Pbl Exam 10 Case 8-2

Front 1

1. What is AIDS?

Back 1

AIDS is a disease caused by the retrovirus HIV and characterized by profound immunosuppression that leads to opportunistic infections, secondary neoplasms, and neurologic manifestations.

Front 2

2. What are the 6 causes or high risk groups of AIDS?

Back 2

1. Homosexual or bisexual men constitute by far the largest group
2. IV drug abusers
3. Hemophiliacs
4. Recipients of blood and blood components
5. Heterosexual contacts
6. Idiopathic

Front 3

3. How is the epidemiology of AIDS different in children under age 13?

Back 3

In this group, more than 90% have results from transmission of the virus from mother to child.

Front 4

4. What are the 3 major routes of transmission of AIDS?

Back 4

1. Sexual contact
2. Parenteral inoculation
3. Passage of the virus from infected mothers to their newborn

Front 5

5. What are the 2 ways in which sexual transmission occurs?

Back 5

1. Direct inoculation into the blood vessels breached by trauma in the rectal or oral mucosa
2. Into dendritic cells or CD4+ cells w/in the mucosa

Front 6

6. Does female to male transmission occur?

Back 6

HIV is present in vaginal secretions, and cervical cells of infected women.

All forms of sexual transmission of HIV are enhanced by coexisting STDs, especially those associated with ulceration in the genitals. Syphilis, chancroid, and herpes are important causes. Gonorrhea and chlamydia are also cofactors for HIV transmission perhaps b/c there is greater concentration of the virus and virus-containing cells in genital fluids, owing to increased numbers of inflammatory cells in the semen.

Front 7

7. What are 3 ways in which mothers can transmit HIV to their infant?

Back 7

1. In utero by transplacental spread
2. During delivery through an infected birth canal
3. After birth by ingestion of breast milk

*Of these, transmission during birth and in the immediate period thereafter is considered to be the most common mode in the US. Higher risk of transmission is associated w/high maternal viral load and low CD4+ T cell counts as well as chorioamnionitis.

Front 8

8. What is the actual risk of contracting HIV via a needle-stick?

Back 8

After needle-stick accidents, the risk of seroconversion is believed to be about 0.3%, and HAART given w/in 24-48 hours of a needle-stick can reduce the risk of infection 8x.

Front 9

9. What are the two forms of HIV?

Back 9

HIV1 and HIV2 have been isolated from pts w/AIDS.

HIV-1 is the most common type associated w/AIDS in the US, Europe, and Central Africa, whereas HIV-2 causes a similar disease principally in West Africa and India.

Front 10

10. What is the structure of HIV? What are the 4 components of the viral core?

Back 10

HIV is spherical and contains and electron dense-cone shaped core surrounded by a lipid enveolope derived from the host cell membrane.

The virus core contains:
1. p24 major capsid protein
2. Nucleocapsid protein p7/p9
3. 2 copies of genomic RNA
4. The three viral enzymes (protein reverse transcriptase, and integrase).

Front 11

11. What is the most readily detected viral antigen in HIV?

Back 11

p24 is the most readily detected viral antigen, and is the target for the antibodies that are used for the Dx of HIV infection in ELISA.

Front 12

12. What surrounds the viral core?

Back 12

A matrix protein called p17, which lies underneath the virion envelop. Studding the viral envelop are two viral glycoproteins, gp120, and gp41, which are critical for HIV infection of cells.

Front 13

13. The HIV-1 RNA genomes contains what genes?

Back 13

gac, pol, and env


These three standard HIV genes code for various viral proteins. The products of the gag and pol genes are translated initially into large precursor proteins that must be cleaved by the viral protease to yield mature proteins.

Front 14

14. What are some other HIV genes?

Back 14

tat, rev, vif, nef, vpr, and vpu

These genes regulate the synthesis and assembly of infectious viral particles and the pathogenicity of the virus. For example, the produce of the TAT (transactivator) gene, for example, is critical for virus replication. The Tat protein functions by causing a 1000x increase in the transcription of viral genes, thus it increases viral replication.

Front 15

15. Where does HIV generate its variations in viral proteins?

Back 15

Most variations are clustered in certain regions of the envelope glycoproteins.

B/c the humoral immune response against HIV-1 is targeted against its envelop, such variability poses problems for the development of a single vaccine.

Front 16

16. What are the 3 subgroups of HIV-1?

Back 16

M (major)
O (outlier)
N (neither M nor O)

Group M viruses are the most common form worldwide and are further divided into several subtypes or clades, designated A thru K.

Front 17

17. Of type M, which is the most common clade?

Back 17

Subtype B is the most common form in western Europe and the US, whereas subtype E is the most common clade in Thailand.

Currently, clade C is the fastest spreading clade worldwide, being present in India, Ethiopia, and Southern Africa.

Front 18

18. Where are the 2 major targets of HIV?

Back 18

The immune system and the CNS.

Profound immunosuppression, primarily affecting CMI, is the hallmark of AIDS. This results chiefly from infection of and a severe loss of CD4+ T cells as well as impairment in the function of surviving helper T cells.

Front 19

19. How does HIV infect? What is the receptor for HIV?

Back 19

The CD4 molecule is a high-affinity receptor for HIV.

Binding to CD4 is not sufficient for infection, however. HIV gp120 must also gind to other cell surface molecules for entry into the cell.

Two chemokine receptors, CCR5 and CXCR4, serve this role.

Front 20

20. What is the initial step in infection?

Back 20

The initial step in infection is the binding of the gp120 envelop glycoprotein to CD4 molecules. This binding leads to a conformational change that results in the formation of a new recognition site on gp120 for the coreceptors of CCR5 or CXCR4.

The next step involves conformational changes in gp41; these changes result in the insertion of a fusion peptide at the tip of gp41 into the cell membrane of the target cells (e.g., T cells or macrophages). After fusion, the virus core containing the HIV genome enters the cytoplasm of the cell.

Front 21

21. What 4 things influence the efficacy of viral infection?

Back 21

1. Nonlymphoid cells engineered to express human CD4 cannot be infected w/HIV unless one of the coreceptors is also expressed in these cells
2. Chemokines sterically hinder HIV infections of cells in culture by occupying their receptors
3. Individuals who inherit 2 defective copies of the CCR5 receptor gene are resistant to infection

Front 22

22. What are the 2 groups of HIV strains?

Back 22

1. Macrophage (M-tropic) strains can infect both monocytes/macrophages and freshly isolated peripheral blood T cells, but not in vitro propagated T cell lines.

2. T-cell line tropic strains can infect only T cells, both freshly isolated and maintained in culture.

Front 23

23. What accounts for the selectivity of these 2 HIV strains?

Back 23

Based on coreceptor usage: M-tropic strains use CCR5, whereas T-tropic strains bind to CXCR4.

B/c CCR5 is expressed on both monocytes and T cells, they are susceptible to infection by M-tropic strains; CXCR4 is expressed on T cells but not on monocytes/macrophages, and hence T cells but not macrophages can be infected w/T-tropic strains.

Primary (freshly isolated) T cells express both CCR5 and CXCR4 and hence can be infected by either of the two strains.

Front 24

24. Which strain is dominant in the early stages of HIV? Later stages?

Back 24

The M-tropic type is the dominant virus found in the blood of acutely infected individuals and early in the course of infection.

Over the course of infection, however, T-tropic viruses gradually accumulate; these are especially virulent and cause the final rapid phase of disease progression.

Front 25

25. What is this transition of strains important?

Back 25

It is though that during the course of HIV infection M-tropic strains evolve into T-tropic strains, owing to mutations in genes that encode gp120.

The resultant transition in the ability of the virus to bind to CXCR4 but not CCR5 probably is important in the pathogenesis of AIDS b/c T-tropic (i.e., CXCR4-tropic) viruses are capable of infecting naive T cells and even thymic T cell precursors and cause greater depletion and impairment.

Front 26

26. What are two possible explanations for why M-tropic strains are more efficient in transmission?

Back 26

1. Dendritic cells w/in the mucosal epithelium richly express CCR5 but not CXCR4, thus making them susceptible to infection by M-tropic viruses.
2. Binding of M-tropic strains to CCR5 on T cells may signal these cells to make chemotactic factors for other T cells, thus increasing the population of potential targets in the vicinity of an infected T cell.

*Envelope glycoproteins of T-tropic viruses do not cause such activation of T-cell signals after binding to CXCR4.

Front 27

27. What happens once the virus is internalized?

Back 27

The RNA genome of the virus undergoes reverse transcription, leading to the formation of cDNA. In dividing T cells, the cDNA circularizes, enters the nucleus and is then integrated into the host genome.

After this integration, the provirus may remain locked into the chromosome for months or years, and hence the infection becomes latent. Alternatively, proviral DNA may be transcribed, with the formation of complete viral particles that bud from the cell membrane. Such productive infection, when associated w/extensive viral budding, leads to cell death.

Front 28

28. What cytokines lead to cell death in HIV infected cells?

Back 28

Antigen induced activation of T cells is associated w/transcription of genes encoding IL-2, and its receptor. At the molecular level, this is accomplished in part by induction of the NF-κB transcription factor.

In resting T cells, NF-κB is sequestered in the cytoplasm in a complex w/members of the I-κB protein (inhibitor).

Cellular activation by antigen or cytokines (e.g., IL-1, IL-2, TNF) induces cytoplasmic kinases that phosphorylate I-κB and target it for enzymatic degradation, thus releasing NF-κB and allowing it to translocate to the nucleus.

Front 29

29. So what happens with induction of NF-κB in the cells?

Back 29

Such induction (a physiologic response) activates the transcription of HIV proviral DNA (a pathologic outcome) and leads to the production of virions and to cell lysis.

