Functional dyspepsia and the role of digestive enzymes supplement in its therapy

Abstract

Functional dyspepsia represents a heterogeneous group of gastrointestinal disorders marked by the presence of upper abdominal pain or discomfort. Reported prevalence of dyspepsia in the world varies from 11-30%. Basic Pathophysiology of functional dyspeptic symptoms is unclear and is considered to occur due to a combination of visceral hypersensitivity, gastric motor dysfunction and psychological factors. Strategies such as acid suppression, prokinetics and H. pylori eradication have been used with some success. Transient deficiency in digestive enzymes is one of the contributors for functional dyspepsia. The primary digestive enzymes are proteases, amylases and lipases. A commonly used therapeutic approach in its treatment is the use of oral enzymes supplementation therapy. Commercially, digestive enzymes are obtained from plant, animal and microbial sources. This review summarizes the pathophysiology of functional dyspepsia, different pharmacological approaches and focuses on the safety and efficacy of digestive enzymes in managing dyspepsia. Keywords including functional dyspepsia, digestive enzymes, lipase, diastase, papain, pepsin, trypsin and chymotrypsin were searched in databases such as Google, Google Scholar, PubMed, pharmacopoeia and textbooks.

Full text

www.ijbcp.com International Journal of Basic & Clinical Pharmacology | May 2017 | Vol 6 | Issue 5 Page 1035
IJBCP International Journal of Basic & Clinical Pharmacology
Print ISSN: 2319-2003 | Online ISSN: 2279-0780
Review Article
Functional dyspepsia and the role of digestive enzymes supplement
in its therapy
Onkar C. Swami*, Neel J. Shah
INTRODUCTION
Dyspepsia can be defined as ‘a symptom or set of
symptoms that most physicians consider originating from
the gastroduodenal area’.1 The symptom complex may be
caused by peptic ulcer disease, gastro-esophageal reflux,
or gastric cancer but is most often due to non-ulcer
dyspepsia. Numerous studies have reported that majority
of dyspepsia cases have minor abnormalities of uncertain
significance or an entirely normal endoscopy, and are
labeled as having functional dyspepsia or non-ulcer
dyspepsia.2
Functional dyspepsia is the commonest cause of
dyspeptic symptoms across the globe, accounting for
more than 70% of the cases of dyspepsia.2 Functional
dyspepsia can be defined as ‘Persistent or recurrent pain
or discomfort centered in the upper abdomen; evidence of
organic disease likely to explain the symptoms is absent,
including at upper endoscopy’.3 For categorizing as
functional, further, the symptoms must have begun 6
months prior to diagnosis and be active for 3 months.4
People with functional dyspepsia have a significantly
reduced quality of life when compared to general
population. Depending on definitions used, the global
prevalence of functional dyspepsia varies from 11-30%,
and Indian prevalence is 30.4%.5
ROME-III criteria have classified functional
gastrointestinal (GI) disorders for adults according to site:
esophageal, gastroduodenal, bowel, abdominal pain, gall
bladder and anorectal disorders. For pediatrics, functional
GI disorders are classified according to age. Functional
gastroduodenal disorders are further classified as
functional dyspepsia, belching disorders, nausea and
vomiting disorders and rumination syndrome.4 Functional
dyspepsia is of two types: postprandial distress and
epigastric pain syndromes. Postprandial distress
represents a dysmotility-like syndrome where there is
early satiety and epigastric pain type represents a
ABSTRACT
Functional dyspepsia represents a heterogeneous group of gastrointestinal
disorders marked by the presence of upper abdominal pain or discomfort.
Reported prevalence of dyspepsia in the world varies from 11-30%. Basic
Pathophysiology of functional dyspeptic symptoms is unclear and is considered
to occur due to a combination of visceral hypersensitivity, gastric motor
dysfunction and psychological factors. Strategies such as acid suppression,
prokinetics and H. pylori eradication have been used with some success.
