1. Lecture:
Celiac Disease and
Inflammatory Bowel Disease

2. Sponsored
Medical Lecture Notes – All Subjects
USMLE Exam (America) – Practice

3. Definition of Celiac disease
• immune-mediated enteropathy
– caused by a permanent sensitivity to gluten
– in genetically susceptible individuals.
• A unique autoimmune disorder:
– environmental trigger (gluten) and the
– autoantigen (tissue Transglutaminase)

4. Gluten, a substance in wheat and other
grains, may be found in a variety of foods
including breads, cakes, pasta, commercial
dairy products and alcoholic beverages

5. Old paradigm - CD is a disease of small intestine
Celiac disease
• villous atrophy
• malnutrition
London, year 1938

6. New paradigm: multi-organ autoimmune disease
Celiac disease
• villous athrophy
• malnutrition
• malignancies
Bone
• osteoporosis, fractures
• arthritis
• dental anomalies
Hepatitis
Cholangitis
Skin & mucosa
• dermatitis herpetiformis
• aphtous stomatitis
• hair loss
Reproductive
• miscarriage, infertility
• delayed puberty
Central nervous system
• ataxia, seizures
• depression
Carditis, cardiomyopathy
Anemia

7. Pathogenesis:
1 A component of gluten,
gliadin, interacts with a specific
genetic form of HLA receptor
on an antigen presenting cell.
2. Tissue transglutaminase
converts glutamine residues to
glutamic acid residues making
an even more potent antigen.
3. T helper cells are activated
and, in turn, activate B and
killer T cells.
4. Plasma cell antibodies bind to
gliadin bound to enterocytes,
tissue transglutaminase and
reticular fibers surrounding gut
smooth muscle (endomysial
ab’s).
5. T cells release (inappropriate)
inflammatory cytokines as well
as inflict tissue damage.
Source:NEJM 346:180, 2002

8. Normal intestinal biopsy
Small intestinal biopsy
in a patient with active
celiac disease

9. Normal intestinal surgical
specimen with distinct villi
Celiac disease specimen with
total loss of villi, the arrows
indicate crypt openings

10. Classification
• Classical Celiac
– Ab positive, histo findings, and classic symptoms
• Atypical Celiac
– Ab positive, histo findings, milder clinical symptoms
– Most common type
• Silent Celiac
– Ab positive, histo findings, asymptomatic
• Potential Celiac
– Ab positive, negative bx, asymptomatic
• Latent Celiac
– Previous diagnosis that responded to gluten-
withdrawal but retained normal villous architecture
after gluten rechallenge

11. Clinical Manifestations
• Classic celiac disease
– Abdominal pain
– Diarrhea, constipation
– Gassiness, distention, bloating
– Anorexia
– Poor weight gain
– Irritability, lethargy
(NIH, 2004)

12. Clinical Manifestations
• Secondary (?) to malabsorption
– Anemia, fatigue
– Vitamin deficiencies
– Muscle wasting
– Osteopenia
– Short stature
– Recurrent abortions / infertility
– Delayed puberty
– Dental enamel hypoplasia
– Aphthous ulcers
(NIH, 2004; Fasano, 2005)

13. Clinical Manifestations
• Additional symptoms (multi-system disease)
– Ataxia
– Hypotonia
– Neuropsychiatric conditions (depression, anxiety, peripheral
neuropathy, headaches)
– Epilepsy
– Alopecia
– Vasculitis
– Cardiomyopathy, recurrent pericarditis
– Psoriasis
(Fasano & Catassi, 2001; Green, 2005; NIH, 2004; Zelnik, et al, 2004)

14. Dermatitis Herpetiformis
• Erythematous macule >
urticarial papule > tense
vesicles
• Severe pruritus
• Symmetric distribution
• 90% no GI symptoms
• 75% villous atrophy
• Gluten sensitive
By permission of Dr. A. Fasano

