1. Small Intestine Pathology
Rachel Roth, MD
Department of Pathology
The Ohio State University Wexner Medical Center
Hello, I’m Dr. Rachel Roth, and in this lecture, we’ll be reviewing small intestinal pathology.

2. Objectives
Describe the pathology and pathophysiology of the following small intestinal conditions:
Congenital anomalies
Vascular lesions
Ulceroinflammatory diseases
Tumors of the small intestine
Malabsorption
Obstructive Lesions
Over the course of this lecture, you’ll be able to describe the pathology and pathophysiology of the following small intestinal conditions: congenital anomalies, vascular lesion, ulceroinflammatory diseases, tumors of the small intestine, malabsorption, and obstructive lesions.

3. Objectives
Define Meckel’s diverticulum, including embryology of origin
List the characteristic small bowel biopsy features of:
Celiac disease
Whipple’s disease
Recognize the gross and histopathologic appearance of Crohn’s disease and ulcerative colitis
Describe the principle manifestations of neoplasms of the small bowel
In addition, I’d like for you to be able to define Meckel’s diverticulum, including embryology of origin, be able to list the characteristic small bowel biopsy features of celiac disease and Whipple’s disease, recognize the gross and histopathologic appearance of Crohn’s disease and ulcerative colitis, and, finally, to describe the principle manifestations of neoplasms of the small bowel.

4. Small Bowel – Congenital Abnormalities
Atresia and Stenosis Diverticula
Heterotopic Pancreas
Let’s begin by discussing congenital abnormalities of the small bowel. In atresia, there is either a segment missing in the bowel or a complete obstruction of the bowel, while in stenosis, there is narrowing of the bowel that can be mild to severe. Atresia and stenosis can occur singly in the small bowel or at multiple different foci, and they typically present with vomiting in the first two weeks of life requiring surgical therapy. Diverticula can be single or multiple, and they tend to occur in the jejunum and ileum. They occur at points of weakness, typically where vessels and nerves enter the small bowel. They’re more frequent in older individuals, and under the microscope, they show a diverticulum lined by mucosa and submucosa protruding through the muscularis propria. Heterotopic pancreas or pancreatic rests can occur anywhere in the small intestine, and they tend to be 1-2 cm in diameter. As you can see in this image, they look like normal pancreas under the small bowel mucosa. Make sure you don’t mistake them for tumor.

5. Small Bowel – Congenital Abnormalities Meckel’s Diverticulum
Failure of involution of omphalomesenteric duct
Located in distal ileum
2% population
2x males > females
2 feet from the ileocecal valve
2 types epithelium
Gastric
Pancreatic
Lastly, there is Meckel’s diverticulum. Meckel’s diverticulum results from a failure of involution of the omphalomesenteric duct. They are located in the distal ileum. The rule of two’s applies to Meckel’s diverticulum. They are seen in 2% of the population, they are twice more common in males than females, they are located two feet from the ileocecal valve, and two types of heterotopic epithelium are present: gastric and pancreatic.
Ileal
Gastric

6. Small Bowel – Causes of Obstruction
Intussusception
Volvulus
Hernias
Adhesions
The small bowel can be thought of a nature’s finest assembly line running from the stomach to the colon and ensuring that food is utilized to its fullest potential. Some things, however, can stop this assembly line. Causes of obstruction can include hernias, in which the small bowel herniates or protrudes out of its normal placement, and adhesions, which lock the small bowel down adhering it to its own loops or adjacent structures and may be post-operative or from previous inflammation in the abdominal cavity. Intussusception is an uncommon disorder typically seen in infants and children in which the proximal bowel telescopes into the distal portion of bowel. In adults, this can be seen as the result of an intestinal lesion. Both infantile and adult intussusceptions can compromise the blood supply to the gut and cause ischemia. In infants, intussusceptions can be reduced and cured by barium enemas. The last cause of obstruction is volvulus, a complete twisting of a loop of bowel around its mesenteric base that can cause intestinal obstruction and infarction.