Transient deficiency in digestive enzymes is one of the contributors for
functional dyspepsia. The primary digestive enzymes are proteases, amylases
and lipases. A commonly used therapeutic approach in its treatment is the use of
oral enzymes supplementation therapy. Commercially, digestive enzymes are
obtained from plant, animal and microbial sources. This review summarizes the
pathophysiology of functional dyspepsia, different pharmacological approaches
and focuses on the safety and efficacy of digestive enzymes in managing
dyspepsia. Keywords including functional dyspepsia, digestive enzymes, lipase,
diastase, papain, pepsin, trypsin and chymotrypsin were searched in databases
such as Google, Google Scholar, PubMed, pharmacopoeia and textbooks.
Keywords: Amylase, Functional dyspepsia, Lipase, Oral digestive enzymes
supplement, Pepsin
DOI: http://dx.doi.org/10.18203/2319-2003.ijbcp20171653
Medical Services, Unichem
Laboratories Limited, Mumbai,
Maharashtra, India
Received: 24 February 2017
Accepted: 28 March 2017
*Correspondence to:
Dr. Onkar C. Swami,
Email:
onkar.swami@unichemlabs.com
Copyright: © the author(s),
publisher and licensee Medip
Academy. This is an open-
access article distributed under
the terms of the Creative
Commons Attribution Non-
Commercial License, which
permits unrestricted non-
commercial use, distribution,
and reproduction in any
medium, provided the original
work is properly cited.

Swami OC et al. Int J Basic Clin Pharmacol. 2017 May;6(5):1035-1041
International Journal of Basic & Clinical Pharmacology | May 2017 | Vol 6 | Issue 5 Page 1036
syndrome where there is burning, ulcer like pain.2
However, there is considerable overlap with almost 35%
patients of functional dyspepsia experiencing both
symptoms.6 A study associated some common risk factors
with functional dyspepsia and found the following
association: female gender (Odds: 2.01), consumption of
betel nuts (Odds: 4.55), non-steroidal anti-inflammatory
drugs (Odds: 6.60), anxiety (Odds: 3.41), concomitant
Irritable Bowel Syndrome (IBS) (Odds: 6.89), H. pylori
(Odds: 1.86), unmarried status (Odds: 4.22), sleep
disturbance (Odds: 2.56) and depression (Odds: 2.34).6
METHODS
The materials for this review were obtained from an
extensive search using electronic databases which
included PubMed, Google Scholar and Google. Articles
were searched till November 2016. Literature on
functional dyspepsia; its classification, management and
digestive enzymes was retrieved. The key words used for
the literature search included functional dyspepsia,
digestive enzymes, lipase, diastase, papain, pepsin,
trypsin, and chymotrypsin. The search included research
articles, reviews, meta-analyses and textbooks including
pharmacopoeias. Articles found in foreign languages
were translated with help of certified translators. Since
this article focuses on a broad area, a systematic review
could not be performed.
Pathophysiology of functional dyspepsia
The proposed pathophysiologic mechanisms associated
with functional dyspepsia include genetic susceptibility,
delayed as well as accelerated gastric emptying, visceral
hypersensitivity to acid or mechanical distention,
impaired gastric accommodation, abnormal fundic phasic
contractions, abnormal antroduodenal motility, acute and
chronic infections, and psychosocial co-morbidity.2
Transient deficiency in digestive enzyme is also a
contributor for functional dyspepsia. Yet the exact
pathophysiological mechanisms that cause symptoms in
an individual patient remain difficult to delineate.7
Epidemiologic studies reported that, there is an
association between functional dyspepsia and
psychological disorders. Symptoms of neurosis, anxiety,
hypochondriasis, and depression are more common in
patients being evaluated for unexplained gastrointestinal
complaints than in healthy controls.4
Treatment of functional dyspepsia
Placebo
The rate of response with placebo was found to be as
high as 50% in a study on functional GI disorders in
children and adolescents.8 This highlights the
involvement of the central nervous system in functional
disorders and the role of reassurance which many
physicians practice in these conditions.
Acid-suppression therapy
Employing acid suppressing agents is logical as there is
evidence that there is impaired duodenal clearance and
increased duodenal sensitivity to acid (exogenously
administered) in dyspeptic patients.9 A comparison of
antacids with digestive enzymes has been summarized in
Table 1.
Table 1: Advantages of digestive enzymes preparation over antacids.
