Download Understanding diabetes and its effects

Understanding diabetes
and its effects on the
gastrointestinal tract
By Jack D. Bragg, DO
B
oth type 1 and type 2
diabetes mellitus can
affect a patient’s entire
gastrointestinal tract, from the
esophagus to the anus. The symptoms
that often accompany the GI effects
of diabetes mellitus cause a great deal
of misery for patients, as well as frustration
for the physicians taking care of them. Because
GI symptoms are common in the general population,
physicians may have difficulty determining whether
diabetes is the root problem.
October 2008 DOs Against DIABETES
AOA Health Watch
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In the past, physicians assumed
that hyperglycemia leads to autonomic
neuropathy, which leads to the
GI abnormalities. In addition,
physicians thought that patients must
have diabetes for 10 years or more
before GI symptoms occur. Recent
findings, however, call both of these
premises into question.
The most common GI problems
encountered in clinical practice among
patients with diabetes are constipation,
diarrhea, abdominal pain, nausea and
vomiting. Several other problems may
be seen from time to time. In this
article, I review the current knowledge
regarding how diabetes affects the
GI tract, how GI problems typically
manifest themselves, and what treatment
options are currently available.
by patients with diabetes and the
underlying pathophysiologic
mechanisms of these symptoms.
According to Sellin and Chang,
Because many pathologic conditions associated with
GI complications of diabetes may become irreversible,
efforts should be made early in the disease process to
achieve the most consistent glucose control possible.
studies have had conflicting conclusions
regarding which gastrointestinal
symptoms are most common in patients
with diabetes. Upper gastrointestinal
tract complaints, such as nausea,
vomiting and heartburn, are the most
reported symptoms in many studies.
Some interesting findings and conflicts
regarding GI symptoms can be found.
For example, one study indicates that
heartburn is decreased in patients with
diabetes mellitus.2 Another study notes
Symptoms and complications
Gastrointestinal complications of diabetes that women seem to be more affected
with GI symptoms than are men.3
include gastroparesis, small bowel
Studies also indicate that there are
enteropathy—which can cause diarrhea,
likely to be multiple etiologic factors
constipation, and fecal incontinence—
behind GI symptoms. For example,
and nonalcoholic fatty liver disease.
autonomic neuropathy was identified as
In a review, J.H. Sellin and E. B.
being the cause of many GI symptoms.
Chang1 examined the frequency and
However, such symptoms may precede
type of GI symptoms experienced
10 AOA Health Watch
or at least not correlate with the
presence of autonomic neuropathy.
Thus, contrary to previous beliefs,
the symptoms of diabetes affecting
the GI tract may not correlate at
all with the duration of a patient’s
disease or degree of glycemic control.4
The pathogenesis of diabetic
autonomic neuropathy is related to
hyperglycemia, neurovascular
insufficiency, autoimmune damage,
and neurohormonal growth factor
deficiency.5 In patients with type 1
diabetes, enteric neurotransmission
may be modulated by a functional
immunoglobulin G autoantibody.
Hypoglycemia, as well as hyperglycemia,
can have a reversible effect on the
metabolic and signaling pathways
of enteric neurons, thereby altering
intestinal function. There is also some
evidence for enteric myopathy in
patients with diabetes mellitus.6
Causes of gastrointestinal problems
in patients with diabetes can include
certain metabolic insults that result
in smooth muscle atrophy or in the
transformation of one cell type to
another.7 The pacemaker cells of the
intestinal tract—the interstitial cells
of Cajal (ICCs)—seem to be disrupted
or altered in some way in diabetes.
Other potential causes of intestinal
dysfunction include ischemia, hypoxia,
and mitochondrial dysfunction.8
Cumulatively, these metabolic
and anatomic changes cause
abnormalities in peristalsis, reflexive
relaxation, sphincter tone, vascular
flow and intestinal segmentation.