Furthermore, TNF, a cytokine produced by activated macrophages, also stimulates NF-κB activity and thus leads to transcriptional activation of HIV-mRNA.

Front 30

30. What else can stimulate HIV replication?

Back 30

It seems that HIV thrives when the host macrophages and T cells are physiologically activated. Such activation can result from antigenic stimulation by HIV itself or by other infecting microorganisms, such as CMV, EBV, hep B, and M. tuberculosis.

Front 31

31. How does HIV cause lysis of CD4+ T cells?

Back 31

Productive infection of T cells and viral replication in infected cells is the major mechanism by which HIV causes lysis of CD4+ T cells.

Early in the course of HIV infection, the immune system can replace the dying T cells, and hence the rate of CD4+ cell loss appears low.

Later in the course of disease, renewal of CD4+ T cells cannot keep up w/the loss of these cells.

Front 32

32. What are the 5 ways in which HIV causes T-cell lysis that does not involve a cytopathic effect of the virus?

Back 32

1. The virus may cause progressive destruction of the architecture and cellular composition of lymphoid tissues
2. Activation induced cell death (numbers of CD4+ T cells that die are far greater than the numbers of infected cells)
3. Loss of immature precursors, of CD4+ T cells, either by direct infection of thymic progenitor cells or by infection of accessory cells that secrete cytokines essential for CD4+ T cell maturation.
4. Fusion of infected and uninfected cells, with formation of syncytia (due to gp120 binding to CD4 molecules of uninfected cells)
5. Apoptosis of uninfected CD4+ T cell, by binding of soluble gp120 to the CD4 molecule, followed by activation through the TCR by antigens - causes CD8 cell death

Front 33

33. What are the qualitative defects in T cells that can be detected even in asymptomatic HIV infected persons?

Back 33

Reported defects include a reduction in antigen induced T-cell proliferation, a decrease in TH1 type responses relative to the TH2 type, defects in intracellular signaling, and many more.

*The imbalance between the TH1 and TH2 responses results in profound deficiency in CMI, leading to increased susceptibility to infections by viruses and other intracellular microbes.

Front 34

34. There is a selective loss of _______ cells early in the infection?

Back 34

There is a selective loss of the memory subset of CD4+ helper T cells early in the course of disease, possibly because memory T cells express higher levels of the HIV-1 coreceptor CCR5 and are the cells that are activated in response to HIV.

Front 35

35. In addition to infection and loss of CD4+ T cells, infection of what is also important in the pathogenesis of HIV infection?

Back 35

Infection of monocytes and macrophages.

In certain tissues, such as the lungs and brain, as many as 10-50% of macrophages are infected.

Front 36

36. What property of the HIV-1 virus is important of infecting terminally differentiated nondividing macrophages?

Back 36

This property of HIV-1 is dependent on the HIV-1 vpr gene. The Vpr proteins allows nuclear targeting of the HIV preintegration complex thru the nuclear pore.

Front 37

37. Why are macrophages reservoirs of HIV?

Back 37

Despite the fact they allow viral replication, they are quite resistant to the cytopathic effects of HIV, in contrast to CD4+ T cells. Thus, macrophages may be reservoirs of infection.

*Initial infection of macrophages or dendritic cells may be important in the pathogenesis of the disease.

Front 38

38. What are the 3 implications of HIV infection in macrophages?

Back 38

1. Monocytes and macrophages represent a virus factory and reservoir, whose output remains largely protected from host defenses.
2. Macrophages provide a safe vehicle for HIV to be transported to various parts of the body, including the nervous system
3. In late stages of HIV infection, when the CD4+ T-cell numbers decline greatly, macrophages may be an important site of continued viral replication.

Front 39

39. Infection of monocytes causes what functional defects?

Back 39

These defects include impaired microbicidal activity, decreased chemotaxis, decreased secretion of IL-1, inappropriate secretion of TNF, and most important, poor capacity to present antigens to T cells.

Front 40

40. How are dendritic cells important in HIV?

Back 40

Mucosal dendritic cells are infected by the virus and transport it to regional lymph nodes, where CD4+ T cells are infected.

Follicular dendritic cells in the germinal centers of lymph nodes are, similar to macrophages, important reservoirs of HIV infection. They have receptors for the Fc portion of Ig, and hence they trap HIV virions coated with anti-HIV antibodies.

*Thus, dendritic cells are major sites of HIV infection and persistence.

Front 41

41. What are the features of B cells in pts with AIDS?

Back 41

AIDS pts have hypergammaglobulinemia and circulating immune complexes owing to polyclonal B-cell activation. This may result from multiple interacting factors: reactivation of or reinfection with CMV and EBV, both which are polyclonal B cell activations; gp1 itself can promote B-cell growth and differentiation; and HIV-infected macrophages produce increased amts of IL-6, which stimulates proliferation of B cells.

****Despite the presence of high levels of activated B cells, pts with AIDS are unable to mount antibody responses to new antigens due to defected T cell function.

Front 42

42. What is the pathogenesis of CNS involvement?

Back 42

Macrophages and microglia, cells in the CNS that belong to the monocyte and macrophage lineage, are the predominant cell types in the brain that are infected with HIV. It is widely believed that HIV is carried into the brain by infected monocytes - HIV isolates are almost exclusively M-tropic.

Front 43

43. What causes the neurologic deficits in HIV?

Back 43

Caused indirectly by viral products and by soluble factors are the usual culprits, such as IL-1, TNF, and IL-6. In addition, NO induced in neuronal cells by gp41 has been implicated.

Also, direct damage by gp120 has also be postulated. These soluble neurotoxins act by triggering excessive entry of calcium into the neurons thru their action of glutamate activated ion channels that regulate intracellular calcium.

Front 44

44. What are the 3 phases of virus host interaction in HIV?

Back 44

1. An acute retroviral syndrome
2. A middle, chronic phase
3. Full blown AIDS

Front 45

45. What occurs in the acute retroviral syndrome?

Back 45

The acute retroviral syndrome represents the initial or primary response of an immunocompetent adult to HIV infection. It is characterized initially by a high level of virus production, viremia, and widespread seeding of the lymphoid tissues. The initial infection, however, is readily controlled by the development of an antiviral immune response.

Clinically, this phase is associated with a self-limited acute illness with nonspecific symptoms, including sore throat, myalgias, fever, rash, weight loss, and fatigue, resembling a flu-like syndrome.

Front 46

46. What occurs in the chronic phase?

Back 46

The middle chronic phase represents a stage of relative containment of the virus, associated w/a period of clinical latency. The immune system is largely intact, but *there is continuous HIV replication, predominantly in the lymphoid tissues, which may last for several years.*

Persistent lymphadenopathy with significant constitutional symptoms (fever, rash, fatigue) reflects the onset of immune system decompensation, escalation of viral replication, and onset of the crisis phase.

Front 47

47. What is the final phase of HIV?

Back 47

Progression to AIDS. It is characterized by a breakdown of host defense, a dramatic increase in plasma virus, and clinical disease. Typically, the pt presents with long lasting fever (>1 month), fatigue, weight loss, and diarrhea. After a variable period, serious opportunistic infections, secondary neoplasms, or clinical neurologic disease supervene, and the pt is said to have AIDS.

Front 48

48. What are nonprogressors?

Back 48

Nonprogressors are defined as untreated HIV-1 infected individuals who remain asymptomatic for 10 years or more, with stable CD4+ T cells counts and low levels of plasma viremia.

Front 49

49. When are p24 antigen levels elevated in the serum?

Back 49

In the acute HIV syndrome, there is high level of virus in plasma and a sever reduction in CD4 cells. During this period, HIV can be isolated from the blood, and there are high levels of HIV p24 antigen in serum. Soon, however, a virus specific immune response develops.

Front 50

50. When are HIV-specific CD8+ T cells detected in the blood?

Back 50

CD8+ cells are detected when viral titers begin to fall and are most likely responsible for the containment of HIV infection.

Front 51

51. What is a marker of HIV progression?

Back 51

The extent of viremia, or HIV-1 RNA, is a useful marker of HIV disease progression and is of clinical value in the management of people with HIV infection.

Front 52

52. What is the strongest indicator of disease progression?

Back 52

For clinical management, blood CD4+ T cell counts are the strongest indicator of disease progression.

The three categories of CD4+ cell counts are: CD4+ greater than or equal to 500 cells/uL, 200-499 cells/uL, and fewer than 200 cells/uL

Front 53

53. What is the significance of the nef gene?

Back 53

In a small subset of nonprogressors , the infecting HIV had deletions or mutations in the nef gene, suggesting that Nef proteins are critical to disease progression.

Front 54

54. What causes most of deaths in pts with AIDS?

Back 54

Opportunistic infections.

The risk of developing P. carinii infection is extremely high in individuals with fewer than 200 CD4+ cells/uL.

Front 55

55. When does CMV retinitis occur?

Back 55

When CD4+ cells fall below 50/uL.

Front 56

56. What causes persistent diarrhea in AIDS pts?

Back 56

Cryptosporidium, Isospora belli, or microsporidia. These pts have chronic, profuse, watery diarrhea with massive fluid loss.

Diarrhea may also result from infection w/enteric bacteria, such as Salmonella and Shigella, as well as MAC.

Front 57

57. What tumors occur with an increased freq in AIDS pts?

Back 57

Kaposi sarcoma, non-Hodgkin B cells lymphoma, cervical CA in women, and anal CA in men.

It is estimated that about 25-40% of HIV infected individuals will eventually develop a malignancy.