Antacid
Digestive enzymes preparation
Does not aid digestion but reduces it
Increases digestive power
Unnatural
Matches the natural metabolism
Provides temporary relief
Lasting solution for GI problems
Some disturb the synthesis of gastric acid
Does not interfere with the internal metabolism
Blocks the absorption of nutrients and drugs
Helps in complete absorption of nutrients
Decreased the anti-microbial activity of stomach
Promotes the anti-microbial activity of stomach
Calcium base leads to several disorders like renal failure,
hypercalcemia and alkalosis
Calcium not present
Side-effects include constipation, dizziness, loss of appetite,
unpleasant taste, nausea, increased thirst
Well tolerated with minimum side effects
Prokinetic agents
These can accelerate gastric emptying and enhance
gastric accommodation. Examples include cisapride,
mosapride and metoclopramide. Older agents like
cisapride are no longer preferred due to their QT
prolongation adverse effect. A new agent, acotiamide has
been tested in functional dyspepsia and was found to
benefit both the above-mentioned parameters based on
real time ultrasonography findings.10 Postprandial
fullness, upper abdominal bloating and early satiation
were also reduced by acotiamide.11
H. pylori eradication
A meta-analysis found that H. pylori eradication led to
symptom relief and reduced the development of peptic
ulcers. On the other hand, it did not improve the quality

Swami OC et al. Int J Basic Clin Pharmacol. 2017 May;6(5):1035-1041
International Journal of Basic & Clinical Pharmacology | May 2017 | Vol 6 | Issue 5 Page 1037
of life of patients with functional dyspepsia and led to
adverse events.12
Other agents including antidepressants and psychological
therapy have also been tried. A comparison of some of
the agents for the treatment of functional dyspepsia has
been summarized in Table 2.
Table 2: Comparison of different therapies for the
treatment of functional dyspepsia.
Therapy
Relative risk reduction compared to
placebo
Prokinetics
33% (95% CI: 18% to 45%)
H2 blockers
23% (95% CI: 8% to 35%)
Proton pump
inhibitors
13% (95% CI: 4% to 20%)
Bismuth
salts
40% (Marginally: 95% CI: -3 to 65%)
Antacids
No statistical difference
Sucralfate
CI-Confidence Intervals, Data adapted from Moayyedi P et al,
Cochrane Database Syst Rev. 2006 Oct 18;(4):CD001960.
Due to multifactorial pathogenesis of functional
dyspepsia no single drug is suitable for all patients. As a
consequence, different categories of drugs described
above have all been tried in different groups of patients
with no single agent emerging as the drug of choice.
Hence, there exists an unmet need in the treatment of
dyspepsia.
Oral digestive enzymes for treating dyspepsia
Digestive enzymes inadequacy or deficiency
Digestive enzymes are often prescribed to patients with
various dyspeptic complaints. Reports suggested a
beneficial role of enzyme preparations in dyspepsia.13 In
addition to consuming adequate levels of raw foods, a
common approach to supporting the patient with
digestive enzyme inadequacy is oral enzyme replacement.
A study pointed the role of pancreatic enzyme
supplementation in functional dyspepsia where the
therapy significantly reduced the symptoms of flatulence,
bloating, belching, fullness and post-prandial distress.14
The rational for prescription of digestive enzymes is that
carbohydrates, proteins and fats are initially converted to
smaller units by various digestive enzymes and are then
assimilated.
By aiding the digestive process, the dyspeptic symptoms
would be ameliorated. Hence, to assist the adequate
digestion of every nutrient, a combination of different
enzymes must be supplemented.
Table 3: Causes of enzyme inadequacy or deficiency.
Factors
Impaired
secretion
Dysfunction of digestive organs, mucosal disease, gastrointestinal surgery and nutritional deficiency
Habits
Poor eating habits (inadequate chewing of food) “eating on the run,” or eating late in the day.
Dietary
choices
Certain dietary choices, such as excessive consumption of alcohol, refined carbohydrates and fat, as well as
a high meat and cooked food diets with few raw, enzyme-rich foods.
Age
Aging alters digestive enzyme secretion with linear decrease reported after 4th decade of life.