These abnormalities manifest
themselves clinically as dysphagia,
gastroparesis, constipation, diarrhea,
intestinal pseudo-obstruction
and anal incontinence.
DOs Against DIABETES October 2008
Esophageal disorders
Esophageal complaints among
patients with diabetes include
heartburn, dysphagia and odynophagia
(ie, painful swallowing). As many as
half of patients with diabetes have
esophageal motility abnormalities
or acid reflux problems—though
many of these patients do not report
symptoms.9 Autonomic neuropathy
and motor neuropathy are likely
causes of these complaints. Abnormal
manometric findings in patients with
diabetes include hypotensive lower
esophageal sphincter pressure,
diminished amplitude of peristaltic
waves, prolonged esophageal transit
time, and reduced rate of
smooth muscle contraction.1
As a result of these pathologic
conditions, gastroesophageal reflux
disease (GERD) and dysphagia are
more common in patients with diabetes
than in other individuals. The presence
of odynophagia should alert physicians
to the possibility of Candida infection in
the esophagus. Physiologic disturbances
that increase risk for Candida infection
include decreased candidacidal activity
of neutrophils, reduced esophageal
clearance for, and increased glucose
content of, oral secretions.10
These various esophageal problems
are manageable to some extent. Patients
with GERD may respond to histamine-2
receptor antagonist therapy or to proton
pump inhibitors. Candida infections
can be cleared with an antifungal agent,
such as fluconazole, and with improved
glycemic control.
Dysphagia secondary to neuropathy
may be more difficult than these other
problems to manage, especially if the
neuropathy is advanced. In patients
older than 50 years who have been
diagnosed as having new-onset
progressive dysphagia, mechanical
obstruction needs to be ruled out with
the use of a barium swallow radiology
test (ie, upper gastrointestinal series)
or a gastroscopic inspection.
Treatment for patients
with diabetic gastroparesis
䡲 blood glucose control
䡲 low-fat, low-fiber diet
䡲 prokinetic drugs
(eg, dopamine antagonists)
䡲 antiemetic agents
䡲 endoscopic therapies
䡲 gastric pacemaker
Figure 1
Gastric abnormalities
Gastric abnormalities in patients with
diabetes usually involve either diabetic
gastroparesis or upper GI bleeding.
Diabetic gastroparesis typically occurs
in patients who have had long-standing
type 1 diabetes. Symptoms may include
nausea, vomiting, early satiety, bloating,
epigastric pain and belching. These
symptoms may wax and wane, or they
may be constant. In patients with severe
conditions, weight loss may result.11
Upper GI bleeding is common
in patients with long-term diabetes,
especially in the setting of diabetic
ketoacidosis.
Normal gastric emptying is the result
of a complex interplay among tonic
contractions of the fundus, phasic
contractions of the antrum, and
inhibitory forces of pyloric and duodenal
contractions. Coordination takes place
among smooth muscle, enteric and
autonomic nerves, and the ICCs.12
Physiologic mechanisms involved in
gastric emptying are thought to cause
many GI symptoms in patients with
diabetes. Specifically, these mechanisms
are hyperglycemia leading to delayed
gastric emptying secondary to vagus
autonomic nerve impairment, as well as
damage to enteric nerves and the ICCs.
The results of these gastric
abnormalities are changes in
antroduodenal motility, failure of
accommodation in the proximal
stomach, pylorospasm, and gastric
dysrhythmias. The precise role that
these conditions play in causing the
symptoms of gastroparesis in patients
with diabetes is unclear.13
Diagnosis
Patients’ medical histories will
often reveal the likely causes of
GI abnormalities. The differential
diagnosis should include any disease
that typically has the symptoms of
nausea, vomiting and early satiety.
Patients may also have pain, though
it is usually not a prominent feature.
If pain is prominent, however, peptic
ulcer disease, cancer, gallbladder
disease and pancreatic problems
should be considered.