A common feature of these tumors is that they are all belived to be caused by oncogenic DNA viruses, that is, Kaposi sarcoma, herpesvirus, EBV (B-cell lymphoma), HPV (cervical and anal CA).

Front 58

58. What do the lesions in Kaposi sarcoma look like?

Back 58

The lesions of KS are characterized by the proliferation of spindle shaped cells that express markers of both endothelial (vascular or lymphatic) and smooth muscle lineages.

There is also a profusion of slit-like vascular spaces, suggesting that the lesions may arise from primitive mesenchymal precursors of vascular channels. In addition, KS lesions display chronic inflammatory cell infiltrates.

Front 59

59. What is the pathogenesis of KS?

Back 59

The pathogenesis of KS involves a complex web of paracrine signaling interactions among different types of cells.

One view is that spindle cells produce pro-inflammatory and angiogenic factor, recruiting the inflammatory and neovascular components of the lesion, while the latter components supply signals that aid in spindle cell survival or growth.

Front 60

50. Is AIDS-related KS more or less freq in individuals who acquire HIV via sexual routes vs. parenterally?

Back 60

AIDS-related KS is 20x more freq in individuals who acquire HIV via sexual routes.

This suggests that a sexually transmitted agent other than HIV is implicated in KS etiology. This is the role of the KS herpesvirus or HHV 8.

Front 61

51. How does KSHV infection lead to KS?

Back 61

KSHV establishes a latent infection which produces inhibitors of p53, which prevents apoptosis.

But in addition to latent infection, a small population of cells in KS is undergoing lytic viral replication, with cell death and the release of viral progeny. The KSHV lytic cycle is remarkable for its production of numerous paracrine signaling molecules, including viral homologues of IL-6 and various CC chemokines. The latter likely play prominent roles in eliciting the inflammatory infiltrations that are an important feature of KS.

Front 62

52. What is the role of vGPCR?

Back 62

Another virally encoded lytic protein is a constitutively active G-protein-coupled receptor (vGPCR). The expression of this protein activates the release of VEGF, which can promote angiogenesis in the surrounding tissue.

Front 63

53. How is AIDS-associated KS different from the sporadic form?

Back 63

In HIV-infected inviduals, the tumor is generally widespread, affecting the skin, mucous membranes, GI tract, lymph nodes, and lungs. These tumors also tend to be more aggressive than classic KS.

Front 64

54. What about the risk of developing NHL in AIDS pts?

Back 64

Approx 6% of all pts with AIDS develop lymphoma during their lifetime.

Thus, the risk of developing NHL is approx 120x greater than in the general population.

*In contrast, to KS, immunodeficiency is firmly implicated as the central predisposing factor. It appear that pts with CD4+ cell counts below 50/uL incur an extremely high risk.

Front 65

55. What are the 3 groups of AIDS-related lymphomas?

Back 65

Based on their location:
1. Systemic lymphomas
2. Primary CNS lymphomas
3. Body cavity based lymphomas

Front 66

56. What are systemic lymphomas?

Back 66

Systemic lymphomas involve lymph nodes as well as extranodal, visceral sites; they constitute 80% of all AIDS-related lymphomas.

Front 67

57. What about primary CNS lymphomas and body cavity-based lymphomas?

Back 67

The CNS is the most common extranodal site affected, followed by the GI tract, and less commonly, virtually any other location. The vast majority of these lymphomas are aggressive B-cell tumors that present in an advanced stage.

*Primary CNS lymphoma is 1000x more common in pts with AIDS than in the general population.

Body-cavity based lymphomas are rare but have an unusual distribution. It grows exclusively in body cavities in the form of pleural, peritoneal, and pericardial effusions, and is associated with the presence of the KSHV genome.

Front 68

58. What is the pathogenesis of AIDS-associated B-cell lymphomas?

Back 68

The pathogenesis probably involves sustained polyclonal B-cell activation, followed by the emergence of monoclonal or oligoclonal B-cell population.

It is believed that during the frenzy of proliferation, some clones undergo mutations or chromosomal translocations involving oncogenes or tumor suppressor genes, and subsequent neoplastic transformation.

Front 69

59. What is the role of EBV in B-cell lymphomas?

Back 69

EBV is a polyclonal mitogen for B cells. The EBV genome is found in approx 50% of the systemic B-cell lymphomas and in virtually all lymphomas primary in the CNS.

Other evidence of EBV infection includes oral hairy leukoplakia, believed to result from EBV driven squamous cell proliferation of oral mucosa.

Front 70

60. What is the morphology of the lymph nodes in the early stages of HIV infection?

Back 70

There is a marked follicular hyperplasia*. The enlarged follicles have irregular, sometimes serrated borders, and they are present not only in the cortex, but also in the medulla and may even extend outside the capsule. The mantle zones that surround the follicles are markedly attenuated, and hence the germinal centers seem to merge w/the interfollicular area.

*These changes, affecting primarily the B-cell areas of the node, are the morphologic reflections of the polyclonal B-cell activation and hypergammaglobulinemia seen in pts with AIDS. *HIV particles can be detected w/in the germinal centers.

Front 71

61. What happens to the lymph nodes w/disease progression?

Back 71

With disease progression, the frenzy of B-cell proliferation subsides and gives way to a pattern of severe follicular involution. The follicles are depleted of cells, and the ***organized network of follicular dendritic cells is disrupted.***

During this advanced stage, viral burden in the nodes is reduced, in part b/c of the disruption of the follicular dendritic cells. These "burnt-out" lymph nodes are atrophic and small and may harbor numerous opportunistic pathogens. Also in later stages of AIDS, the spleen and thymus also appear to be "wastelands".

Front 72

62. What is amyloid? What is amyloidosis?

Back 72

Amyloid is a pathologic proteinaceous substance, deposited between cells in various tissues and organs of the body in a wide variety of clinical settings.

Amyloid is not a chemically distinct entity, and thus amyloidosis should not be considered a single disease; rather is is a group of diseases having in common the deposition of similar appearing proteins.

Front 73

63. What does amyloid look like?

Back 73

With the light microscope and standard tissue stains, amyloid appears as an amorphous, eosinophilic, hyaline, extracellular substance that, with progressive accumulation, encroaches on an produces pressure atrophy of adjacent cells.

The most widely used stain is the Congo red stain, which under ordinary light imparts a pink or red color to tissue deposits, but far more dramatic and specific is the green birefringence of the stained amyloid when observed by polarized microscopy.

Front 74

64. What is amyloid composed of?

Back 74

By EM, amyloid is seen to be made up largely of nonbranching fibrils of indefinite length and a diameter of approx 7.5 to 10nm.

X-ray crystallography demonstrates a characteristic cross-β-pleated sheet conformation. This conformation is seen regardless of the clinical setting or chemical composition and is responsible for the distinctive staining and birefringence of Congo-red stained amyloid.

Approx 95% of the amyloid material consists of fibril proteins, the remaining 5% being the P component and other glycoproteins.

Front 75

65. What are the 3 most common forms of amyloid proteins?

Back 75

1. AL (Amyloid Light chain)
-derived from plasma cells and contains Ig light chains

2. AA (Amyloid Associated)
-a unique non-Ig protein synthesized by the liver

3. Aβ amyloid
-found in there cerebral lesions of Alzheimer disease

Front 76

66. What is AL?

Back 76

Most of the AL proteins are composed of λ light chains or their fragments. The AL type is produced by Ig-secreting cells, and their deposition is associated with some form of monoclonal B-cell proliferation.

***This type is associated with primary amyloidosis or (immunocyte dyscrasias with amyloidosis)

Front 77

67. What is AA?

Back 77

AA has a molecular weight of 8500 and consists of 76 amino acid residues. AA fibrils are derived from a larger precursor in the serum called serum amyloid-associated protein that is synthesized in the liver and circulates in association with the HDL3 subclass of lipoproteins.


***This AA protein in found in those clinical settings described as secondary amyloidosis (reactive systemic amyloidosis).

Front 78

68. What is transthyretin (TTR)?

Back 78

TTR is a normal serum protein that binds and transports T4 and retinol.

*A mutant form of transthyretin is deposited in a group of genetically determined distinct disorders referred to as familial amyloid polyneuropathies.

*TTR is also deposited in the heart of aged individuals (senile systemic amyloidosis).

Front 79

69. What is β2-microglobulin?

Back 79

β2-microglobulin, a component of the MHC class I molecules and a normal serum protein, has been identified as the amyloid fibril subunit in amyloidosis that complicates the course of pts on long term hemodialysis.

Front 80

70. What is β-amyloid protein (Aβ)?

Back 80

Aβ is a 4000 dalton peptide that constitutes the core of cerebral plaques found in Alzheimer disease as well as the amyloid deposited in walls of cerebral blood vessels in pts with Alzheimer's.

Front 81

71. What is immunocyte dyscrasia with amyloidosis (primary amyloidosis)?

Back 81

Amyloid in this category is of the AL type. This is the most common form of amyloidosis. In many of these cases, pts have some form of plasma cell dyscrasia. Best defined is the occurrence of systemic amyloidosis in 5-15% of pts with multiple myeloma.

In this condition, the malignant B cells characteristically synthesize abnormal amts of a single Ig, producing an M(myeloma) protein spike on serum electrophoresis. In addition to the synthesis of whole Ig molecules, only the light chains (Bence Jones protein) may be elaborated and found in the serum or excreted in the urine.

Front 82

72. Do all pts with myeloma who develop amyloidosis have Bence Jones proteins in the serum or urine?

Back 82

Almost all pts with myeloma who develop amyloidosis have Bence Jones proteins in the serum or urine, or both, but a great majority of myeloma pts who have free light chains do not develop amyloidosis.

