Pbl Exam 9 Case 1-2

Front 1

1. What is idiopathic inflammatory bowel disease?

What are the two disorders in this classification?

Back 1

This is a set of chronic inflammatory conditions resulting from inappropriate and persistent activation of the mucosal immune system, driven by the presence of normal intraluminal flora.

The two disorder known as IBD are Crohn disease and ulcerative colitis.

These diseases share many common features but have distinctly different clinical manifestations.

Both CD and UC are chronic, relapsing inflammatory diseases of obscure origin. CD is an autoimmune disease that may affect any portion of the GI tract from esophagus to anus, but most often involves the distal small intestine and colon. UC is a chronic inflammatory disease limited to the colon and rectum. Both exhibit extraintestinal inflammatory manifestations.

Front 2

2. What is the pathogenesis of IBD?

What are the two key abnormalities?

Back 2

In IBD, the normal immune properties of the GI tract are disrupted, leading to two key pathogenic abnormalities: (1) strong immune responses against normal flora, and (2) defects in epithelial barrier function.

It is postulated that IBD results from unregulated and exaggerated local immune responses to commensal microbes in the gut, in genetically susceptible individuals. Thus, it involves failure of immune regulation, genetic susceptibility, and environmental triggers.

Front 3

3. What are the genetic susceptibility components to IBD?

Back 3

HLA associations: HLA-DR1/DR1/DQw5 allelic combination has been observed in 27% of white patients with CD, whereas HLA-DR2 is increased in patients with UC.

A gene called NOD2 *nucleotide-binding oligomerization domian) has recently been shown to be associated with CD.

Front 4

4. What does the NOD2 protein do?

Back 4

The NOD2 protein is expressed in many types of leukocytes as well as epithelial cells, and is thought to function as an intracellular receptor for microbes.

Upon binding microbial components, it may trigger the NF-κB pathway; recall that NF-κB is a transcription factor that triggers the production of cytokines and other proteins involved in innate immune defense against infectious pathogens.

Front 5

5. How are NOD2 mutations associated with CD?

Back 5

The NOD2 mutations that are associated with CD may reduce the activity of the protein, resulting in the persistence of intracellular microbes and uncontrolled, prolonged immune responses.

Front 6

6. What is the role of intestinal flora in IBD?

Back 6

Animal studies have definitively established the importance of gut flora in IBD. If gene-knockout mice that normally develop IBD are made germ-free, the disease disappears. However, the hunt for a specific microbe as the underlying cause has been largely fruitless.

There is also no clear evidence that reducing intestinal flora has a beneficial effect on the course of IBD in humans. Microbes could exacerbate immune reactions by providing antigens and inducing costimulators and cytokines, all of which contribute to T-cell activation. Defects in the barrier function of the intestinal epithelium could allow luminal flora to gain access to the mucosal lymphoid tissue, and thus trigger immune responses.

Front 7

7. What is the responsible party in the exaggerated local immune responses in IBD?

Back 7

It is believed that the exaggerated local immune response in IBD is a consequence of too much T-cell activation and/or too little control by regulatory T lymphocytes.

In both CD and UC, the prime culprits appear to be T-cells, particular CD4+ T-cells, and the lesions are likely caused by T-cells and their products.

Although antibodies against certain self-antigens, such as tropomyosin, have been detected in some patients with UC, it is not clear if these autoantibodies play a pathogenic role.

Front 8

8. What is the autoimmune basis behind CD?

Why?

Back 8

CD appears to be the result of a chronic delayed-type hypersensitivity reaction induced by IFN-γ-producing TH1 cells.

The nature of the inflammatory infiltrate, especially the presence of granulomas, is consistent with a TH1 response.

Front 9

9. What is the autoimmune basis behind UC?

Back 9

Although animal models suggest that ulcerative colitis is caused by excessive activation of TH2 cells, in human disease the signature TH2 cytokine, IL-4, has not been found in the lesions.

It may be that the lesions are caused by an atypical TH2 response, or that there is no consistent pattern of T cell activation or dominant cytokine production.

Front 10

10. How can we Dx IBD?

Back 10

Since the exact etiology of IBD is not known, the diagnosis of IBD and the distinction between CD and UC are dependent on clinical history, radiographic examination, laboratory findings, and pathologic examination of tissue. There is no single test upon which a diagnosis is made. Even with the best efforts, the distinction between the two diseases still cannot be made in some cases.

Pathologic appearance, both macroscopic and microscopic, plays a central role in establishing a definitive diagnosis.

Front 11

11. What two antibody tests are useful for the Dx of IBD?

Back 11

The pANCA (perinuclear antineutrophilic cytoplasmic antibody) is positive in 75% of patients with UC and in only 11% with CD.

Another test detects an antibody against the cell wall mannan polysaccharide of Saccharomyces cerevisiae (ASCA). This antibody appears to be elevated in CD patients. The clinical utility of these tests remains to be proven.

Front 12

12. What is Crohn disease?

What are the 3 pathological characterizations?

Back 12

When fully developed, CD is characterized pathologically by:

1. Sharply delimited and typically transmural involvement of the bowel by an inflammatory process w/mucosal damage
2. The presence of noncaseating granulomas
3. Fissuring w/formation of fistulae

Front 13

13. What is the prevalence of CD?

Back 13

3/100,000

It occurs at any age, from young childhood to advanced age, but peak ages of detection are the second and third decades of life with a minor peak in the sixth and seventh decades. Females are affected slightly more often than males. Whites appear to develop the disease two to five times more often than do nonwhites. In the United States, CD occurs three to five times more often among Jews than among non-Jews. Smoking is a strong exogenous risk factor.

Front 14

14. What is the morphology of CD?

Back 14

In CD, there is gross involvement of the small intestine alone in about 40% of cases, of small intestine and colon in 30%, and of the colon alone in about 30%. CD may involve the duodenum, stomach, esophagus, and even mouth, but these sites are distinctly uncommon.

In diseased bowel segments, the serosa is granular and dull gray, and often the mesenteric fat wraps around the bowel surface (creeping fat). The mesentery of the involved segment is also thickened, edematous, and sometimes fibrotic.

*The intestinal wall is rubbery and thick, as a consequence of edema, inflammation, fibrosis, and hypertrophy of the muscularis propria. As a result, the lumen is almost always narrowed; in the small intestine this is evidenced on xrays as the "string sign", a thin stream of barium passing thru the diseased segments. Strictures may occur in the colon but are usually less severe.***

Front 15

15. What is a classic feature of Crohn disease?

Back 15

The sharp demarcation of diseased bowel segments from adjacent uninvolved bowel.

When multiple bowel segments are involved, the intervening bowel is essentially normal ("skip" lesions).

Front 16

16. What is a characteristic sign of early CD?

Back 16

Focal mucosal ulcers resembling canker sores (aphthous ulcers), edema, and loss of the normal mucosal texture.

Front 17

17. What happens as CD develops?

Back 17

With progressive disease, mucosal ulcers coalesce into long, serpentine linear ulcers, which tend to be oriented along the axis of the bowel. As the intervening mucosa tends to be relatively spared, the mucosa acquires a coarsely textured, cobblestone appearance.

*Narrow fissures develop between the folds of the mucosa, often penetrating deeply thru the bowel wall and leading to bowel adhesions and serositis.

Further extension of fissures leas to fistula or sinus tract formation, either to an adherent viscus, to the outside skin, or into a blind cavity. Free perforation or localized abscesses may also develop.

Front 18

18. What are the six histologic changes in CD?

Back 18

1. Mucosal inflammation
2. Chronic mucosal damage
3. Ulceration
4. Transmural inflammation affecting all layers
5. Noncaseating granulomas
6. Other mural changes

Front 19

19. Mucosal inflammation in CD

Back 19

The earliest lesion in CD appears to be focal neutrophilic infiltration into the epithelial layer, particularly overlying mucosal lymphoid aggregates. As the disease becomes more established, neutrophils infiltrate isolated crypts; when a sufficient number of neutrophils have traversed the epithelium of a crypt (both in the small and large intestines), a CRYPT ABSCESS is formed, usually w/ultimate destruction of the crypt.

Front 20

20. Chronic mucosal damage in CD

Back 20

The hallmark of inflammatory bowel disease, both CD and UC, is chronic mucosal damage.

Architectural distortion is manifested in the small intestine as variable villus blunting; in the colon, crypts exhibit irregularity and branching. The degree of the glandular architectural distortion in CD is usually less severe than in UC.

Crypt destruction leads to progressive atrophy, particularly in the colon. The mucosa may undergo metaplasia; this may take the form of gastric antral type glands (pyloric metaplasia) or the development of Paneth cells in the distal colon, where they are normally absent (Paneth cell metaplasia).

Front 21

21. Ulceration in CD

Back 21

Ulceration is the usual outcome of severe active disease. It may be superficial, may undermine adjacent mucosa in a lateral fashion, or may penetrate deeply into underlying tissue layers.

There is often an abrupt transition between ulceration and adjacent normal mucosa.

Front 22

22. Noncaseating granulomas in CD

Back 22

In about 1/2 of the cases, sarcoid-like granulomas may be present in all tissue layers, both w/in areas of active disease and in uninvolved regions of the bowel.

Granulomas have been documented throughout the GI tract, from mouth to rectum, in patients with CD limited to one bowel segment.

Conversely, the absence of granulomas does not preclude the Dx of CD.

Front 23

23. What are the other mural changes in CD?

Back 23

In diseased segments, the muscularis mucosa usually exhibits reduplication, thickening, and irregularity.

Fibrosis of the submucosa, muscularis propira, and mucosa eventually leads to stricture formation.

Less common findings are mucosal and submucosal lymphangiectasia, hypertrophy of mural nerve fibers, and localized vasculitis.

Front 24

24. What are the clinical features of CD?

Back 24

The clinical manifestations of Crohn disease are extremely variable. They are generally more subtle than those of UC. The disease usually begins with intermittent attacks of relatively mild diarrhea, fever, and abdominal pain, spaced by asymptomatic periods lasting for weeks to many months.

Often the attacks are precipitated by periods of physical or emotional stress. Although emotional influences are thought not to have any direct role in the initiation of the disease, they may contribute to flare-ups.

In those with colonic involvement, occult or overt fecal blood loss may lead to anemia over time, but massive bleeding is uncommon.

In about one-fifth of patients the onset is more abrupt, with acute right lower quadrant pain, fever, and diarrhea sometimes suggesting acute appendicitis or an acute bowel perforation. The course of the disease includes bouts of diarrhea with fluid and electrolyte losses, weight loss, and weakness.

Front 25

25. What complications may arise from long term CD?

Back 25

Fribrosing strictures, particularly of the terminal ileum, and fistulas to other loops of bowel, the urinary bladder, vagina, or perianal skin, or into a peritoneal abscess.

Extensive involvement of the small bowel, including the terminal ileum, may cause marked loss of albumin, generalized malabsorption, specific malabsorption of B12, or malabsorption of bile salts, leading to steatorrhea.

Front 26

26. What are ten extraintestinal manifestations of CD?

Back 26

1. Migratory polyarthritis
2. Sacroiliitis
3. Ankylosing spondylitis
4. Erythema nodosum
5. Clubbing of the fingertips
6. Hepatic primary sclerosing cholangitis occurs, but the association is not as strong as in UC
7. Uveitis
8. Nonspecific mild hepatic pericholangitis
9. Renal disorders secondary to trapping of the ureters in the inflammatory process sometimes develop
10. Systemic amyloidosis is a rare late complication

Front 27

27. What is ulcerative colitis?

How is it similar/different to CD?

Back 27

UC is an ulceroinflammatory disease limited to the colon and affecting only the mucosa and submucosa except in the most severe cases.

Unlike CD, UC extends in a continuous fashion proximally from the rectum. Well-formed granulomas are absent. Like CD, UC is a systemic disorder associated in some patients with migratory polyarthritis, sacroiliitis, akylosing spondylitis, uveitis, hepatic involvement, and skin lesions.

Front 28

28. What is the prevalence of UC?

Back 28

4-12/100,000

In the United States it is more common among whites than among blacks, and females are affected more often than males. The onset of disease peaks between ages 20 and 25, but the condition may arise in both younger and considerably older individuals.

Nonsmoking is associated with UC; ex-smokers are at higher risk for developing UC than never-smokers.

Front 29

29. What is the morphology of UC?

Back 29

UC involves the rectum and extends proximally in a retrograde fashion to involve the entire colon ("pancolitis") in the more severe cases.

***It is a disease of continuity and no skip lesions are found. In 10% of those with severe pancolitis, the distal ileum may develop mucosal inflammation ("backwash ileitis"). This is probably due to the incompetence of the iliocecal valve, resulting in reflux of the inflammatory material from the colon.

In contrast to CD, the ileitis is often diffuse and limited to within 25 cm from the ileocecal valve. The appendix may be involved w/both CD and UC.

Front 30

30. What is the colonic involvement with UC like as the disease progresses?

1/2

Back 30

In the course of the colonic involvement w/UC, the mucosa may exhibit slight reddening and granularity w/friability and easy bleeding. W/fully developed severe active inflammation, there may be extensive and broad based ulceration of the mucosa int eh distal colon or throughout its length.

Isolated islands of regenerating mucosa bulge upward to create pseudopolyps. Often the undermined edges of adjacent ulcers interconnect to create tunnels covered by tenuous mucosal bridges.

Front 31

31. What is the colonic involvement with UC like as the disease progresses?

2/2

Back 31

As with CD, the ulcers of UC are frequently aligned along the axis of the colon, but rarely do they replicate the linear serpentine ulcers of CD.

With indolent chronic disease or with healing of active disease, progressive mucosal atrophy leads to a flattened and attenuated mucosal surface.

Unlike CD, mural thickening does not occur in UC, and the serosal surface is usually completely normal. Only in the most severe cases of ulcerative disease (UC, CD, and other severe inflammatory diseases) does toxic damage to the muscularis propria and neural plexus lead to complete shutdown of neuromuscular function. In this instance the colon progressively swells and becomes gangrenous (toxic megacolon)

Front 32

32. What is the course of mucosal inflammation in UC?

Back 32

First, a diffuse predominantly mononuclear inflammatory infiltrate in the lamina propria is almost universally present, even at the time of clinical presentation. Neutrophilic infiltration of the epithelial layer may produce collections of neutrophils in crypt lumina (crypt abscesses). These are not specific for UC and may be observed in CD or any active inflammatory colitis. Unlike CD, there are no granulomas, although rupture of crypt abscesses may incite a foreign body reaction in the lamina propria.