An upper GI radiographic or
endoscopic examination should be
performed to rule out any structural
cause of the symptoms. Some patients
will retain food in their stomachs
even after an overnight fast. Physical
examination may reveal epigastric
fullness, succussion splash or both.
A definitive diagnosis of GI
abnormalities can often be made
with nuclear scintigraphic evaluation
of solid-phase gastric emptying.
Delayed emptying of a technetiumlabeled solid meal in the absence of
any anatomic abnormality is considered
to be diagnostic of gastroparesis.
Although the patient’s symptoms
may not correlate well with
quantification of gastric emptying,
therapy options can be evaluated
to some extent based on the results
of gastric emptying studies.
The cause of upper GI bleeding
may be difficult to diagnose, even with
the use of endoscopy. Causes include
esophagitis and erosive gastritis.
Bleeding may also be caused by a
Mallory-Weiss tear, which can result
from vomiting and retching.11 At the
initial bleed, the use of endoscopy in the
evaluation of the upper GI tract may be
able to rule out other causes of bleeding.
(continued on the next page)
October 2008 DOs Against DIABETES
AOA Health Watch 11
Treatment
Treatment for patients with
diabetic gastroparesis is multimodal
(see Figure 1). It should begin with
controlling blood glucose levels.
Dietary changes to achieve control
should include adopting a low-fat,
low-fiber soft diet, with frequent
small meals. Fat takes longer to leave
the stomach in patients with diabetic
gastroparesis, aggravating the
symptoms of this condition. Under
usual circumstances, liquid emptying
is not impaired in diabetic gastroparesis.
Thus, blended or liquid meals or
nutritional supplements are generally
well tolerated by patients.1
Beyond dietary changes, the
management of diabetic gastroparesis
consists of prokinetic drugs (eg,
dopamine antagonists), antiemetic
agents, endoscopic treatments
and gastric pacing.14
The dopaminie antagonists
metoclopramide and domperidone
12 AOA Health Watch
increase antral contractions and
decrease receptive relaxation of the
proximal stomach. Unfortunately,
metoclopramide crosses the bloodbrain barrier, and it has the potential
for producing irreversible adverse
neurologic effects, such as tardive
dyskinesia.15 Some clinicians advocate
obtaining informed consent from
patients before prescribing metoclopramide, which can be administered
as a tablet or liquid or parenterally.
Other adverse effects that can result
from using metoclopramide include
drowsiness, restlessness, fatigue and
irritability. Rarely, acute dystonic
reactions or Parkinsonian-like symptoms
may occur with metoclopramide.15
Domperidone does not cross the
blood-brain barrier, so it does not cause
adverse neurologic effects. At present,
domperidone is approved in several
countries outside the United States to
treat certain gastric disorders.
Another prokinetic drug that
is available is erythromycin, which
is administered either orally or
parenterally. Erythromycin acts as a
motilin receptor agonist that accelerates
gastric emptying. Several studies have
suggested that erythromycin can relieve
symptoms for patients with diabetic
gastroparesis,16-18 but the long-term
efficacy of this drug is unproved. The
adverse effects of nausea and cramping
may limit erythromycin’s usefulness.
Cisapride has been shown to be as
effective as erythromycin in patients
with gastroparesis, but its use has been
severely restricted by the FDA because
of proarrhythmic effects.19
Antiemetic agents, such as
promethazine and prochlorperazine,
help relieve nausea and vomiting in
patients with diabetic gastroparesis
and can be administered either
in oral form or as a suppository.
However, these drugs do not alter
gastric emptying or improve stomach
function, and their long-term use
is limited because of adverse effects.
When dietary and pharmacologic
measures do not provide relief, other
medicines that may help manage nausea
and vomiting in these patients include
ondansetron, dronabinol and the
scopolamine transdermal patch.
