The exocrine pancreas

Pancreatic enzymes; the missing link in health and disease?

Leo Pruimboom
2014

Abstract

This seminar text reviews various forms of enzyme supplementation used

clinically in digestive and absorption disorders. Enzyme supplementation plays
an integral role in the management of various digestive disorders, particularly
with regard to exocrine pancreatic insufficiency. However, application of
enzymes may also be beneficial for other conditions associated with poor
digestion including lactose intolerante and coeliac disease. Historically, porcine
and bovine pancreatic enzymes have been the preferred form of
supplementation for exocrine pancreatic insufficiency. Use of microbe-derived
lipase has shown promise with studies indicating benefit similar to pancreatic
enzymes, but at a lower dosage concentration and with a broader pH range.
Safety and efficacy of enzymes derived from microbial species in the treatment
of conditions such as malabsorption and lactose intolerance is promising. Plant-
based enzymes, such as bromelain from pineapple, serve as effective digestive
aids in the breakdown of proteins. Synergistic effects have been observed using
a combination of animal-based enzymes and microbe-derived enzymes or
bromelain.
Pancreatic enzyme activity depends on different pathways including local
duodenal mechanism and central parasympathetic (acetylcholinergic)
signalling. Local and central mechanisms use cholecystokinin as signal.
Cholecystokinin is considered an anorexigenic compound and is produced by
duodenal gut lining cells. Once pancreatic enzymes are activated, they
degrdadate fats, proteins and carbohydrates in absorbable microsubstances.
Insufficiency of the exocrine pancreas could therefore produce malabsorbtion
syndrome, nutritional deficiency (vitamin A, vitamin D and vitamin E),
steatorrhea and multiple organ disorder. The use of pancreatic enzyme
supplementation has been proven to be effective in several disorders including
colitis ulcerosa, morbos Crohn, systemic diseases, irritable bowel syndrome (IBS),
chronic and acute pancreatitis and pancreas cancer.

Introduction

Pancreatic exocrine insufficiency is a major consequence of diseases leading

to a loss of pancreatic parenchyma (eg, chronic pancreatitis, cystic fibrosis),
obstruction of the main pancreatic duct (eg, gallstones, pancreatic and
ampullary tumors), decreased pancreatic stimulation (eg, nutricional fibers of
cereals and legumes, celiac disease), or acid-mediated inactivation of
pancreatic enzymes (microbiota disorders, use of certain medicines, acid
based nutrients such as cheese). In addition, gastrointestinal and pancreatic
surgical resection (eg, gastrectomy or duodenopancreatectomy) leading to
post-cibal asynchrony, decreased pancreatic stimulation (cereal lectin, soy
lectin), and loss of pancreatic parenchyma is a frequent cause of pancreatic
exocrine insufficiency. The main clinical consequence of pancreatic exocrine
insufficiency is fat maldigestion and steatorrhea (Dominguez-Muñoz 2007).
Lipase is the most unstable pancreatic enzyme during gastrointestinal transit
most probably due to the high sensitivity of pancreatic lipase to proteolysis and
acidic pH. Due to proteolytic degradation, most amylase activity and more
than 20% of trypsin activity but only 1% of lipase activity produced by the
pancreas and secreted into the duodenum after a pure carbohydrate meal,
are still present within terminal ileum. Lipase also suffers irreversible inactivation
at acidic pH, which is frequently present within the duodenum and jejunum in
patients with pancreatic exocrine insufficiency due to low pancreatic
bicarbonatesecretion [zinc deficiency syndrome]. In patients with pancreatic
exocrine insufficiency, the reduced luminal action of pancreatic amylase and
proteases is compensated for by salivary amylase, intestinal glycosidase,
colonic flora, gastric pepsin, and intestinal peptidases. However, it has been
generally accepted that digestive action of pancreatic lipase is hardly
compensated by extrapancreatic mechanisms. Steatorrhea does not develop
until pancreatic lipase output is below 10% of normal, which has been
classically interpretedas the consequence of a very large reserve capacity of
the exocrine pancreas for enzyme secretion. In contrast, more recent studies
have demonstrated a rather linear correlation between inhibition of duodenal
lipolysis and fatexcretion levels.
This finding is also supported by the fact that human pancreatic lipase-specific
activity on meal triglycerides is three orders of magnitude lower than the very
high specific activity usually measured under experimental conditions in
aspirated duodenal juice. Finally, human gastric lipase output is increased
three- to fourfold in patients with pancreatic exocrine insufficiency, which can
be responsible for a relevant proportion of dietary
triglyceride digestion in these patients. Gastric lipase activity therefore is
capable of compensating for pancreatic lipase deficiency in patients with
pancreatic exocrine insufficiency, thus explaining at least in part the absence
of steatorrhea in patients with more that 10% of normal pancreatic lipase
secretion. Despite the proposition by some authors that impairment of lipase
secretion occurs earlier than for other enzymes in the context of chronic
pancreatitis, which could be an additional factor for fat maldigestion as the
major clinical consequence of pancreatic exocrine insufficiency, other authors
could not confirm these data; thus, this factor is probably of minor clinical
relevance.
Together with abdominal cramps and the typical characteristics of fatty stools
associated with steatorrhea (loose, greasy, foul-smelling voluminous stools that
are difficult to flush), which are not always evident because patients tend to
limit fat ingestion, fat maldigestion causes important clinical problems.

Fat maldigestion can cause deficiency of vitamin D, vitamin A and vitamin E

(Dominguez-Muñoz 2007ª). Maldigestion of protein and carbohydrates is able
to induce the production of methylmercaptane, putrescine and cadaverine
which are responsible for the bad odor of stool, breath and sometimes vagina
in people suffering from exocrine pancreas insufficiency (Lewis 1998). The
physiological role of these substances is to attack s-adenosylmethionine (SAMe)
converting it in spermidine (Kakhi 2007). SAMe is the universal donor of methyl-
groups used by methyltransferases in methylation processes. An excess of the
protein based putrifactors could produce a lack of SAMe and therefore
deficient methylation of certain monoamines such as serotonin with decreased

  2  
production of essential melatonin in the gut. Melatonin has been proven to
regulate the production of insulin and pancreatic enzymes, as does its
precursor triptophane (Jaworek 2007). Triptophan and melatonin are able to
increase the production of pancreas enzymes in exocrine pancreas deficiency
syndrome and protect the pancreas against chronic stimulation (figures 1 and
2). The use of exogenous triptophan in patients suffering from exocrine
pancreas insufficiency syndrome has been proven effective in vitro and in vivo
(Jawrok 2007, Leja-Szpac 2004), while human trials still lacking.