7. Small Bowel – Ischemia Predisposing Conditions Arterial thrombosis
Atherosclerosis
Vasculitis
Arterial embolism – vegetation
Venous thrombosis – hypercoagulable
Non-occlusive – shock
Miscellaneous - volvulus
This moves us along to small bowel ischemia. In general terms, ischemia occurs when there is any insult to the blood supply to the small intestine. Predisposing conditions include causes of arterial thrombosis, including atherosclerosis and vasculitis, causes of arterial embolism, including vegetations, causes of venous thrombosis, including hypercoagulable states, non-occlusive conditions such as shock, and other miscellaneous conditions including volvulus. Looking at small bowel ischemia grossly, we find hemorrhagic, edematous, and thick-walled bowel filled with blood. As you can see in this image, there is a geographic distribution with the arterial occlusions showing sharper demarcations than venous occlusions. There are areas of no visible injury adjacent to areas of ischemia. This is due to the collateral circulation of the small bowel. Histology shows preserved villi and crypts with no evidence of inflammation in these areas. Mural ischemia, which is limited to the mucosa, can be caused by acute or chronic ischemic injury and is due to hypoperfusion.

8. Small Bowel - Ischemia Ischemia Normal
In this example, we can see the crypt bases appear to wither and the mucosal surface appears to dissolve. The lamina propria becomes hyalinized or smudgy. Transmural ischemia, which involves the full thickness of the bowel wall, is caused by occlusion of major mesenteric vessels. It shows full thickness inflammation and necrosis and often leads to perforation.
Clinically, small bowel ischemia presents with a sudden onset of pain, decreased bowel sounds and peristalsis, abdominal rigidity, nausea, and vomiting. Shock and mortality can affect greater than 50% of patients if untreated. Treatment is typically by hydration and resolution of the underlying circulatory issue and/or surgical resection.

9. Small Bowel - Inflammatory Bowel Disease (IBD)
Ulcerative Colitis
Crohn’s Disease
Inflammatory bowel disease can be divided into ulcerative colitis and Crohn’s disease. As we can see from this picture, ulcerative colitis tends to be limited to the distal portion of the colon but can show some small bowel involvement with “backwash ileitis.” Crohn’s disease is much patchier, and can involve any location in the GI tract from esophagus to anus. Involvement of the small bowel is common. We have included the discussion of ulcerative colitis and Crohn’s disease in both the small bowel and colon lectures for the sake of completeness.

10. Small Bowel - IBD
Conditions with chronic recurring immune response and inflammation involving GI tract
Immune system mistakes food, bacteria, and other materials for destructive foreign substances and attacks the cells of the intestines with chronic inflammatory infiltrate
Inflammatory bowel disease includes two conditions associated with chronic recurring immune responses and inflammation involving the gastrointestinal tract. The immune system mistakes food, bacteria, and other materials in the intestines for destructive foreign substances, and attacks intestinal cells with a chronic inflammatory infiltrate.

11. Small Bowel - Crohn’s disease
Likely multifactorial etiology – environmental trigger in predisposed individuals
Increased incidence in Northern Europe, US, Jewish populations
Peak: (smaller peak 60-70)
Smoking exacerbates Crohn’s  Increased risk of recurrence/relapse
Crohn’s disease is likely multifactorial in etiology with environmental triggers causing the disease in predisposed individuals. There is an increased incidence in populations in Northern Europe and the United States, and it peaks usually in the 20s-30s with a smaller peak in the 60s-70s. Smoking exacerbates Crohn’s with an increased risk of recurrence and relapse.

12. Small Bowel - Crohn’s disease
Associations
Perinuclear antineutrophil cytoplasmic antibodies (p-ANCA) – UC > Crohn’s
Non-GI Involvement – 25% of Crohn’s
Joints – Arthritis/Arthralgia, Ankylosing spondylitis
Hepatobiliary – Primary sclerosing cholangitis (UC > Crohn’s)
Important associations include perinuclear antineutrophil cytoplasmic antibodies (or p- ANCA), though they are less common in Crohn's than in ulcerative colitis, and non-GI involvement seen in up to 25% of Crohn's patients who can have arthritis or arthralgias, primary sclerosing cholangitis (again much less common than in ulcerative colitis), erythema nodosum, and ocular manifestations.