*Therefore, the presence of Bence Jones proteins, although necessary, is by itself not enough to produce amyloidosis.

Front 83

73. Do most pts with AL amyloid have classic multiple myeloma or overt B-cell neoplasm?

Back 83

The great majority do not have classic multiple myeloma or B-cell neoplasm; such cases are termed primary amyloidosis b/c their clinical features derive from the effects of amyloid deposition w/o any other associated disease.

In virtually all such cases, however, monoclonal Ig or free light chains, or both, can be found in the serum or urine.

***These pts must clearly have an underlying B-cell dyscrasia in which production of an abnormal protein, rather than production of tumor masses, is the predominant manifestation.

Front 84

74. What is reactive systemic amyloidosis (aka secondary amyloidosis)?

Back 84

The amyloid deposits in this pattern are systemic in distribution and are composed of AA protein. Reactive systemic amyloidosis is associated with an inflammatory condition.

*The feature common to most conditions associated with this form is protracted breakdown of cells resulting from a wide variety of infectious and noninfectious chronic inflammatory conditions.

Front 85

75. What are these inflammatory conditions that cause reactive systemic amyloidosis?

Back 85

Used to be tuberculosis and chronic osteomyelitis, but now it is associated with RA and ankylosing spondylitis, and IBD, particularly CD and UC.

*Among these, the most freq associated condition is RA.

Front 86

76. What is the most common form of heredofamilial amyloidosis?

Back 86

The most common form is an autosomal recessive condition called familial Mediterranean fever.

This is a febrile disorder of unknown cause characterized by attacks of fever accompanied by inflammation of serosal surfaces, including peritoneum, pleura, and synovial membrane. This disorder is encountered largely in individuals of Armenian, Sephardic Jewish, and Arabic origins.

*The amyloid proteins are made up of AA proteins, suggesting that this form of amyloidosis may be associated to recurrent bouts of inflammation that characterize this disease.

Front 87

77. What is responsible for regulated acute inflammation in Mediterranean fever?

Back 87

The gene for familial Mediterranean fever encodes a product called pyrin. It has been suggested that pyrin is responsible for regulating acute inflammation, presumably by inhibiting the function of neutrophils.

Front 88

78. What are the familial amyoidotic neuropathies?

Back 88

A group of autosomal dominant familial disorders is characterized by deposition of amyloid predominantly in the nerves - peripheral and autonomic. These familial amyloidotic polyneuropathies occur in different parts of the world.

***In all of these genetic disorders, the fibrils are made up of mutant transthyretins (ATTR).

Front 89

79. What is localized amyloidosis?

Back 89

Sometimes, amyloid deposits are limited to a single organ or tissue w/o involvement of any other site in the body. Nodular tumor forming deposits of amyloid are most often encountered in the lung, larynx, skin, urinary bladder, tongue, and the region about the eye.

At least in some cases, the amyloid consists of AL protein, and may therefore represent a localized form of immunocyte derived amyloid.

Front 90

80. What is endocrine amyloid?

Back 90

Microscopic deposits of localized amyloid may be found in certain endocrine tumors, such as Medullary CA of thyroid, islet tumors of the pancreas, pheochromocytomas, and undifferentiated CAs of the stomach, and in the islets of Langerhans in pts with type II DM.

*In these settings, the amyloidogenic proteins seem to be derived either from polypeptide hormones (e.g., medullaru CA) or from unique proteins (e.g., islet amyloid polypeptide).

Front 91

81. What is senile systemic amyloidosis?

Back 91

Senile systemic amyloidosis refers to the systemic deposition of amyloid in elderly pts (usually in 70's or 80's). B/c of the dominant involvement of the heart, this form was previously called senile cardiac amyloidosis. Those who are symptomatic present with a restrictive cardiomyopathy and arrhythmias.

Front 92

82. What causes senile systemic amyloidosis?

Back 92

***The amyloid in this form is composed of the *normal* TTR molecule.

In addition to the sporadic senile systemic amyloidosis, another form, affecting predominantly the heart, that results from the deposition of a mutant form of TTR has also been recognized:

Approx 4% of the black population in the US is a carrier of the mutant allele (ATTR), and cardiomyopathy has been identified in both homozygous and heterozygous pts.

Front 93

83. What is the pathogenesis of amyloidosis?

Back 93

Amyloidosis results from abnormal folding of proteins, which are deposited as fibrils in extracellular tissues and disrupt normal function.

Misfolded proteins are often unstable and self-associated, ultimately leading to the formation of oligomers and fibrils that are deposited in tissues. Each of the conditions in amyloidosis results in excessive production of proteins that are prone to misfolding.

Front 94

84. What are the 2 general categories of proteins that form amyloid?

Back 94

1. Normal proteins that have an inherent tendency to fold improperly, associate and form fibrils, and do so when they are produced in increased amts

2. Mutant proteins that are structurally unstable and prone to misfolding and subsequent aggregation

Front 95

85. So what causes the proteins to accumulate?

Back 95

Normally, misfolded proteins are degraded intracellularly in proteasomes, or extracellularly by macrophages. It appears that in amyloidosis, these quality control mechanisms fail so that too much of a misfolded protein accumulates outside cells.

Individuals who develop amyloidosis have an enzyme defect that results in incomplete breakdown of SAA (which is produced by the liver during inflammation), thus generating insoluble AA molecules. Alternatively, a genetically determined structural abnormality in the SAA molecule itself renders it resistant to degradation by macrophages.

Front 96

86. What organs are most commonly affected by amyloidosis?

Back 96

Amyloidosis secondary to chronic inflammatory disorders tends to yield the most severe systemic involvements. Kidneys, liver, spleen, lymph nodes, adrenals, and thyroid as well as many other tissues are classically involved.

Although immunocyte-associated amyloidosis cannot reliably be distinguished from the secondary form by its organ distribution, more often it involves the heart, kidney, GI tract, peripheral nerves, skin, and tongue.

Front 97

87. What is the appearance of the organs affected by amyloidosis?

Back 97

Macroscopically the affected organs are often enlarged and firm and have a waxy appearance. if the deposits are sufficiently large, painting the cut surface w/iodine imparts a yellow color that is transformed to blue violet after application of sulfuric acid.

Front 98

88. What is the morphology of the kidney in amyloidosis?

Back 98

Amyloidosis of the kidney is the most common and potentially the most serious form of organ involvement. In most cases, renal amyloidosis is the major cause of death.

On gross inspection, the kidney may appear normal in size and color, or it may be enlarged.

Front 99

89. Where is the amyloid deposited in the kidney?

Back 99

Histologically, the amyloid is deposited in the glomeruli, but the interstitial peritubular tissue, arteries, and arterioles are also affected. The glomerular deposits first appear as subtle thickenings of the mesangial matrix, accompanied usually by uneven widening of the BM of the glomerular cappilaries. In time, the mesangial depsoitions and the deposits along the BM cause capillary narrowing and distortion of the glomerular vascular tuft.

With progression of the glomerular amyloidosis, the capillary lumens are obliterated, and the obsolescent glomerulus is flooded by confluent masses or interlacing broad ribbons of amyloid.

Front 100

90. What is the morphology of the spleen in amyloidosis?

Back 100

May be unapparent grossly or may cause splenomegaly.

There are two patterns:
1. Sago spleen:
-the deposit is largely limited to the splenic follicles, producing tapioca-like granules

2. Lardaceous spleen:
-the amyloid appear to spare the follicles and instead involves the walls of the splenic sinuses and CT framework in the red pulp. Fusion of the early deposits gives rise to large, maplike areas of amyloidosis.

Front 101

91. What is the morphology of the liver in amyloidosis?

Back 101

Again, the deposits may be unapparent grossly or may cause hepatomegaly.

The amyloid first appears in the space of Disse and then progressively encroaches on adjacent hepatic parenchymal cells and sinusoids. In time, deformity, pressure atrophy, and disappearance of hepatocytes occur, causing total replacement of large areas of liver parenchyma.

Vascular involvement and deposits in Kupffer cells are freq. Normal liver function is preserved despite sometimes quite severe involvement.

Front 102

92. What is the morphology of the heart in amyloidosis?

Back 102

May occur in any form of systemic amyloidosis, but more commonly in persons with immunocyte derived disease and senile systemic amyloidosis.

The heart may be enlarged and firm, but more often it shows no significant changes.

Histologically the deposits begin in focal subendocardial accumulations and within the myocardium btwn the muscle fibers. Expansion of these myocardial deposits eventually causes pressure atrophy of myocardial fibers.

These can cause conduction systems problems.

Front 103

93. What is the morphology of the adrenals in amyloidosis?

Back 103

The intercellular deposits begin adjacent to the BM's of the cortical cells, usually first in zona glomerulosa. W/progression, large sheets of amyloid may replace considerable amts of the cortical parenchyma.

Front 104

94. What is a tumor-forming amyloid of the tongue?

Back 104

Nodular depositions in the tongue may cause macroglossia, giving rise to the designation tumor-forming amyloid of the tongue.

Front 105

95. Deposition of amyloid occurs where in pts on long term hemodialysis?

Back 105

Depositions are most prominent in the carpal ligament of the wrist, resulting in compression of the median nerve (carpal tunnel syndrome).

Front 106

96. What are the clinical features of amyloidosis?

Back 106

At first they are nonspecific, such as weakness, weight loss, light-headedness, or syncope. Somewhat more specific findings appear later and most often relate to renal, cardiac, and GI involvement.

Prognosis is poor.

Front 107

97. What is cardiac amyloidosis?

Back 107

Cardiac amyloidosis may present as an insidious congestive heart failure. The most serious aspects are conduction disturbances and arrhythmias, which may prove fatal.