Figure 1 Melatonin and triptophane upregulate the production of

pancreas enzymes in exocrine pancreas insufficiency syndrome
(Jaworek 2007)

  3  
 Figure 2 Melatonin and triptophane protect the pancreas against chronic
stimulation by caerulin (CIP, a CCK analog) and ischeamic insult
(Jaworek 2007)

SAMe is further an important precursor of the pancreas protecting compound

glutathion. Glutathion functions in the pancreas are 1. protection against
oxidative stress and 2. induction of exocytosis of pancreatic enzymes in the
duodenal lumen (Braganza 2010). Free radicals play an essential role in the
development of exocrine pancreas insufficiency and pancreatitis, mainly by
upregulation of the enzym complex NADPH oxidase (Masumane 2008).
NADPH oxidase activity converts oxigen in the superoxid radical which possibly
damages the cell membrane of the pancreas cells and the lysosomes in which
inactive pancreas enzymes are embedded; Acute pancreatitis could therefore
develop.

Pancreatic anatomy

Figure 3 shows the anatomy of a normal human pancreas. The acinar cells
produce pancreatic enzymes, whereas the islet cells are responsible for the
production of insulin (beta cells of Langerhans), glucagon (alpha cells of
Langerhans) and somatostatin (delta cells of Langerhans). Duct cells produce
a large amount of bicarbonate through carbon anhydrase activity. The
enzymes and the bicarbonate are excreted in the pancreatic ducts, which join
the bile duct, reaching the duodenal lumen through the sphincter of Oddi
(figure 4).

  4  
Figure 4 The pancreatic juice and the bile join eachother in the common
duct to be excreted in the duodenal lumen. In this figure
gallstones obstruct the duct giving raise to the possibility of
developing gallbladder en pancreas inflammation; one of the
most common death causes in the world. Th sphincter of Oddi

  5  
 (not mentioned) separates the duodenum from the common
duct

The sphincter of Oddi, a circular muscular, impedes the exchange of duodenal

content with the pancreas/liver duct. Cholecystokinin produced by duodenal
gut lining cells produces relaxation of the sphincter, facilitating the entrance of
bile and pancreatic juice in the duodenal lumen. Several factors influence the
tonus of the sphincter (Barreto 2010):

• alcohol abuse
• high calorie diet (225 kcal/100 gram food, Dossus 2008)
• High carbohydrate diet
• Sympathetic hypertonus
• Insulin resistance
• Gallstones
• Gall inflammation
• Tobaco (DeBenedet 2009)

Situations with sphincter spasm has been related with the development of
endocrine pancreas insufficiency and pancreatitis (Barreto 2010).

Function of pancreatic products

 
The pancreas is comprised of an endocrine and an exocrine portion. The
endocrine portion consists of the islets of Langerhans, which are responsible for
the secretion of insulin, glucagon, and somatostatin. Pancreatic exocrine tissues
(the acini) produce digestive enzymes that are mixed with sodium bicarbonate
from the ductules connecting the acini to the pancreatic duct. This pancreatic
“juice” flows through the pancreatic duct, connecting with the hepatic duct,
and ultimately emptying into the duodenum via the sphincter of Oddi. The
digestive enzymes in the pancreatic juice break down carbohydrates, proteins,
and fats (Table 1). Sodium bicarbonate neutralizes the acidic chyme that will
make its way from the stomach to mix with the juice in the duodenum and start
the enzyme-activating process.

  6  
  

Table 1 The pancreatic juice products, their function and the optimal
working pH (roxas 2008)

Problems can occur when there is a dysfunction in the ability of the pancreas
to produce enzymes or the body’s demand for enzymes exceeds the supply.
This dysfunction can occur for a variety of reasons, including genetic
predisposition, illness, injury/trauma, excessive exercise, aging, toxic exposure,
or a combination thereof. A deficiency of pancreatic enzymes could
potentially contribute to the development of numerous illnesses and
degenerative conditions (Roxas 2008).

The normal chronology of pancreas enzyme production and activation;

disorders based on fracture of chronology

Figure 5 shows the chronological production and activation of enzymes and

other compounds involved in the digestion of normal food. At the time food
reaches the duodenum it will be wrapped in gastric juice and gastric acid. The
acid will lower duodenal pH which induces the production of secretine
releasing peptide (SLP) by glandular pancreas cells. SLP will consequently
stimulate S cells in the so called crypts of Lieberkühn in the duodenum,
responsible for the production of secretin. At the same time cholecystokinin
(CCK) is liberated by I-cells in the duodenal lining as a response of entering
proteins and fat-rich chyme in the duodenum. Secretin induces bicarbonate
(HCO3) production by duct cells which neutralizes the gastric acid and
optimizes the duodenal pH (8) for consequent enzyme activation. CCK
receptors on acinar cells sense CCK and secrete chymotrypsin in the
pancreatic duct which is then transported to the duodenal lumen.
Chymotrypsin entering the duodenum will now be spliced and trypsin is
liberated. The active trypsin is capable of hydrolizing peptides and thus
produce amino acids which can be absorbed. Trypsin further activates other

  7  
digestive enzymes such as pre-amylases and pre-lipases which become
carbohydrate and fat digesting enzymes. Proteins, carbohydrates and fat are
converted in respectively amino acids, monosaccharides and fatty acids by
this pathway making food available for the human body (figure 5).