Several factors cause enzyme inadequacy and deficiency,
some of which are enumerated in Table 3.15 Aging leads
to decrease in both basal and stimulated pepsin output. In
elderly, pepsin output is reduced by approximately
40%.16 In a study on pancreatic secretion in the elderly, it
was found that the concentrations of lipase,
phospholipase and chymotrypsin decreased linearly from
the 3rd decade onwards.15 It is fairly common for elderly
individuals to experience both a decrease in hydrochloric
acid production as well as a general decline in digestive
enzyme secretion.16 With a growing elderly population,
unhealthy diets and stressful life styles, it is likely that
healthcare professionals will find more and more patients
developing digestive problems.
It is estimated that 58% of the population suffers from
some type of digestive disorder. A lack of optimal
digestive function associated with enzyme inadequacy
may lead to malabsorption and a host of related
conditions.
Role of primary digestive enzymes
Amylase is the most important enzyme for digestion of
carbohydrates. Amylase is a glycoside hydrolase and acts
on α-1, 4-glycosidic bonds of polysaccharides (starch and
glycogen) and degrades them into dextrins, disaccharides
(maltose) and monosaccharides (glucose). Amylases are
classified into endoamylase and exoamylase according to
the manner in which the glycosidic bond is attacked.
Endoamylases attack the α-1, 4-glycosidic linkage at
random while exoamylase hits from the non-reducing
outer polysaccharide chain ends.17
α-amylase is a kind of endoamylase that rapidly
hydrolyzes α-1,4 glycosidic linkage present in gelatinized
starch, amylase and pullulan to produce soluble dextrin,

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International Journal of Basic & Clinical Pharmacology | May 2017 | Vol 6 | Issue 5 Page 1038
some maltose, and glucose.13 It is a type of endoamylase
present in human saliva and pancreatic secretion and can
be exogenously isolated from Bacillus subtilis,
Aspergillus oryzae, and barley malt. β-amylase and
glucoamylase are of vegetable or microbial origin. β-
amylase yields β-limit dextrins and maltose, and
glucoamylase yield glucose. Amylase from a variety of
sources is being used as an ingredient of preparations of
mixed digestive enzymes.17
Fungal Diastase (diastase is another name for amylase) is
derived from a fungus, Aspergillus oryzae and contains
high activity of enzyme α-amylase. In saccharification,
fungal source α-amylase has higher efficiency compared
to bacterial enzyme.18 Fungal diastase digests granular
starch in coordination with mucosal α-glucosidases.19 Its
starch digesting capacity is convincingly good over wide
range of pH with maximum activity at pH 5. Further,
diastase can get reactivated in intestine after it leaves
acidic environment of stomach. The reaction velocity for
dextrinising starch molecule by fungal diastase is very
rapid. It is common constituent of mixed digestive
enzymes for treatment of indigestion.13
Pepsin is one of the three main proteolytic enzymes in the
digestive system, the other two being chymotrypsin and
trypsin. Pepsinogen is a pro-form zymogen of pepsin. It
is released in the stomach by chief cells. This zymogen is
activated by hydrochloric acid released from parietal cells
in the stomach linings. Gastrin is the hormone that
triggers the release of pepsinogen and also controls the
secretion of hydrochloric acid from the stomach lining
once food is ingested.20
Pepsin’s function is to break down proteins into smaller
pieces called polypeptides. Pepsin breaks proteins only at
certain points so that the protein is not digested
completely to the amino acid level. For this effect, the
food needs to pass to the intestines where other enzymes
complete the digestion process. Pepsin functions in acidic
environment with pH of 1.5 to 2 and gets denatured if the
pH is more than 5.0. Pepsin needs optimum temperature
of range 37°C to 42°C.20
Commercially, pepsin is prepared from gastric mucosa of
pigs, cattle or sheep. It contains proteinases which are
active at a pH of 1-5. Pepsin is most proficient in
cleaving bonds involving the aromatic amino acids,
phenylalanine, tryptophan, and tyrosine. Pepsin has been
regularly used as an adjunct in the treatment of gastric
hypochlorhydria, in dyspepsia and to treat deficiencies of
digestive enzyme secretion.20
Trypsin is a proteolytic enzyme obtained by the
activation of trypsinogen extracted from mammalian
pancreas. Crystallized trypsin is obtained from extract of
the pancreas of healthy bovine or porcine animals, or
both. It is used in mixture with other enzyme in treatment
of gastrointestinal disorder. Furthermore, it is used
locally in debridement of wounds and orally with
chymotrypsin for treatment of inflammation.21
Chymotrypsin is another proteolytic enzyme produced by
pancreas. It is selective for peptide bonds with aromatic
or large hydrophobic side chains on the carboxyl side of
this bond. In addition, chymotrypsin catalyzes the
hydrolysis of ester bonds. Along with other proteolytic
enzyme it helps in digestion of proteins. It is used in
management of inflammation and as a multienzyme
supplement in digestive disorder.22
Papain is a non-specific proteolytic enzyme obtained
from latex of the fruit of the papaya tree (Carica papaya).