Second, further destruction of the mucosa leads to outright ulceration, extending into the submucosa and sometimes leaving only the raw, exposed muscularis propria.

Third, with remission of active disease, granulation tissue fills in the ulcer craters, followed by regeneration of the mucosal epithelium. Submucosal fibrosis and mucosal architectural disarray and atrophy remain as residua of healed disease.

Front 33

33.What is a key feature of UC?

Back 33

The mucosal damage is continuous from the rectum and extending proximally.

In CD, mucosal damage in the colon may be continuous but is just as likely to skip areas. It should be noted that quiescent UC, particularly treated disease in which active neutrophilic inflammation is not present, may appear virtually normal histologically. This does not preclude risk for dysplasia.

Front 34

34.What is a significant consequence of UC?

Back 34

The spectrum of epithelial changes signifying dysplasia and the progression to frank carcinoma. Nuclear atypia and loss of cytoplasmic differentiation may be present in inflamed or uninflamed colonic mucosa. Epithelial dysplasia is referred to as being low-grade or high-grade; cytologic features are the key to evaluating dysplasia.

Distinguishing between regenerative changes and dysplasia can be very difficult and sometimes impossible. Plaque-like dysplastic lesions, overt polypoid dysplasia (adenomas), or invasive carcinoma are the ultimate lesions arising from flat dysplasia. It should be noted that elderly patients with UC are also at risk for sporadic adenomas.

Distinction between IBD-associated dysplasia and a coexistent incidental adenoma may be difficult.

Front 35

35. What are the clinical features of UC?

Back 35

UC typically presents as a relapsing disorder marked by attacks of bloody mucoid diarrhea that may persist for days, weeks, or months and then subside, only to recur after an asymptomatic interval of months to years or even decades. If you're lucky, the first attack is your last.

At the other end, the explosive initial attack may lead to such serious bleeding and fluid and electrolyte imbalance as to constitute a medical emergency.

In most patients, bloody diarrhea containing stringy mucus, accompanied by lower abdominal pain and cramps usually relieved by defecation, is the first manifestation of the disease.

In a small number of paitnets, constipation may appear paradoxically due to disruption of normal peristalsis.

Front 36

36. What can cause UC to begin?

Back 36

Often the first attack is preceded by a stressful period in the patient's life. Spontaneously, or more often after appropriate therapy, these symptoms abate in the course of days to weeks.

Flare-ups, when they do occur, may be precipitated by emotional or physical stress and rarely by concurrent intraluminal growth of enterotoxin-forming C. difficile.

Sudden cessation of bowel function with toxic dilatation (toxic megacolon) rarely develops with severe acute attacks; perforation is a potentially lethal event.

Front 37

37. What two factors determine the prognosis of those w/UC?

Back 37

1. The severity of the active disease
2. Its duration

About 60% of patients have clinically mild disease. In these individuals, the bleeding and diarrhea are not severe, and systemic signs and symptoms are absent. However, almost all patients (97%) have at least one relapse during a 10-year period, and about 30% of patients require colectomy within the first 3 years of onset due to uncontrollable disease. On rare occasion, the disease runs a fulminant course; unless medically or surgically controlled, this toxic form of the disease can lead to death soon after onset.

Front 38

38. What is the most feared long-term complication of UC?

Back 38

Cancer.

There is a tendency for dysplasia to arise in multiple sites, and the underlying inflammatory disease may mask the symptoms and signs of carcinoma.

UC is characterized by DNA damage with microsatellite instability in mucosal cells. More recently, genomic instability was detected in non-dysplastic areas of patients with UC, suggesting that these patients have DNA repair deficiency and genomic instability throughout the intestinal tract.

The associated carcinomas are often infiltrative without obvious exophytic masses, further underscoring the importance of early diagnosis.

Front 39

39. What is ischemic bowel disease?

Back 39

Acute occlusion of one of the three major supply trunks of the intestines, celiac, SMA, and IMA, may lead to infarction of several meters of intestine.

Severity of injury ranges from:
1. Transmural infarction (most severe)
2. Mural infarction
3. Mucosal infarction

*Almost always, transmural infarction is caused by mechanical compromise of the major mesenteric blood vessels.

Front 40

40. What are the five predisposing condition for bowel ischemia?

Back 40

1. Arterial thrombosis
2. Arterial embolism
3. Venous thrombosis
4. Nonocclusive ischemia
5. Misc

Front 41

41. An embolic arterial occlusion most often involves which of the three major vessels?

Why?

Back 41

Embolic arterial occlusion most often involves the branches of the SMA.

The origin of the IMA from the artery is more oblique and this may contribute to the relative sparing of this arterial axis from embolism.

Front 42

42. What are the two phases of ischemic injury?

Which is more harmful?

Back 42

1. Initial hypoxic injury
2. Secondary reperfusion

Most of the intestinal injury in ischemic bowel disease is actually caused by reperfusion.

Among the most important factors in this process are the generation of oxygen free radicals, neutrophil infiltration, and the production of inflammatory mediators in tissue that has insufficient metabolic reserve to detox injurious free radicals and other mediators.

Front 43

43. What ares of the bowel are at greatest risk of bowel infarction?

Back 43

Small intestinal infarction following sudden and total occlusion of mesenteric arterial blood flow may involve only a short segment, but more often involves a substantial portion.

The splenic flexure of the colon is at greatest risk of ischemic injury b/c it is the watershed between the distribution of the SMA and IMA.

Front 44

44. What is the morphology of "transmural" infarction?

1/2

Back 44

Regardless of whether the arterial or venous side is occluded, the infarction appears hemorrhagic b/c of blood reflow into the damaged area. In the early stages, the infarcted bowel appears intensely congested and dusky to purple-red, with foci of subserosal and submucosal ecchymotic discoloration. With time,t he wall becomes edematous, thickened, rubbery, and hemorrhagic.

Front 45

45. What is the morphology of "transmural" infarction?

2/2

Back 45

Histologically, there is obvious edema, interstitial hemorrhage, and sloughing necrosis of the mucosa. Normal features of the mural musculature, particularly cellular nuclei, become indistinct. Within 1-4 days, intestinal bacterial produce gangrene and sometimes perforation of the bowel.

Front 46

46. How do arterial occlusions appear morphologically compared to venous occlusions?

Back 46

In arterial occlusions the demarcation from normal bowel is usually sharply defined.

In venous occlusions the area of dusky cyanosis fades gradually into the adjacent normal bowel, having no clear-cut definition between viable and nonviable bowel.

Front 47

47. What is the morphology of "mucosal and mural" infarction?

1/2

Back 47

Mucosal and mural infarction may involve any level of the gut from the stomach to the anus. The lesions may be multifocal or continuous and widely distributed. Affected areas may appear dark red or purple.

On opening the bowel, there is hemorrhagic, edematous thickening of the mucosa, which may penetrate more deeply into the submucosa and muscle wall. Superficial ulceration may be present.

Front 48

48. What is the morphology of "mucosal and mural" infarction?

2/2

Back 48

In the mildest form of ischemic injury, the superficial epithelium of the colon or the tips of the small intestinal villi may be necrotic or sloughed. Inflammation is absent.

With complete mucosal necrosis, epithelial sloughing leaves behind only the acellular scaffolding of the lamina propria. When severe, there is extensive hemorrhage and necrosis of multiple tissue layers. Bacterial infections may induce superimposed pseudomembranous inflammation, particularly in the colon.

Front 49

49. What is the morphology of chronic bowel ischemia?

Back 49

With chronic vascular insufficiency to a region of intestine, mucosal inflammation and ulceration may develop, mimicking both acute enterocolitis from other causes and idiopathic IBD. Submucosal chronic inflammation and fibrosis may lead to stricture.

Although colonic structures typically occur in the watershed area of the splenic flexure, both acute and chronic mucosal ischemia are notoriously segmental and patchy.

Front 50

50. What are the clinical features of bowel ischemia?

Back 50

Total bowel infarction has a 50-75% mortality rate. It tends to occur in older individuals, when cardiac and vascular diseases are most prevalent. Typically occurring in severely ill patients, it presents as severe abdominal pain, bloody diarrhea, or gross medlema, nausea, vomiting, bloating, and abdominal wall rigidity.

With incomplete infarction, there are nonspecific abdominal complaints.

Front 51

51. What are 3 clinical conditions that cause ischemic intestinal injury?

Back 51

1. Severe atherosclerosis of the aorta and mesenteric vasculature. Cholesterol emboli dislodged from large vessels occlude smaller vessels downstream.

2. Vasculitis affecting the mesenteric vasculature may cause ischemic injury. The commonly seen vasculatides that affect the intestine are polyarteritis nodosum, Hemoch-Schonlein disease, and Wegener granulomatosis.

3. Amyloidosis often present as chronic intestinal ischemia.

Front 52

52. What is an angiodysplasia?

Back 52

Angiodysplasia is a non-neoplastic intestinal lesion of vascular dilation and malformation. These dilations of submucosal and mucosal blood vessels are seen most often in the cecum or right colon, usually only after the 6th decade of life.

Although they are rare, they account for 20% of significant lower intestinal bleeding; intestinal hemorrhage may be chronic and intermittent, or acute and massive.

Front 53

53. What is the pathogenesis of angiodysplasia?

Which part of the bowel has the greatest wall tension?

Back 53

Acquired ectasias are attributed to partial, intermittent occlusion of submucosal veins. These occur largely in the cecum.

B/c the cecum has the widest diameter of the colon, it develops the greatest wall tension, perhaps explaining the distribution of these lesions.

Front 54

54. What is the morphology of hemorrhoids?

Back 54

The varicosities may develop in the inferior hemorrhoidal plexus and thus are located below the anorectal line (external hemorrhoids). Alternatively, they may develop from dilation of the superior hemorrhoidal plexus and produce internal hemorrhoids. Commonly, both plexuses are affected.

Histologically, these lesions consist only of thin-walled, dilated, submucosal varices that protrude beneath the anal or rectal mucosa. In their exposed, traumatized position, they tend to become thrombosed, and in the course of time, recanalized. Superficial ulceration, fissure formation, and infarction w/strangulation may develop.

Front 55

55. Where is the most common site for diverticula?

In which population do they most commonly occur?

Back 55

Acquried diverticula may occur in the esophagus, stomach, and duodenum, but the most common site is the left side of the colon, w/the majority in the sigmoid colon.

Colonic diverticula are rare in persons under the age of 30, but in Western adult populations over 60 the prevalence approaches 50%. They generally occur multiply and are referred to as diverticulosis.

Front 56

56. What is the morphology of colonic diverticula?

Back 56

Most colonic diverticula are small, flask-like or spherical outpouchings, usually .5 - 1 cm in diamtere and located int eh sigmoid colon. They tend to occur alongside the taeniae coli and are elastic, compressible, and easily emptied of fecal contents.

Histologically, they have a thin wall composed of a flattened or atrophic mucosa, compressed submucosa, and attenuated or totally absent muscularis propria. Hypertrophy of the circular layer of the muscularis propria in the affected bowel segment is usually seen.

Front 57

57. Obstruction and/or perforation of diverticula leads to...?

Back 57

Inflammatory changes, producing peridiverticulitis and dissecting into the immediately adjacent pericolic fat. In time, the inflammation may lead to marked fibrotic thickening in and about the colonic wall, sometimes producing narrowing sufficient to resemble a colonic cancer.

Front 58

58. What two factors are important in the pathogenesis of colonic diverticula?

Back 58

1. Focal weakenss in the colonic wall
-The colon is unique in that the longitudinal muscle coat is not complete, providing points of weakness for herniations.

2. Increased intraluminal pressure
Exaggerated peristaltic contractions, with spasmodic sequestration of bowel segments are the likely cause of increased intraluminal pressure.

Front 59

59. What are the clinical features of colonic diverticula?

Back 59

Most individuals remain asymptomatic, but may be associated with cramping, abdominal discomfort, and constipation. Diverticulitis can result in pericolic abscesses, sinus tracts, and peritonitis.

Front 60

60. What are the four categories of intestinal obstruction?

What are the clinical manifestations of intestinal obstruction?

Back 60

1. Hernias
2. Intestinal adhesions
3. Intussusceptions
4. Volulus

The clinical manifestations are abdominal pain and distention, vomiting, constipation and failure to pass flatus.

Front 61

61. What are hernias, and where do they commonly occur?

Back 61

A weakness or defect in the wall of the peritoneal cavity may permit protrusion of a pouch-like, serosa-lined sac of peritoneum called a hernial sac. The usual sites of such weakness are anterior at the inguinal and femoral canals, umbilicus, and in surgical scars. Rarely, retroperitoneal hernias may occur, chiefly about the ligament of Trietz.

Front 62

62. Why are hernias a concern?

Back 62

Segments of viscera frequently protrude and become trapped in them. This is particularly true to inguinal hernias. The most frequent intruders are small bowel loops, but portions of omentum or large bowel also may become trapped. Pressure at the neck of the pouch may impair venous drainage of the trapped viscus. The resultant stasis and edema increase the bulk of the herniated loop, leading to permanent trapping or incarceration.

With time, compromise of arterial supply and venous drainage (strangulation) leads to infarction of the trapped segment.

Front 63

63. What are bowel adhesions and what causes them?

Back 63

Surgical procedures, infection, and even endometriosis often cause localized or more general peritoneal inflammation (peritonitis). As the peritonitis heals, adhesions may develop between bowel segments and/or the abdominal wall and operative site. These fibrous bridges can create closed loops thru which other viscera may slide and eventually become trapped (internal herniation). The sequence of events that follow is the same as herniation.

Front 64

64. What is intussusception?

Back 64

Intussusception occurs when one segment of the intestine, constricted by a wave of peristalsis, suddenly becomes telescoped into the immediately distal segment of bowel. Once trapped, the invaginated segment is propelled by peristalsis farther into the distal segment, pulling its mesentery along behind it.