Figure 5 The chronology of production and activation of pancreatic

enzymes during digestion of normal food

The activated pancreas enzymes are gradually degraded by deconjugated

bilirubin which develops through the deconjugating capacity of another
enzyme called beta-glucuronidase (β-GCD); an enzyme normally released by
the gut mucosa and certain bacteria belonging to the normal microbiota of
the human gut. Free deconjugated bilirubin (in contrast with the conjugated
form) can be considered as the mayor protective compound of gut lining
against the possible damaging effect of active proteases and lipases in parts of
the gut where they not should be active (Qin 2002). Beta-glucuronidase is
produced in high amounts in the healthy large intestine by Escherichia coli and
Streptococcus pyogenesis, which can only do so in a relative acid environment
(pH 4 – 5); An environment based on the production of lactic acid by
bifidobacteria (Qin 2007).

  8  
Figure 6 The inhibiting capacity of bilirubin compaired with biliverdin. The
increasing beta-glucuronidase activity in distal parts of the gut is
responsible for the deconjugation of bilirubin, producing free
active bilirubin and break-down capacity of activated
pancreatic enzymes (adapted from Qin 2007)

Figure 6 shows that trypsin and chymotrypsin are significantly inhibited by free
bilirubin, but not conjugated bilirubin or biliverdin (not showed). The nature of
this inhibition and its physiological relevance were further explored for trypsin.
Important is the fact that the inhibition is non-competitive, suggesting that free
bilirubin can inactivate the enzyme. The effect of free bilirubin on protein
digestion by trypsin was further investigated using chymotrypsinogen as the
substrate. Bilirubin (10 mmol/l) showed 61% inhibition for the proteolytic
activation of chymotrypsinogen A to chymotrypsin in a system containing 1
mg/ml trypsin and 1 mg/ml chymotrypsinogen for 30 min. Digestive proteases
are inhibited by free bilirubin but not conjugated bilirubin. As bilirubin is secreted
from the bile to the lumen mainly in the conjugated form, the digestion of
dietary proteins in the upper small intestine would proceed smoothly.
Deconjugation of bilirubin by beta-glucuronidase from the mucosal cells would
form a protective layer on the surface of the gut. A more dramatic
deconjugation of bilirubin by the high amounts of beta-glucuronidase from gut
bacteria would further cause a prompt and effective inactivation of these
digestive proteases in the lower intestine. Here we can see the wonderful
design of nature that turns a waste byproduct into a precious treasure. The

  9  
amount of digestive proteases secreted by the pancreas largely depends on
the amount of protein in the diet.
This would provide an explanation for the observation that bilirubin-
predominant species tend to be carnivores or omnivores, while
biliverdin-predominant species tend to be herbivores. Large amounts of bilirubin
exist in the bile of cats, dogs, opossums, armadillos, alligators, African clawed
toads, bullfrogs, mudpuppies, sharks (spiny dogfish), small skates, trout,
goosefish, perch and humans, while biliverdin is the main bile pigment of
rabbits, nutrias (rodents that eat water plants), sloths (leaf eaters), birds and
tilapia (fish that eat algae).

Heme oxygenase catalyzes heme(from hemoglobin, cytochrom enzymes,

cyclo-oxygenase) in biliverdin, which is further metabolized in bilirubin by
biliverdin reductase. This happens in animals (including homo sapiens) which
ingest a high amount of proteins and animal fat (carnivores). Heme oxigenase
is produced by the so called vitagenes which are under control of indirect anti-
oxidants such as curcumin (in turmeric root), resveratrol (in grapes, chocolat)
and alliicin (in garlic). These substances are recognized for their protecting
effect of the digestive system probably through upregulation of the production
of (free) bilirubin (Calabrese 2006).

Evidence in vitro and vivo shows that deficiency of beta-glucuronidase and the
subsequent lack of free bilirubin can be responsible for the development of
irritable bowel syndrom (IBS), colitis ulcerosa (CU) and morbus Crohn (MC, Qin
2007). A meta-anaylisis about the use of probiotics with a high concentration of
bifidus bacteria and lactobacillus showed a positive effect for probiotics in
people suffering from IBS, UC and MC (Sang 2010). The proposed mechanisms
for this positive effect are:

• recovering of the relationship between physiological bacteries and

pathogenes
• restauration of immune tolerance
• increased production of beta-glucuronidase and free bilirubin,
degradating possible ulcerating proteases in the large gut

Carbon anhydrase, expressed in duct cells of the pancreas and responsible for
the production of bicarbonate, is dependent on nutritional zinc intake and
absorbtion (Lukaski 2005). The mayor role of bicarbonate in the duodenum is to
optimize pH, making pancreatic enzymes capable of executing their digestive
role (figure 8 and table 1). Carbon anhydrase is a zinc dependent enzyme
(figure 7).

Figure 7 Carbon anhydrase, the most important enzyme for pH regulation

not only in the digestive tract but also in the rest of the body
including kidney nefrons and brain, contain in the centre of the
molecule a zinc ion

  10  
Figure 8 The average time food spends in each part of the digestive
system related with average/optimal pH. The basic environment
of the duodenum is necessary for optimal function of pancreatic
enzymes (see table 1).

Zinc deficiency, a pandemic situation, has been related with carbon

anhydrase insufficiency in multiple investigations (Lusaski 2005, Komai 2000) and
is recognized as one of the mayor nutritional causes of diseases in developed
and developing countries (www.who.int/whr/2002/chapter4/en/index3.html)
One of the most valuable measurements for zinc deficiency is the preferred
salt-taste test (figure 9, Komai 2000). This test, developed in rodents, shows a
decreased oral salt sensibility when zin is deficient. A test which is also validated
in humans (Stewart-Knox 2005).
Zinc supplementation can recover salt-sensibility through upregulation of
carbon anhydrase production (Prasad 1998).