It requires the presence of sulfhydryl groups (eg,
cysteine) to stimulate activity.23 Hence, is classified under
cysteine protease. It has been used in wound
debridement.23 An interesting use is in the emergency
department for resolving esophageal meat impaction.24
Lipase (triacylglycerol acylhydrolases) catalyzes the
partial or complete hydrolysis of triacylglycerols.
Lingual, pancreatic and enteric lipases are involved in
complete digestion of lipids. They hydrolyze ester bond
of triglycerides into free fatty acid and glycerol. They are
commonly used in enzyme supplementation for treatment
of digestive disorder of lipids.25
Lipases can be produced by all biological systems, viz.
animals, plants and microorganisms. However, microbial
lipases are receiving more attention because of a variety
of catalytic activities, high yields, ease of genetic
manipulation, regular supply due to absence of seasonal
fluctuations, rapid growth of microorganisms on
inexpensive media, greater stability than the
corresponding plant and animal enzymes and since their
production is more convenient and safer.26 Lipase
produced by C. cylindracea has been one of the most
widely used enzymes due to its high activity in hydrolytic
reactions.27 A study on 16 healthy volunteers reported
improvement of post-prandial fullness after ingestion of
a fatty meal.28
Other digestive enzymes which aid in digestion of
macromolecules are lactase, alpha galactosidase,
cellulase, beta glucanase, invertase and peptidase.
Clinical evidence of efficacy and safety of oral enzymes
supplement
Banka et al., evaluated the efficacy and safety of fungal
diastase and papain in patients (n = 100) of non-ulcer
dyspepsia. Efficacy and tolerability were assessed at
baseline, at day 7 and at day 14 of treatment. Significant
improvement in frequency and severity of all symptoms
of indigestion (fullness, belching, bloating, flatulence and
postprandial distress) was noted at day 14 of treatment
compared to baseline (Table 4). Total 67% and 29% of
physicians rated excellent and good efficacy,
respectively, in resolving dyspeptic symptoms. Similarly,
65% and 27% of patients rated excellent and good
tolerability, respectively. The combination was well

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International Journal of Basic & Clinical Pharmacology | May 2017 | Vol 6 | Issue 5 Page 1039
tolerated with minor adverse effects (nausea and skin
problems).13
Table 4: Mean change in severity of indigestion
symptoms score.
Symptom
Baseline
Day 7
Day 14
Fullness
0.60
0.19*
0.06*
Belching
1.20
0.67*
0.40*
Bloating
1.20
0.30*
0.08*
Flatulence
1.10
0.40*
0.04*
Postprandial distress
0.30
0.04*
0.04
(*P<0.05: Significant; Severity Score: 0= Mild; 1= Moderate;
2= Severe). Data adopted from Banka et al
A post-marketing surveillance study was conducted to
evaluate the efficacy and tolerability of a multienzyme
preparation containing amylase, protease, lipase, lactase
and alpha-galactosidase.14 The FDC was given for 14
day. Treatment was associated with a significant
reduction in frequency and severity of every abdominal
symptom (flatulence, bloating, belching, dyspepsia,
feeling of fullness, abdominal discomfort, heart burn and
anorexia) (p <0.0001). In the overall assessment by
physicians 55% rated the preparation as excellent and
41% as good. Assessment by patients in terms of
tolerability and effectiveness was also carried out with
51% rated the preparation as excellent and 44% rated it as
good.