Some cases are associated w/rotavirus infection, suggesting that localized intestinal inflammation may serve as a traction point for the intussusception. However, intussusception in adults signifies an intraluminal mass or tumor as the point of traction. Intestinal obstruction ensues, and trapping of mesenteric vessels leads to infarction.

Front 65

65. What is a volvulus?

Where does it usually occur?

Back 65

Complete twisting of a loop of bowel about its mesenteric base of attachment also produces intestinal obstruction and infarction.

This lesion occurs most often in large redundant loops of sigmoid, followed by the cecum, small bowel, stomach or (rarely) transverse colon.

Front 66

66. What type of CA makes up most of the colorectal CAs?

Back 66

Adenocarcinomas constitute the vast majority of colorectal cancers and represent 70% of all malignancies arising in the GI tract.

Curiously, the small intestine is an uncommon site for benign or malignant tumors despite its great length.

Front 67

67. What are adenomas of the small bowel, and where do they most commonly occur?

Back 67

Most adenomas occur in the region of the ampulla of Vater. The usually presentation is that of a 30-60 y.o patient with occult blood loss, rarely w/obstruction or intussusception.

Macroscopically, the ampulla of Vater is enlarged and exhibits a velvety surface. Microscopically, these adenomas resemble their counterparts in the colon. Frequently, there is extension of adenomatous tissue into the ampullary orifice, rendering surgical excision difficult. It is a premalignant lesion.

Front 68

68. What are adenocarcinomas of the small bowel?

Back 68

The large majority of small intestinal adenocarcinomas occur in the duodenum, usually in 40-70 y/o patients. These tumors grow in a napkin-ring encircling pattern or as polypoid exophytic masses. Tumors in the duodenum, especially those involving the ampulla of Vater, may cause obstructive jaundice early in their course.

The typical presentation is intestinal obstruction, w/symptoms of cramping pain, nausea, vomiting, and weight loss.

At the time of Dx, most have already penetrated the bowel wall, invaded the mesentery or other segments of the gut, spread to regional nodes, and sometimes metastasized to the liver.

Front 69

69. What is the definition of a polyp?

Back 69

A polyp is a tumorous mass that protrudes into the lumen of the gut. Presumably all polyps start as small, sessile lesions w/o a definable stalk. In many instances, traction on the mass may create a stalked, or pedunculated polyp.

Front 70

70. Are polyps neoplastic?

Back 70

Polyps may be formed as the result of abnormal mucosal maturation, inflammation, or architecture. These polyps are non-neoplastic and do not have malignant potential. An example is the hyperplastic polyp.

Those epithelial polyps that arise as the result of proliferation and dysplasia are termed adenomatous polyps, or adenomas. They are true neoplastic lesions and are precursors of carcinoma.

Front 71

71. What are non-neoplastic polyps?

Which one is most common?

Back 71

The majority of intestinal polyps occur on a sporadic basis, particularly in the colon, and increase in frequency w/age. Non-neoplastic polyps include the hyperplastic polyp, the hamartomatous polyp, the inflammatory polyp, and the lymphoid polyp.

Hyperplastic polyps are the most common (90%), and are found in more than half of all persons age 60+.

Front 72

72. What is the pathogenesis of hyperplastic polyps?

Back 72

It is believed that the hyperplastic polyp results from decreased epithelial cell turnover and accumulation of mature cells on the surface.

Front 73

73. What is the pathogenesis of harmatomatous, inflammatory, and lymphoid polyps?

Back 73

Harmatomatous polyps are malformations of the glands and the stroma. They can occur sporadically or in the setting of genetic syndromes.

Inflammatory polyps, AKA pseudopolyps, represent islands of inflamed regenerating mucosa surrounded by ulceration. These are primarily seen in patients w/severe, active IBD.

Lymphoid polyps are an essentially normal variant of the mucosal bumps containing intramucosal lymphoid tissue.

Front 74

74. What is the morphology of hyperplastic polyps?

Back 74

*No malignant potential! These are small (usually <5 mm in diameter) epithelial polyps that appear as nipple-like, hemispheric, smooth, moist protrusions of the mucosa, usually positioned in the tops of mucosal folds. They may occur singly but more often are multiple, and over half are found in the rectosigmoid colon.

Histologically, they are composed of well formed glands and crypts lined by non-neoplastic epithelial cells, most of which show differentiation into mature goblet or absorptive cells.

The delayed shedding of surface epithelial cells leads to infoldings of the crowded epithelial cells and fission of the crypts, creating a serrated epithelial profile and an irregular crypt architecture.

Front 75

75. What is the morphology of juvenile hamartomatous polyps?

Back 75

Juvenile polyps represent focal hamartomatous malformations of the mucosal epithelium and lamina propria. For the most part they are sporadic lesions, w/the majority occurring in children younger than 5.

Most occur in the rectum. They tend to be large (1-3cm) rounded, smooth or slightly lobulated lesions w/stalks up to 2 cm in length.

Front 76

76. What is the morphology of retention hamartomatous polyps?

What are the histological characteristics of hamartomatous polyps?

Back 76

Isolated hamartomatous polyps may be identified in the colon of adults; these incidental lesions are referred to as retention polyps. They also mostly occur in the rectum.

Retention polyps tend to be smaller (<1 cm in diameter).

Histologically, both retention and juvenile hamartomatous polyps have the lamina propria comprising the bulk, enclosing abundant cystically dilated glands. Inflammation is common, and the surface may be congested or ulcerated. In general they occur singly and being hamartomatous lesions have no malignant potential.

Front 77

77. What is juvenile polyposis syndrome?

What genetic mutations cause this syndrome?

Back 77

The rare autosomal dominant juvenile polyposis syndrome, in which there are multiple (50-100) juvenile polyps in the GI tract, does carry a risk of adenomas and hence adenocarcinoma.

Mutations in the SMAD4/DPC4 gene (which encodes a TGF-β signaling intermediate) account for some cases of juvenile polyposis syndrome.

Front 78

78. What are Peutz-Jeghers polyps?

Back 78

Peutz-Jeghers polyps are hamartomatous polyps that involve the mucosal epithelium, lamina propria, and muscularis mucosa. These lesions may also occur singly or multiply in the Peutz-Jeghers syndrome.

These polyps can be large and pedunculated with a firm lobulated contour.

Front 79

79. What is Peutz-Jeghers syndrome?

What is the underlying genetic basis for this syndrome?

Back 79

This rare autosomal dominant syndrome is characterized by multiple hamartomatous polyps scattered thru the entire GI tract and melanotic mucosal and cutaneous pigmentation around the lips, oral mucosa, face, genitalia, and palmar surfaces of the hands. Patients with this syndrome are at increased risk for intussusception, which is a common cause of mortality.

*Mutation of the gene (STK11 (LKB1) located on chromosome 19 is the genetic basis. This gene encodes a protein with serine/threonine kinase activity.

Front 80

80. What is the morphology of Peutz-Jeghers polyps?

Back 80

Again, they tend to be large and pedunculated w/a firm lobulated contour. HIstologically, an arborizing netowrk of connective tissue and well-developed smooth muscle extends into the polyp and surrounds normal abundant glands lined by normal intestinal epithelium rich in goblet cells.

While these polyps themselves do not have malignant potential, patients w/the syndrome have an increased risk of developing CA of the pancreas, breast, lung, ovary and uterus.

Front 81

81. What is Cowden syndrome?

What is the genetic basis underlying this syndrome?

Back 81

Cowden syndrome is an autosomal dominant genetic syndrome characterized by multiple hamartomas involving organs derived from all three germinal layers. The commonly involved sites are GI tract and mucocutaneous locations.

Intestinal hamartomatous polyps, facial trichilemmomas, acral keratoses, and oral papillomas are characteristic. While these hamartomas do not have malignant potential, the syndrome predisposes the patient to develop thyroid and breast cancers.

*Mutations in the PTEN gene

Front 82

82. What is Cronkhite-Canada syndrome?

Back 82

Cronkhite-Canada syndrome is a nonhereditary disorder characterized by the presence of GI hamartomatous polyposis and ectodermal abnormalities such as nail atrophy, skin pigmentation, and alopecia.

Front 83

83. What are adenomas of the bowel?

Back 83

Adenomas (adenomatous polyps) are intraepithelial neoplasms that range from small, often pedunculated lesions to large neoplasms that are usually sessile.

Prevalence of adenomas approaches 50% after age 60; they are frequently multiple.

*All adenomatous lesions arise as the result of epithelial proliferative dysplasia, which may range from low to high grade dysplasia (carcinoma in situ).

*These lesions are a precursor for invasive colorectal adenocarcinomas.

Front 84

84. What are the three subtypes of adenomatous polyps?

Which is the most common?

Back 84

1. *Tubular adenomas: tubular glands

2. Villous adenomas: villous projections

3. Tubulovillous adenoma: a mixture of the above

*Most common

Front 85

85. The malignant risk with an adenomatous polyp is correlated with what three interdependent features?

Back 85

1. Polyp size (cancer is rare in tubular adenomas smaller than 1 cm)

2. Architecture (the risk of CA is high (40%) in sessile villous adenomas more than 4 cm)

3. Severity of epithelial dysplasia (severe dysplasia, when present, is often found in villous areas)

Front 86

86. What is the morphology of tubular adenomas?

1/2

Back 86

Most tubular adenomas are found in the colon, bu they can occur in the stomach and small intestine, especially in the ampulla of Vater.

The smallest tubular adenomas are smooth contoured and sessile; large ones tend to be coarsely lobulated and have slender stalks.

Histologically, the stalk is composed of fibromuscular tissue and it is usually covered by normal, non-neoplastic mucosa. However, adenomatous epithelium may extend down the stalk and into adjacent regions of the mucosa, particularly in the stomach.

Front 87

87. What is the morphology of tubular adenomas?

2/2

Back 87

Whether small or large, adenomatous lesions are composed of neoplastic epithelium, which lines glands as a tall hyperchromatic somewhat disordered epithelium that may or may not show mucin vacuoles.

In the benign tubular adenoma, the branching glands are well separated by lamina propria and the degree of dysplasia is low grade.

However, high grade dysplasia may be present and may merge w/areas of overt malignant change confined to the mucosa (intramucosal CA).

Front 88

88. What is the morphology of villous adenomas?

Back 88

Villous adenomas are the larger and more ominous of the epithelial polyps. They tend to occur in older persons, most commonly in the rectum and rectosigmoid colon, but they may be located elsewhere.

They generally are sessile, up to 10 cm in diameter, velvety or cauliflower-like masses projecting 1-3 cm above the surrounding normal mucosa.

Their histology is that of frondlike villiform extensions of the mucosa covered by dysplastic, sometimes very disorderly columnar epithelium.

Front 89

89. What is the morphology of tubulovillous adenomas?

Back 89

Tubulovillous adenomas are typically intermediate between the tubular and villous lesions in terms of their frequency of having a stalk or being sessile. their size, and the general level of dysplasia found in such lesions.

The risk of harboring in situ or invasive CA generally correlates w/the proportion of the lesion that is villous.

Front 90

90. What are the clinical features of colorectal adenomas?

Back 90

Adenomas may be asymptomatic or may cause occult bleeding w/anemia. Small intestine adenomas can cause obstruction and intussusception. Rarely, large villous adenomas in colon hypersecrete copious amts of protein-and potassium-rich mucus, leading to either hypoproteinemia or hypokalemia.

tubular (and tubulovillous adenomas)

Front 91

91. What are five things that the clinical impact of malignant change depend upon?

Back 91

1. High-grade dysplasia (CA in situ) has not yet acquired the ability to metastasize and is still a clinically benign lesion.
2. Intramucosal CA w/lamina propria invasion is only regarded also as having little or no metastatic potential (b/c of no lymphatic channels in the colonic mucosa)
3. Endoscopic removal of a pedunculated adenoma is regarded as an adequate excision (more on next card).
4. Invasive adenocarcinoma arising in a sessile polyp cannot be adequately resected by polypectomy, and further surgery may be required.
5. The only adequate treatment for a pedunculated or sessile adenoma is complete resection.

Front 92

92. Endoscopic removal of a pedunculated adenoma is regarded as an adequate excision as long as what three histologic conditions are met?

Back 92

1. The adenocarcinoma is superficial and does not approach the margin of excision across the base of the stalk.
2. There is no vascular or lymphatic invasion.
3. The carcinoma is not poorly differentiated.

Front 93

93. What is familial adenomatous polyposis (FAP) syndrome?

What are the 4 types?

Back 93

FAP exhibits innumerable adenomatous polyps and has a frequency of progression to colon adenocarcinoma approaching 100%. It is caused by mutations of the APC gene.

Subtypes:
1. Classic FAP
2. Attenuated FAP
3. Gardner syndrome
4. Turcot syndrome

Front 94

94. What is the classic FAP syndrome?

Back 94

In the classic FAP syndrome, patients typically develop 500-2500 colonic adenomas that carpet the mucosal surface. A minimum of 100 polyps is necessary for Dx.

Histologically, the vast majority of polyps are tubular adenomas; occasional polyps may have villous features. Some patients already have cancer of the colon or rectum at the time of Dx.

Front 95

95. What is the attenuated FAP syndrome?

Back 95

In attenuated FAP, patients tend to develop fewer polyps (avg = 30) and most of the polyps are located in the proximal colon. The lifetime risk of CA is around 50%.

Front 96

96. What is Gardner syndrome?

Back 96

Patients with Gardner syndrome exhibit intestinal polyps identical to those in class FAP, combined w/multiple osteomas (particularly of the mandible, skull, and long bones), epidermal cysts, and fibromatosis.

Less frequent are abnormalities of dentition, such as unerupted and supernumerary teeth, and a higher freq of duodenal and thyroid CA.

Front 97

97. What is Turcot syndrome?

Back 97

Turcot syndrome is a rare clinical syndrome marked by the combo of adenomatous colonic polyposis and tumors of the CNS system.

2/3rds of patients with Turcot syndrome have APC gene mutations and develop brain medulloblastomas.

The remaining 1/3rd have mutations in one of the genes associated with HNPCC and develop brain glioblastomas.