Figure 9
Preferred Salt-taste
related with zinc
deficiency (Komai 2000)

  11  
Zinc deficiency rate differ from 6 – 73% in selected countries and is often
neglected as mayor cause of pathologies and disorders such as growth
retardation, male hypogonadism, neuro-sensory changes (abnormal dark
adaptation and changes in taste acuity), delayed wound healing, abnormal
immune functions, and impaired cognitive functions, all of them reversible with
zinc supplementation (Prasad 1998). A mild deficiency of zinc in pregnant
women is associated with increased maternal morbidity, abnormal taste
sensation, prolonged gestation, inefficient labor, atonic bleeding, and
increased risks to the fetus.

Another mentioned enzyme in the digestive cascade is enteropeptidase.

Enteropeptidase (synonym: enterokinase) was discovered, by N. P.
Schepovalnikow in 1899, as a factor that is contained in the duodenum
and that is capable of activating pancreatic juice to digest fibrin.
Enteropeptidase acts as a sequence-specific protease activating trypsinogen
by cleaving off an inhibitory portion. Trypsin, in turn, releases chymotrypsin,
carboxypeptidases, elastases, and also lipases from their inactive pancreatic
precursors. Intestinal activation of pancreatic precursors is the physiologic
mechanism preventing the damage that proteases would cause if they were
active within the pancreatic-duct system. Consequently, protein digestion is
expected to be largely dependent on enteropeptidase activity.
Enteropeptidase is exclusively expressed in the brush border of the proximal
small intestine. Recently, enteropeptidase has been reported to be activated
from an inactive precursor (proenteropeptidase) by duodenase, a newly
discovered serine protease expressed in the duodenum (Holzinger 2002).
Enteropeptidase deficiency is not a common disorder and needs no further
explanation.

The exocrine pancreas insufficiency; etiology and central vagal mechanisms;

the role of stress in pancreatic function

Exocrine pancreas insufficiency (EPI) is a syndrome characterized by a lack of

active pancreatic enzymes in the duodenal lumen. It is a mayor consequence
of primary pancreatic diseases such as chronic pancreatitis, cystic fibrosis,
acute pancreatitis, pancreatic cancer and secundary pancreas disorders
including celiac disease, morbus Crohn, lactose malabsorbtion and
gastrointestinal – pancreatic surgical resection (Dominguez-Muñoz 2007).
Exocrine pancreas insufficiency syndrome (EPI) can be caused by a variety of
etiological factors. The most investigated factors are genetical ones, relating
recurrent EPI with cystic fibrosis and the Schwachman-Diamond syndrome. The
EPI syndrome in these disorders are very frequent and results of different human
trials concerning the efficacy of use of pancreatic enzyme formulas make this
intervention evidence based (Graff 2010).
Alcohol misuse, tobaco, micronutrient deficiency, high carbohydrate diet, high
calorie diet, mayor intake of legumes and cereals, exercise deficit and exercise
abundance are factors related with EPI in animal and in human studies
(Braganza 2010, Barreto 2010, Taylor 2010, Dominguez-Muñoz 2007). The
mentioned factors include the mayor intake of legumes (such as soy) and
cereals as possible causal factors of EPI. Studies published already in the
nineties and eighties of last century showed that cereal fibers and so called
protease-inhibitors in legumes are able to inhibit the production and activation

  12  
of pancreatic enzymes (Hendrick 1991, Jacobs 1983, Dunaif 1981). The cientific
excellent cereal paper of Cordain (Cordain 1999) adds to the fiber influence of
legumes and cereals, the effects of lectins, saponins and protease-inhibitors
(such as Bowman-Birk factors in legumes and Kunnitz factors in potato) on the
exocrine pancreas.

EPI is normally characterized by steatorrhea (fatty steaky stool), flatulence, bad

breath and inflammation of the upper part of the abdomen (Roxas 2008).
Symptoms are dued to deficient digestion of fats, proteins and carbohydrates.
Lipases seem te be the most vulnerable in EPI (Dominguez-Muñoz 2007). This is
the reason for the fact that people suffering from EPI almost always have
steatorrhea.
EPI can develop in acute and chronic pancreatitis when secretion of the
pancreatic juice is impeded by gallstones in the pancreatic duct or by spasm
of the sphincter of Oddi (see page 5). One of the mayor causes of gallstone is
high carbohydrate intake (HCHD). HCHD seems to diminish the volume of the
gall-bladder, augment cholesterol-gallstone formation and increases the cristal
mass (Mathur 2007).
The combined production of secretin and CCK activates the pancreas and
opens the sphincter of Oddi through three pathways (Konturek 2003). The
secretion starts almost immediately after the meal with three overlapping
phases: cephalic, gastric, and intestinal phases, contributing, respectively, to
about 20%, 10%, and 70% of the total postprandial response to a meal.
The postprandial phases, especially the cephalic phase, have been attributed
mainly to vagal stimulation, with the efferent cholinergic nerves releasing
acetylcholine in the pancreas and GRP-releasing neurons releasing gastrin from
antral G-cells. It, in turn, stimulates acinar cells via CCK2 receptors. This cephalic
phase can be induced by sham feeding in dogs or modified sham feeding in
humans, as well as by insulin hypoglycemia or 2-deoxy-D glucose
glucocytopenia, which stimulates the bulbar vagal centers with subsequent
cholinergic excitation of exocrine pancreas, and GRPergic release of gastrin,
which contributes to the activation of pancreatic acinar cells. Blocking vagal
activity reduces the bicarbonate production by over 50%, which means that
not only acinar cells are under vagal control, but duct cells as well.
During the intestinal phase, the major role has been attributed to CCK and
secretin, released from endocrine I and S-cells by protein and fat digestion
products and by gastric acid entering the duodenum, respectively, but the
relative contribution of these hormones and their potentiating interaction on
postprandial pancreatic secretion has not been fully elucidated. There is little
doubt that CCK plays a crucial role in the overall stimulation of pancreatic
secretion as documented by the rise in plasma CCK level and the
inhibitory effect of blockade of CCK1 receptors on this secretion, but its major
pathways of action appear not to be endocrine, as was proposed in the past,
but neural, involving the sensory receptors at afferent nerves and long
vagovagal reflexes or short enteropancreatic reflexes, as depicted in figure 10,
(Konturek 2003)
CCK appears to affect, through the same neural pathway, not only pancreatic
secretion, but also bile secretion and gall bladder contraction as well as gastric
emptying and pancreatic regeneration (growth).