13. Small Bowel - Crohn’s disease
Anatomic Findings
Can involve any part of GI tract (mouth to anus)
Mostly ileocolonic involvement (10-30% show upper GI involvement)
Rectal sparing (50%)
“Skip lesions” – abrupt transition between involved and uninvolved bowel  “cobblestone” pattern
Formation of strictures, fistulas, adhesions, serositis, serosal exudates, peri-intestinal abscess and fat wrapping
Anatomically, Crohn’s disease can involve any part of the gastrointestinal tract from the mouth to the anus. It tends to predominantly show ileocolonic involvement with 10-30% showing upper GI involvement. An important feature to note is that the rectum is spared in up to 50% of patients. The key anatomic finding to remember in Crohn’s disease is “skip lesions,” which are abrupt transitions between involved and uninvolved mucosa. When we look a bit closer at this image, we can see sharp fissuring linear ulcers running between uninvolved mucosa forming a “cobblestone” pattern, which is typical of Crohn’s disease. Crohn’s can be complicated by the formation of strictures, fistulae, adhesions, serositis, serosal exudates, peri-intestinal abscesses, and fat wrapping.
Abscess
Fistulae

14. Small Bowel - Crohn’s disease
Microscopic Findings
Active colitis
Cryptitis
Crypt abscess formation
Mucosal ulceration
Inflammatory pseudopolyps
Inflammation involves all wall layers (transmural)
Chronic colitis
Increased lymphoplasmacytic lamina propria infiltrate
Pseudopyloric gland and gastric surface (foveolar) metaplasia
Paneth cell hyperplasia – small bowel and right colon
Paneth cell metaplasia – left colon
Under the microscope, we see many of the same features that we see in ulcerative colitis. Active colitis is typified by cryptitis, crypt abscess formation, mucosal ulceration, and inflammatory pseudopolyp formation, but one difference is the inflammation involves all wall layers when we have a resection specimen. Chronic colitis features include increased lymphoplasmacytic lamina propria infiltrate, Paneth cell metaplasia in the left colon, and architectural distortion with crypt dropout and crypt branching. We also see architectural distortion of the colonic crypts with dilated or irregular crypts.Some unique features of Crohn's include pseudopyloric gland and/or gastric surface metaplasia as well as Paneth cell hyperplasia in the small bowel and right colon.

15. Small Bowel - Crohn’s disease
Microscopic Findings
Transmural linearly-distributed lymphoid aggregates (“string of beads”)
Non-necrotizing granulomata
Architectural distortion
Crypt dropout
Branched, dilated irregular crypts
Crypts no longer reach the muscularis mucosae
Other important distinguishing features to remember are transmural lymphoid aggregates and granuloma formation.
Granuloma
Lymphoid aggregate

16. Small Bowel - Crohn’s disease
Clinical Course
Variable abdominal pain, diarrhea, malabsorption
Can be “inherently indolent” (non-perforating, slow recurring) or “inherently aggressive” (perforating, rapidly evolving)
Complications
Perforations (1.5%), fistula tracts, abscesses, obstruction due to stricture, toxic megacolon
Dysplasia/carcinoma – 5% of patients develop GI carcinoma, small bowel cancer 10-20x increased risk
Treatment
Pharmaceutical – Cyclosporine, 5-ASA, corticosteroids, azathioprine
Surgical – most patients undergo some degree of resection
Crohn’s patients present with many of the same features as ulcerative colitis patients with variable abdominal pain and diarrhea, but they can show more malabsorption due to more frequent small bowel involvement. In some patients, Crohn’s can be inherently indolent, in which there is no evidence of perforation and it can be slow and recurring, or inherently aggressive, with perforation and rapidly evolving disease. Crohn’s is complicated in some patients by perforations, fistula tracts, abscesses, obstruction due to stricture, and toxic megacolon. Again, like ulcerative colitis, dysplasia and carcinoma can occur with 5% of patients develop GI carcinoma, and small bowel cancer risk is increased 10-20x normal. Treatment is with corticosteroids or other immunosuppressants, and surgical treatment can be performed in many patients to relieve symptoms with most patients undergoing some degree of resection at some point in time.

