Transcript Ambulatory Care Lecture: Inflammatory Bowel Disease

Medical management of
ulcerative colitis
Y.Bafandeh;MD.
Professor of Gastroenterology and
Hepatology
Residents-1391/10/16
What is IBD?
• Chronic Inflammation of the bowel
• Idiopathic
• Relapsing course
IBD Spectrum
Ulcerative colitis
Crohn’s Disease
Indeterminant colitis
Epidemiology
Incidence of ulcerative colitis
Representation of the relatively constant reported rates of ulcerative colitis
The incidence of Crohn's disease rose progressively in
various parts of the world from 1955 to 1985.
IBD Facts
• Approx 1,000,000 Americans have IBD
• men and women affected equally
• first peak occurs between the ages of 15-30
a later peak occurs in the 7th decade
Normal Intestine Vs. IBD
Environmental
triggers (infection,
bacterial products)
Failure to downregulate
Chronic uncontrolled
inflammation = IBD
Moderately
inflamed
Normal gut
controlled inflammation
Down-regulate
Normal gut
controlled inflammation
Diet
The data suggest that a "Western" style diet (processed, fried and
sugary foods) is associated with an increased risk of developing CD,
and maybe UC.
Food antigens are thought to be a factor in the pathogenesis of IBD.
This is the rationale by which patients are given nothing by mouth as a
component of their treatment for a flare of IBD.
It remains to be seen if dietary factors are a cause of an immunologic
response resulting in the development of IBD. However, a number of
studies have implicated cow's milk, refined sugar, decreased vegetable
intake, and high fat intake as dietary risk factors for the development
IBD.
Oral contraceptives
Some case-control studies have not found an association between the
use of oral contraceptives and the development of either ulcerative
colitis or Crohn's disease .Furthermore, oral contraceptives do not
appear to influence the course of patients with established Crohn's
disease .
If oral contraception predisposes to the development of IBD, it may
be doing so through thrombotic effects on the microvasculature.
Given the uncertainty, it is reasonable to continue oral contraception
in patients with IBD who are doing well. However, in those who
remain symptomatic despite conventional drug therapy, cessation of
oral contraception should be considered.
NSAIDs
A number of reports suggest that NSAIDs increase the risk for the
development of IBD and may exacerbate underlying IBD ,although
some patients with IBD appear to be able to tolerate them, particularly
when given in low doses .
Experience with the COX-2 selective inhibitors in patients with IBD
is limited. In theory, because COX-2 activity promotes epithelial
proliferation and wound healing, COX-2 inhibition may have a
deleterious effect in patients with IBD .However, the available data
suggest that most patients can tolerate at least short-term treatment
without exacerbation of disease.
Psychosocial factors
Analyses conclude that there is no consistent type of
psychopathology among patients with either Crohn's disease or
ulcerative colitis .
Stress does not appear to be related to the onset of IBD, but even if
not causally related, it may have a role in the exacerbation of
symptoms ,possibly via activation of the enteric nervous system and
the elaboration of proinflammatory cytokines.
Proportion of Patients with
Family History of IBD by Age of
Diagnosis
% Patients with Positive
Family History of IBD
30%
25%
*
20%
*
15%
10%
<20
20-39
>40
5%
0%
Age at Diagnosis
*p<0.005
Polito JM et al. Gastro.1996;111:580
Diagnosis
Diagnosis
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Clinical history
Physical examination
Laboratory tests
Endoscopic findings
Radiographic findings
Histology
Differential Diagnosis
•
•
•
•
•
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•
•
Lymphoma
Infectious etiologies
Appendicitis
Diverticulitis
Carcinoma
Celiac Disease
Ischemic colitis
Irritable Bowel Syndrome
Antibody tests
Antineutrophil cytoplasmic antibodies (pANCA) and antiSaccharomyces cerevisiae antibodies (ASCA) – pANCA and ASCA
have been proposed as a means for diagnosing IBD and
distinguishing CD from ulcerative colitis.
One study included 582 adult patients with established diagnoses
(407 with CD, 147 with ulcerative colitis, and 28 with indeterminate
colitis) .
The sensitivity of the antibody tests alone or in combination was in
the range of 40 to 60 percent, and the specificity was greater than 90
percent for distinguishing patients with IBD from controls.