  13  
Figure 10 The overall regulation of exocrine pancreatic function through
three different pathways; local duodenal liberation of CCK and
secretin, stimulation via gastric juice and three, through vagal
activity and acetylcholin release in the exocrine pancreas
(Konturek 2003).

The exocrine pancreas, controlled by these three pathways, influences and is

influenced by the endocrine pancreas which produces insulin, glucagon and
somatostatine. In consequence of the close anatomical and functional links
between the exocrine and endocrine pancreas, any disease affecting one of
these parts will inevitably affect the other. Pancreatic conditions which might
cause diabetes mellitus include acute and chronic pancreatitis, pancreatic
surgery, cystic fibrosis and pancreatic cancer. The development of diabetes
greatly influences the prognosis and quality of life of patients with exocrine
pancreatic diseases. It may cause life threatening complications, such as
hypoglycemia, due to the lack of glucagon and the impaired absorption of
nutrients, or the micro- and macrovascular complications may impair the organ
functions. Diabetes mellitus is an independent risk factor of mortality in those
with exocrine pancreatic diseases. The treatment of pancreatic diabetes, a
distinct metabolic and clinical form of diabetes, requires special knowledge.
Diet and pancreatic enzyme replacement therapy, together with substances
which improve insulin sensitivity may be sufficient in the early stages. Oral
antidiabetic drugs are not recommended. If the diet proves inadequate to
reach the glycemic goals, insulin treatment with multiple injections is

  14  
required. Impairments of the exocrine pancreatic function and morphology in
diabetic patients are frequent and well known. Atrophy of the exocrine tissue
may be caused by the lack of trophic insulin, whereas pancreatic fibrosis can
result from activation of stellate cells by hyperglycemia, or from
microangiopathy and neuropathy. The regulation of the exocrine pancreatic
function is also damaged because of the impaired effect of islet hormones. In
the event of a proven impairment of the pancreatic exocrine function in
diabetes mellitus, pancreatic enzyme replacement therapy is indicated.
This may improve the nutritional condition of the patient and decrease the
metabolic instability (Czako 2009). Normal insulin seems to increase the
production of pancreatic enzymes postprandial. Hyperinsulinemia (part of the
metabolic syndrome) and hyperglicemia inhibit the release of secretin and
CCK which can lead to severe lack of activated pancreatic enzymes,
maldigestion and malabsorbtion (Pap 2004).
People with acute or chronic pancreatitis express a higher activity of amylase
enzymes, leading to a faster digestion of polysaccharides and a secular
increase in blood glucose. The resulting chronic hyperglicemia seems to
exhaust beta cells of the pancreas with a subsequent loss of insulin signalling.
Insulin is necessary for pancreas regeneration after an pancreatic insult leading
to pancreatitis, which means that a lack of insulin could impede pancreas
recovery, produce multiple organ disorder, multiple organ failure and in the
end death (Pap 2004).

Figure 11 shows the possible interaction between diabetes and pancreatitis; a

situation which can be considered a devils vicious circle.

Figure 11. The interaction between DM and pancreatitis; a vicious circle

(Czako 2009)
Table 2 shows the overall influence from different states of insulin on exocrine
pancreatic function. Therapy of EPI should therefore not only regulate exocrine
function but also the endocrine function of the pancreas (Lam 1999, Lam 1999ª,
Lam 1997, Berry 1996).

  15  
 • Hypo-insulinemia
Atrophy from the pancreas
Steatosis from acinar cells
Loss of CCK receptors

• Insulin resistance
Decrease of CHO3 production
Decrease of CCK production
Decrease of vagal tonus

• Hyperglyceamia

Decrease of CHO3
Decrease of CCK and basal pancreatic enzym
production  

Table 2 The effect of different amounts of insulin and glucose on the

exocrine pancreas function

Exocrine pancreas function is influenced by insulin through two pathways; the

insulino-acinar pathway (Konturek 2003) and the pathway involving the central
nervous system (Pruimboom 2005). Paradigmatic thinking has ruled medical
thinking about interactions between the endocrine pancreas, the liver and the
exocrine pancreas for decades. A non-inhibited liver will normally produce
glucose output in the bloodstream. Postprandial pancreatic insulin is secreted
in the portal vein and arrives for the fully 100% in the liver where
neoglucogenesis is inhibited for just 20%. Non-used insulin reaches arterial blood
through which it enters the brain. Insulin will activate anorexigenic neurons in
the hypothalamus. These neurons are connected with and activate the nucleus
tractus solitaris, which in turn activates the motorneurons of the nervus vagus.
Efferents from these motorneurons innervate the liver and the pancreas, where
they respectivily inhibit neoglucogenesis (for the resting 80%) and induce
secretion of pancreatic juice of the exocrine part (figure 12). Insulin resistance
and fatty liver (NAFLD and AFLD) disease can disturb the function of this so
called pancreas-liver-brain axis (Lustig 2006). Deficiency of central insulin
signalling decreases activity of the vagus motorneurons; liver neoglucogenesis
will be desinhibited, pancreatic output of enzymes decreased and EPI will be a
logical consequence. The final conclusion is that chronic insulin resistance can
be considered exocrine pancreas toxic through direct effects (insulino-acinar
connection) and through long vagal reflex deficiencies. Probiotics, omega 3
fatty acids, curcumin and sylibum extracts should be considered as first choice
treatment for fatty liver disease, insulin resistance and restoration of the normal
function of the pancreas-liver-brain axis (Masterton 2010, Esposito 2009, Solga
2008)

  16  
Figure 12 The pancreas, liver, brain axis. Explanation see text
Ht = hypothalamus, NTS = nucleus tractus solitaris, MNV =
motorneurons of the nervus vagus