16. Involve the secondary dentition
Dental Enamel Defects
By permission of Dr. C. Catassi

17. Osteopenia/Osteoporosis
Low bone mineral density by DEXA in a child with untreated CD
By permission of Dr. S. Mora

18. Occipital Calcification & Epilepsy
By permission of Drs. C. Catassi and G, Holmes

19. Screening
• Who should be tested?
– Children with
• GI symptoms including IBS
• Family history of CD
• Short stature, delayed puberty
• Osteopenia
• Iron deficiency anemia, fatigue
– Women with infertility or recurrent fetal loss
– High risk groups include children with
• Diabetes type1, Downs, IgA deficiency, Turners, Williams
• Other autoimmune conditions, i.e., thyroiditis, hepatitis
• Unexplained neurological symptoms
– ataxia, peripheral neuropathy, hypotonia, epilepsy, depression, anxiety

20. Safe Foods

21. Treatment
• Gluten contained in wheat, rye, barley
– Triticale, kamut, spelt, semolina, farina, einkorn, bulgur,
and couscous
– Malt made from barley
• Malt syrup, malt extract, malt flavoring, malt vinegar
• Beer, whiskey
– Food additives
• Soy sauce, carmel color, bouillon, modified food starch
• Mono or diglycerides, emulsifiers, vegetable protein
– Processed foods
• Sausage, luncheon meat, gravies and sauces
• TV dinners, pot pies

22. Background
Inflammatory bowel disease (IBD) is an idiopathic disease, probably
involving an immune reaction of the body to its own intestinal tract. The 2 major
types of IBD are ulcerative colitis and Crohn disease. As the name suggests,
ulcerative colitis is limited to the colon; Crohn disease can involve any segment of
the gastrointestinal tract from the mouth to the anus.
In the population, the incidence of ulcerative colitis is 7.3 cases per
100,000 people per year and the prevalence is 116 cases per 100,000 people; the
incidence of Crohn disease is 5.8 cases per 100,000 people per year and the
prevalence is 133 cases per 100,000 people.
Ulcerative colitis and Crohn disease are most commonly diagnosed in
young adults (ie, late adolescence to the third decade of life).

23. Etiology
The precise cause of inflammatory bowel disease are unknown.
THEORIES OF INFLAMMATORY BOWEL DISEASE ETIOLOGYTHEORIES OF INFLAMMATORY BOWEL DISEASE ETIOLOGY
• Toxic response to luminal contents
- Specific microbial pathogen
- Abnormal luminal constituents
- Increased absorption of luminal macromolecules
• Enhanced immunologic response to normal constituents
• Autoimmune response
- To epithelial cell or mucus glycoproteins
- Molecular mimicry (cross-reactivity of intestinal microflora and epithelia)
- To immune cells

24. Pathophysiology
The pathophysiology of IBD is under active investigation. The common
end pathway is inflammation of the mucosal lining of the intestinal tract, causing
ulceration, edema, bleeding, and fluid and electrolyte loss.
Persons with IBD have a genetic predisposition (or perhaps
susceptibility) for the disease. The triggering event for the activation of the
immune response has yet to be identified. In any case, activation of the immune
system leads to inflammation of the intestinal tract, both acute (neutrophilic) and
chronic (lymphocytic, histiocytic).

25. Microscopically, the initial lesion starts as a focal inflammatory infiltrate
around the crypts, followed by ulceration of superficial mucosa. Later, inflammatory
cells invade deep layers and, in that process, begin to organize into noncaseating
granulomas. The granulomas extend through all layers of the intestinal wall and into
the mesentery and the regional lymph nodes. Although granuloma formation is
pathognomonic of Crohn disease, absence does not exclude the diagnosis.
Macroscopically, the initial abnormality is hyperemia and edema of the
involved mucosa. Later, discrete superficial ulcers form, which become deep
serpiginous ulcers located transversely and longitudinally over an inflamed mucosa,
giving the mucosa a cobblestone appearance. The lesions are often segmental, being
separated by healthy areas, and are often referred to as skip lesions.
Transmural inflammation results in thickening of the bowel wall and
narrowing of the lumen. As the disease progresses, it is complicated by obstruction,
fistulization by way of the sinus tracts penetrating the serosa, microperforation,
abscess formation, adhesions, and malabsorption.
Pathophysiology of Crohn disease