Front 98

98. What is hereditary nonpolyposis colorectal cancer syndrome (HNPCC)?

Back 98

HNPCC is an autosomal dominant familial syndrome. It is characterized by an increased risk of colorectal CA and extraintestinal CA, particularly of the endometrium.

Adenomas can occur in low numbers and considerably earlier than in the general adult population. However, the colonic malignancies that develop often are multiple and are not usually associated with pre-existing adenomas.

*Hallmark of HNPCC is mutations in DNA repair genes, leading to microsatellite instability.

Front 99

99. What is the adenoma-carcinoma sequence?

Six parts...

Back 99

☑ Populations that have a high prevalence of adenomas also have a high prevalence of colorectal CA, and vice versa.
☑ The distribution of adenomas within the colorectum is more or less comparable to that of colorectal CA.
☑ The peak incidence of adenomatous polyps antedates by some years the peak for colorectal CA.
☑ When invasive CA is identified at an early stage, surrounding adenomatous tissue is often present.
☑ The risk of CA is directly related to the # of adenomas, and hence the virtual certainty of CA in FAP syndromes.
☑ Programs that assiduously follow patients for the development of adenomas and remove all that are suspicious reduce the incidence of colorectal CA.

Front 100

100. What are the two pathogenetically distinct pathways for the development of colon cancer?

Back 100

1. APC/β-catenin pathway

2. DNA mismatch repair genes

Front 101

101. What is the role of the APC gene?

Loss of APC causes?

Back 101

This dual function tumro suppressor gene encodes a protein that binds to microtubule bundles and promotes cell migration and adhesion. APC also acts as a gatekeeper protein, as it regulates levels of β-catenin, an important mediator of the Wnt/β-catenin signaling pathway.

Normal APC function promotes cell adhesion and regulates cell proliferation; *absence of APC function leads to decreased cell adhesion and increased cellular proliferation. Loss of this gene is believed to be the earliest event in the formation of adenomas.

Front 102

102. What is β-catenin, and what does it do?

Back 102

β-catenin is a member of the cadherin-based cell adhesive complex. When it is not bound to E-cadherin and participating in cell-to-cell adhesion, a cytoplasmic degradation complex (APC+Axin+GSK-3β+β-catenin) leads to β-catenin phosphorylation and degradation.

In the setting of APC mutations, β-catenin accumulates in the cytoplasm and is translocated to the nucleus to bind to a family of transcription factors called T-cell factor proteins (TCF). The TCF contributes a DNA binding domain and β-catenin contributes a transactivation domain. Genes activated by the β-catenin-TCF complex are thought to include those regulating cell proliferation and apoptosis, such as c-MYC and CYCLIN D1. ***Absence of APC function leads to decreased cell adhesion and increased cellular proliferation.

Front 103

103. What is the most frequently activated oncogene in adenomas and colon cancers?

Back 103

K-RAS oncogene.

K-RAS plays a role in intracellular signal transduction and is mutated in fewer than 10% of adenomas less than 1 cm in size, in about 50% of adenomas larger than 1 cm, and in approx 50% of carcinomas.

Front 104

104. Loss of SMAD4 leads to...?

Back 104

Loss of SMAD4 (tumor suppressor gene) increases GI tumorigenesis.

Front 105

105. Mutation in what other tumor suppressor gene is important in colon cancers?

Back 105

Losses of p53 have been found in 70-80% of colon cancers, yet comparable losses are infrequent in adenomas.

This suggests that mutations in p53 occur late in colon carcinogenesis.

Front 106

106. How is telomerase activity in colorectal cancers compared to its activity in adenomas?

Back 106

Telomerase activity is increased in most cancers; whereas most adenomas lack telomerase activity.

Front 107

107. What are the two most common human mismatch repair genes that become mutated?

What is the result?

Back 107

The majority of mutations (90%) involve MSH2 and MLH1.

Mutations in the mismatch repair genes cause alteration of microsatellites, leading to microsatellite instability. Loss of mismatch repair leads to the accumulation of mutations in other growth-regulating genes, culminating in the emergence of colorectal CA.

Front 108

108. What are four distinctive morphological features in fully developed tumors that are a result of mutated DNA mismatch repair genes?

Back 108

1. Proximal colonic location
2. Mucinous histology
3. Infiltration by lymphocytes
4. In general, these tumors have better prognosis than stage-matched tumors that arise by the APC pathway.

Front 109

109. What is the pathogenesis of colorectal CA?

Back 109

Hereditary polyp syndromes, HNPCC, and IBD significantly increase the risk of developing CA. However, most colonic CAs arise sporadically in polypoid adenomas. Diet likely contributes to risk in these sporadic cancers. These diets may promote increased mucosal exposure to bile acids and bacterial degradative byproducts.

Front 110

110. What are five features of such diets that promote colon cancer?

Back 110

1. Energy intake greater than requirement
2. Low vegetable fiber intake
3. High content of refined carbs
4. High intake of red meat
5. Decreased intake of protective micronutrients (vitamins A, C, and E)

Front 111

111. Can aspirin or other NSAIDs exert a protective effect against colon cancer?

Back 111

Yes, aspirin reduces the risk of recurrent adenomas in patients w/previous coloretal CA or adenomas.

This is because of the inhibition of COX-2. This enzyme is overexpressed in neoplastic epithelium and seems to regulate angiogenesis and apoptosis.

Thus, COX-2 inhibitors are chemoprotective agents in patients with FAP syndrome.

Front 112

112. Where are most cancers in the colorectum found?

Which sides (right/left) tend to have greater microsatellite instability?

Back 112

Rectosigmoid (55%)
Cecum/ascending colon (22%)
Transverse colon (11%)
Descending colon (6%)
Other (6%)

The right-sided colon cancers tend to have greater microsatellite instability.

Front 113

113. What is the morphology of colon CAs in the proximal colon?

Back 113

Tumors in the proximal colon tend to grow as polypoid, exophytic masses that extend along one wall of the capacious cecum and ascending colon. Obstruction is uncommon.

Front 114

114. What is the morphology of colon CAs in the distal colon?

Back 114

When CA in the distal colon are discovered, they tend to be annular, encircling lesions that produce so-called napkin-ring constrictions of the bowel.

The margins of the napkin ring are classically heaped up, beaded and firm, and the midregion is ulcerated. The lumen is markedly narrowed, and the proximal bowel may be distended.

Front 115

115. What is the morphology of colon CAs?

Back 115

Both forms (distal/proximal) directly penetrate the bowel wall over time and may appear as subserosal and serosal white, firm masses, freq causing puckering of the serosive surface.

On microscopic exam, differentiation may range from tall, columnar cells resembling their counterparts in adenomatous lesions, which now invade the sumucosa and muscularis propria, to undifferentiated, frankly anaplastic masses.

Front 116

116. Invasive colon tumors incites what type of response?

Back 116

Invasive tumor incites a strong desmoplastic stromal response, leading to the characteristic firm, hard consistency of most colonic carcinomas.

Front 117

117. What are some specific features of colorectal CAs?

Back 117

1. In some cancer the cells take on a signet-ring appearance.
2. The small cell undifferentiated CA appears to arise from endocrine cells per se and elaborates a variety of bioactive secretory products.
3. Many tumors produce mucin which dissects thru the gut wall and aids in the extension of malignancy and worsens the prognosis.
4. Tumors associated with HNPCC tend to be poorly differentiated and rich in mucin.

Front 118

118. Cancers in the distal colon vs. anorectal canal...

Back 118

Some cancers, particular in the distal colon, have foci of squamous cell differentiation and are therefore referred to as adenosquamous CAs.

In contrast, CAs arising in the anorectal canal constitute a distinct subgroup of tumors, dominated by squamous cell CA.

Front 119

119. What are the clinical features in colorectal cancers?

What is the single most important prognostic indicator of colorectal CA?

Back 119

Colorectal CA is usually asymptomatic at first. Fatigue, iron deficiency, anemia, abdominal discomfort, progressive bowel obstruction, and liver enlargement (metastases) eventually occur.

The single most important prognostic indicator of colorectal CA is the extent of the tumor at the time of Dx; the so called stage.

Currently, only surgery can be curative.

Front 120

120. Iron deficiency anemia in an older male most always means what until proven otherwise...?

Back 120

It is a clinical maxim that iron-deficiency anemia in an older male means GI cancer until proven otherwise.

Front 121

121. What are carcinoid tumors?

Back 121

Carcinoid tumors are derived from resident endocrine cells, w/the GI tract and lung as the predominant sites of occurrence. Many elaborate bioactive produces (e.g. amines or peptides)

Although most arise in the gut, they can also occur in the pancreas, lungs, biliary tree, and liver.

Carcinoid tumors represent 50% of small intestine cancers; peak incidence is in the 6th decade.

Front 122

122. Which type of carcinoid tumors rarely metastasize?

Which type metastasize?

Back 122

Appendiceal and rectal carcinoids infrequently metastasize, even though they show extensive spread.

By contrast, 90% of ileal, gastric, and colonic carcinoids that have penetrated halfway thru the muscle wall have spread to lymph nodes and distant sites such as the liver at the time of Dx.

Front 123

123. Where is the most common site for carcinoid tumors in the gut?

Back 123

The appendix is the most common site, followed by the small intestine (primarily ileum), rectum, stomach, and colon.

In the appendix they appear as bulbous swellings of the tip, which frequently obliterate the lumen.

Front 124

124. What is the morphology of carcinoid tumors of the gut?

1/2

Back 124

A characteristic feature is a solid, yellow-tan appearance on transection.

Histologically, the neoplastic cells may form discrete islands, trabeculae, stands, glands, or undifferentiated sheets. Whatever their organization the tumor cells are monotonously similar, having a scant, pink granular cytoplasm and a round to oval stippled nucleus. In most tumors there is minimal variation in cell and nuclear size and mitoses are infrequent.

Front 125

125. What is the morphology of carcinoid tumors of the gut?

2/2

Back 125

Rarely, tumors arise resembling small cell carcinomas of the lung or contain abundant psammoma bodies similar to those seen in thyroid CA.

By electron microscopy, the cells in most tumors contain membrane-bound secretory granules w/osmophilic centers (dense-core granules) in the cytoplasm.

Most carcinoids contain chromogranin A, synaptophysin, and neuron-specific enolase.

Front 126

126. What are the clinical features of carcinoids?

Back 126

Carcinoid tumors are generally asymptomatic, although local symptoms can occur from obstruction or bleeding. Symptoms can also be caused by tumor secretory products:
●Gastrin causing Zollinger-Ellison syndrome with peptic ulceration
●Corticotropin causing Cushing syndrome
●Insulin causing hyperinsulinism
●Serotonin and other bioactive amines causing carcinoid syndrome

Front 127

127. What is carcinoid syndrome?

Back 127

Some neoplasms are associated w/a distinctive carcinoid syndrome; this occurs in about 1% of all patients w/carcinoids and in 20% of those w/widespread metastases.

Carcinoid syndrome is seen only with extraintestinal carcinoid or w/extensive hepatic metastases (allowing bioactive amines, specifically 5-HT, to reach the systemic circulation without being metabolized). Thus, hepatic metastases are usually not required for the production of a carcinoid syndrome.

Front 128

128. What are the symptoms of carcinoid syndrome?

Back 128

1. Vasomotor disturbances: flushing, cyanosis
2. Intestinal hypermotility: diarrhea, cramps, nausea, vomiting
3. Asthmatic bronchoconstriction: cough, wheezing, dyspnea
4. Hepatomegaly from hepatic metastases
5. Systemic fibrosis: pulmonary and tricuspid valve thickening and stenosis, endocardial fibrosis, retroperitoneal and pelvic fibrosis.

Front 129

129. How is carcinoid syndrome diagnosed?

Back 129

Dx via documenting excess urinary 5-hydroxyindoleacetic acid, a breakdown product of serotonin.

Front 130

130. What is a gastrointestinal lymphoma?

Back 130

The gut is the most common location for the 40% of lymphomas arising in extranodal sites.

By definition, primary GI lymphomas exhibit no evidence of liver, spleen, mediastinal lymph node, or bone marrow involvement at the time of Dx- regional lymph node involvement may be present.

Front 131

131. Primary GI lymphomas usually arise as sporadic neoplasms but also occur more frequently in which 6 patient populations?

Back 131

1. Chronic gastritis caused by H. pylori
2. Chronic sprue-like syndromes
3. Natives of the Mediterranean region
4. Congenital immunodeficiency states
5. Infection w/HIV
6. Following organ transplantation w/immunosuppression

Front 132

132. What are the different categories of GI lymphomas?

Back 132

Intestinal tract lymphomas can be classified into B-cell and T-cell lymphomas.

The B-cell lymphoma can be subdivided into MALT lymphoma, immunoproliferative small-intestinal disease (IPSID), and Burkitt lymphoma.

Front 133

133. What is MALT lymphoma?

Back 133

MALT lymphoma is a sporadic lymphoma, which arises from the B-cells of MALT (mucosa-associated lymphoid tissue). This type of lymphoma is the most common form in the Western hemisphere.

This type of lymphoma usually affects adults, has no gender predilection, and may arise anywhere in the gut.

Front 134

134. What are four biologic factors of MALT lymphomas?

Back 134

1. Many behave as focal tumors in their early stages and are amenable to surgical resection
2. Relapse may occur exclusively in the GI tract
3. Genotypic changes are different than those observed in nodal lymphomas: the t(11;18) translocation is relatively common in MALT lymphoma
4. The cells are usually CD5- and CD10-negative

Front 135

135. What is the pathogenesis of MALT lymphomas?

Back 135

The idea is that lymphomas of MALT origin arise in the setting of mucosal lymphoid activation and that these lymphomas are the malignant counterparts of hypermutated, postgerminal-center memory B cells.

H. pylori associated chronic gastritis has been proposed as a driving force, the result of antigen-driven somatic mutation of gastric lymphoid tissue.

Front 136

136. What is immunoproliferative small-intestinal disease (IPSID)?

Back 136

Immunoproliferative small-intestinal disease (IPSID) is also referred to as Mediterranean lymphoma. It is an unusual intestinal B-cell lymphoma arising in patients w/Mediterranean ancestry, having a background of chronic diffuse mucosal plasmacytosis. The plasma cells synthesize an abnormal IgA heavy chain, in which the variable portion has been deleted.