Pancreatitis

Acute and chronic pancreatitis belong to the diseases with the highest
morbidity (Saluja 2007). Although there still exist a huge gap in our
understanding of pancreatitis, some mechanisms are considered current
opinion. Risk factors such as smoking, alcohol abuse, high calorie diet, but also
several chemicals (e.g. pesticides, Barreto 2010, Braganza 2010) are able to
overstimulate the exocrine pancreas and at the same time producing sphincter
of Oddi spasm. The consequence is that pancreatic enzymes are not excreted
in the duodenum lumen and stay in the pancreatic duct or in the acinar cells.
Activation by a lysosomal enzyme called cathepsin beta can actually activate
trypsin in the pancreas itself, producing activation of proteases, lipases and
amylases in acinar cells, through which these cells will be damaged. The
damaged cells attract neighbouring immune cells which infiltrate the pancreas
and produce pro-inflammatory cytokines (IL1beta, TNF, IL6). The pancreas will
now suffer a inflammation which can lead to multiple organ disorder, multiple
organ failure and death (figure 13, Saluja 2007).
Pancreatic enzyme therapy seems to be the only valuable intervention
together with withdrawal of alcohol, low carbohydrate diet, rest, direct and
indirect antioxidants (Lieb 2009, Bhardwaj 2009). Candidates are selenium,
vitamin C, vitamin E and cystein.

  17  
Figure 13 The development of acute and chronic pancreatitis (see text)

The clinical use of pancreatic enzymes

Exocrine Pancreas Insufficiency is a frequent disorder which can exists as

primary disease and a secondary pathology of disorders like cystic fibrosis and
NAFLD. Therapy for pancreatic exocrine insufficiency is based on oral
administration of exogenous pancreatic enzymes. In addition, dietary
modifications have classically played an important role that should probably
be reconsidered. Indications for therapy, the role of dietary modifications,
the basis and critical aspects of enzyme substitution therapy, factors inhibiting
normalization of fat digestion despite correct enzyme substitution therapy, ways
to improve the efficacy of enzyme therapy, and future developments
are discussed in the last part of this seminar text.

Mayor indications

People suffering from primary EPI show symptoms such as steatorrhea,

abdominal cramps, taste deficiency, abdominal swelling, nutrient intolerance
and general malaise. Treatment should be based on oral pancreatic enzymes,
probiotics and fat soluble vitamins such as vitamin D, vitamin A and vitamin E
(Cavelot 2006). Omega 3 fatty acids are needed for recovering of pancreas
lipase transport and need to be supplemented.
Secondary EPI has to be treated as primary; pancreas function disorders can
be responsible for lack of body energy up to 20% (of basal metabolic rate of
1600 kcal = 320 kcal/24 hours, Dominguez-Muñoz 2007). This can lead to
multiple organ disorder, involving organs such as the liver and the kidneys.
Pancreatic enzymes have been proven to be effective in diseases such as
(Roxas 2008, Dominguez Muñoz 2007, Dominguez-Muñoz in press):

  18  
 • pancreatic carcinoma
• Primary EPI
• Celiac disease
• Lactose intolerance
• Systemic disease
• IBS, morbus Crohn, colitis ulcerosa
• NAFLD

The dosis of oral pancreas enzymes is based on the amount of lipase in the
supplement. Lipase is the most unstable pancreatic enzyme during
gastrointestinal transit most probably due to the high sensitivity of pancreatic
lipase to proteolysis and acidic pH. Due to proteolytic degradation, most
amylase activity and more than 20% of trypsin activity but only 1% of lipase
activity produced by the pancreas and secreted into the duodenum after a
pure carbohydrate meal, are still present within the terminal ileum. Lipase also
suffers irreversible inactivationat acidic pH, which is frequently present within
the duodenum and jejunum in patients with pancreatic exocrine insufficiency
due to low pancreatic bicarbonate secretion. In patients with pancreatic
exocrine insufficiency, the reduced luminal action of pancreatic amylase and
proteases is compensated for by salivary amylase, intestinal glycosidase,
colonic flora, gastric pepsin, and intestinal peptidases. However, it has been
generally accepted that digestive action of pancreatic lipase is hardly
compensated by extrapancreatic mechanisms.
Many people suffer from helicobacter pylori and pH disorders, which means
that oral enzyme therapy efficacy could be less than expacted. If so, dosis
should be raised and anti-acids (such as magnesium) should be added to the
treatment.
Oral pancreatic enzyme therapy can be very effective and relieve a great
variety of disorders. If the initial dosis has not been efficient, dosis should be
doubled or tripled. After 2 weeks of tretament symptoms should be significant
less. Non-responding patients should be tested on bacterial overgrowth and
possibly a carcinogenic proces.

Conclusion

The exocrine pancreas, producing pancreatic enzymes and carbon

anhydrase, plays a central role in maintaining human health by digesting food
and making nutrients available for the body. Disorders of the exocrine pancreas
are frequent and can be primary (caused by alcohol abuse, high calorie diet)
or secondary to other pathologies (cystic fibrosis, celiac disease). Disturbtions of
exocrine function influences the endocrine pancreas and viceversa. Insulin
protects the exocrine pancreas and is responsible for pancreas regeneration.
Disorders of insulin signalling can cause (severe) malfunction of the exocrine
pancreas, multiple organ failure and death.
Exocrine pancreas insufficiency is often not recognized while the incidence of
people suffering from this disorder increases continously. EPI is characterized by
steatorrhea, abdominal swelling and cramps, bad breath and flatulence.
Lipase deficiency, the most vulnerable enzyme of the total pancreatic juice, is
responsible for the mayority of symptoms. Lipase deficiency further causes
malabsorbtion of fat soluble vitamines (vitamin A, D, E) and omega 3 fatty

  19  
acids.
Gallstones are considered one of the most frequent etiological factors for EPI.
High calorie and high carbohydrate diet are causal for gallstones. Gallstones
can block the sphincter of Oddi through which pancreatic juice and bile
should be excreted in the duodenal lumen. Obstruction can lead to acute and
chronic pancreatitis and is considered one of the most frequent detah causes
in developing and developed countries. Pancreatic enzymes have to be
inactivated during gut travelling by free bilirubin. Free bilirubin is formed through
activation of mucosal and bacterial produced beta-glucuronidase. A lack of
this enzyme can cause IBS, CU and MC; one of the mayor causes of beta-
glucuronidase deficiency is the intake of saccharin (Qin 2002).