17. Ulcerative Colitis Idiopathic
F>M, increased incidence in European descent
Three peaks of incidence
Early 20s, early 40s, and early 60s
Associations
Perinuclear antineutrophil cytoplasmic antibodies (p-ANCA) – UC > Crohn’s
Arthralgias
Primary Sclerosing Cholangitis
5% of UC patients have PSC
70% of PSC patients have UC
Ulcerative colitis (or UC) is an idiopathic disease predominantly seen in females and patients with European descent. It typically shows three peaks: the early 20s, early 40s, and the early 60s. It is associated with perinuclear antineutrophil cytoplasmic antibodies (or p-ANCA), as seen in this image. Patients with ulcerative colitis can have arthralgias and primary sclerosing cholangitis (or PSC). The important fact about PSC to remember is that while only 5% of UC patients have PSC, 70% of PSC patients have UC.

18. Ulcerative Colitis Anatomic Findings Classically involves only colon
Contiguous involvement by inflammation
Rectum usually involved
“Backwash ileitis” and appendiceal involvement can occur in continuity with pancolitis
No strictures, fistulae, serositis, or fat wrapping
Ulcerative colitis classically shows involvement of the colon in a contiguous fashion usually involving the rectum. “Backwash ileitis” and appendiceal involvement can occur in continuity with pancolitis. No strictures, fistulae, serositis, or fat wrapping are usually seen.

19. Ulcerative Colitis Anatomic Findings Acute activity Chronic changes
Mucosal erythema and bleeding
Oozing shallow ulcers (no deep fissuring ulcerations)
Chronic changes
Loss of normal vascular pattern
Loss of mucosal folds
Mucosal granularity
When active, mucosal erythema and bleeding as well as oozing shallow ulcers can be seen, excluding deep fissuring ulcers. Chronic changes of ulcerative colitis can include a loss of the normal vascular pattern, a loss of mucosal folds, and mucosal granularity, even in the absence of acute inflammation.

20. Ulcerative Colitis Microscopic Findings Active colitis Chronic colitis
Cryptitis
Crypt abscess formation
Mucosal ulceration
Inflammatory pseudopolyps
Chronic colitis
Increased lymphoplasmacytic lamina propria infiltrate
Architectural distortion
Branched, dilated irregular crypts
Crypts no longer reach the muscularis mucosae
Paneth cell metaplasia in left colon
Under the microscope, active ulcerative colitis is again typified by cryptitis, crypt abscess formation, mucosal ulceration, and, in some cases, inflammatory pseudopolyps. Chronic mucosal changes again include Paneth cell metaplasia in the left colon, increased lymphoplasmacytic lamina propria infiltrate, and architectural distortion showing branched, dilated, and irregular crypts no longer reaching the muscularis mucosa.

21. Ulcerative Colitis Clinical Course
Abdominal pain, diarrhea, urgency, weight loss
Classically characterized by periods of remission and relapse (“UC flares”)
Distal disease (proctitis) at presentation, may continue as limited or may spread
Patients with ulcerative colitis have abdominal pain, diarrhea, urgency, and weight loss and classically, their course is characterized by periods of remission and relapse, or “UC flares.”

22. Ulcerative Colitis Clinical Course Treatment Complications
Toxic megacolon – dilated colon with decreased motility and thinning of wall
Colitis-associated dysplasia – markedly increased risk of dysplasia, 1-2% risk of carcinoma each year
Treatment
Pharmaceutical – 5-ASA, corticosteroids, azathioprine
Surgical – definitive operation, total abdominal colectomy with ileal pouch-anal anastomosis
Ulcerative colitis can be complicated by toxic megacolon, which is a large dilated colon with decreased motility and thinning of the wall, or colitis-associated dysplasia, which leads to a 1-2% risk of carcinoma each year for ulcerative colitis patients. Treatment of ulcerative colitis can be pharmaceutical, with corticosteroids and other immunosuppressants, or it can be definitively treated by a total abdominal colectomy.