26. T i f l i t i s
T r a n s v e r s i t i s
S i g m o i d i t i s
P r o c t i t i s
A n g u l i t i s

28. Crohn’s Disease:
Anatomic Distribution
Small bowelSmall bowel
alonealone
(33%)(33%)
Colon aloneColon alone
(20%)(20%)
IleocolicIleocolic
(45%)(45%)
LeastLeastMostMost
Freq of involvementFreq of involvement

29. History:
• Frequent episodes of rectal bleeding occur, with or without mucus. The characteristic
feature is blood in each bowel movement.
• Urgency and tenesmus
• Abdominal cramps
• Weight loss in severe cases
Physical:
• Mild fever
• Tachycardia
• Dehydration
• Malnutrition
• Abdominal tenderness
• Blood on digital rectal examination
Ulcerative colitis

30. Patients with Crohn disease most commonly present with symptoms related to a
chronic inflammatory process involving the ileocolic region.
Low-grade fever, prolonged diarrhea with abdominal pain, weight loss, and
generalized fatigability are usually reported.
The patients may develop crampy or steady right lower quadrant or periumbilical
pain. The pain precedes and may be partially relieved by defecation. Diarrhea is usually
nonbloody and often intermittent.
If the colon is involved, patients may report diffuse abdominal pain accompanied by
mucus, blood, and pus in the stool.
Patients may also present with complaints suggestive of intestinal obstruction.
Initially, the obstruction is secondary to inflammatory edema and spasm of the bowel
and manifests as postprandial bloating, cramping pains, and loud borborygmi. Once the
bowel lumen becomes chronically narrowed, patients may complain of constipation and
obstipation. Complete obstruction may sometimes be caused by impaction of undigested
foods.
Crohn disease
History:

31. • Physical findings may typically reveal right lower quadrant tenderness. A mass
can sometimes be felt secondary to thickened or matted loops of inflamed bowel.
• Perianal involvement manifests as skin tags, fistulae, abscesses, and scarring.
• Extraintestinal manifestations of the skin include erythema nodosum and
pyoderma gangrenosum.
• Eye involvement is usually manifested as uveitis or episcleritis.
• A peripheral arthritis involving the large joints may also be present
Crohn disease
Physical:

32. Extraintestinal manifestations of IBDExtraintestinal manifestations of IBD
- Arthropathies. The arthritides associated with the IBD are of 2 varieties, axial (or
central) arthritis and peripheral arthritis. The axial arthritis associated with IBD consists
of ankylosing spondylitis and sacroiliitis.
- Diseases of the eye associated with ulcerative colitis are episcleritis and iritis (uveitis).
- The major skin diseases associated with IBD are erythema nodosum and pyoderma
gangrenosum. Erythema nodosum is a painful, tender, raised, purplish lesion on the
anterior surface of the tibia. Pyoderma gangrenosum starts as an inflamed patch of skin
ranging from one to several centimeters in diameter that progresses until it ulcerates.
- Sclerosing cholangitis.
- Gallstones and kidney stones.
- The anemia associated with IBD may be of 2 types, (1) iron deficiency anemia
secondary to chronic blood loss and (2) anemia of chronic disease.
- A hypercoagulable state is associated with IBD.

33. Inflammatory bowel disease. Arthritis.

34. Inflammatory bowel disease. Episcleritis.

35. Inflammatory bowel disease. Uveitis.

36. Inflammatory bowel disease. Orofacial.

37. Inflammatory bowel disease. Erythema nodosum.

38. Inflammatory bowel disease. Pyoderma gangrenosum.Pyoderma gangrenosum.

39. Inflammatory bowel disease. Pyoderma gangrenosum.

40. IBD. Severe advanced pyoderma gangrenosum of the medial aspect of the
left ankle.

41. IBD. Early pyoderma gangrenosum, before skin breakdown. Medial aspect of the
right ankle. Same day and same patient.

42. Inflammatory bowel disease.
Primary sclerosing cholangitis

43. Investigations at admissionInvestigations at admission
• Haemogram, general blood picture
• Platelet Count
• Acid – Base balance
• Electrolytes: Na, K, Ca, Mg, CL
• Serum creatinine, total proteins, albumin
• CRP
• Serum iron
• Liver function tests

44. Serology in IBDSerology in IBD
• pANCA – perinuclear antineutrophil cytoplasmic
antibody: marker for ulcerative colitis
• ASCA – anti Saccharomyces cervisiae antibody: marker
for Crohn’s
ASCA + ANCA - : CD in 8/10 pts
ASCA - ANCA + : UC in 7/11 pts

45. Normal mucosa on colonoscopy

46. The transverse colon is the most varied in contour of all of the colon sections.
Bound by the splenic flexure on the left and the hepatic flexure on the right, the
transverse colon can have the characteristic triangular folds.