Occasionally, cardiac amyloidosis produces a restrictive pattern of cardiomyopathy and masquerades as chronic constrictive pericarditis.

Front 108

98. What is the most rapid and specific test for amyloidosis?

Back 108

Congo red has low specificity, so scintigraphy with radiolabeled serum amyloid P (SAP) component is a rapid and specific test since SAP binds to the amyloid deposits and reveals their presence.

It also gives a measure of the extent of amyloidosis and can be used to follow pts undergoing treatment.

Front 109

99. What is vasculitis?

Back 109

Inflammation of the walls of vessels, called vasculitis, is encountered in diverse clinical settings.

Clinical manifestations often include constitutional signs and symptoms such as fever, myalgias, arthralgias, and malaise, or local manifestations of downstream tissue ischemia.

Front 110

100. What are the two most common mechanisms of vasculitis?

Back 110

1. Direct invasion of vascular walls by infectious pathogens
2. Immune mediated mechanisms

Front 111

101. What are the 3 main immunologic mechanisms that initiate noninfectious vasculitis?

Back 111

1. Immune complex deposition
2. Antineutrophil cytoplasma antibodies
3. Anti-endothelial cell antibodies

Front 112

102. What is the evidence for immune complexes in noninfectious vasculitis?

Back 112

1. The vascular lesions resemble those found in the Arthus phenomenon and serum sickness. Immune reactants and complement can be detected in the serum or vessels of patients with vasculitis.
2. Hypersensitivity to drugs causes approx 10% of vasculitic skin lesions, largely thru vascular deposits of immune complexes.
3. In vasculitis associated w/viral infection, immune complexes can be found in the serum and in the vascular lesions of some pts, particularly in the cases of polyarteritis nodosa (for example, HBsAg-anti-HbsAg in hepatitis induced vasculitis).

Front 113

103. What are antineutrophil cytoplasmic antibodies (ANCAs)?

Back 113

ANCA are a heterogeneous group of autoantibodies directed against enzymes mainly found within the azurophil or primary granules in neutrophils, in the lysosome of monocytes, and in ECs.

Two main patterns are recognized, those in the cytoplasm (c-ANCA with the most common target proteinase-3 - PR3) and those in the perinucleus (p-ANCA) and is usually specific for myeloperoxidase - MPO.

Front 114

104. In which disorders is c-ANCA typically found?

p-ANCA?

Back 114

c-ANCA is typically found in Wegener granulomatosis and p-ANCA is found in most cases of microscopic polyangiitis and Churg-Straus syndrome.

Front 115

105. How are ANCAs useful?

Back 115

They serve as useful quantitative diagnostic markers for ANA-associated vasculitis, and their levels may reflect the degree of inflammatory activity.

ANCAs rise in episodes of recurrence, and thus are useful in management. In addition, the close association btwn ANCA titers and disease activity suggests they may be important in the pathogenesis of this disease.

Front 116

106. What is a hypothesis for the causative role of ANCAs in vasculitis?

Back 116

1. An underlying disorder (infection) elicits pro-inflammatory cytokines such as TNF and GMCSF, and endotoxin, which together cause neutrophils and other inflammatory cells to express PR3 and MPO on their surfaces.
2. These stimulate the formation of ANCAs
3. ANCAs react w/circulating cytokine primed neutrophils and cause them to degranulate
4. PMNs activated by ANCA cause endothelial cell toxicity and other direct tissue injury

Front 117

107. What are anti-endothelial cell antibodies?

Back 117

Antibodies, to ECs, perhaps induced by defects in immune regulation, may predispose to certain vasculitides, such as those associated w/SLE and Kawasaki disease.

Front 118

108. What is giant cell (temporal) arteritis?

Back 118

Giant cell arteritis, the most common form of systemic vasculittis in adults, is an acute and chronic, often granulomatous, inflammation of arteries of large to small size.

It principally affects the arteries in the head, especially the temporal, vertebral, and ophthalmic arteries. Ophthalmic arterial involvement may lead to permanent blindness. Therefore, visual loss caused by giant cell arteritis is a medical emergency.

Front 119

109. What is the morphology of giant cell (temporal) arteritis?

Back 119

Characteristically, segments of affected arteries develop nodular thickenings w/reduction of the lumen and may become thrombosed. In the more common variant there is granulomatous inflammation of the inner half of the media centered on the internal elastic membrane marked by a mononuclear infiltrate, multinucleate giant cells, and fragmentation of the internal elastic lamina.

The healed stage reveals collagenous thickening of the vessel wall; organization of the luminal thrombus sometimes transforms the artery into a fibrous cord.

Front 120

110. What is the pathogenesis of giant cell arteritis?

Back 120

The granulomatous nature of the inflammation, association w/certain HLA-DR haplotypes, and the response to corticosteroid therapy are consistent w/T-cell mediated and antigen-driven injury.

Striking features of the disorder are the rarity of the disease in persons younger than 50, the predilection for the superficial temporal arteries, and the high incidence in populations of Nordic origins.

Front 121

111. What are the clinical features of giant cell arteritis?

Back 121

Rare before age 50. Temporal arteritis typically presents w/headache and facial pain; 50% of patients have systemic symptoms, including a flu-like syndrome w/myalgias, arthralgias, and fever, called polymyalgia rheumatica.

It may cause visual disturbances (diplopia) and even blindness (an acute emergency). It responds well to corticosteroids.

Front 122

112. What is Takayasu arteritis?

Back 122

This granulomatous vasculitis of mediuma nd larger arteries is characterized principally by ocular disturbances and marked weakening of the pulses in the upper extremities (pulseless disease)

The pathologic findings that account for the clinical picture are vasculitis and subsequent fibrous thickening of the aorta, particularly the aortic arch and its branches, w/narrowing or virtual obliteration of the origins or more distant portions.

Front 123

113. What is the prevalence of Takayasu arteritis?

Back 123

The illness is seen predominantly in females younger than 40. The cause and pathogenesis are unknown, although autoimmune mechanisms are suspected.

A high frequency of the HLA-A24-B52-DR2 has been found in Japanese patients but not in other populations.

Front 124

114. What is the morphology of Takayasu arteritis?

1/2

Back 124

Takayasu arteritis classically involves the aortic arch, but in 1/3 of cases it also affects the remainder of the aorta and its branches. In 1/2 the cases it affects the pulmonary arteries.

*The gross morphologic changes include irregular thickening of the aortic or branch vessel wall w/intimal wrinkling.

Histologically, the changes range from an adventitial mononuclear infiltrate w/perivascular cuffing of the vasa vasorum to intense mononuclear inflammation of the media.

Front 125

115. What is the morphology of Takayasu arteritis?

2/2

Back 125

Granulomatous inflammation, replete w/giant cells and patchy necrosis of the media in some cases may be indistinguishable from those in giant cell arteritis.

Thus, distinctions among active giant cell lesions of the aorta are based largely on the age of the patient, and most giant cell lesions of the aorta in young patients are designated Takayasu arteritis.

Front 126

116. What are the clinical features of Takayasu arteritis?

Back 126

The salient clinical features include markedly lower BP and weaker pulses in the upper extremities with coldness or numbness of the fingers; ocular disturbances, including visual defects, retinal hemorrhages and total blindness; hypertension, and neurological deficits.

Involvement of the more distal aorta may lead to claudication of the legs; that of pulmonary arteries may lead to pulmonary hypertension.

Front 127

117. What is polyarteritis nodosa (PAN)?

Back 127

PAN is a systemic vasculitits of small or medium-sized muscular arteries (but not arterioles, capillaries, or venules), typically involving renal and visceral vessels but sparing the pulmonary circulation. Clinical manifestations result from ischemia and infarction of affected tissues and organs.

Front 128

118. What is the morphology of PAN?

Back 128

Classic PAN occurs as segmental transmural necrotizing inflammation of arteries of medium to small size, in any organ w/the possible exception of the lung, and most freq kidneys, heart, liver, and GI tract. Segmental erosion w/weakening of the arterial wall due to the inflammatory process may cause aneurysmal dilation or localized rupture. Impairment of perfusion, causing ulcerations, infarcts, ischemic atrophy, or hemorrhages in the area supplied by these vessels may provide the first clue to the existence of the underlying disorder.

Front 129

119. What are the histologic characteristics of PAN?

Back 129

The histologic picture during the acute phase is characterized by transmural inflammation of the arterial wall w/neutrophils, eosinophils, and mononuclear cells, freq accompanied by fibrinous necrosis. The lumen may become thrombosed.

Later, the acute inflammatory infiltrate infiltrate disappears and is replaced by fibrous thickening of the vessel wall that may extend into the adventitia. Firm nodularity sometimes marks the lesions.

Particularly characteristic of PAN is that all stages of activity may coexist in different vessels or even within the same vessel.

Front 130

120. What is the clinical course of PAN?

Back 130

PAN is largely a disease of young adults, w/protean and nonospecific clinical presentation related to whatever tissue is involved (e.g., hematuria, albuminuria, and hypertension [kidneys]; abdominal pain and melena [GI tract]; diffuse myalgias; and peripheral neuritis.

The most common systemic manifestations include fever, malaise, and weight loss.

PAN may be associated w/HBV antigenemia, and deposited immune complexes may play a role in pathogenesis. Untreated, the disease is generally fatal, but a 90% remission rate is achieved w/immunosuppressive therapy.

Front 131

121. What is Kawasaki disease (mucocutaneous lymph node syndrome)?

Back 131

Kawasaki disease is an arteritis that often involves the coronary arteries, usually in young children and infants (80% of cases are <4 y/o), and is the leading cause of acquired heart disease in children in the US and Japan.