A high proportion of patients have malabsorption and weight loss preceding the development of the lymphoma. The Dx is made most commonly in children and young adults, and both sexes are affected equally.

Front 137

137. What is the intestinal T-cell lymphoma?

Back 137

The intestinal T-cell lymphoma is usually associated w/a long standing malabsorption syndrome (such as celiac disease) that may not constitute a true gluten-sensitive enteropathy. This lymphoma occurs in relatively young individuals (age 30-40) often following a 10- to 20-year history of symptomatic malabsorption.

Alternatively, a diffuse enteropathy w/malabsorption may accompany the development of a lymphoma. Intestinal T-cell lymphomas arise most often in the proximal small bowel and its prognosis is poor.

Front 138

138. What is the morphology of GI lymphomas?

1/2

Back 138

Since all gut lymphoid tissue is mucosal and submucosal, early lesions appear as plaque-liek expansions of the mucosa and submucosa. Diffusely infiltrating lesions may produce full-thickness mural thickening, with effacement of the overlying mucosal folds and focal ulceration. Others may be polypoid, protruding into the lumen, or form large, fungating, ulcerated masses.

Tumor infiltration into the muscularis propria splays the muscle fibers and destroys them. B/c of this feature, advanced lesions freq cause motility problems w/secondary obstruction.

Front 139

139. What is the morphology of GI lymphomas?

2/2

Back 139

In the earliest histological lesions, atypical lymphoid cells may be seen infiltrating the mucosa, w/effacement and loss of glands and massive expansion of lymphoid tissue. Extreme number of atypical lymphoid cells may populate the superficial or glandular epithelium (lymphoeptiehlial lesion).

**W/established lymphomas, the mucosa, submucosa, and the muscle wall are replaced by a monotonous infiltrate of malignant cells and immunoblasts in varying proportions. Lymphoid follicles are occasionally formed.

Front 140

140. What are the clinical features of GI lymphomas?

Back 140

Sporadic lymphomas are amenable to surgical resection and are chemoresponsive. Outcome depends on size, grade, and tumor invasiveness at resection.

Low grade lymphomas associated w/H. pylori infection may be treated by eradicating the H. pylori organism.

Front 141

141. What are mesenchymal tumors?

What is the most common type?

Back 141

Mesenchymal tumors may occur anywhere in the GI tract.

Lipomas are the most common GI mesenchymal tumor, generally found in the small intestine or colon submucosa.

Other types are GIST, Leimyoma, Leiomyosarcoma, and Kaposi sarcoma

Front 142

142. What is the morphology of lipomas?

Back 142

Lipomas are usually well demarcated, firm nodules (almost always less than 4 cm in diameter) arising w/in the submucosa or muscularis propria. The overlying mucosa is stretched and attenuated. Rarely, they grow to larger size and produce hemispheric elevation of the mucosa w/ulceration over the dome of the tumor.

Front 143

143. What is GIST?

Back 143

Gastrointestinal stromal tumors (GISTs) are now considered to be a distinctive tumor type characterized by c-KIT immunoreactivity.

The small intestine is the second most common location for this tumor (the stomach being the most common). Both benign and malignant versions of GIST may occur at any age and in either sex.

Front 144

144. What is the morphology of leiomyosarcomas?

Back 144

Malignant stomal tumors (primarily leiomyosarcomas) tend to produce large, bulky, intramural masses that eventually fungate and ulcerate into the lumen or project subserosally into the abdominal space.

Large size and a high mitotic rate are correlated w/an aggressive course.

Front 145

145. What are the clinical features of mesenchymal tumors?

Back 145

Most mesenchymal tumors are asymptomatic. Larger lesions may cause mucosal ulceration w/bleeding (especially in stomach), obstruction, or intussusception.

Benign lesions are easily resectable. Surgical removal is usually possible for the malignant lesions as well, since they tend to grow as cohesive masses.

Front 146

146. What are the three patterns of differentiation for tumors in the anal canal?

Back 146

1. Basaloid pattern
2. Squamous cell CA
3. Adenomcarcinoma

Front 147

147. What are the features of basaloid anal carcinomas?

Back 147

Anal canal carcinoma w/basaloid differentiation is a tumor populated by immature proliferative cells derived from the basal layer of a stratified squamous epithelium. These tumors may occur sporadically and be uniform in their histologic features.

Alternatively, basaloid differentiation may be a component of a tumor that exhibits more genuine squamous cell differentiation and or the mucin vacuole-containing features of adenocarcinoma.

Front 148

148. What are the features of pure squamous cell CAs of the anal canal?

Back 148

Pure squamous cell CAs of the anal canal are closely associated w/chronic HPV infection. Some rare cases are also related to immunosuppression, as encountered in renal transplantation and in AIDS patients.

As w/the genital tract, chronic HPV infection of the anal canal often causes precursor lesions such as condyloma acuminatum, squamous epithelium dysplasia, and carcinoma in situ.

Front 149

149. What are the features of pure adenocarcinomas of the anal canal?

Back 149

Pure adenocarcinoma of the anal canal is often the extension of rectal adenocarcinoma.

Rarely, other tumors may arise from the anal canal, notably Paget disease, small-cell carcinoma, and melanoma.

Front 150

150. How does one estimate the hematopoietic marrow activity?

Back 150

A reasonable estimate of marrow activity is obtained by examining the ratio of fat cells to hematopoietic elements in bone marrow biopsy samples. In normal adults, this ratio is about 1:1, but with marrow hypoplasia (e.g., aplastic anemia), the proportion of fat cells is greatly increased.

Conversely, fat cells may disappear completely in diseases characterized by increased hematopoiesis (e.g., hemolytic anemias).

Front 151

151. What can cause marrow cells to be inaspirable?

Back 151

Certain disorders such as metastatic CAs and granulomatous diseases induce local marrow fibrosis, rendering the cells inaspirable.

Front 152

152. What are the limitations of biopsies?

Back 152

The limitation of biopsies is that tissue fixation and decalcification alter the appearance of marrow cells, making them less recognizable than in air dried aspirate.

Often tentative identification is based on the company they keep. Thus, a primitive cell found w/in a focus of maturing granulocytes is likely a myeloblast.

Front 153

153. What is the definition of anemia?

Back 153

Anemia is defined as a reduction below normal limits of the total circulating red cell mass.

In routine practice, anemia is defined as a reduction below normal in the volume of packed red cells, as measured by the HCT, or a reduction in the Hb concentration of the blood.

Front 154

154. What is MCV?

MCH?

Back 154

MCV is the mean cell volume; it is the average volume of a RBC

MCH is the mean cell Hb; it is the average content of Hb/RBC

Front 155

155. What is MCHC?

What is RBC distribution width?

Back 155

MCHC is the mean cell hemoglobin concentration; it is the average concentration of Hb in a given volume of packed RBCs.

RBC distribution width is the coefficient of variation of RBC volume.

Front 156

156. What are the common features of anemia?

Back 156

Whatever its cause, anemia leads to certain clinical features when severe. Pts appear pale. Weakness, malaise, and easy fatigability are common problems. The lowered O2 concentration of the circulating blood leads to dyspnea on mild exertion. The nails can become brittle. Anoxia can cause fatty change in the liver, myocardium, and kidney.

If fatty changes are severe enough, cardiac failure can develop and compound the respiratory difficulty caused by reduced oxygen transport. With acute blood loss and shock, oliguria and anuria can develop due to renal hypoperfusion.

Front 157

157. What are the effects of acute blood loss mainly due to?

Back 157

The effects of acute blood loss are mainly due to the loss of intravascular volume, which can lead to cardiovascular collapse, shock, and death.

If the pt survives, the blood volume is rapidly restored by shift of water from the interstitial fluid compartment. The resulting hemodilution lowers the HCT.

Front 158

158. How long does it take for the progeny of the CFU-Es to fully differentiate after blood loss?

Back 158

It takes about 5 days, and the differentiation is marked by the appearance of increased numbers of newly released red cells (reticulocytes) in the peripheral blood.

Front 159

159. What is the earliest change in the peripheral blood immediately after acute blood loss?

Back 159

The earliest change in the peripheral blood immediately after acute blood loss is leukocytosis, due to the mobilization of granulocytes from marginal pools.

Initially, RBCs appear normal in size and color. ***However, as marrow production increases, there is a striking increase in the reticulocyte count, reaching 10-15% after 7 days.***

Front 160

160. Does chronic blood loss induce anemia?

Back 160

Chronic blood loss induces anemia only when the rate of loss exceeds the regenerative capacity of the marrow or when iron reserves are depleted.

Front 161

161. What are 3 shared features of hemolytic anemias?

Back 161

1. A shortened red cell life space; i.e. premature destruction of red cells
2. Elevated erythropoietin levels and increased erythropoiesis in the marrow and other sites, to compensate for the loss of red cells
3. Accumulation of the products of Hb catabolism, due to an increased rate of red cell destruction

Front 162

162. Where does the physiologic destruction of senescent red cells take place?

Back 162

W/in the mononuclear phagocytic cells of the spleen.

In the great majority of hemolytic anemias, the premature destruction of red cells also occurs within the mononuclear phagocyte system (extravascular hemolysis), and causes splenomegaly.

Front 163

163. What causes intravascular hemolysis?

Back 163

Intravascular hemolysis of red cells is caused by mechanical injury, complement fixation, infection by intracellular parasites such as falciparum malaria, or exogenous toxic factors.

Mechanical injury caused by defective cardiac valves, thrombi w/in the microcirculation, or physical trauma can physically lyse red cells.

Complement fixation can occur on antibody-coated cells during transfusion of mismatched blood.

Front 164

164. What are 5 manifestations of intravascular hemolysis?

Back 164

1. Hemoglobinemia
2. Hemoglobinuria
3. Jaundice
4. Hemosiderinuria
5. ***Decreased serum haptoglobin is characteristic of intravascular hemolysis***

Front 165

165. In hemolytic anemias, is the serum bilirubin conjugated or unconjugated?

Back 165

Unconjugated - the level of hyperbilirubinemia depends on the functional capacity of the liver and the rate of hemolysis.

Front 166

166. What is extravascular hemolysis?

Back 166

Extravascular hemolysis takes place whenever red cells are rendered "foreign" or become less deformable.

Since extreme alterations in shape are required for red cells to navigate the splenic sinusoids successfully, reduced deformability makes the passage difficult and leads to sequestration w/in the cords, followed by phagocytosis.

Front 167

167. What are the features of extravascular hemolysis?

Back 167

W/extravascular hemolysis, hemoglobinemia and hemoglobinuria are not observed, and its principal features are anemia and jaundice.

However, some Hb escapes from phagocytes, leading to decreases in plasma haptoglobin.

Front 168

168. What is the morphology of hemolytic anemias?

Back 168

Anemia and lowered tissue oxygen tension stimulate increased production of erythropoietin, which leads to the appearance of increased numbers of erythroid precursors (normoblasts) in the marrow.

If the anemia is severe, extramedullary hematopoiesis can appear in the liver, spleen, and lymph nodes.

The accelerated erythropoiesis leads to a prominent reticulocytosis in the peripheral blood. Elevated biliary excretion of bilirubin promotes cholelithiasis.

Front 169

169. In general, hereditary disorders are due to _____ defects and acquired disorders are due to _____ factors...?

Back 169

In general, hereditary disorders are due to intrinsic defects and acquired disorders are due to extrinsic factors such as autoantibodies.

Front 170

170. What is hereditary spherocytosis?

Back 170

This is an inherited disorder caused by intrinsic defects in the RBC cytoskeletal membrane which renders erythrocytes spheroidal, less deformable, and vulnerable to splenic sequestration and destruction.

An autosomal dominant inheritance pattern is seen in 75% of cases.

Front 171

171. What is the chief protein component of the red cell membrane?

Back 171

Its chief protein component, spectrin, consists of two polypeptide chains, alpha and beta. The head regions of spectrin dimers self associate to form tetramers, while the tails associate w/actin oligomers. Each actin oligomer can bind multiple spectrin tetramers, thus creating a 2D spectrin-actin skeleton that is connected to the cell membrane by two distinct interactions.

Front 172

172. What are these two distinct interactions?

Back 172

1. involving proteins ankyrin and band 4.2; which binds spectrin to the transmembrane ion trnasporter, band 3.

2. Protein 4.1; binds the tail of spectrin to another transmembrane protein, glycophorin A.

Front 173

173. What is the most common cause of autosomal dominant HS?

Back 173

The most common cause is a mutation of red cell ankyrin.

Another 20% of autosomal dominant cases are caused by mutations in band 3.

Front 174

174. So what's the problem in HS?

Back 174

Reduced membrane stability leads to loss of membrane fragments during exposure to shear stresses in the circulation. The loss of membrane relative to cytoplasm "forces" the cells to assume the smallest possible diameter for a given volume, namely, a sphere.

The spleen is the villain - red cells must undergo extreme deformation to leave the cords of Billroth and enter the sinusoids. As spherocytes are trapped in the spleen, the already sluggish circulation of the cords stagnates further, producing a progressively more hostile environment. Lactic acid accumulates and the pH falls, inhibiting glycolysis.

Front 175

175. What is the treatment for HS?

Back 175

The role of the spleen in the premature demise of the spherocytes is proved by the beneficial effect of splenectomy. The spherocytes persist, but the anemia is corrected.

Front 176

176. What is the most outstanding morphologic finding in HS?

Back 176

The spherocytes, apparent on smears as abnormally small, dark-staining (hyperchromic) red cells lacking the normal central zone of pallor.

Present also are changes associated w/all hemolytic anemias, including reticulocytosis, marrow hyperplasia due to increased erythropoiesis, hemosiderosis, and mild jaundice. Cholelithiasis occurs in 40-50% of affected adults. Moderate splenic enlargement is characteristic.

Front 177

177. What are the clinical features of HS?

Back 177

Anemia, spenomegaly, and jaundice. In a minority, HS presents at birth w/marked jaundice, requiring exchange transfusion. In 20-30% of pts, the disease is virtually asymptomatic b/c the decreased red cell survival is readily compensated for by increased erythropoiesis. In most, however, the compensatory changes are outpaced, producing a chronic hemolytic anemia.