47. IBD. Severe colitis noted during colonoscopy. The mucosa is
grossly denuded, with active bleeding noted.

48. It is visible ulcers, edema and vulnerability of mucosa

49. Endoscopic picture

50. IBD. Stricture in the terminal ileum noted during colonoscopy.
Relatively little active inflammation is present, indicating that this is a
cicatrix stricture.

51. Endoscopic features of Crohn's disease of the terminal ileum. A diffuse
inflammation is depicted with characteristic large irregular ulcers that are often
stellate or longitudinal.

52. Severe Crohn's colitis. A characteristic "cobblestone" appearance is the result of
multiple longitudinal ulcers and exuberant inflammation with pseudopolyp
formation as well as thickening of the intestinal wall because of transmural
inflammation.

53. Severe ulcerative colitis. The mucosa shows extensive ulceration and diffuse
thickening with an inflammatory infiltrate. In contrast to Crohn's colitis, the
ulceration lacks depth.

54. Severe ulcerative colitis
with pseudopolyps. In
addition to severe
mucosal ulceration and
inflammation, chronic
ulcerative colitis is often
associated with the
formation of
pseudopolyps, which
represent islands of
regenerating mucosa
and exuberant
inflammation amidst
diffuse mucosal
destruction.
Pseudopolyps have no
malignant potential

55. Gross pathologic specimen of resected colon from a patient with severe
ulcerative colitis. Inflammation is diffuse and continuous, involving the mucosa
and extending from the rectum without interruption to the ascending colon.

56. Gross specimen of a colon resected from a patient with Crohn's colitis. The
mucosa demonstrates a typical cobblestone appearance with linear and discrete
ulcers and a narrow lumen. The inflammation is patchy with "creeping fat,"
reflecting extension of the transmural inflammation into the serosa.

57. • Plain X-Ray abdomen: Supine, erect, may
show small intestinal dilatation, ‘impending
megacolon’, mucosal edema, or perforation
• Barium enema: may show fine mucosal
granularity, superficial ulcers, loss of
haustrations, shortening, narrowing of colon,
polyps
Radiology

58. A normal barium enema, as seen in
the irritable bowel syndrome (IBS).
The investigation is not always
necessary, but may sometimes be
needed to exclude other causes of
abdominal symptoms or change in
bowel habit. Colonoscopy also
reveals no abnormal findings in IBS.

59. Aphthous ulcers in a patient with
Crohn’s colitis are seen
radiographically as multiple, small
collections of barium surrounded by
radiolucent halos.

60. Crohn disease.
Aphthous ulcers.

61. Crohn’s colitis with cobblestoning.
Enlargement of aphthous lesions to
form longitudinal and serpiginous
ulcers creates the cobblestone
appearance.

62. Barium enema demonstrates
various defects of ulcerative
colitis and Crohn’s disease.
Left-sided disease with
continuous involvement from
the rectum proximally and
sparing of the right and
transverse colon.

63. Pancolitis with extensive
involvement of the entire colon

64. Long-standing chronic ulcerative colitis is characterized by shortening and
straightening of the colon with loss of haustrations, resulting in the appearance
of a featureless tube. No ulcerations are seen.

65. Intestinal complications
• Strictures and obstructions
• Fistulae and perianal disease
• Toxic megacolon
• Malignancy

66. Air-contrast examination of
the colon in a patient with
ulcerative colitis
demonstrates a benign-
appearing stricture in the
descending colon (arrow).

67. The cutaneous opening of a
perirectal fistula is shown. Such
fistulas may arise from the
crypts of Morgagni in the anus
and spread through the internal
anal sphincter, resulting in
perineal or rectovaginal fistulas,
ischiorectal abscesses, or
intersphincteric abscesses.