Treatment with oral pancreatic enzymes have been proven effective in a wide
range of disorders and pathologies, including acute/chronic pancreatis,
pancreatic surgery, EPI, celiac disease, irritable bowel syndrome, colitis, morbus
Crohn, lactose intolerance, trauma and systemic disease. Dosis depends on the
reaction of the patient. Doubling or tripling of the initial dosis can be necessary.

  20  
Literature

Barreto SG, Gino T.P. Saccone Alcohol-induced acute pancreatitis: The ‘critical
mass’ concept. Medical Hypotheses xxx (2010) xxx–xxx
Berry SM, Fink AS. Insulin inhibits secretin stimulated pancreatic bicarbonate
output by a dosedependent neurally mediated mechanism. Am J
Physiol 1996; 270:G163-170.
Bhardwaj, Payal, Pramod Kumar Garg, Subir Kumar Maulik, Anoop Saraya,
Rakesh Kumar Tandon, and Subrat Kumar Acharya. "A Randomized Controlled
Trial of Antioxidant Supplementation for Pain Relief in Patients with Chronic
Pancreatitis." Gastroenterology 136, no. 1 (2009):
doi:10.1053/j.gastro.2008.09.028.
Braganza J, Dormandi. Micronutrient Therapy for Chronic Pancreatitis: Rationale
and ImpactJ Pancreas (Online) 2010 Mar 5; 11(2):99-112.
Cavalot F, Katia Bonomo, Elisa Fiora, Elisa Bacillo, Paola Salacone, Massimo
Chirio, Ezio Gaiamariella Trovati. Does Pancreatic Elastase-1 in Stools
Predict Steatorrhea in Type 1 Diabetes? Diabetes Care, VOLUME 29, NUMBER 3,
MARCH 2006 (3): 719-721
Czakó L, Péter Hegyi, Zoltán Rakonczay, Jr. Tibor Wittmann
Makoto Otsuki. Interactions between the Endocrine and Exocrine Pancreas
and Their Clinical Relevance. Pancreatology 2009;9:351–359
DeBenedet A, T. Raghunathan, J. Wing, E. Wamsteker, M. Dimagno. Alcohol Use
and Cigarette Smoking as Risk Factors for Post–Endoscopic Retrograde
Cholangiopancreatography Pancreatitis. Clinical Gastroenterology and
Hepatology, 2009, Volume 7, Issue 3, Pages 353-358.e4
Cordain L. Cereal Grains: Humanity’s Double-Edged Sword Simopoulos AP (ed):
Evolutionary Aspects of Nutrition and Health. Diet, Exercise, Genetics and
Chronic Disease. World Rev Nutr Diet. Basel, Karger, 1999, vol 84, pp 19–73
Dominguez-Muñoz, JE . Pancreatic Enzyme Therapy for Pancreatic Exocrine
Insufficiency. Current Gastroenterology Reports 2007, 9:116–122
Domínguez-Muñoz JE, Iglesias-García J, Vilariño-Insua M, Iglesias-Rey M: 13C-
mixed triglyceride breath test to assess oral enzyme substitution therapy in
patients with chronic pancreatitis. Clin Gastroenterol Hepatol, in press.
Dossus L, Kaaks R. Nutrition, metabolic factors and cancer risk. Best Practice &
Research Clinical Endocrinology & Metabolism. Vol. 22, No. 4, pp. 551–571, 2008
Dunaif B, Schneeman G. The effect of dietary fiber on human pancreatic
enzyme activity in vitro. The American Journal of Clinical Nutrition, 1981, 34:
1034-1035
Esposito E, Iacono A, Bianco G, Autore G, Cuzzocrea S, Vajro Probiotics reduce
the inflammatory response induced by a high-fat diet in the liver of young rats.
J Nutr. 2009 May;139(5):905-11. Epub 2009 Mar 25
Graff, McNamara J, Royall J, Caras S, Forssmann K. Safety and Tolerability of a
New Formulation of Pancrelipase Delayed-Release Capsules (CREON(R)) in
Children Under Seven Years of Age with Exocrine Pancreatic Insufficiency due
to Cystic Fibrosis: An Open-Label, Multicentre, Single-Treatment-Arm Study. Clin
Drug Investig. 2010;30(6):351-64
Hendrick JA, Tadahiro Tadokoro, Curt Emenhiser, Owe Nienaber, and Owen R.
Fennema. Various Dietary Fibers Have Different Effects on Lipase-Catalyzed
Hydrolysis of Tributyrin in Vitro. The American Journal of Nutrition 1991