It is associated w/the mucocutaneous lymph node syndrome, an acute but usually *self-limited illness manifested by fever, conjunctival and oral erythema and erosion, edema of the hands and feet, erythema of the palms and soles, a skin rash often w/desquamation, and enlargement of the cervical lymph nodes.*

Front 132

122.What is the pathogenesis of Kawasaki disease?

Back 132

The cause is uncertain, but there is evidence that the vasculitis results from an immune reaction characterized by T-cell and macrophage activation to an unknown antigen, secretion of cytokines, polyclonal B-cell hyperactivity, and the formation of autoantibodies to endothelial cells and SMC, leading to acute vasculitis.

Front 133

123. What is the morphology of Kawasaki disease?

Back 133

The vasculitis is PAN like, with necrosis and pronounced inflammation affecting the entire thickenss of the vessel wall, but fibrinoid necrosis is usually less prominent in Kawasaki disease.

Although the acute vasculitis subsides spontaneously or in response to treatment, it can be complicated by aneurysm formation, thrombosis, and/or MI. As w/other causes of arteritis, healed lesions may cause obstructive intimal thickening.

Front 134

124. What is the clinical course of Kawasaki disease?

Back 134

Approx 20% of pts develop cardiovascular sequelae, ranging in severity from asymptomatic vasculitis of the coronary arteries, coronary artery ectasia, or aneurysm with rupture or thrombosis, MI, or sudden death.

Acute fatalities occur in approx 1% of pts. Pathologic changes outside the cardiovascular system are rarely significant.

The use of aspirin and IV IgG has had a significant effect on lower the rate of coronary artery aneurysms and death from the disease.

Front 135

125. What is microscopic polyangiitis?

Back 135

This type of necrotizing vaculitis generally affects arterioles, capillaries, and venules - vessels smaller than those involved in PAN.

In contrast to PAN, all lesions tend to be of the same age. It typically presents as "palpable purpura" involving the skin, or invovlement of the mucous membranes, lungs, brain, heart, GI tract, kidneys, and muscle. Skin biopsy is often diagnostic.

In contrast to PAN, necrotizing GN and pulmonary capiillaritis are particularly common.

Front 136

126. What are the major clinical features of microscopic polyangiitis?

Back 136

The major clinical features are hemoptysis, arthralgia, abdominal pain, hematuria, proteinuria, hemorrhage, and muscle pain or weakness. In many cases, an immunologic reaction to an antigen such as drugs (i.e. penicillin), microorganisms (streptococci), heterologous proteins, and tumor antigens are the precipitating cause.

*in 70% of pts, p-ANCAs are present.

Front 137

127. What is the morphology of microscopic polyangiitis?

Back 137

The lesions of microscopic polyangiitis are often histologically similar to those of PAN. In contrast to PAN, muscular and large arteries are usually spared; thus, macroscopic infarcts similar to those seen in PAN are uncommon.

Granulomatous inflammation is absent.

Histologically, segmental fibrinoid necrosis of the media may be present, but some lesions have changes limited to infiltration w/neutrophils, which become fragmented as they follow the vessel wall (leukocytoclasia).

The term leukocytoclastic angiitis (LCA) is given to such lesions, most commonly found in postcapillary venules.

Ig's and complement are often present in the vascular lesions of the skin; they is a paucity of Ig demonstrable via pauci-immune injury.

Front 138

128. What is the clinical course of microscopic polyangiitis?

Back 138

W/the exception of those who develop widespread renal or brain involvement, most pts respond well simply to removal of the offending agent.

Disseminated vascular lesions of hypersensitivity angiitis may also appear in Henoch-Schonlein purpura, essential mixed cryoglobulinemia, vasculitis associated w/some of the CT disorder, and vasculitis associated w/malignancy.

Front 139

129. What is allergic granulomatosis and angiitis (Churg-Strauss syndrome)?

Back 139

In Churg-Strauss syndrome, vascular lesions may be histologically similar to those of classic PAN or microscopic polyangiitis, but they characteristically have necrotizing vasculitis accompanied by granulomas w/eosinophilic necrosis. p-ANCAs are present in 1/2 of pts.

Coronary arteritis and myocarditis are the principal causes of morbidity and mortality.

Front 140

130. What is the pathogenesis of Churg-Strauss syndrome?

Back 140

There is a strong association w/allergic rhinitis, bronchial asthma, and eosinophilia.

The disorder is thought to result from hyperresponsiveness to an allergic stimulus; in asthmatics, cysteinyl leukotriene receptor type 1 antagonists are reported to trigger it.

Front 141

131. What is Wegener granulomatosis?

Back 141

Wegener granulomatosis is a necrotizing vasculitis characterized by the triad of: (1) acute necrotizing granulomas of the upper respiratory tract (ENT), the lower respiratory tract (lung), or both; (2) necrotizing or granulomatous vasculitis affecting small to medium-sized vessels (e.g., capillaries, venules, arterioles, and arteries), most prominent in the lungs and upper airways; and (3) renal disease in the form of focal necrotizing, often crecentic, glomerulitis.

Patients who do not manifest the full triad are said to have "limited" Wegener granulomatosis, in which the involvement is restricted to the respiratory tract.

Front 142

132. What is the morphology of Wegener granulomatosis?

Back 142

Vascular lesions resemble those of acute PAN (sharply circumscribed arterial fibrinoid necrosis, w/associated neutrophilic infiltrates that may extend to the adventitia), but they are frequently accompanied by granuloma formation.

Front 143

133. What is the pathogenesis of Wegener granulomatosis?

Back 143

The resemblance to PAN and serum sickness suggest that Wegener granulomatosis may represent some form of hypersensitivity, possibly to an inhaled infectious or other environmental agent.

Immune complexes have been seen in the glomeruli and vessel walls in occasional patients.

Front 144

134. What are the clinical features of Wegener granulomatosis?

Back 144

Peak incidence is from ages 40-50 years. Typical symptoms include persistent pneumonitis w/bilateral nodular and vacitary infiltrates, chronic sinusitis, mucosal ulcerations of the naspharynx, and evidence of renal disease.

W/o treatment, 80% of pts die w/in 1 year; in contrast 90% respond to immunosuppression, particularly w/cyclophosphamide.

c-ANCA is present in more than 90% of pts w/active disease, and is a good marker of disease activity.

Front 145

135. What is lymphomatoid granulomatosis?

Back 145

Lymphomatoid granulomatosis is characterized by pulmonary nodules of lymphoid and plasmacytoid cells, often w/cellular atypia. It probably represents an evolving lymphoproliferative disorder, b/c up to 1/2 of pts develop a lymphoid malignancy, most commonly non-Hodgkin lymphoma.

This condition is sometimes difficult to differentiate from Wegener granulomatosis.

Front 146

136. What is thromboangiitis obliterans (Buerger disease)?

Back 146

Thromboangiitis obliterans is a distinctive disease that often leads to vascular insufficiency, and is characterized by segmental, thrombosing, acute and chronic inflammation of medium and small arteries, principally the tibial and radial arteries and sometimes secondarily extending to veins and nerves of the extremities.

*This disease is highly associated w/cigarette smoking; there is an increased prevalence of HLA-A9 and HLA-B5 in these pts.

Front 147

137. What is the morphology of thromboangiitis obliterans (Buerger disease)?

Back 147

Thomboangiitis obliterans is characterized by sharply segmental acute and chronic vasculitis of medium-sized an small arteries, mostly of the upper and lower extremities.

Microscopically, acute and chronic inflammation permeates the arterial walls, accompanied by thrombosis of the lumen, which may undergo organization and recanalization. Typically, the thrombus contains small microabscesses w/a central focus of neutrophils surrounded by grnulomatous inflammation.

Front 148

138. What are the complications of thromboangiitis obliterans (Buerger disease)?

Back 148

Later complications are chronic ulcerations of the toes, feet or fingers, and frank gangrene in some pts. In contrast to atherosclerosis, Buerger disease involves smaller arteries and is accompanied by severe pain, even at rest, related to the neural involvement.

Abstinence from cigarette smoking in the early stages of the disease often prevents further attacks.

Front 149

139. What is infectious arteritis?

Back 149

Localized arteritis may be caused by the direct invasion of infectious agents, usually bacteria or fungi, particularly Aspergillus and murcomycosis.

Vascular infections may weaken the arterial wall to result in a mycotic aneurysm or induce thrombosis and infarction.

Front 150

140. What is Raynaud phenomenon?

Back 150

Raynaud phenomenon refers to paroxysmal pallor or cyanosis of the digits of the hands or feet and, infrequently, the tips of the nose or ears (acral parts) owing to cold-induced vasoconstriction of the digital arteries, precapillary arterioles, and cutaneous AV shunts.

Front 151

141. What are the clinical features of Raynauds?

Back 151

Characteristically, the fingers change color in the sequence white-blue-red.

Raynauds reflects an exaggeration of normal central and local vasomotor responses to cold or emotion. It mostly affects young, otherwise healthy women.

Front 152

142. What is secondary Raynaud phenomenon?

Back 152

Secondary Raynauds refers to arterial insufficiency of the extremities caused by various conditions, including SLE, scleroderma, atherosclerosis, or Buerger disease.

Features suggestive of secondary Raynaud phenomenon include age of onset > 30 years, more severe episodes, associated skin lesions, and clinical features of CT disease.

Front 153

143. What is the morphology of varicose veins?

Back 153

Veins with varicosities are dilated, tortuous, elongated, and scarred, with thinning at the points of maximal dilation.

Intrluminal thrombosis and valvular deformities (thickening, rolling, and shortening of the cusps) are freq discovered when the vessels are opened.