Deyneko NF et al., assessed the efficacy and safety for
the Fixed Dose Combination (FDC) of Fungal diastase,
papain, nicotinamide and simethicone in 68 patients of
intestinal indigestion. Among them 23 patients had
chronic pancreatitis (leading to insufficient function), 30
had chronic non-ulcer colitis, 10 had initial stages of
hepatic cirrhosis, and 5 had cholelithiasis. Patients
received 2 pills of study drug twice a day for first 5 days
followed by 1 pill thrice a day for 10-12 days. The FDC
was well tolerated and no side effect was reported. Post
treatment flatulence and pain was completely eliminated
in patients with chronic pancreatitis and colitis.
Additionally, defecation was normalized and
borborygmus was eliminated.29
Meteorism is a symptom that refers to a swollen
abdomen, generated by the increase in the amount of
intestinal gas, exerting more pressure than usual inside
the digestive system, causing various discomforts,
especially more or less intense pain and flatulence to
eliminate the gas. Beryozov VM et al., evaluated efficacy
and safety of FDC of fungal diastase, papain, activated
carbon, simethicone and nicotinamide in treatment of
patients with meteorism (n=118) in comparison with
carboenterosorbent. Among them 31 patients had hepatic
cirrhosis, 36 patients had chronic pancreatitis, 35 patients
had IBS and 16 patients had non-specific ulcerative
colitis. The FDC group (n=57) received one pill with
every meal and carboenterosorbent group received 1.5
gm/day before every meal. After 10 days of treatment,
there was a significant increase in ultrasound availability
ratio (an ultrasound method of evaluating meteorism
activity intensity based on visualization of internal
organs) and decrease in pain index (P <0.05), with the
FDC of fungal diastase, papain, activated carbon,
simethicone and nicotinamide compared to
carboenterosorbent group.30
Ran et al. assessed patients (n=151, 18 to 75 years)
diagnosed with chronic digestive diseases presenting with
two or more dyspepsia symptoms such as epigastric pain,
abdominal distension, epigastric burn, belching, diarrhea
and constipation. The efficacy of an enzyme preparation
containing 24-mg enzyme extract of Aspergillus oryzae
(cellulase, protease and amylase) and 220 mg pancreatin
(lipase, proteinase and amylase) given post-meal (2
tablets), thrice a day was assessed in these patients.
Patients recruited included functional dyspepsia, GERD,
a peptic ulcer (without complications such as bleeding,
perforation, stenosis and malignancy), chronic gastritis,
partial gastrectomy, small or large intestinal resection,
diverticulosis, liver cirrhosis (without serious
complications), chronic biliary disease including
cholecystitis, cholelithiasis, polyps of the gallbladder,
cholecystectomy, chronic pancreatic disease including
chronic pancreatitis, chronic pancreatic insufficiency,
diabetes mellitus with dyspepsia symptoms and geriatric
reduction of digestive function. Compared with placebo,
2 weeks of enzymatic treatment decreased the severity
index of dyspepsia symptoms significantly. The efficacy
rates of enzyme preparation and the placebo on dyspepsia
were 90% and 22%, respectively (P <0.01).31
SUMMARY
Functional dyspepsia is a commonly encountered
complaint arising due to a variety of causes, not clearly
understood. Drugs targeting different pathologies
including acid suppression, H. Pylori eradication,
prokinetics, anti-flatulents and anti-depressants have been
tried. Digestive enzyme combinations have been in use
since a long time and have a modest response in
ameliorating various symptoms of dyspepsia due to both
functional and organic causes. Amylase, pepsin and
lipase are the main enzymes involved in digestion of
carbohydrates, proteins and fats, respectively. They are
widely available in combination with other digestive
enzymes across the world and are safe and devoid of
serious adverse effects.
Funding: No funding sources
Conflict of interest: None declared
Ethical approval: Not required
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Cite this article as: Swami OC, Shah NJ. Functional
dyspepsia and the role of digestive enzymes
supplement in its therapy. Int J Basic Clin Pharmacol
2017;6:1035-41.