68. Typical perianal changes of
Crohn's disease. The large skin
tags of granulation tissue, which
are firm and thickened, give an
"elephant-ear" appearance.

69. IBD. Note that barium is just starting to enter the cecum in the right lower
quadrant (viewer's left), but that barium has also started to enter the sigmoid
colon toward the bottom of the picture, thus indicating the presence of a fistula
from the small bowel to the sigmoid colon.

70. Barium enema demonstrates a
fistula from the descending colon to
the left paracolonic soft tissue as a
result of Crohn's disease.

71. Barium enema reveals an
enteroenteric fistula between the
terminal ileum and mid-transverse
colon in a patient with Crohn’s
disease.

72. Inflammatory bowel disease.
Toxic megacolon.

73. This colonic resection specimen shows an erythematous-raised tumor with a
central umbilication typical of colon cancer.
Adenocarcinoma of the colon

74. As malignancies advance and encompass the lumen of the colon, the annular
appearance, often referred to as the apple core lesion, may be seen on positive-
contrast studies. In this figure, the features of a malignant-circumferential
carcinoma are well displayed. Notice the circumferential luminal narrowing of the
colon. Sharp margins with overhanging edges are seen on both ends of the lesion
(arrows).

75. Barium enema demonstrates a malignant stricture in a patient with long-standing
ulcerative colitis.

76. Lung cancer is by far the most common fatal cancer in men, followed by prostate,
and colon and rectum cancer. In women, lung, breast and colorectal cancers are
the leading sites of cancer mortality.

77. The sigmoid colon. Diverticula with fold thickening should be closely evaluated in
the sigmoid colon. Knowledge of the existence of diverticula is important in
evaluating patients with left lower quadrant pain.

78. An air-contrast barium
enema demonstrates
scattered diverticulosis of
the left colon. Most of the
30 million Americans with
diverticulosis have no
symptoms. The prevalence
of diverticulosis increases
from 5% in patients over 40
years of age to 50% in
patients over 80 years of
age. Only 1% to 2% of the
population under 30 years
of age has diverticulosis.

79. Endoscopic appearance of pseudomembranous colitis. Pseudomembranous
colitis characteristically results from the use of antibiotics and is caused by the
toxin produced by Clostridium difficile. The characteristic appearance is yellow-
white pseudomembranes on a background of diffuse colonic inflammation.

80. The endoscopic view of the rectum of a patient with pseudomembranous colitis
demonstrates the typical plaque-like lesion caused by Clostridium difficile.

81. Pathologic features of pseudomembranous colitis. The gross appearance
demonstrates the characteristic yellow-white plaquelike pseudomembranes.

82. Goals of Therapy for IBD
• Inducing remission
• Maintaining remission
• Restoring and maintaining nutrition
• Maintaining patient’s quality of life
• Surgical intervention (selection of optimal time
for surgery)

83. 1. The first step in medication therapy is usually aminosalicylates
2. If the IBD fails to respond to aminosalicylates, the second step is corticosteroids.
3. If patients have difficulty reducing the dose of corticosteroids, have IBD that is
refractory to corticosteroid therapy, or have frequent flares that require corticosteroid
therapy, the third step for medication is one of the immunomodulatory agents, either 6-
MP or azathioprine.
An alternative third step is available for persons with IBD. This alternative is
infliximab, a monoclonal antibody against tumor necrosis factor (TNF)–a. Administer this
agent by intravenous infusion.
4. The final step for the treatment of IBD involves agents that have less well-
demonstrated levels of efficacy but have been shown to be useful in some subsets of
patients. For Crohn disease, methotrexate at 12.5-25 mg/wk may fall into this category.
For ulcerative colitis, cyclosporine A fall into this category.
TREATMENT

84. Therapeutic Pyramid
for Active Crohn’s Disease
SevereSevere
ModerateModerate
Aminosalicylates/AntibioticsAminosalicylates/Antibiotics
CorticosteroidsCorticosteroids
ImmunomodulatorsImmunomodulators
SurgerySurgery
InfliximabInfliximab
??
(Prednisone)(Prednisone)
MildMild
(Budesonide)(Budesonide)

