for pure human pancreatic lipase 8000 IU/mg on tributyrin or 1785 U/mg on triolein), and for

d 1-h period,

e 3-h period,

f 4-h period,

g 90-min period; For lipase activity measurement the authors also used a different concentration and type of bile salts that was not reported in the “Method of measurement.” Test meals:

h Formula Shak Iso (500 mL, 14 g proteins [P], 12.5 g lipids [L], 52 g carbohydrates [C]);

i Formula Ensure (500 mL, 16.8 g P, 13.4 g L, 53.4 g C);

j Formula 10% Intralipid (500 mL, 550 kcal);

k Formula Shak Iso (500 mL, 19 g P, 17 g L, 69 g G);

l mixed solid/liquid meal (700 mL, 80 g string beans, 90 g beef meat, 70 g French fries, 10 g butter);

m Mixed solid/liquid meal (700 mL, 80 g string beans, 90 g beef meat, 70 g fried potatoes, 10 g butter, 15 mL olive oil).

Abbreviations: ATEE, N-acetyl-L-tyrosine ethyl ester; ELISA, enzyme-linked immunosorbent assay.

Table 4 Etiologies of exocrine pancreatic insufficiency

Mechanism	Etiology
Decreased lipase production and delivery, increase lipase destruction	Chronic pancreatitis, cystic fibrosis, diabetes
Pancreatic duct obstruction	Periampullary tumor, pancreatic head cancer, IPMN, benign tumors
Decreased endogenous lipase stimulation and production	Celiac disease, Crohn’s disease, Shwachman–Diamond syndrome
Motility disorders (decrease contact time, interaction with chyme, decrease stimulation of pancreatic enzymes)	Gastrectomy, gastric bypass, extensive small bowel resection

Abbreviation: IPMN, intraductal papillary mucinous neoplasm.

Table 5 Baseline or postprandial activity of the main pancreatic enzymes in transitory or irreversible pancreatic insufficiency^a

	Activity (Units)^b	Collection condition	Method of measurement	Age, number, references
Preterm infants
Lipase	378 (145–1121)	CCK + secretin	Olive oil emulsion, pH 9.1, 37°C^f	32–34 wk GA, n = 36, Zoppi^Citation23
	149–586	Baseline	Tributyrin, pH 8, 25°C	16–38 d, n = 7, Fredrikzon^Citation24
	50–100	Test meal^c	Tributyrin, pH 8, 25°C	16–38 d, n = 7, Fredrikzon^Citation24
	8.4–15.1	Baseline	Triolein, pH 7.4	23–26 d, n = 35, Boehm^Citation42
CEL	12.2–32.9	Baseline	p-nitrophenyl acetate, pH 7.4	16–38 d, n = 7, Fredrikzon^Citation24
	2.5–9	Test meal^c	p-nitrophenyl acetate, pH 7.4	16–38 d, n = 7, Fredrikzon^Citation24
Trypsin	292 (0–682)	CCK + secretin	BAEE, pH 8, 25°C	32–34 wk GA, n = 36, Zoppi^Citation23
	5.2–8.6	Baseline	TAME, pH 8.1	23–26 d, n = 35, Boehm^Citation42
Amylase	4.3 (0–5.1)	CCK + secretin	Starch, pH 6.9, 25°C	32–34 wk GA, n = 36, Zoppi^Citation23
CF infants
Lipase	7 ± 3	CCK + secretin	Olive oil emulsion, pH 9.1, 37°C^f	1–30 mo, n = 6, Moreau^Citation40
(PS)	6300–28,200 IU/kg/h	CCK + secretin	Tributyrin, pH 8.5, 37°C	0.5–17 yr, n = 5, Nouri^Citation45
(PI)	0	CCK + secretin	Tributyrin, pH 8.5, 37°C	12–13 yr, n = 2, Nouri^Citation45
Phospholipase (PS)	25–33 mmol/kg/h	CCK + secretin	^31P NMR spectra, pH 7.44, 37°C	0.5–17 yr, n = 5, Nouri^Citation45
(PI)	0	CCK + secretin	^31P NMR spectra, pH 7.44, 37°C	12–13 yr, n = 2, Nouri^Citation45
Adult Mild-EPI
Lipase	458 ± 83	Test meal^d	Olive oil emulsion, pH 9, 25°C^f	21–73 yr, n = 15, Bozkurt^Citation44
	2000–6000	Test meal^e	Tributyrin, pH 8.0, 37°C	40–60 yr, n = 5, Carrière^Citation35
Adult Severe-EPI
Lipase	52 ± 31	Test meal^d	Olive oil emulsion, pH 9, 25°C^f	21–73 yr, n = 18, Bozkurt^Citation44
	480 ± 125	CCK + secretin	Olive oil emulsion, pH 9.1, 37°C^f	16–72 yr, n = 13, Moreau^Citation40
	160	Test meal^e	Tributyrin, pH 8.0, 37°C	43–61 yr, n = 7, Carrière^Citation35

Notes:

a Samples are duodenal aspirates;

b Units are expressed per mL of fluid except otherwise indicated. 1 IU of lipase activity corresponds to 1 μmole free fatty acid released/min; 1 U of phospholipase activity is expressed as mmoles of lysophospatidylcholine produced/kg body weight in total volume of duodenal juice secreted for 1 hour; 1 IU of CEL activity corresponds to 1 μmol p-nitrophenol produced/min; 1 IU of amylase activity corresponds to 1 μmole of maltose equivalent released/min; 1 IU of trypsin activity corresponds to 1 μmole of substrate hydrolyzed/min (TAME) or 1 U of trypsin activity corresponds to 1 μg/mL (BAEE); For lipase activity measurement the authors used also different concentration and type of bile salts that was not reported in the “Method of measurement”. Test meals:

c Human milk;

d Lundh test meal (300 mL, 5% proteins [P], 6% lipids [L], 15% carbohydrates [C]);

e Mixed solid/liquid meal (700 mL, 80 g string beans, 90 g beef meat, 70 g fried potatoes, 10 g butter, 15 mL olive oil);

f Olive oil emulsion stabilized by Arabic gum.

Abbreviations: BAEE, N-benzoyl-L-arginine ethyl ester; CCK, cholecystokinin; CEL, carboxyl ester lipase; PI, pancreatic insufficient; PS, pancreatic sufficient; TAME, p-toluene sulfonyl-L-arginine methyl ester.

Figure 1 Failure of pancreatic enzyme therapy: a systematic approach.

Notes: *Restrict fat intake to 50–75 g/day, reduction in fiber, alcohol, calcium and magnesium containing antacids; **Histamine-2 receptor blockers or Proton pump inhibitors; ^†Small intestinal bacterial overgrowth, giardiasis, blind loop syndrome, malabsorption of other etiology.

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