Several endoscopic treatments are
available for patients with diabetic
gastroparesis. Research studies on
intrapyloric injection of botulinum
toxin type A (BTX-A, or Botox) suggest
that about half of those patients treated
with BTX-A responded with improved
gastric emptying or symptom relief.1
As of mid-2008, however, no placebocontrolled, prospective study has clearly
demonstrated the efficacy of BTX-A
in managing diabetic gastroparesis.
Endoscopic or surgical treatments
that have been tried for patients
with diabetic gastroparesis include
venting gastrostomy tubes and jejunal
feeding tubes.1 Venting tubes help
relieve symptoms, and feeding tubes
allow for nutrition to be uninterrupted,
yet little conclusive literature on
these modalities exists.
One gastric pacemaker—EnterraTM
Therapy—has been approved by
the FDA for treating patients with
DOs Against DIABETES October 2008
gastroparesis.11 When using this device,
electrodes are placed surgically on the
patient’s stomach and attached to a
neurostimulator inserted subcutaneously
in the abdominal wall. The stimulator
device delivers high-frequency, lowenergy gastric pacing, resulting in
notable reduction in vomiting after
12 months. Infection is the most serious
complication reported for this device.
After five years of evaluation, the
stimulator has been shown to improve
glycemic control and nutrition
parameters, to enhance quality of
life and to decrease healthcare costs.11
Managing upper GI bleeding in
patients with diabetes may involve
both endoscopic and pharmacologic
treatments. Should active bleeding
be visualized during an upper
endoscopic examination, endoscopic
therapy would be appropriate. Useful
treatment modalities include endoscopic
clips, injection of epinephrine around
the bleeding vessel, and treatment with
a thermal device, such as a heater probe.
After an upper endoscopic
examination is performed, drug
therapy with proton pump inhibitors
or histamine-2 receptor antagonists
is standard care for patients with
upper GI bleeding and diabetes.
These medicines can be administered
either orally or parenterally.
Medications that
can cause diarrhea
䡲 metformin
䡲 acarbose
䡲 miglitol
䡲 magnesium-containing
antacids
䡲 antibiotics
䡲 proton pump inhibitors
䡲 quinidine
䡲 beta-adrenergic receptor
blocking drugs
䡲 nonsteroidal
anti-inflammatory drugs
Figure 2
function in the gut and by reducing
input from alpha-2 adrenergic receptors.
These changes lead to decreased fluid
and electrolyte absorption.
Gastrointestinal dysmotility, which
has been documented in patients with
diabetes, can cause diarrhea if it slows
small bowel transit time, leading to
bacterial overgrowth. However, there
is some evidence that bowel transit
times may be faster in some individuals
with diabetes.20 It is important that
physicians evaluate patients’ bowel
transit times. Antibiotics are more likely
Diabetic diarrhea
to benefit patients with slower transit
Although constipation is more common
times because bacterial overgrowth
than diarrhea among patients with
would be most likely in these patients.
diabetes, diarrhea is the more troubling In contrast, antidiarrheal medications,
complication. According to one estimate, such as loperamide and diphenoxylate,
3.7% of individuals with diabetes suffer
would be appropriate for patients with
from diarrhea.11 Diarrhea is most
fast transit times.
common in patients with type 1 diabetes
Another cause of diarrhea to rule
mellitus and in men, and it may
out in patients with diabetes is celiac
alternate with normal bowel function or disease, which occurs more commonly
constipation. It is seldom accompanied
in patients with diabetes.21 Serologic
by bleeding or pain.
testing and small bowel biopsy at the
Several factors are likely to contribute time of an esophagogastroduodenoscopy
to diabetic diarrhea. Autonomic
can be used to diagnose celiac disease.
neuropathy certainly plays a role in
Pancreatic disease, fecal incontinthis condition by altering sympathetic
ence, and various medications should
October 2008 DOs Against DIABETES
also be considered. Fecal incontinence
can be diagnosed by medical
history, physical examination and—
if available—manometric testing.
A list of medications that can cause
diarrhea can be found in Figure 2.