Front 178

178. What is an aplastic crisis in HS?

Back 178

The generally stable clinical course is sometimes punctuated by an aplastic crisis, usually triggered by an acute parvovirus infection. Parvovirus infects and kills red cell progenitors, causing red cell production to cease until an effective immune response occurs in usually 1-2 weeks.

B/c the lifespan of red cells in HS is shortened to 10-20 days, cessation of erythropoiesis for even short time periods leads to sudden worsening of the anemia accompanied by reticulocytopenia.

Front 179

179. What is a hemolytic crisis in HS?

Back 179

Hemolytic crises are produced by intercurrent events leading to increased splenic destruction of red cells (e.g., infectious mononucleosis); these are clinincally less significant than aplastic crises.

Front 180

180. What is osmotic lysis in HS?

Back 180

In 2/3 of pts, the red cells are abnormally sensitive to osmotic lysis. Spherocytes retain most of the cytoplasm they were born with and lose sodium and water during conditioning in the circulation, ***leading to an increased MCHC in most pts.***

Front 181

181. What about abnormalities in the hexose monophosphate shunt?

Back 181

Abnormalities in the hexose monophosphate shunt or glutathione metabolism resulting from deficient or impaired enzyme function reduce the ability of red cells to protect themselves against oxidative injuries, leading to hemolytic disease.

Front 182

182. What are the variants of G6PD?

Back 182

This is an X-linked disorder

Although there are several variants, only two, G6PD A- and G6PD Mediterranean, lead to clinically significant hemolysis.

A- is present in about 10% of American blacks, and is associated with progressive loss of G6PD in older RBCs. B/c the younger cells are not affected, hemolytic episodes are self limited.

In the Mediterranean variant, G6PD levels are much lower and hemolytic episodes are more severe. Ingestion of fava beans can cause hemolysis in G6PD deficiency b/c these legumes generate oxidants.

Front 183

183. How does deficiency in G6PD cause hemolysis?

Back 183

Compared to the most common normal variant, G6PD B, the half-life of G6PD Mediterranean is more markedly abnormal.

Both disease associated mutations result in misfolding of the protein, making it more susceptible to proteolytic degradation. B/c mature red cells do not synthesize new proteins, G6PD A- or G6PD Mediterranean enzyme activities fall quickly as red cells age to levels inadequate to protect against oxidant stress.

Front 184

184. What causes oxidant stress?

Back 184

This can occur due to ingestion of certain drugs or foods, or more commonly exposure to oxidant free radicals generated by leukocytes in the course of infections. Some drugs cause hemolysis only in those with the more severe Mediterranean variant. Many infections can trigger hemolysis; viral hepatitis, pneumonia, and typhoid fever are examples.

Fava beans can also cause hemolysis.

Front 185

185. What is the morphology of G6PD deficiency?

Back 185

In G6PD deficient cells, high levels of oxidants cause oxidation of reactive sulfhydryl groups on globin chains, which become denatured and form membrane bound precipitates, known as Heinz bodies. induce hemoglobin denaturation. The altered Hb precipitates as Heinz bodies, which attach to the inner cell membrane.

These are seen w/in red cells stained w/crystal violet as dark inclusions. Heinz bodies can damage the membrane sufficiently to cause intravasular hemolysis.

Front 186

186. How do Heinz bodies play a role in G6PD deficiency?

Back 186

As inclusion bearing red cells pass thru the splenic cords, macrophages pluck out the Heinz bodies. Due to membrane damage, some of these partially "bit" cells retain an abnormal shape ("bite cells").

Both bite cells and spherocytes are highly prone to trapping in splenic cords and rapid removal via erythrophagocytosis.

Front 187

187. What causes sickle cell disease?

Back 187

This is a hereditary hemoglobinopathy resulting from the substitution of a valine for a glutamic acid at the 6th position of the β-globin chain, transforming normal hemoglobin A into the mutant hemoglobin S.

Front 188

188. What are the common types of sickle cell disease?

Back 188

About 8% of black Americans are heterozygous for HbS. If an individual is homozygous for the sickle mutation, almost all the Hb in the red cell is HbS.

In heterozygotes, only about 40% of the Hb is HbS, the remainder being normal hemoglobins.

Where malaria is endemic in Africa, as many as 30% of the native population is heterozygous.

Front 189

189. What happens to HbS molecules when they are deoxygenated?

Back 189

When dexoygenated, HbS molecules undergo aggregation and polymerizaiton. Initially, the red cell cytosol converts from a freely flowing liquid to a viscous gel as HbS aggregates form. With continued deoxygenation, aggregated HbS molecules assemble into long needle-like fibers w/in red cells, producing a distorted sickle or holly-leaf shape.

Front 190

190. What happens w/repeated episodes of sickling?

Back 190

W/repeated episodes of sickling, membrane damage occurs and cells become irreversibly sickled, retaining their abnormal shape even when fully oxygenated.

The precipitation of HbS fibers also causes oxidant damage, not only in irreversibly sickled cells but also in normal appearing cells.

Front 191

191. How does calcium play a role in sickled cells?

Back 191

With membrane injury, red cells become loaded w/calcium, which is normally excluded rigorously.

Calcium ions activate a potassium ion channel, leading to the efflux of potassium and water, intracellular dehydration, and an increase in the MCHC.

Front 192

192. What is the most important factor in HbS?

Back 192

The most important factor is the amount of HbS and its interaction w/the other Hb chains in the cell.

Front 193

193. What is a sickle cell trait?

Back 193

Both the low concentraiton of HbS and the presence of interfering HbA act to prevent efficient HbS aggregation and polymerization, and thus red cells in hetero pts do not sickle except under conditions of severe hypoxia.

Such individuals have sickle cell trait, and asymptomatic carrier state.

In contrast, homozygous HbS individuals have full blown sickle cell anemia

Front 194

194. How does HbF affect HbS?

Back 194

Fetal Hb (HbF) inhibits the polymerization of HbS, and hence newborns do not manifest the disease until they are 5-6 mos of age, when the amt of HbF in the cells falls close to adult levels.

Front 195

195. How does HbC affect HbS?

Back 195

HbC, which has a point mutation in the β-globin chain leading to a substitution of lysine for glutamate at position 6.

HbC has a greater tendency to form aggregates w/deoxygenated HbS than HbA.

As a result, individuals with HbS and HbC have a symptomatic sickling disorder (HbSC) disease) that is generally milder than sickle cell anemia.

Front 196

196. The rate of HbS polymerization is strongly dependent upon...?

Back 196

The rate of HbS polymerization is strongly dependent upon the Hb concentration per cells, that is the MCHC.

Higher HbS concentrations increase the probability that aggregation and polymerization will occur during any given period of deoxygenation. ***Thus, intracellular dehydration which increases teh MCHC, facilitates sickling and vascular occlusion.***

Conversely, conditions that decrease the MCHC (α-thalassemia) reduce disease severity.

Front 197

197. How does pH affect sickling?

Back 197

A decrease in pH reduces the oxygen affinity of Hb, thereby increasing the fraction of deoxygenated HbS at any given oxygen tension and augmenting the tendency for sickling.

Front 198

198. How is the length of time red cells are exposed to low oxygen tension important?

What 2 factors play a role in this matter?

Back 198

Sickling of red cells is confined to microvascular beds where blood flow is sluggish. This is normally the case in the spleen and the bone marrow, which are affected by sickle cell disease.

Two factors play important roles in this matter: (1) inflammation, and (2) increased red cell adhesion.

As a result, inflamed vascular beds have longer red cell transit times and are prone to induce clinically significant sickling.

Front 199

199. What are the 2 main clinical manifestations of sickle cell disease?

Back 199

1. Chronic hemolysis
2. Ischemic tissue damage resulting from microvascular occlusions

Front 200

200. The red cell survival correlates with...?

Back 200

The red cell survival correlates with the percentage of irreversibly sickled cells in the circulation, supporting the concept that the hemolytic anemia results primarily from premature removal of irreversibly sickled cells.

Front 201

201. How is NO related to microvascular occlusions?

Back 201

It is thought that in pts with sickle cell anemia, plasma Hb (released from lysed RBC) binds to an inactivates NO.

Such reduction in bioavailable NO predisposes to increased vascular tone (narrowing) and platelet aggregation. These finding provide rationale for NO therapy in sickle cell disease.

Front 202

202. What is the morphology of the bone marrow in sickle cell disease?

Back 202

The bone marrow is hyperplastic b/c of a compensatory hyperplasia of eythroid progenitors. Expansion of the marrow leads to bone resporption and secondary new bone formation, resutling in prominent cheekbones and changes in the skill that resemble a crew cut appearance on xray.

Extramedullary hematopoiesis can also appear.

Front 203

203. What is the morphology of the spleen in sickle cell disease?

Back 203

The spleen is commonly enlarged. On histo exam, there is marked congestion of the red pulp, mainly due to the trapping of sickled red cells in the splenic cords and sinuses. This erythrostasis in the spleen leads to marked tissue hypoxia, thrombosis, infarction, and fibrosis.

Continued scarring causes progressive shrinkage of the spleen so that by adolescence or early adulthood only a small nubbin of fibrous tissue is left (autosplenectomy).

Front 204

204. What are some other morphologic features to know about sickle cell disease?

Back 204

Infarction secondary to vascular occlusions and anoxia can occu rin other tissues as well, including the bones, brain, kidney, liver, retina, and pulmonary vessels, the latter sometimes producing cor pulmonale.

Vascular stagnation in subcutaneous tissues often leads to leg ulcers in adult pts.

Gallstones can develop as well as jaundice.

Front 205

205. What are the three clinical problems in sickle cell disease?

Back 205

1. Severe anemia
2. Vaso-occlusive complications
3. Chronic hyperbilirubinemia

Front 206

206. Are those with sickle cell disease susceptible to infections?

Back 206

Increased susceptibility to infection with encapsulated organsism has two causes:

1. Splenic function is impaired
2. Defects in the alternative complement pathway impair opsonization of encapsulated bacteria such as penumococci and H. influenzae. Septicemia and meningitis caused by these two organisms are the most common causes of death in children with sickle cell anemia.

Front 207

207. What are vaso-occlusive crises (aka pain crises)?

Back 207

These represent episodes of hypoxic injury and infarction associated w/severe pain in the affected region. Although infection, dehydration and acidosis sometimes act as triggers, in most instance no causes are identified.

The most commonly involved sites are the bones, lungs, liver, brain, spleen, and penis. *In children, painful bone crises are common and often difficult to distinguish from acute osteomyelitis. They frequently manifest as the hand-foot syndrome, a dactylitis of the bones of the hands or feet or both.

Particularly dangerous are the crises involving the lungs, which typically present with fever, cough, chest pain, and pulmonary infiltrate (acute chest syndrome).

Front 208

208. What are sequestration crises?

Back 208

Sequestration crises occur in children w/intact spleens. Massive sequestration of sickled red cells leads to rapid splenic enlargement, hypovolemia, and sometimes shock.

Front 209

209. What are aplastic crises?

Back 209

In aplastic crises, there is a transient cessation of bone marrow erythropoiesis due to an acute infection of erythroid progenitor cells by parvovirus B19.

Reticulocytes disappear from the peripheral blood, causing a sudden and rapid worsening of anemia.

Front 210

210. What is one possible treatment for sickle cell anemia?

Back 210

Hydroxyurea acts as an anti-inflammatory agent by inhibiting the production of white cells, which may reduce inflammation-related red cell stasis and sickling.

Also, hydroxyurea increases the mean red cell volume and thereby decreases the concentration of HbS.

Lastly, hydroxyurea can be oxidized by heme groups to produce NO.

Front 211

211. What is the abnormality common to all β-thalassemias?

Back 211

Diminished synthesis of structurally normal β-globin chains, coupled with unimpaired synthesis of α-chains.

Front 212

212. What are the two categories of β-thalassemia?

Back 212

1. β⁰-thalassemia, associated w/total absence of the β-globin chains in the homozygous state
2. β⁺-thalassemia, characterized by reduced (but detectable) β-globin synthesis in the homozygous state.

*Most are point mutations - gene deletions are uncommon in β-thalassemia.

Front 213

213. What are the 3 mechanisms of mutations in β-thalassemia?

Which is most common?

Back 213

1. Promoter region mutations - produces β⁺-thalassemia
2. Chain terminator mutations - produces β⁰-thalassemia
3. Splicing mutations *MOST COMMON FORM* - produces β⁰ or β⁺ forms

Front 214

214. What are the two mechanisms by which impaired β-globin synthesis results in anemia?

Back 214

1. Deficit in HbA synthesis produces "under-Hb", hypochromic, microcytic red cells w/subnormal oxygen transport capacity.

2. Diminished survival or red cells and their precursors, resulting from the imbalance in the alpha and beta chain synthesis. Thus, free α-chains precipitate w/in the normoblasts, forming insolubule inclusions.

Front 215

215. What is the proximal cause of most red cell pathology in β-thalassemia?

Back 215

Cell membrane damage is the proximal cause of most red cell pathology. Many developing normoblasts in the marrow succumb to these membrane lesions, undergoing apoptosis.

In severe β-thalassemia, about 70-85% of normoblasts suffer this fate, leading to ineffective erythropoiesis. Also, the inclusion bearing red cells deprived from precursors escaping intramedullary death are prone to splenic sequestration and destruction.

Front 216

216. In β-thalassemia, marked anemia produced by ineffective erythropoiesis and hemolysis leads to what other problems?

Back 216

Erythropoietin secretion in the setting of severe uncompensated anemia leads to massive erythroid hyperplasia in the marrow and sites of extramedullary hematopoiesis.

Extramedullary hematopoiesis involves the liver, spleen, and lymph nodes, and in extreme cases, produces extraosseous masses in the thorax, abdomen,a nd pelvis.

***Also another disastrous complication seen in severe β-thalassemia is excessive absorption of dietary iron. This can sometimes induce secondary hemochromatosis.

Front 217

217. What is β-thalassemia major?

Back 217

In general, individuals homozygous for β-thalassemia genes β⁺β⁺ or β⁰β⁰) have a severe, transfusion-dependent anemia called β-thalassemia major.