85. Drug Category: Aminosalicylates (step I)
Effective in reducing inflammatory reactions.
Drug Name
Adult Dose
Sulfasalazine (Azulfidine, Azulfidine EN-tabs)
500 mg PO bid, may increase to 1000 mg PO qid (usual dose)
Drug Name
Adult Dose
Mesalamine (Asacol, Pentasa)
Asacol: 400 mg PO bid to 1200 mg PO qid, usual 800 mg PO tid
Pentasa: 500 mg PO bid to 1000 mg PO qid (usual dose)
Drug Name
Adult Dose
Balsalazide (Colazal)
3 cap (2.25 g) PO tid for 8-12 wk
Drug Name
Adult Dose
Olsalazine (Dipentum)
500-1000 mg PO bid

86. Drug Category: Antibiotics (step IA)
Antimicrobial therapy must cover all likely pathogens in the context of the clinical setting.
Drug Name
Adult Dose
Metronidazole (Flagyl)
250-500 mg PO tid
Drug Name
Adult Dose
Ciprofloxacin (Cipro)
500 mg PO bid

87. Drug Category: Corticosteroids
Have anti-inflammatory properties and cause profound and varied metabolic effects.
Modify the body's immune response to diverse stimuli.
Drug Name
Adult Dose
Hydrocortisone (Solu-Cortef), methylprednisolone (Solu-Medrol, Depo-
Medrol)
Hydrocortisone: 100 mg IV tid
Methylprednisolone: 20-40 mg IV q6h
Drug Name
Adult Dose
Prednisone (Deltasone), prednisolone (AK-Pred, Pred Forte), budesonide
(Entocort)
Typical maximum doses
Prednisone: 40-60 mg PO qd
Prednisolone: 32-40 mg PO qd
Budesonide: 9-15 mg PO qd
Drug Name
Adult Dose
Hydrocortisone (Cortenema)
Cortenema (100-mg hydrocortisone): 1 enema PR bid
Cortifoam (80-mg hydrocortisone): 1 applicator PR bid
Anusol-HC supp: 1 suppository PR bid; others available

88. Drug Category: Immune modifiers (step III)
These agents modify immune reactions resulting from diverse stimuli.
Drug Name
Adult Dose
Azathioprine (Imuran)
1-2 mg/kg PO qd
Drug Name
Adult Dose
6-Mercaptopurine (Purinethol)
1-2 mg/kg PO qd

89. Investigations during therapyInvestigations during therapy
Sulphasalazine
Haemolytic anemia
Agranulocytosis
Hepatitis
Azathioprine
Pancreatitis - serum amylase
Hepatic dysfunction

90. Drug Category: Immunosuppressants
Interfere with development of immunological responses.
Drug Name
Adult Dose
Infliximab (Remicade)
5 mg/kg IV as single infusion over 2 h
Drug Name
Adult Dose
Adalimumab (Humira)
Induction dose: 160 mg SC once (administer by either dividing dose into 4
injections on day 1 or over 2 days), then follow with 80 mg SC once at week 2
Maintenance: 40 mg SC q2wk beginning at week 4

91. Healing of Colonic Ulceration
with Infliximab
Van Dullemen HM et al. Gastroenterology 1995;109:129-135
PretreatmentPretreatment 4 weeks4 weeks
post-treatmentpost-treatment

92. Drug Category: Antidiarrheal agents
Reduce prevalence of diarrhea.
Drug Name
Adult Dose
Loperamide (Imodium), diphenoxylate and atropine (Lomotil),
cholestyramine (Questran)
Loperamide: 1-2 scoop PO prn (as high as 8/d)
Diphenoxylate/atropine: 1-2 scoop PO prn (as high as 8/d)
Cholestyramine: 1 scoop PO qd/tid
Drug Category: Antispasmodic agents
Treat spastic disorders of the GI tract.
Drug Name
Adult Dose
Dicyclomine (Bentyl), hyoscyamine (Levbid, Levsin)
Dicyclomine 10-40 mg PO qid
Hyoscyamine - Levbid: 1 PO bid; Levsin: 1 PO qid