23. Let’s take a second to examine this picture which shows some of the distinguishing features of Crohn’s disease and ulcerative colitis. The left column highlights a drawing as well as microscopic and endoscopic pictures of normal colon. The middle column highlights findings in Crohn’s disease, including fat wrapping and cobblestone mucosa with ulceration. The right column highlights findings in ulcerative colitis, including ulceration, pseudopolyps, and crypt distortion.

24. Small Bowel - Malabsorption
Introduction
Abnormality in absorption of food nutrients across small bowel
Impairment can be of single or multiple nutrients
Increased fat excretion, with variable deficiencies of vitamins, proteins, carbohydrates, minerals and water
Mechanism may be decreased digestion, decreased absorption or decreased transport of absorbed products
Clinically, patients may show weight loss, anorexia, abdominal distension, borborygmi, diarrhea and/or vitamin deficiencies
Malabsorption is an abnormality in the absorption of food nutrients across the small bowel. Impairment can be of a single nutrient or multiple nutrients. Symptoms can include increased fat excretion with variable deficiencies of vitamins, proteins, carbohydrates, minerals, and water. The mechanism of malabsorption may be decreased digestion, decreased absorption, or decreased transport of absorbed products. Clinically, patients may show weight loss, anorexia, abdominal distention, diarrhea, or vitamin deficiencies.

25. Small Bowel - Malabsorption
Celiac disease
Gluten-sensitive enteropathy due to hypersensitivity to gliadin
HLA-DQ2 or HLA-DQ8
Dx: Tissue transglutaminase
Endoscopy:
Mucosal scalloping
Loss of mucosal folds
Microscopy:
Increased intraepithelial T lymphocytes,
Villous blunting
Increased lamina propria plasma cells
Treatment: Avoid gluten
Associated with Enteropathy-associated T cell lymphoma
Normal
One cause of malabsorption is celiac disease. Celiac disease is a gluten-sensitive enteropathy caused by hypersensitivity to gliadin, a protein constituent of gluten. Celiac shows a hereditary tendency, with virtually all patients showing HLA-DQ2 or HLA-DQ8. Diagnosis of celiac disease is made by tissue biopsy and tissue transglutaminase. Endoscopically, the small bowel shows mucosal scalloping and a loss of folds. Under the microscope, we see increased intraepithelial T lymphocytes, villous blunting, and increased lamina propria plasma cells. Treatment for celiac is by a gluten-free diet, and patients with celiac disease have an increased risk of developing enteropathy-associated T-cell lymphoma.
Celiac disease

26. Small Bowel - Malabsorption
Tropical Sprue
Similar morphology to Celiac disease, but different disease process
Thought to be secondary to aerobic bacterial contamination of small bowel
Clinical Course: diarrhea, weight loss, B12/folate deficiency
Endemic to Caribbean, Columbia, Mexico, India and SE Asia
Microscopic Findings
Increased intraepithelial lymphocytes with variable villous blunting
Treatment
Tetracycline and folate for 6 months
Tropical sprue is so named for its histologic similarities to celiac disease. However, other than the histology, it is entirely different. Tropical sprue is thought to be secondary to bacterial contamination of the small bowel. Its clinical course includes diarrhea, weight loss, and vitamin B12 and folate deficiencies. Tropical sprue is endemic to the Caribbean, Mexico, India, and SE Asia. Microscopically, you can see why this is considered similar to celiac disease as it shows increased intraepithelial lymphocytes, though it only shows variable villous blunting. Treatment includes tetracycline and folate supplement for 6 months.