Front 218

218. What is β-thalassemia minor or β-thalassemia trait?

Back 218

Heterozygotes with one β-thalassemia gene and one normal gene usually have a mild microcytic anemia that causes no symptoms. This conditionon is referred to as β-thalassemia minor or β-thalassemia trait

Front 219

219. What is β-thalassemia intermedia?

Back 219

β-thalassemia intermedia is of intermediate severity and is genetically heterogeneous. This category includes milder variants of β⁺β⁺ or β⁺β⁰-thalassemia and unusually severe variants of heterozygous β-thalassemia.

Front 220

220. What about individuals with β-thalassemia and α-thalassemia gene defects?

Back 220

Ironically, the presence of an α-thalassemia gene defect often decreases the severity of β-thalassemia major, since the imbalance in α and β chain synthesis is lessened; this combination can also result in a clinical phenotype resembling β-thalassemia intermidia.

Front 221

221. What are the features of thalassemia major?

Back 221

β-thalassemia is most common in Mediterranean countries and parts of Africa and Southeast Asia.

In this type, the anemia manifests 6-9 mos after birth, as Hb synthesis switches from HbF to HbA.

The peripheral blood smear shows severe red cell morphologic abnormalities, including marked anisocytosis and poikilocytosis, microcytosis, and hypochromia.

Inclusions of aggregated alpha chains are efficiently removed by the spleen and not easily found in peripheral blood smears.

*HbF is markedly increased and indeed constitutes the major red cell hemoglobin.

Front 222

222. What is the morphology of the β-thalassemias?

Back 222

In the untransfused pt, there is striking expansion of hematopoietically active marrow, particularly in facial bones. This erodes existing cortical bone and induces new bone formation, giving rise to a crew cut appearance on X-rays.

Both mononuclear phagocytic cell hyperplasia and extramedullary hematopoiesis contribute to enlargement of the spleen.

*Iron deposition often causes damage to several organs, most notably the heart, liver, and pancreas.

Front 223

223. What is the clinical course of β-thalassemia major?

Back 223

The clinical course of β-thalassemia major is brief unless blood transfusions are given. untreated children suffer from growth retardation and die at an early age from the profound effects of anemia. Blood transfusions not only improve the anemia but also suppress secondary features related to excessive erythropoiesis.

Cardiac disease resulting from progressive iron overload and secondary hemochromatosis is an important cause of death. Administration of iron chelators can forestall this complication.


Bone marrow transplantation from an HLA-identical sibling is currently the only therapy offering a cure.

Front 224

224. What is the clinical course in β-thalassemia minor?

Back 224

Thalassemia minor is much more common than thalassemia major and effects the same ethnic groups. Most pts are heterozygous carriers. Thalassemia trait may offer resistance against faciparum amlaria, accounting for its prevalence in parts of the world where malaria is endemic. This pts are usually asymptomatic, and anemia is mild if present.

Hb electrophresis characteristically reveals an increase in HbA₂, to 4-8% of the total Hb (normal = 2.5%). HbF levels can be normal or slightly increased.

Front 225

225. Why is recognition of β-thalassemia trait important?

Back 225

1. Differentiation from the hypochromic microcytic anemia of iron deficiency
2. Genetic counseling

Front 226

226. What are the α-thalassemias?

Back 226

The α-thalassemias are characterized by reduced or absent synthesis of α-globin chains.

The anemia that results stems from both lack of adequate Hb and the effects of excess unpaired non-α chains (β,γ,δ).

Front 227

227. What are the pathologic mechanisms in α-thalassemia?

Back 227

In the newborn with α-thalassemia, excess unpaired γ-globin forms γ4-tetramers known as hemoglobin Barts, whereas in adults excess β-globin chains form β4-tetramers known as HbH.

Since free β and γ chains are more soluble than free α chains and form fairly stable homotetramers, hemolysis and ineffective erythropoiesis are less severe than in β-thalassemias.

Front 228

228. What are the most common causes of reduced α-chain synthesis in α-thalassemia?

Back 228

Deletion of α-globin genes.

Thalassemia syndromes stem from combos of deletions that remove 1-4 α-globin gene copies. The severity of the syndrome is related to the number of missing α-globin genes.

Front 229

229. What is the silent carrier state of α-thalassemia?

Back 229

This occurs if a single α-globin gene is deleted. These individuals are completely asymptomatic.

Front 230

230. What is the α-thalassemia trait?

Back 230

This is caused by a deletion of two α-globin genes.

The two involved genes can be from the same chromosome (α/α -/-) or one α-globin gene can be deleted from each of the two chromosomes (α/- α/-).

Both genotypes produce similar deficiencies of α-globin chains and are clinically identical.

***Only matings involving individuals with the (α/α -/-) genotype are at risk for producing offspring with hydrops fetalis.***

Front 231

231. What is Hemoglobin H disease?

Back 231

This is caused by deletion of three α-globin genes.

With only one normal α-globin gene, the synthesis of α chains is markedly reduced and tetramers of excess β-glboin, called HbH, form. HbH has extremely high affinity for oxygen and therefore is not useful for oxygen exchange, leading to tissue hypoxia disproportionate to the level of hemoglobin.

*The instability of HbH is a major cause of anemia, as precipitates of oxidized HbH form in older red cells, which are then removed by splenic macrophages. This produces a moderately severe anemia resembling β-thalassemia intermedia.

Front 232

232. What is hydrops fetalis?

Back 232

This most severe form of α-thalassemia is caused by deletion of all four α-globin genes.

Signs of fetal distress usually become evident by the third trimester of pregnancy. The fetus shows severe pallor, generalized edema, and massive hepatosplenomegaly similar to that seen in erythroblastosis fetalis.

Front 233

233. What is paroxysmal nocturnal hemoglobinuria?

Back 233

This is the only hemolytic anemia caused by an acquired intrinsic defect in the cell membrane.

PNH results from acquired mutations in phosphatidylinositol glycan A (PIGA), which is essential for the synthesis of the GPI anchor.

Only the active PIGA gene needs to be mutated to produce a functional deficiency; all its clonal progeny (red cells, white cells, and platelets) are deficient in proteins attached to the cell membrane via GPI. ***Several GPI-linked proteins inactivate complements; this absence in PNH renders blood cells unusually sensitive to lysis by complement.***

Front 234

234. What are the 3 GPI-linked proteins that regulate complement?

Back 234

1. Decay accelerating factors (CD55)
2. Membrane inhibitor of reactive lysis (CD59)
3. C8 binding protein

*All of these are deficient in PNH.

Front 235

235. Which GPI-linked protein is the most important in PNH?

Back 235

CD59. It is a potent inhibitor of C3 convertase, and thereby prevents spontaneous activation of the alternative complement pathway in vivo.

Front 236

236. What is the hemolysis like in PNH?

Back 236

The intravascular hemolysis is actually paroxysmal and nocturnal in only 25% of cases. Chronic hemolysis w/o dramatic hemoglobinuria is more common.

During the disease course, hemosiderinuria eventually leads to iron deficiency. Episodic venous thrombosis, often involving the hepatic, portal, or cerebral veins can sometimes manifest in some cases and be fatal.

Front 237

237. PNH often arises in which settings?

Back 237

PNH often arises in the setting of primary bone marrow failure (aplastic anemia), which can be caused by immune-mediated destruction or suppression of marrow stem cells.

PNH pts are also at increased risk for developing acute myelogenous leukemia.

Front 238

238. The Dx of immunohemolytic anemias requires what tests?

Back 238

The Dx of immunohemolytic anemias require the detection of antibodies and/or complement on pt red cells. This is done using the direct Coombs antiglobulin test. In this test, pt red cells are mixed with antisera specific for human Igs or complement. if either is present, red cells are crosslinked causing clumping or agglutination.

The indirect Coombs antiglobulin test, in which pt serum is tested for its ability to agglutinate defined test red cells, can then be used to characterize the target of the autoantibody. *Also, the temperature dependence of this reaction helps to define the type of antibody responsible.

Front 239

239. What is warm antibody immunohemolytic anemia?

Back 239

This is teh msot common form of immune hemolytic anemia. About half of cases are idiopathic (primary); the remainder arise secondarily in teh setting of a predisposing condition or drug exposure.

Most causative antibodies are of the IgG class; sometimes IgA are present.

Front 240

240. What is the hemolysis like in warm antibody immunohemolytic anemia?

Back 240

Most red cell destruction in this form is extravascular. IgG coated red cells bind Fc receptors on monocytes and splenic macrophages, which results in loss of red cell membrane during "partial" phagocytosis.

*Moderate splenomegaly is characteristic of this form of anemia*

In many cases, the antibodies are directed against the Rh blood group antigens.

Front 241

241. What is cold antibody immunohemolytic anemia?

Back 241

This form is caused by so called cold agglutinins, IgM antibodies that bind and agglutinate red cells avidly at low temps. It is less common than warm antibody immunohemolytic anemia.

Such antibodies appear acutely durign the recovery phase of certain infectious disorders, such as mycoplasma pneumonia and IM. Other agents associated with this form of anemia include CMS, influenza virus, and HIV.

Front 242

242. What is the pathophysiology behind cold antibody immunohemolytic anemia?

Back 242

These symptoms result form binding of IgM to red cells at sites such as exposed fingers, toes, and ears where the temp is cold. IgM binding agglutinates red cells and rapidly fixes complement on their surface. As the blood recirculates and warms, IgM is rapidly released, usually before complement mediated hemolysis can occur. However, the transient interaction w/IgM is sufficient to deposit sublytic quantities of C3b, leading to rapid removal of affected red cells in the liver and spleen.

Front 243

243. What are the clinical symptoms of cold antibody immunohemolytic anemia?

Back 243

The hemolysis is of variable severity. Vascular obstruction caused by red cell agglutinates results in pallor, cyanosis of the body parts exposed to cold temps, and Raynaud phenomenon.

Front 244

244. What is cold hemolysin hemolytic anemia?

Back 244

This anemia occurs in paroxysmal cold hemoglobinuria, manifesting as acute intermittent massive intravascular hemolysis after exposure to cold.

Autoantibodies are IgG directed against the P blood group antigen.

They attach to the RBCs and fix complement at low temps; when the temp is elevated, hemolysis occurs.

Most cases follow infections such as mycoplasma pneumonia, measles, mumps, and ill-defined viral and flu syndromes.

Front 245

245. What are Donath-Landsteiner antibodies?

Back 245

The autoantibodies in cold hemolysin hemolytic anemia (IgG directed against the P blood group antigen) are also known as Donath-Landsteiner antibodies. This was first recognized in associated with syphilis.

Front 246

246. What are the hemolytic anemias caused by trauma?

Back 246

Hemolytic anemias caused by cardiac valve prostheses, or narrowing or obstruction of the microvasculature, are most important clinically.

Severe traumatic hemolytic anemia is more frequently associated with artificial mechanical valves than bioprosthetic porcine valves.

Front 247

247. What is microangiopathic hemolytic anemia?

Back 247

Microangiopathic hemolytic anemia occurs when red cells are forced to squeeze thru abnormally narrowed small vessels. Narrowing is most often caused by fibrin deposition in association with DIC.

Front 248

248. What is the common feature among all hemolytic anemias caused by trauma?

Back 248

A microvascular lesion that causes mechanical injury to circulating red cells. This damage is evident in peripheral blood smears in the form of red cell fragments (schstocytes), "burr cells", "helmet cells", and "triangle cells").

Front 249

249. What is the main problem that causes megaloblastic anemias?

Back 249

The magaloblastic anemias constitute a diverse group of entities, having in common impaired DNA synthesis and distinctive morphologic changes in the blood and bone marrow.

Erythroid precursors and red cells are abnormally large due to defective cell maturation and division.

Front 250

250. How does vitamin B12 and folic acid cause megaloblastic anemia?

Back 250

Vitamin B12 and folic acid are coenzymes required for synthesis of thymidine, one of the four bases found in DNA.

A deficiency of these vitamins or impairment in their metabolism results in defective nuclear maturation due to deranged or inadequate DNA synthesis with an attendant delay or block in cell division.

Front 251

251. What does the peripheral blood exam show in megaloblastic anemias?

Back 251

It reveals pancytopenia, as all myeloid lineages are affected. There is marked variation in the size and shape of red cells (anisocytosis), which nonetheless are normochromic.

*Many red cells are macrocytic and oval, with MCV above 100 fl. The MCHC is not elevated.

*Neutrophils are also larger than normal and hypersegmented; that is, they have 5-6 or more nuclear lobules. The marrow is usually marked hypercellular.

Front 252

252. In what cells is megaloblastic change detected?

Back 252

In all stages of red cell development. The most primitive cells (promegaloblasts) are large, with a deeply basophilic cytoplasm, prominent nucleoli, and a distinctive fine nuclear pattern. As these cells differentiate and begin to accumulate Hb, the nucleus retains its finely distributed chromatin, and thus fails to undergo the chromatin clumping typical of the normoblast.

B/c DNA synthesis is impaired in all proliferation cells, granulocytic precursors also display nuclear cytoplasmic asynchrony in the form of giant metamyelocytes and band forms.

Front 253

253. What about the marrow in megaloblastic anemia?

Back 253

The marrow hyperplasia usually seen in megaloblastic anemias is a response to increased levels of growth factors such as erythropoietin. However, due to the derangement in DNA synthesis, most myeloid precursors undergo apoptosis in the marrow, leading to pancytopenia.

The anemia is further exacerbated by increased hemolytic destruction of red cells in the periphery.

Front 254

254. What is pernicious anemia?

Back 254

Pernicious anemia is a specific form of megaloblastic anemia caused by atrophic gastritis and an attendant failure of intrinsic factor production that leads to vitamin B12 deficiency.

Absorption of vitamin B12 requires intrinsic factor, which is secreted by the parietal cells of the fundic mucosa.

Front 255

255. What is the fundamental cause of impaired DNA synthesis in vitamin B12 deficiency?

Back 255

The fundamental cause of impaired DNA synthesis is the reduced availability of FH4, most of which is trapped as N5-methyl FH4.