Diarrhea caused by the diabetes
medication metformin, a biguanide
derivative with structural similarity
to 5-HT3 receptor agonists, can
be improved by switching to the
extended-release form of this drug.
Other diabetes medications that
may be responsible for diarrhea
include acarbose and miglitol. Certain
nondiabetes medications, including
antibiotics and magnesium-containing
antacids, may also cause diarrhea.
While the management of diabetic
diarrhea may be unsatisfactory, it can
be helpful in some cases. Improving
glycemic control and using dietary
fiber products may be of some benefit
to patients with diabetic diarrhea.
Some patients will respond to
clonidine, an alpha-2 adrenergic agonist,
which may help reverse damage to
alpha-2 adrenergic receptor function
and improve fluid and electrolyte
absorption. However, it is important
to monitor a patient’s blood pressure
during the use of clonidine.
Narcotics, such as codeine sulfate
or tincture of opium, should be used
only with caution.
Unexplained abdominal pain
Patients with neuropathy may be
troubled by chronic abdominal pain
that defies etiologic explanation. This
pain is usually in the upper abdomen
and generally occurs in a girdle
distribution. Endoscopy, laboratory
tests, and imaging techniques seldom
reveal disease in these patients.
Research suggests that radiculopathy
(ie, diabetic plexus neuropathy) of
thoracic nerve roots may be the cause
of this chronic abdominal pain.22
And, this pain may respond to
amitriptyline or phenytoin.22
AOA Health Watch 13
Colonic disease
Constipation, typically requiring laxative
use, is the most common gastrointestinal
complaint reported by patients with
diabetes. Smooth muscle myopathy and
loss of ICC function are the most likely
causes of constipation among these
patients. Autonomic neuropathy and
neuroendocrine imbalances could also
contribute to the problem.23 In severe
cases, megacolon or, rarely, chronic
intestinal pseudoobstruction can result.
Treatment of patients for diabetic
constipation is not unlike that for
Gastric abnormalities
in patients with diabetes
mellitus usually involve
either diabetic gastroparesis
or upper GI bleeding.
idiopathic constipation—except that
improved glycemic control is part of
the regimen. Dietary fiber, increased
fluid intake, stool softeners, and
laxatives are the mainstays of treatment.
Lubiprostone, a selective type 2
chloride channel agonist, might be
of benefit to patients with diabetic
constipation because it has been
shown to help patients with
idiopathic constipation. Avoiding
certain medications, such as
aluminum-containing antacids,
narcotics, and tricyclic antidepressants,
may also be beneficial.
Fecal incontinence is sometimes
the most troublesome problem of
all for patients with diabetes. Thought
to be a complication of autonomic
neuropathy, fecal incontinence may
coincide with the onset of diabetic
diarrhea. Internal sphincter resting
tone and relaxation are adversely
affected in such cases.
Treatment options consist of
increased dietary fiber; antidiarrheal
medications, such as loperamide; and
biofeedback. Patients with severe cases
of fecal incontinence may benefit from
surgery or sacral nerve stimulation.11
Final notes
This article reviews some of the most
recent findings regarding the
pathogenesis and management of
GI complications of diabetes. Clearly,
improving control of blood glucose
levels with a balanced diet, adequate
exercise and appropriate medications
is the cornerstone of treatment. Because
many pathologic conditions associated
with GI complications of diabetes may
become irreversible, effort should be
taken early in the disease process to
achieve the most consistent glucose
control possible.
Through their thorough care of
the entire person and not merely the
management of symptoms, osteopathic
primary care physicians are ideally
positioned to help their patients
minimize the destructive effects
of diabetes. HW
References
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Jack D. Bragg, DO, is an associate
professor of internal medicine at the
University of Missouri School of
Medicine in Columbia. He is AOA
board certified in Internal Medicine
and Gastroenterology and is a fellow
of the American College of Osteopathic
Internists. Dr Bragg can be reached
at braggj@ health.missouri.edu.
AOA Health Watch 15