Frequently there is elastic tissue degradation and spotty calcifications within the media (phlebosclerosis).

Front 154

144. What is the clinical course of varicose veins?

Back 154

Vein dilation or deformation renders the valves incompetent, w/consequent stasis, persistent edema, and trophic skin changes, ultimately resulting in stasis dermatitis and ulceration (varicose ulcers).

Affected tissues may have impaired circulation and poor healing.

Front 155

145. Are embolisms common in varicose veins?

Back 155

No, embolism or other serious complication is very rare. This is in sharp contrast to the relatively frequent thromboembolism that arise from DVT.

Front 156

146.What is thrombophlebitis and phlebothrombosis?

Back 156

The deep leg veins account for more than 90% of cases for thrombophlebitis and phlebothrombosis, two designations for inflammation and venous thrombosis.

Predisposing factors for DVT include CHF, neoplasia, pregnancy, postoperative state, prolonged immobilization or local infection. Although 90% occur in deep leg veins, periprostatic plexus in men and ovarian and pelvic veins in women are other important site.

DVT are common sources of pulmonary emboli.

Front 157

147. What is migratory thrombophlebitis (Trousseau sign)?

Back 157

Migratory thrombophlebitis (Trousseau sign) is an entity consisting of multiple evanescent venous thrombi cropping up sporadically in multiple sites.

It is attributed to malignancy-associated hypercoagulability (particularly adenocarcinomas), and may be associated w/nonbacterial thrombotic endocarditis.

Front 158

148. What is plegmasia alba dolens (painful white leg)?

Back 158

This is a special variant of primary phlebothrombosis and refers to iliofemoral venous thrombosis occurring in pregnant women prior to or following delivery.

It is postulated that the thrombus initiates phlebitis, and the perivenous inflammatory response induces lymphatic blockage w/painful swelling.

Front 159

149. What is SVC syndrome?

Back 159

The SVC syndrome is usually caused by neoplasms compressing or invading the SVC (e.g., primary bronchogenic CA or mediastinal lymphoma). The resulting obstruction produces a distinctive complex manifested by dusky cyanosis and marked dilation of head, neck, and arm veins.

Front 160

150. What is IVC syndrome?

Back 160

The IVC syndrome is caused by similar processes. Moreover, certain neoplasms, particular HCC and renal cell CA, show a striking tendency to grow within veins, extending into the IVC and occasionally up to the heart.

IVC obstruction induces marked leg edema, distention of the lower abdominal superficial collateral veins, and when renal veins are involved - massive proteinuria.

Front 161

151. What is lymphatitis?

Back 161

Bacterial infections may spread into and thru the lymphatics to create acute inflammatory involvement in these channels (lymphangitis).

The most common etiologic agents are the group A beta-hemolytic stroptococci.

Lymphagitis presents as painful subcutaneous red streaks along involved lymphatics, with regional lymphadenopathy.

Front 162

152. What is obstructive lymphedema?

Back 162

Occlusion of lymphatic drainage is followed by the abnormal accumulation of interstitial fluid in the affected part, called obstructive lymphedema.

Front 163

153. What are the 5 causes of secondary lymphatic blockage?

Back 163

1. Spread of malignant tumors obstructing either the lymphatic channels or the regional lymph nodes
2. Radical surgical procedures w/removal of regional groups of lymph nodes
3. Postirradiation fibrosis
4. Filariasis
5. Postinflammatory thrombosis and scarring

Front 164

154. What causes primary lymphedema?

Back 164

In contrast, primary lymphedema may occur as an isolated congential defect or as the familial Milroy disease (heredofamilial congenital lymphoma).

A third form of primary lymphedema, AKA lymphedema praecox, appears btwn the ages 10-25 years, usually in females. Of unknown cause, the edema begins in the feet and slowly accumulates thru life.

Front 165

155. What are the consequences of chronic lymphedema in the subcutaneous tissue?

Back 165

Lymphedema leads to increased subcutaneous interstitial fibrous tissue, w/consequent enlargement of the affected part, brawny induration, "peau d'orange" appearance of the skin, and skin ulcers.

Front 166

156. What is bacillary angiomatosis?

Back 166

These are non-neoplastic reactive vascular proliferations.

Front 167

157. Where do most neoplasms of the blood and lymphatic vessels occur?

Back 167

Most lesions occur in soft tissues and viscera. Primary tumors of the large vessels (aorta, pulmonary artery, and vena cava) are extremely rare, most being connective tissue sarcomas.

Front 168

158. What are the two main differences between benign and malignant neoplasms in the blood vessels?

Back 168

1. Benign tumors produce readily recognized vascular channels filled w/blood cells or lymphatics w/transudate; these channels are lined by a layer of normal endothelial cells, w/o atypia.

2. Malignant tumors are more solidly cellular, w/cytologic anaplasia, including mitotic figures, and usually do not form well-organized vessels.

Front 169

159. What is a hemangioma?

Back 169

Hemangiomas are most commonly localized; however, some involve large segments of the body such as an entire extremity (agiomatosis). The majority are superficial lesions, often of the head or neck, but they may occur internally, w/nearly 1/3rd in the liver.

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160. What is a capillary hemangioma?

Back 170

Capillary hemangiomas are the most common type of vascular tumor; they occur primarily in skin or mucous membranes, but also in viscera. Tumors range from 1-2 mm to several cm in diameter.

All are well defined, unencapsulated lesions composed of closely packed aggregates of capillary-sized, thin-walled vessels. They may be partially or completely thrombosed.

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161. What are juvenile capillary (strawberry) hemangiomas?

Back 171

Juvenile capillary (strawberry) hemangiomas are a specific variant that are present at birth, grow rapidly for a few months, and begin regressing at age 1-3 years. Almost all disappear by age 7.

Front 172

162. What is the morphology of capillary hemangiomas?

Back 172

Varying in size from a few mm to several cm, hemangiomas are bright red to blue and are level w/the surface of the skin or slightly elevated.

Histologically, they are usually lobulated but unencapsulated aggregates of closely packed, thin-wall capillaries, usually blood filled and lined by a flattened endothelium, separated by scant connective tissue stroma.

Rupture of vessels causes scarring and accounts for the hemosiderin pigment occasionally found.

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163. What are cavernous hemangiomas?

Back 173

Less common than the capillary variety, cavernous hemangiomas share age and anatomic distribution, but they are usually larger, less well circumscribed, and more frequently involve deep structures than do capillary hemangiomas.

As they may be locally destructive and show no tendency to regress, many require surgery.

*Those in the brain are most threatening - in von Hippel-Lindau disease, they occur in the brain, cerebellum, and eye.

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164. What is the morphology of cavernous hemangiomas?

Back 174

Grossly, the usual cavernous hemangioma is a red-blue, soft, spongy mass 1-2 cm in diameter. Rarely, giant forms occur that affect large subcutaneous areas of the face, extremities, or other regions.

Histologically, the mass is sharply defined, but not encapsulated, and is made up of large, cavernous vascular spaces, partly or completely filled w/blood separated by a scant connective tissue stroma.

Intravascular thrombosis w/associated dystrophic calcification is common.

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165. What is a pyogenic granuloma (lobular capillary hemangioma)?

Back 175

This polypoid form of capillary hemangioma occurs as a rapidly growing exophytic red nodule attached by a stalk to the skin and gingival or oral mucosa. The lesions bleeds easily and is often ulcerated. Approx 1/3 of lesions develop after trauma. The proliferating capillaries are often accompanied by extensive edema and acute and chronic inflammatory infiltrate.

They have a striking resemblance to exuberant granulation tissue. Recurrence occurs infrequently as a solitary nodule or as satellite nodules.

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166. What is granuloma gravidarum?

Back 176

Granuloma gravidarum is a pyogenic granuloma that occurs in the gingiva or 1% of pregnant women and regresses after delivery.

These lesions, like the spider telangiectasias, highly the role of estrogen in vascular growth and proliferation.

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167. What is lymphangioma circumscriptum (capillary lymphangioma)?

Back 177

These lesions are composed of small lymphatic channels; they are typically 1-2 cm in diameter, exudate filled blister-like blebs, w/a predilection for head, neck and axillary subcutaneous tissue.

Histologically, they are composed of a network of endothelium-lined lymph spaces beneath the epidermis and **can be distinguished from capillary channels only by the absence of blood cells.**

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168. What is a cavernous lymphangioma (cystic hygroma)?

Back 178

Cavernous lymphangiomas occur in children in the neck or axilla and rarely retroperitoneally. They occasionally achieve considerable size, up to 15 cm in diameter, and may fill the axilla or produce gross deformities in the neck area. These lesions are not well encapsulated, and complete surgical resection can be difficult.

Microscopically, they are composed of highly dilated cystic spaces lined by endothelium w/scant stroma.

*Cystic hygromas of the neck occur in Turner syndrome

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169. What is a glomus tumor?

Where are they most commonly found?

Back 179

A glomus tumor is a biologically benign but often exquisitely painful tumor that arises from the modified smooth muscle cells of the glomus body, a specialized AV anastomosis that is involved in thermoregulation.

Glomus tumors are most commonly found in the distal portion of the digits, especially under the fingernails.

Front 180

170. What is the morphology of a glomus tumor?

Back 180

Grossly, the tumors are less than 1 cm in diameter, slightly elevated, rounded, red-blue, and firm, and may be pinpoint under the nail.

***Histologically, there are branching vascular channels separated by a connective tissue stroma that contains aggregates, nests, and masses of the specialized glomus cells that typically are arranged around vessels.*** Individual cells are usually small, regular in size, and round or cuboidal, w/scant cytoplasm and features very similar to SMC.