  21  
Holzinger A, Esther M. Maier, Cornelius Bu¨ck, Peter U. Mayerhofer,
Matthias Kappler, James C. Haworth, Stanley P. Moroz, Hans-Beat Hadorn,
J. Evan Sadler, and Adelbert A. Roscher. Mutations in the Proenteropeptidase
Gene Are the Molecular Cause of Congenital Enteropeptidase Deficiency. Am.
J. Hum. Genet. 70:20–25, 2002
Jacobs LR. The American Journal of Clinical Nutrition 1983; 37: 954-960
Jaworek J, et al. Melatonin as modulator of pancreatic enzyme and pancreas
protector. Journal of Physiology and Pharmacology, 2007, 58. Suppl. 6: 65-80
Kamhi, Ellen, Ph.D., RN, HNC (2007). Alternative Medicine Magazine's Definitive
Guide to Weight Loss. Celestial Arts. pp. 14. ISBN 1587612593. "Ornithine is
converted by bowel bacteria into a toxic substance called putrescine, which in
turn degrades into polyamines, such as spermadine, spermine, and cadaverine
(literally meaning "the essence of dead cadavers").
Komai M, Tomoko Gotoa, Hitoshi Suzukib, Tomohiko Takedaa and Yuji
Furukawa. Zinc deficiency and taste dysfunction; Contribution of carbonic
anhydrase, a zinc-metalloenzyme, to normal taste sensation BioFactors 12
(2000) 65–70
Konturek SJ, Romuald Zabielskib, Jan W. Konturekc, John Czarnecki.
Neuroendocrinology of the pancreas; role of brain–gut axis
in pancreatic secretion European Journal of Pharmacology 481 (2003) 1–14
Lam WF, Masclee AA, Souverijn JH, Lamers CB. Effect of acute hyperglycemia
on basal, secretin and secretin + cholecystokinin stimulated exocrine
pancreatic secretion in humans. Life Sci 1999; 64:617-626.
Lam WF, Muller ES, Souverijn JH, et al. Effect of acute hyperglycaemia on basal
and fat-induced exocrine pancreatic secretion in humans. Clin Sci (Lond) 1997;
93:573-580.
Lam WF, Gielkens HA, Coenraad M, et al. Effect ofinsulin and glucose on basal
and cholecystokininstimulated exocrine pancreatic secretion in humans.
Pancreas 1999; 18:252-8.
Leja-Szpakb A, j. Jaworekb, r. Tomaszewskaa, k. Nawrotb, J. Boniorb, M. Kotb ,
M. Palonekb, J. Stachuraa, A. Czuprynab, S. J. Kontureka, W.W. Pawlika.
Melatonin precursor, l-tryptophan protects the pancreas from development of
acute pancreatitis through the central site of action. Journal of Physiology and
Pharmacology 2004, 55, 1: 239-254
Lewis, Robert Alan (1998). Lewis' Dictionary of Toxicology. CRC Press. pp. 212
Lieb, J G, and C E Forsmark. "Pain and Chronic Pancreatitis." Alimentary
pharmacology & therapeutics (2009)doi:10.1111/j.1365-2036
Lukaski HR. Low dietary zinc decreases erythrocyte carbonic anhydrase
activities and impairs cardiorespiratory function in men during exercise. Am J
Clin Nutr 2005;81:1045–51.
Lustig RH. Childhood obesity: behavioral aberration or biochemical drive?
Reinterpreting the First Law of Thermodynamics. Nature Clinical Practice
endocrinology & metabolism, 2006, 2 (8): 447 - 458
Masterton GS, Plevris JN, Hayes PC. Review article: omega-3 fatty acids - a
promising novel therapy for non-alcoholic fatty liver disease •Aliment
Pharmacol Ther. 2010 Apr;31(7):679-92.
Mathur, Abhishek MD, Marine Megan, BS, Hayder H. Al-Azzawi, MD, Debao Lu,
MD, Deborah A. Swartz -Basile, PhD, Attila Nakeeb, MD, and Henry A. Pitt, MD.
High dietary carbohydrates decrease gallbladder volume and enhance
cholesterol crystal formation. Surgery 2007;141:654-9
Masamune Atsushi,* Takashi Watanabe,* Kazuhiro Kikuta, Kennichi Satoh, and

  22  
Tooru Shimosegawa. NADPH oxidase plays a crucial role in the activation of
pancreatic stellate cells Am J Physiol Gastrointest Liver Physiol 294: G99–G108,
2008
Pap A. Effects of insulin and glucose metabolism on pancreatic exocrine
function. Int J Diabetes & Metabolism (2004) 12: 30-34
Prasad SA. Zinc Deficiency in Humans: A Neglected Problem. Journal of the
American College of Nutrition, Vol. 17, No. 6, 542–543 (1998)
Pruimboom, L. Eetstoornissen. Van Nature 2005, 1: 38 - 40
Roxas M. The role of enzyme supplementation in digestive disorders. Alternative
Medicine Review Volume 13, Number 4 2008  
Saluja AK, Markus M. Lerch, Phoebe A. Phillips, and Vikas Dudeja. Why Does
Pancreatic Overstimulation Cause Pancreatitis? Annu. Rev. Physiol. 2007.
69:249–69
Sang LX, Bing Chang, Wen-Liang Zhang, Xiao-Mei Wu, Xiao-Hang Li, Min Jiang  
Remission induction and maintenance effect of probiotics on
ulcerative colitis: A meta-analysis. World J Gastroenterol 2010;
16(15): 1908-1915
Solga SF, Buckley G, Clark JM, Horska A, Diehl AM.The effect of a probiotic on
hepatic steatosis. J Clin Gastroenterol. 2008 Nov-Dec;42(10):1117-9
Stewart-Knox BJ *, EEA Simpson, H Parr, G Rae, A Polito, F Intorre, N Meunier, M
Andriollo-Sanchez, JM O’Connor, C Coudray and JJ Strain. Zinc status and taste
acuity in older Europeans: the ZENITH study. European Journal of Clinical
Nutrition (2005) 59, Suppl 2, S31–S36
Taylor, J R, T B Gardner, A K Waljee, M J Dimagno, and P S Schoenfeld.
"Systematic Review: Efficacy and Safety of Pancreatic Enzyme Supplements for
Exocrine Pancreatic Insufficiency." Alimentary pharmacology & therapeutics 31,
no. 1 (2010): doi:10.1111/j.1365-2036.2009.04157.x.
Qin X. Inactivation of Digestive Proteases: Another Mechanism That Probiotics
May Have Conferred a Protection. The American Journal of Gastroenterology
(2007) 102, 2109; doi:10.1111/j.1572
Qin XF. Inactivation of digestive proteases by biliverdin the possible
evolutionary driving force for bilirubin or deconjugated bilirubin predominance
in animals: Gut 2007 56: 1641-1642
Qin XF. Impaired inactivation of digestive proteases by deconjugated bilirubin:
The possible mechanism for inflammatory bowel disease. Medical Hypotheses
(2002) 59(2), 159–163    

  23