Specificity was slightly less for distinguishing ulcerative colitis from
CD .
Crohn’s Disease
History
• In 1932, Drs. Crohn, Oppenheimer and
Ginzburg at Mount Sinai Medical Center
described a subacute inflammatory process
affecting the distal ileum
– “terminal ileitis”
– “granulomatous ileitis”
• In 1952, Dr. Wells reported colonic
involvement
What is Crohn’s Disease?
• Crohn’s disease (CD)
is an inflammatory
bowel disorder that
Esophagus
may affect any part of
the gastro-intestinal
(GI) tract
Small
Intestine
Large
Intestine
(Colon)
Appendix
• The inflammation
Stomach
penetrates the lining
of the GI tract and
Rectum
often causes ulcers
Crohn’s Disease
Crohn's disease may involve the entire gastrointestinal tract from mouth to perianal
area:
Approximately 80 percent of patients have small bowel involvement, usually in the
distal ileum, with one-third of patients having exclusively ileitis.
Approximately 50 percent of patients have ileocolitis, which refers to involvement of
both the ileum and colon.
Approximately 20 percent have disease limited to the colon. Although this pattern is
similar to that in ulcerative colitis, roughly one-half of such patients have sparing of
the rectum, which is rare in ulcerative colitis.
A small percentage of patients have predominant involvement of the mouth or
gastroduodenal area, while fewer patients have involvement of the esophagus and
proximal small bowel.
Approximately one-third of patients have perianal disease.
CLINICAL MANIFESTATIONS - CD
Patients can have symptoms for many years prior to diagnosis .
Fatigue, prolonged diarrhea with abdominal pain, weight loss, and
fever, with or without gross bleeding, are the hallmarks of CD .
Crohn’s Disease: Fistula
Fistulas
Fistulas are tracts or communications that connect two epitheliallined organs.
Common sites for fistulas connect the intestine to bladder
(enterovesical), to skin (enterocutaneous), to bowel (enteroenteric),
and to the vagina (enterovaginal).
In a population-based study of patients with CD, the cumulative risk
of developing a fistula was 33 and 50 percent after 10 and 20 years,
respectively .
Up to 45 percent of patients develop a fistula before diagnosis of CD.
Enterocutaneous fistulas can cause bowel contents to drain to the
surface of the skin
Phlegmon/abscess
All sinus tracts do not lead to fistulas. Sinus tracts may present as a
phlegmon, a walled off inflammatory mass without bacterial
infection that may be palpable on physical examination.
Ileal involvement is suggested by a mass in the right lower quadrant.
Some sinus tracts lead to abscess formation and an acute
presentation of localized peritonitis with fever, abdominal pain and
tenderness.
Diffuse peritonitis due to abscess perforation is a rare but recognized
complication of CD.
Malabsorption
Steatorrhea (disease or resection of more than 100 cm of the terminal
ileum, leading to depletion of the bile salt pool and fat malabsorption
)can lead to severe malnutrition, clotting abnormalities, osteomalacia,
and hypocalcemia, which may cause tetany.
Extraintestinal manifestations
CD and ulcerative colitis share a number of
extraintestinal manifestations generally related to
inflammatory disease activity and includes:
Musculoskeletal , Skin and mouth , Hepatobiliary ,
Ocular , Metabolic and Less common as Blood and
vascular , Renal and genitourinary tract ,
Neurological , Airway and parenchymal lung disease ,
Cardiac , Pancreas , Autoimmune .
DIAGNOSIS - CD
The diagnosis of CD is usually established with endoscopic findings
or imaging studies in a patient with a compatible clinical history.
Physical examination may be normal or show nonspecific signs
(pallor, weight loss) suggestive of CD. More specific findings
include perianal skin tags, sinus tracts, and abdominal tenderness.
Presenting symptoms frequently determine the order of subsequent
testing. Colonoscopy is the most appropriate initial test for patients
presenting with predominant diarrhea, while imaging studies may be
more appropriate for those presenting with abdominal pain.
Laboratory studies - CD
Routine laboratory tests may be normal or they may reveal anemia,
iron deficiency, elevated white blood cell count, B12 deficiency,
and/or elevated erythrocyte sedimentation rate or CRP.
If diarrhea is present, a stool specimen should be sent for culture
and examination for ova and parasites.