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171. What does telangiectasis mean?

Back 181

Telangiectasis designates a congenital anomaly or an acquired exaggeration of preformed vessels, composed of prominent capillaries, venules, and arterioles that creates a small focal red lesion, usually in the skin or mucous membranes.

Front 182

172. What is nevus flammeus?

Back 182

(Birthmark) This most common form of ectasia characteristically forms on the head and neck, is flat, and ranges in color from light pink to deep purple.

Histologically, these lesions show only dilation of vessels in the dermis.

Front 183

173. What is a port-wine stain?

Back 183

A special form of birthmark, this type may grow proportionately w/a child, thicken the skin surface, become unsightly, and demonstrate no tendency to fade.

Front 184

174. What is Sturge-Weber syndrome (AKA encephalotrigeminal angiomatosis)?

Back 184

Port-wine stains in the distribution of the trigeminal nerve may be associated w/Sturge-Weber syndrome, an extremely uncommon congenital disorder attributed to the faulty development of certain mesodermal and ectodermal elements.

Front 185

175. What are the clinical characteristics of Sturge-Weber syndrome?

Back 185

Sturge-Weber syndrome is characterized by venous angiomatous masses in the leptomeninges over the cortex and by ispilateral port-wine nevi of the face. It is associated w/mental retardation, seizures, hemiplegia, and radiopacities in the skull.

Thus, a large vascular malformation in the face may indicate the presence of more extensive vascular malformation in a child who exhibits some evidence of mental deficiency.

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176. What are spider telangiectasias?

Back 186

This non-neoplastic vascular lesion is a more or less radial and often pulsatile array of dilated subcutaneous arteries or arterioles about a central core that blanches when pressure is applied to its center.

These lesions tend to be on the face, neck. or upper chest and are most frequent in pregnant women and in patients w/cirrhosis. The hyperestrinism found in these two settings is believed to play a role in their development.

Front 187

177. What is Osler-Weber-Rendu disease?

Back 187

In the autosomal dominant Osler-Weber-Rendu disease, telangiectases are genetic malformations consisting of dilated capillaries and veins. They are present from birth and distributed widely over the skin and mucous membranes of the oral cavity, lips, and respiratory, GI, and urinary tracts. Rupture may occur, causing serious nosebleeds, bleeding into the gut, or hematuria.

Front 188

178. What is bacillary angiomatosis?

Back 188

Bacillary angiomatosis is an opportunistic infection in immunocompromised persons and manifests as vascular proliferations that clinically resemble tumors and involve skin, bone, brain, and other organs.

It is caused by infection with gram-negative bacilli of the Bartonella family, particularly Bartonella henselae, the organism that causes cat-scratch disease in immunocompetent person, and B. quintana, the cause of trench fever.

Front 189

179. What is the morphology of bacillary angiomatosis?

Back 189

Grossly, skin lesions have one or more red papules or nodular subcutaneous masses. Microscopically, these are tumor-like capillary proliferations composed of atypical ECs.

In contrast to pyogenic granuloma, Kaposi sarcoma, or angiosarcoma, there are also numerous neutrophils, nuclear dust, and purplish granular material (bacteria).

Tx is w/erythromycin.

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180. What are the four forms of Kaposi sarcoma?

Back 190

1. Chronic, or classic KS
2. Lymphadenopathic, or African KS
3. Transplant-associated KS
4. AIDS associated KS

Front 191

181. What is chronic or classic KS?

Back 191

Occurs primarily (90%)of older men in Eastern European descent (Ashkenazi Jews). This form is not associated w/HIV, but homosexual men may be at increased risk.

Clinically, chronic KS commences w/multiple red to purple skin plaques or nodules, primarily on the arms or legs, slowly increasing in size and number, spreading to more proximal sites and often becoming confluent.

The tumors freq remain asymptomatic and localized to the skin and subcutaneous tissues but are locally persistent, w/an erratic course of lapses and remissions.

Front 192

182. What is lymphadenopathic (African or edemic) KS?

Back 192

This form is common in portions of Africa and is common among young Bantu children of S. Africa. (Same regions of Burkitt lymphoma) They present w/generalized lymphadenopathy. Skin lesions are sparse.

W/the high prevalence of HIV-associate disease in Africa and the association with AIDS with KS, KS in HIV-negative and HIV-positive patients is now the most frequently occurring tumor in Central Africa.

Front 193

183. What is transplant associated KS?

Back 193

Transplant associated KS occurs typically several months to a few years postoperatively in organ transplant recipients who receive high doses of immunosuppressants.

This type of KS tends to be aggressive, involving lymph nodes, mucosa, and visceral organs in 1/2 of pts, and skin lesions may be absent.

Organ and internal involvement is usually fatal.

Front 194

184. What is AIDS-associated KS?

Back 194

KS is the most common AIDS-associated cancer in the US.

W/the use of HAART, KS incidence has declined.

AIDS-associated KS lesions have no site of preference, but involvement of lymph nodes and the gut and wide dissemination tend to occur early in the course.

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185. What is the morphology of KS?

Back 195

Three stages can be identified: patch, plaque, and nodule.

The pathces are pink to red to purple solitary or multiple macules that are usually confined to the distal lower extremities or feet.

OVer times, lesiosn spread proximally, and usually convert into larger, violaceous raised plaques that reveal dermal, dilated, jagged, vascular channels lined by plump spindle cells.

A still later stage, the lesions may become nodular and neoplastic and may be composed of sheets of plump proliferating spindle cells.

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186. What are the characteristics of the nodular stage of KS?

Back 196

Particularly characteristic in this cellular background are scattered small vessels and slit-like spaces that often contain row of red cells and hyaline droplets.

Marked hemorrhage, hemosiderin pigment, lymphocytes, and occasional macrophages may be mixed with this cellular background.

The nodular stage is often accompanied by involvement of lymph nodes and of viscera, particular in the African and AIDS-associated KS.

Front 197

187. What is the pathogenesis of KS?

Back 197

Nearly all KS lesions are infected w/human herpesvirus 8, AKA KS-associated herpesvirus (KSHV).

This agent is both necessary and sufficient for KS development, although immunosupression is an important cofactor in disease pathogenesis and clinical expression.

*KSHV proteins may disrupt cellular control by inhibiting p53 and making a viral homologue of cyclin D67.

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188. What are hemangioendotheliomas?

Back 198

This term is used to denote a wide spectrum of vascular neoplasms showing histologic features and clinical behavior intermediate between the benign, well differentiated hemangiomas and the frankly malignant angiosarcomas.

Front 199

189. What is an epithelioid hemangioendothelioma?

Back 199

This a unique vascular tumor occurring around medium sized and large veins in the soft tissue of adults.

In such tumors, well-defined vascular channels are inconspicuous and the tumor cells are plump and often cuboidal, thus resembling epithelial cells.

The differential Dx includes metastatic CA, melanoma, and those sarcomas that assume an epithelioid appearance.

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190. What is an angiosarcoma?

Back 200

Angiosarcomas are malignant endothelial neoplasms w/structure varying from highly differentiated tumors that resemble hemangiomas (hemangiosarcoma) to whose whose anaplasia makes them difficult to distinguish from malignant neoplasms.

They occur in both sexes, more often in older adults, anywhere in the body but most commonly in the skin, soft tissue, breast, and liver.

Front 201

191. What are hepatic angiosarcomas?

Back 201

The rare hepatic angiosarcomas are associated w/distinct carcinogens (arsenic, Thorotrast, and PVC).

With all three agents, there is a very long latent period of many years btwn exposure and the development of tumors.

Front 202

192. What is the morphology of angiosarcomas?

Back 202

Grossly, cutaneous angiosarcoma may begin as small, well-demarcated red nodules evolving into large, fleshy, gray-white soft tissue masses.

*Microscopically, all degrees of differentiation of these tumors may be found.

EC derivation is demonstrated by staining for CD31, CD34, or vWF.

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193. What is a hemangiopericytoma?

Back 203

Hemangiopericytoma is a tumor of pericytes, most commonly arising on the lower extremities (especially the thigh) or in the retroperitoneum.

50% metastasize. Most are small, but can grow up to 8 cm. Microscopically, they are composed of numerous capillary channels encased by nests and masses of spindle-shaped to round cells extrinsic to the EC basement membrane (resembling pericytes).

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194. What are the key elements of luminal expansion in angioplasty?

Back 204

1. Plaque rupture
2. Medial dissection
3. Stretching of the media of the dissected segment

Front 205

195. What is proliferative restenosis?

Back 205

The long-term success of angioplasty is limited by the development of proliferative restenosis, which results from intimal thickening and occurs in approx 30-50% of pts w/in the first 4-6 mos following angioplasty.

The factors causing restenosis probably relate to muscle cell injury, elaboration of cytokines and growth factors from the inflammatory cells in the plaque, local thrombosis, and elastic recoil of the dilated segment.

Front 206

196. What are the most widely used small vessel replacement?

Failing of the small vessel prostheses is due to...?

Back 206

Aulogous saphenous vein (pt's own vein) and expanded polytetrafluoroethylene (a spongy Teflon fabric).

Failing of the small diameter prostheses are frequently due to thrombotic occlusion, intimal fibrous hyperplasia, or occasionally atherosclerosis.

Front 207

197. CABG surgery grafts are done with what prostheses?

Back 207

Bypasses are done using grafts of either reversed autologous saphenous vein, or internal mammary artery (usually the left internal mammary artery, owing to proximity to the heart).

***Internal mammary artery grafts have a greater than 90% patency at 10 years, vs. only 50% patency with saphenous vein grafts.