27. Small Bowel - Malabsorption
Whipple’s disease
Infection by Tropheryma whippelii bacillus
Bacilli in macrophages and cells throughout body
Caucasian middle-age males; association with HLA-B27
Clinical Course: malabsorption, fever, arthralgia, enlarged lymph nodes
Gross: thickened and blunted mucosal folds
Micro: Massive infiltration of lamina propria by foamy macrophages containing PAS-positive granules (bacilli)
Treatment with long-term antibiotics
Whipple’s disease was described by Dr. George Hoyt Whipple, a famous pathologist, in 1907; however, it was not until 1991 that the bacilli which cause this infection were named. This disease is caused by an infection with Tropheryma whippelii, a bacillus that lives in macrophages and cells throughout the body. The disease usually presents in Caucasian middle-aged males and is associated with HLA-B27. The clinical course is that of malabsorption, fever, arthralgia, and enlarged lymph nodes, and grossly, we see thickened and blunted mucosal folds. Microscopically, massive infiltration of the lamina propria by foamy macrophages containing PAS-positive bacilli is noted. Treatment for Whipple’s disease involves long-term antibiotics.

28. Small Bowel - Malabsorption
Other Etiologies
Bacterial overgrowth – non-specific villous blunting, often due to decreased motility
Disaccharidase deficiency – absorption evident with milk feeding, which causes explosive, watery, frothy stools and abdominal distension
Abetalipoproteinemia – defect in synthesis and export of apoprotein B from intestinal mucosal cells
Microvillous inclusion disease – defect in intestinal cytoskeleton; clear vacuoles in surface epithelium
Other etiologies of malabsorption include, but are not limited to, bacterial overgrowth, disaccharidase deficiency, abetalipoproteinemia, and microvillous inclusion disease.

29. Small Bowel – Tumors < 6% GI tumors Benign Malignant Leiomyoma
Adenoma
Malignant
Adenocarcinoma
Neuroendocrine
Lymphoma
Sarcoma
Small bowel tumors are relatively rare, accounting for less than 6% of GI tumors. These tumors can be benign, including leiomyomas, lesions composed of spindled smooth muscle cells, or adenomas, low grade dysplastic lesions similar to those seen in the colon and can progress to carcinomas. Malignant tumors of the small bowel include adenocarcinomas, showing the distinctive malignant glands that were addressed in other organ systems, or neuroendocrine tumors, formerly called carcinoid tumors. Neuroendocrine tumors are composed of nests or trabeculae of well differentiated cells with abundant cytoplasm and large nuclei containing distinctive “salt-and-pepper” chromatin. Less commonly, lymphomas and sarcomas can also involve the small bowel.

30. SUMMARY
Meckel’s diverticulum - failure of involution of omphalomesenteric duct, distal ileum, rule of 2’s
Celiac disease – hypersensitivity to gliadin, ↑ tTG, ↑ intraepithelial lymphocytes and villous blunting
Tropical sprue – endemic, infectious etiology, increased intraepithelial lymphocytes with variable villous blunting
Whipple's disease - Tropheryma whippelii, foamy macrophages in the lamina propria
Crohn's disease - patchy distribution, cobblestone pattern, full thickness inflammatory extension
Neoplasms – adenoma, adenocarcinoma, NET
In summary, there are many disease processes that can involve the small intestine. To name a few, Meckel’s diverticulum is a congenital anomaly caused by failure of involution of the omphalomesenteric duct usually occurring in the distal ileum. Don’t forget the rule of 2’s for Meckel’s diverticulum. Celiac disease is caused by a hypersensitivity to gliadin with increased tissue transglutaminase, and the hallmark microscopic findings are increased intraepithelial lymphocytes and villous blunting. Tropical sprue, on the other hand, is infectious in etiology and may or may not have villous blunting. Whipple’s disease is also infectious in etiology, caused by Tropheryma whippelii, and microscopically shows foamy macrophages in the lamina propria. Crohn’s disease is one of the two main types of inflammatory bowel disease, and some common features include patchy distribution throughout the gastrointestinal tract, cobblestone mucosa, and full-thickness inflammatory extension. Although small intestinal tumors are rare, some common entities include tubular adenoma, adenocarcinoma, and neuroendocrine tumors.

31. Test Your Knowledge!
It’s time again to test your knowledge with the following review questions.

32. Small Intestine

33. Small Intestine 2

34. Small Intestine 3

35. Please send questions to
THANK YOU
This ends the lecture on small intestinal pathology. Again, if you have any questions, please send them to
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