Imaging studies - CD
Imaging studies are most useful to evaluate the upper
gastrointestinal tract and allow documentation of the length and
location of strictures in areas not accessible by colonoscopy.
Imaging has traditionally involved barium studies, such as
barium enema or upper gastrointestinal series with small bowel
follow through (SBFT), though the use of computed tomography
(CT) and magnetic resonance imaging (MRI) is becoming more
common.
Aphthoid ulcers in Crohn's disease
Colonic disease
T2-weighted axial magnetic resonance imaging (MRI) study showing
perianal fistulas (arrows) in a patient with Crohn's disease.
Small bowel disease
Radiologic imaging is generally needed to evaluate patients with
probable small bowel disease. Several imaging modalities are
available, including conventional upper gastrointestinal series
with SBFT, CT and CT enterography, enteroclysis, and MRI and
MR enterography.
While CT enterography and MR enterography are being done
more frequently, in general, the initial study remains the
conventional upper gastrointestinal series with SBFT.
Small bowel disease
Upper gastrointestinal series with SBFT involves ingestion of
a barium solution with subsequent radiologic imaging of the
small intestine.
Typical features of small bowel CD include narrowing of the
lumen with nodularity and ulceration, a "string" sign when
luminal narrowing becomes more advanced or with severe
spasm, a cobblestone appearance, fistulas and abscess
formation, and separation of bowel loops, a manifestation of
transmural inflammation with bowel wall thickening.
Crohn's disease of the upper gastrointestinal tract
Fibrostenotic Crohn’s Disease
Single axial CT scan of the lower abdomen demonstrates an abscess (arrowheads) extending
from the markedly thickened and inflamed terminal ileum (arrow). The presence of contrast
material within the abscess confirms a communication with the adjacent ileum
.
Endoscopic findings in Crohn's disease: Endoscopic findings in Crohn's disease
include: aphthous ulcers, which are the earliest lesions seen in Crohn's disease (panel A);
large ulcers interspersed with normal mucosa, which are typical for the segmental
distribution of Crohn's disease (panel B); a cobblestone appearance that is characterized by
nodular thickening, with linear or serpiginous ulcers (panel C); and strictures due to fibrosis
(panel D).
Crohn’s Disease Histology
The major findings on intestinal biopsy are focal ulcerations, and
acute and chronic inflammation. These findings are usually
confirmatory rather than diagnostic.
The focality of the inflammation differs from the diffuse pattern seen
typically in ulcerative colitis.
Granulomas may be noted in up to 30 percent of patients with CD
and are diagnostic of the disorder if appropriate infections are
excluded .Thus, demonstration of a granuloma is not required for
establishing the diagnosis, nor does its presence confirm the
diagnosis, since granulomas may be seen with other disorders
including Yersinia spp., Behçet's disease, tuberculosis, and
lymphoma.
Crohn’s Disease Histology
Crohn’s Disease Histology
CANCER RISK
The AGA concluded that the risk of colorectal cancer
associated with ulcerative colitis and Crohn's colitis is similar
for comparable extent, duration, and age of onset of
inflammatory disease. As a result, the surveillance strategy
discussed for UC also applies for Crohn's colitis.
Ulcerative Colitis
History
• 1859, Samuel Wilks described “simple
idiopathic colitis”
• 1909
– Hawkins described the natural history of UC
– Hurst describe the sigmoidoscopic appearance
SIGNS AND SYMPTOMS -UC
• Patients with ulcerative colitis can have a
variable presentation.
• For therapeutic and prognostic purposes, it
has been useful to classify these
presentations as mild, moderate, or severe.
• The severity of the symptomatology often
correlates with the anatomic extent of
disease, another parameter that will guide
therapy.
Mild disease
• Patients whose disease is confined to the rectum (proctitis)
or rectosigmoid (proctosigmoiditis or distal colitis), often
present insidiously with intermittent rectal bleeding
associated with the passage of mucus, and the development
of mild diarrhea with fewer than four small loose stools per
day.
• Mild crampy pain, tenesmus, and periods of constipation
are also common, but severe abdominal pain, profuse
bleeding, fever, and weight loss are not part of the
spectrum of mild disease.