Whatever the mechanism, lack of folate is the proximate cause of anemia in vitamin B12 deficiency, as the anemia inevitably improves w/admin of foflic acid.

Front 256

256. A deficiency in vitamin B12 leads to increased levels of what...?

Back 256

Leads to increased plasma and urine levels of methylmalonic acid. interruption of the succinyl pathway and consequent build-up of methylmalonate and propionate could lead to the formation and incorporation fo abnormal fatty acids into neuronal lipids.

*It has been suggested that this biochemical abnormality predisposes to myelin breakdown and thereby produces the neurologic complications of vitamin B12 deficiency.

Front 257

257. What are 7 things that can cause vitamin B12 deficiency?

Back 257

Can result from impaired absorption, which has several causes:
1. Achlorhydria, which impairs viatamin B12 release from teh R protein bound form
2. Gastrectomy, which leads to the loss of intrinsic factor
3. Pernicious anemias
4. Resection of the distal ileum, which prevents absorption of intrinsic factor-B12 complex
5. Malabsorption syndromes
6. Increased requirements (i.e. pregnancy)
7. Inadequate diet (very uncommon)

Front 258

258. What are the causes of pernicious anemia?

Back 258

Pernicious anemia is believed to result form immunologically mediated, possibly autoimmune, destruction of gastric mucosa.

The resultant chronic atropic gastritis is marked by a loss of parietal cells, a prominent infiltrate of lymphocytes and plasma cells, and megaloblastic changes in mucosal cells similar to those found in erythroid precursors.

Front 259

259. What are the three types of antibodies that are present in many but not all with pernicious anemia?

Back 259

1. Type I antibody that blocks binding of vitamin B12 to intrinsic factor (75%)
2. Type II antibodies prevent IF or IF-B12 complex from binding to the ileal receptor
3. Antibodies against the gastric proton pump bind to parietal cells and affect acid secretion (85-90%).

-Type III antibodies are not specific for pernicious anemia or other autoimmune diseases.

Front 260

260. What type of immune response is generated by these autoantibodies?

Back 260

It is believed that an autoreactive T-cell (CD4+ T cells) response initiates gastric mucosa injury, triggering the formation of autoantibodies, which may exacerbate epithelial injury.

When the mass of intrinsic factor-secreting cells falls below a threshold, anemia develops.

Front 261

261. What is the morphology of the GI system in pernicious anemia?

Back 261

Abnormalities are found in the tongue and stomach. The tongue is beefy, shiny and glazed (atrophic glossitis). The changes in the stomach are those of atrophic gastritis.

*The most characteristic histologic alteration is the atrophy of the fundic glands, affecting both chief cells and parietal cells, the latter being virtually absent. The glandular lining epithelium is replaced by mucus-secreting goblet cells that resemble those lining the large intestine, a form of metaplasia referred to as intestinalization.*

Front 262

262. Patients w/pernicious anemia have an increased risk of...?

Back 262

Gastric cancer. The gastric atrophic and metaplastic changes are due to autoimmunity and not B12 deficiency; hence, parenteral admin of B12 corrects the bone marrow changes, but gastric atrophy and achlorhydria persist.

Front 263

263. What are the morphologic changes in the CNS in pernicious anemia?

Back 263

The principal alterations involve the spinal cord, where there is degeneration of myelin in the dorsal and lateral tracts, sometimes followed by loss of axons.

These changes give rise to spastic paraparesis, sensory ataxia, and severe paresthesias in the lower limbs. Less freq, degenerative changes occur in the ganglia of the posterior roots and in peripheral nerves.

Front 264

264. What are the 10 diagnostic features in pernicious anemia?

Back 264

1. A moderate to severe megaloblastic anemia
2. Leukopenia with hypersegmented granulocytes
3. Mild to moderate thrombocytopenia
4. Mild jaundice due to ineffective erythropoiesis and peripheral hemolysis of red cells
5. Neurologic changes related to involvement of the posterolateral spinal tracts
6. Achlorhydria even after histamine stimulation
7. Inability to absorb an oral dose of cobalamin (Schilling test)
8. Low serum levels of B12
9. Elevated levels of homocysteine and methylmalonic acid in the serum
10. A striking reticulocytic response and improvement in HCT levels beginning about 5 days after admin of B12.

****Serum antibodies to intrinsic factor are highly specific for pernicious anemia.

Front 265

265. Can high dose vitamin B12 treat pernicious anemia?

Back 265

With parenteral or high dose oral vitamin B12, the anemia can be cured and the peripheral neurologic changes reversed, or at least halted in their progression, but the changes in the gastric mucosa are unaffected.

Overall longevity can be restored virtually to normal.

Front 266

266. What is anemia of folate deficiency?

Back 266

A deficiency of folic acid, more properly pteroylmonoglutamic acid, results in a megaloblastic anemia having the same characteristics as that caused by vitamin B12 deficiency. However, the neurologic changes seen in vitamin B12 deficiency do not occur.

Front 267

267. Again, what is the common problem in folate deficiency?

Back 267

Suppressed synthesis of DNA is the immediate cause of megaloblastosis.

This is the same denominator in vitamin B12 deficiency, and thus it is essential to exclude vitamin B12 deficiency in megaloblastic anemia before initiating therapy with folate.

Front 268

268. If folic acid is common in normal diets in adequate amts, how can a deficiency occur?

Back 268

The folic acid in these foods is largely in the form of folylpolyglutamates. Despite their abundance in raw foods, polyglutamates are sensitive to heat; boiling, steaming, or frying of foods for 5-10 minutes destroys up to 95% of the folate content.

Front 269

269. What are the 4 major causes of folic acid deficiency?

Back 269

1. Inadequate intake, usually in those living on marginal diets (i.e.chronic alcoholics, elderly, and the indigent)
2. Malabsorption syndromes (e.g., tropical and nontropical sprue)
3. Increased demand (pregnancy, infancy, hemolytic anemias, or disseminated CA)
4. Admin of folate antagonists such as methotrexate, a chemotherapeutic agent.

Front 270

270. How is the Dx of megaloblastic anemia resulting from a deficiency of folic acid made?

Back 270

Induces a megaloblastic anemia clinically and hematologically indistinguishable from that seen in vitamin B12 deficiency.

*Dx can be made only by demonstration of decreased folate levels in the serum or red cells. As in vitamin B12 deficiency, serum homocysteine levels are also increased.

Front 271

271. What maintains the body's iron balance?

Where is iron found in the body?

Back 271

Iron balance is maintained largely by regulated the absorption of dietary iron.

Approx 80% of the functional iron is found in Hb; myoglobin and iron containing enzymes such as catalase and cytochromes contain the rest. The storage pool represented by hemosiderin and ferritin contains approx 15-20% of the total body iron.

Front 272

272. Serum levels of _______ correlate well with body iron stores...?

Back 272

Plasma ferritin is derived largely from the storage pool of body iron and thus its levels correlate well with body iron stores.

Front 273

273. Where is most iron absorbed in the GI tract?

Back 273

Most is absorbed in the duodenum via the DMT1 transporter.

The HFE gene, which encodes and HLA-like transmembrane protein, is also clearly involved in regulation of iron absorption.

Front 274

274. What is hepcidin?

Back 274

An excellent candidate for a negative "iron metabolism regulatory hormone" is hepcidin, a small, liver-derived plasma peptide.

Hepcidin inhibits iron uptake in the duodenum and iron release from macrophages. The concentration of hepcidin falls as iron stores become depleted, and hepcidin knockout mice develop hemochromatosis. Conversely, overexpression of hepcidin in transgenic mice causes an iron defcieincy anemia.

***These findings suggest the existence of a hepcidin receptor on duodenal enterocytes.

Front 275

275. What are 4 causes of iron deficiency?

Back 275

1. Low dietary intake (rarely the cause of iron deficiency by itself in the US b/c the avg daily intake is more than enough for men and adequate for most women) malabsorption, excessive demand, and chronic blood loss.

2. Malabsorption caused by sprue and celiac disease or after gastrectomy

3. Increased demands (pregnancy, menstruating women)

4. Chronic blood loss; this is the most common cause of iron deficiency in the western world.

Front 276

276. A deficiency in iron in adult men and postmenopausal women must be attributed to...?

Back 276

Must be attributed to GI blood loss (cancer, ulceration, lesion) until proven otherwise.

Front 277

277. What are the clinical features of iron deficiency?

Back 277

***Induces a hypochromic, microcytic anemia.***

Also, depletion of iron enzymes in cells throughout the body can cause koilonychia, alopecia, atrophic changes in the tongue and gastric mucosa, and intestinal malabsorption.

Front 278

278. What is the Plummer-Vinson triad?

Back 278

1. Microcytic hypochromic anemia
2. Atrophic glossitis
3. Esophageal webs

Front 279

279. What is a diagnostically significant finding in iron deficiency in the bone marrow?

Back 279

The disappearance of stainable iron from mononuclear phagocytic cells in the bone marrow, which is assessed by performing Prussian blue stains on aspirated or sections bone marrow.

Poikilocytosis (abnormal shapes) in the form of small, elongated red cells (pencil cells) is also characteristic.

Front 280

280. What are the serum iron and ferritin levels and the TIBC in iron deficiency anemia?

Back 280

The serum iron and ferritin levels are low, and the TIBC is high.

Low serum iron with increased TIBC results in a reduction of transferrin saturation levels to below 15%.

Front 281

281. What are three groups of anemia of chronic disease?

Back 281

1. Chronic microbial infections, such as osteomyelitis, bacterial endocarditis, and lung abscess
2. Chronic immune disorders, such as RA and regional enteritis
3. Neoplasms, such as Hodgkin lymphoma and carcinomas of the lung and breast

Front 282

282. What are the common features characterizing anemia in these chronic diseases?

Back 282

There is low serum ion and reduced TIBC in association with abundant stored iron in the mononuclear phagocytic cells.

This combo suggests some impediment in the transfer of iron from the storage pool to the erythroid precursors.

Front 283

283. Why do marrow erythroid progenitors NOT proliferate adequately in anemia of chronic disease?

Back 283

This is b/c erythropoietin levels are inappropriately low for the degree of anemia.

The reduction in renal erythropoietin generation is caused by IL-1, TNF, and IFN-y, secretion of which is triggered by the underlying chronic inflammatory or neoplastic disease.

These cytokines also stimulate hepcidin synthesis in the liver, which in turn inhibits the release of iron from the storage pool.

Front 284

284. What is aplastic anemia?

Back 284

Characterized by a failure or suppression or disappearance of multipotent myeloid stem cells; neutropenia, anemia, and thrombocytopenia (pancytopenia) result.

Most cases of aplastic anemia of known etiology follow exposure to chemical and drugs.

Front 285

285. What are the 4 known causes of aplastic anemia?

Back 285

Idiopathic in 60% of cases

Known causes are:
1. Myelotoxic drugs or chemicals (6-MP, vincristine, and busulfan)
2. Total body irradiation
3. Infections (viral hepatitis of non-A, non-B, non-C, and non-G types)
4. Inherited diseases (e.g. Fanconi anemia)

Front 286

286. What is Fanconi anemia?

Back 286

Fanconi anemia is a rare autosomal recessive disorder caused by defects in a component of a multiprotein complex required for DNA repair.

Marrow hypofunction in Fanconi anemia becomes evident early in life and is accompanied by multiple congenital anomalies, such as hypoplasia of the kidney and spleen and hypoplastic anomalies of bone, often involving the thumbs or radii.

Front 287

287. What is the pathogenesis of aplastic anemia?

Back 287

Stem cell alterations may be due to environmental insults, drug exposure, or infections. In idiopathic cases, stem cell failure may be due to:

1. Primary defect in the number or function of stem cells; in some case due to mutagen exposure. Occasionally, genetically damaged stem cells can transform to acute leukemias.

2. Suppression of antigenically altered stem cells by T cell mediated immune mechanisms.

Front 288

288. What is the morphology of aplastic anemia?

Back 288

The markedly hypocellualr bone marrow is largely devoid of hematopoietic cells; often only fat cells, fibrous stroma, and scattered or clustered foci of lymphocytes and plasma cells remain. A marrow aspirate often yields little material (a "dry tap").

Front 289

289. What is the clinical course of aplastic anemia?

Back 289

The onset is usually insidious. Initial manifestations depend on which cell line is affected. Anemia can cause progressive weakness, pallor, and dyspnea. Petechiae and ecchymoses can herald thrombocytopenia. Granulocytopenia can manifest as frequent and persistent minor infections or the sudden onset of chills, fever, and prostrations.

***Splenomegaly is characteristically absent; if present, the Dx of aplastic anemia should be seriously questioned.***

Front 290

290. How does one distinguish aplastic anemia from other causes of pancytopenia, such as myelodysplastic syndromes?

Back 290

In aplastic anemia, the marrow is hypocellular, whereas myeloid neoplasms are associated with hypercellular marrow filled with abnormal myeloid progenitors.

Front 291

291. What is pure red cell aplasia?

Back 291

Pure red cell aplasia is a form of marrow failure characterized by a marked hypoplasia of marrow erythroid elements in the setting of normal granulopoiesis and thrombopoiesis.

Pure red cell can be primary, or they can arise secondarily to neoplasms, particularly thymic tumors (thymomas) and large granular lymphocytic leukemia. due to the absence of RBC precursors.

Front 292

292. What is myelophthisic anemia?

Back 292

Space occupying lesions that destroy or distort the marrow architecture depress productive capacity.

Associated w/pancytopenia and frequently w/the appearance of white and red blood cell precursors in the peripheral blood.

Most common cause is metastatic cancer, most often carcinomas arising in the breast, lung, and prostate.

Front 293

293. What are two other conditions that can be associated with anemia?

Back 293

Diffuse liver disease and chronic renal failure.

Front 294

294. Diffuse liver disease (toxic, infectious or cirrhotic) and anemia

Back 294

The anemia is primarily due to bone marrow failure; often exacerbated by variceal bleeding or folate deficiency

Front 295

295. Chronic renal failure and anemia

Back 295

Chronic renal failure is almost always associated w/anemia.

The basis is multifactorial, but inadequate erythropoietin production is most important.

Treatment w/recombinant erythropoietin usually yields significant improvement.