Moderate disease
• Moderate disease is usually characterized
anatomically by involvement of more than the
distal colon, with the inflammatory process
extending to at least the splenic flexure (left-sided
colitis).
• The clinical picture is characterized by frequent
loose, bloody stools (up to 10 per day), mild
anemia not requiring blood transfusions,
abdominal pain that is not severe, and low grade
fever. Adequate nutrition is usually maintained.
Severe disease
• Patients with a severe or fulminant presentation usually have extensive
colonic involvement, often but not always extending to the cecum
(pancolitis). These patients typically have frequent loose stools (greater
than 10 per day) with severe cramps, fever up to 39.5ºC, and bleeding
often necessitating blood transfusion. They may suffer rapid weight
loss, leading to a poor nutritional state.
• In severely ill patients, the inflammatory process may extend beyond
the mucosa to involve the muscle layers of the colon. In this setting,
colonic motility is impaired, the colon dilates, bowel movements may
become less frequent, and a pattern termed toxic megacolon ensues.
Extension of the disease process to the serosa may lead to colonic
perforation.
Disease Distribution at Presentation
n=1116
37%
46%
17%
Farmer RG. Dig Dis Sci;38:1137-1146
DIAGNOSIS - UC
• The diagnosis of ulcerative colitis can
usually be established by the characteristic
history coupled with a typical endoscopic
appearance of the mucosa and confirmatory
histology seen on colonic biopsy.
• CT may also show marked thickening of
the bowel wall, but this finding is
nonspecific .
Flexible sigmoidoscopy -UC
• Since treatment is based in part on the
extent of disease, it is useful at the initial
presentation to document the extent of
inflammation by flexible sigmoidoscopy
• Total colonoscopy is usually not necessary
at this time unless there is confusion about
the underlying diagnosis. Furthermore, it
may induce megacolon or perforation in the
severely ill patient with extensive disease.
Flexible sigmoidoscopy -UC
• The normal colonic mucosa has well demarcated vessels and a shiny
pale appearance.
• The vascular markings are lost due to engorgement of the mucosa,
giving it an erythematous appearance. In addition, petechiae, exudates,
touch friability, and frank hemorrhage may be present.
• More severe cases may be associated with macroulcerations, profuse
bleeding, and copious exudates .
• Colonic involvement is continuous in ulcerative colitis, in contrast to
the patchy nature of Crohn's disease .
• Pseudopolyps, as a reaction to prior inflammation and signifying some
degree of chronicity, may be present in areas of disease involvement.
Local complications
• Massive hemorrhage occurs in up to 3 percent of
patients with ulcerative colitis and may necessitate
urgent colectomy .
• Fulminant colitis is seen in up to 15 percent of
patients, up to 20 percent of whom progress to
toxic megacolon which carries with it the risk of
perforation and death .
• Perforation with peritonitis has been associated
with a 50 percent mortality in ulcerative colitis.
Local complications
• Benign stricture can occur due to repeated episodes of
inflammation and, in some cases, to muscle hypertrophy.
Stricture is most common in the rectosigmoid area, occurs
in about 10 percent of cases with ulcerative colitis, and
may cause symptoms of obstruction.
• Strictures in ulcerative colitis should be considered
malignant until proven otherwise by endoscopic evaluation
with biopsy.
• Surgery is indicated for strictures that cause continued
symptoms of obstruction or that cannot be fully evaluated
to exclude malignancy.
Local complications
• A major concern in the evolution of ulcerative colitis is the
potential for the development of colon cancer .
• The risk of acquiring colon cancer is related to both the
duration and extent of the disease.
• The incidence of colon cancer begins to increase relative to
the general population seven to eight years after the onset
of disease in those patients with disease beyond the splenic
flexure. It is generally agreed that, for the patient at
increased risk, the risk goes up about 0.5 percent per year
after this time. There also appears to be an increased risk
of colon cancer in patients with ulcerative colitis if they
also have a family history of colon cancer .
Local complications
• There is emerging evidence that patients
with left-sided colitis up to the splenic
flexure have almost the same risk of colon
cancer as those with disease beyond that
point .
• In contrast, patients with proctitis and distal
colitis appear to be at low risk regardless of
the duration of disease.
Ulcerative Colitis Histology
• Colonic biopsy can be used to confirm the diagnosis. It
may be particularly helpful if the visual findings are
equivocal, since it can detect abnormalities with significant
inflammation in such settings.
• The biopsy characteristically reveals crypt abscesses and
chronic changes including branching of crypts, atrophy of
glands, and loss of mucin in goblet cells. These findings
distinguish ulcerative colitis from other disorders, such as
an acute self-limited infectious process.
Ulcerative Colitis Histology
Medical Treatment
Goals of Therapy
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Relieve symptoms
Prevent recurrence of symptoms
Prevent or cure complications
Control inflammation of the GI tract
Improve quality of life
Steroid sparing
Reduce the need for surgery
Disease Activity
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Number of bowel movements a day
presence of blood in stool
abdominal exam (tenderness)
Weight loss
Extraintestinal manifestation
Overall well-being
Vitals: fever, tachycardia
Labs: anemia,
Medications for Mild-Moderate
Disease
• Aminosalicylates
– Sulfasalazine
– Mesalamine (Pentasa, Asacol, Colazal, Rowasa
enema and Canasa Suppositories)
• Antibiotics
– Metronidazole (Flagyl)
– Quinolones (Cipro)
Medications for Moderate-Severe
Disease
• Steroids
– Prednisone
– Solumedrol
– Budesonide (Entocort)
• Immunosuppressives
–
–
–
–
Azathioprine (Imuran)
6-mercaptopurine (Purinethol)
Methotrexate
Cyclosporin
Medications for Moderate-Severe
Disease
• Biologics
– Infliximab (Remicade)
Side Effects of Sulfasalazine
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Fever
Headache
Rash
Nausea/vomiting
Diarrhea
Loss of appetite
Oral 5-ASA Release Sites
Pentasa®
Asacol®
Olsalazine
Sulfasalazine
COLAZAL™
Stomach
Small
Intestine
Large
Intestine
Mesalamine in
microgranules
Mesalamine
w/ eudragit-S
Azo bond
Mesalamine Side Effects
•
•
•
•
•
Nausea/vomiting
Heartburn
Diarrhea
Headache
Allergic Reaction
Antibiotic Side Effects
• Flagyl
–
–
–
–
–
–
metallic taste
headache
nausea/vomiting
dizziness
diarrhea
peripheral neuropathy
• Cipro
–
–
–
–
–
headache
rash
nausea/vomiting
dizziness
Achilles tendon rupture
Steroid Side Effects
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GI upset
Acne
Moon face
Fluid Retention
Diabetes
HTN
Striae
Weight gain
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Cataracts
Glaucoma
Depression
Osteoporosis
Infection
Growth retardation
Outcome of Steroid Therapy for
Patients with CD
1-Month
Outcomes
(n=109)
12-Month
Outcomes
(n=87)
Remission
48%
Remission
54%
Improved
32%
Relapse
46%
Summary Steroid Dependent
Outcomes
36%
(n=39)
(n=109)
Improved
57%
Prolonged Response
44%
(n=48)
No
response
20%
Relapse
43%
Steroid Resistant
20%
(n=22)
Munkholm P et al. Gut 1994;35:360
Purine Metabolism
6Methyl Mercaptopurine
TPMT
AZA
HPRT
6MP
Xanthine oxidase
6Thiouric Acid
6TGN
Immunosuppressant Side Effects
• AZA/6MP
– Bone marrow
suppression
– pancreatitis
– hepatitis
– allergic reaction
– lymphoma
– infections
• MTX
–
–
–
–
–
hepatotoxicity
pneumonitis
teratogenic
alopecia
allergic reaction
Infliximab
Infliximab Side Effects
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•
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Reactivation of TB
Headache
Nausea
Upper respiratory tract infection
Other serious infections
Fatigue
Fever
Referral to Surgeon
• Symptoms not relieved by medications
• Serious complications
–
–
–
–
abscesses
fistula
intestinal blockage
uncontrolled bleeding
Conclusion
• Crohn’s Disease and Ulcerative Colitis are
the two major types of IBD
• The inflammatory bowel diseases are
chronic diseases the are caused by genetic,
environmental factors and immunologic
abnormalities
• Medical treatment options should be
tailored based of disease type, distribution
and pattern
Conclusion
• Medical treatment will usually relieve
symptoms but relapse is common and
therefore treatment is lifelong