Cardiovascular

Question 1

Arteriosclerosis is classified into what 3 lesions?

Answer 1

Atherosclerosis, Monckeberg medial calcific sclerosis, and arteriolosclerosis. Atherosclerosis is a disease of elastic and large muscular arteries in which the atheroma is the characteristic lesion. The lesions of atherosclerosis enlarge the arterial intima with variable amounts and types of lipids, connective tissues, inflammatory cells, and a variety of extracellular components including matrix proteins and enzymes and calcium deposits. Although “sclerosis” means hardening, atherosclerotic vessels may not be harder than normal and may even be softer. “Athero” literally means gruel-like, so the term atherosclerosis is a misnomer. Monckeberg medial calcific sclerosis is a calcification process that affects the media of large and medium-sized arteries. By Monckeberg’s definition, the calcific lesions involve only the tunica media of arteries without any compromise of the arterial lumen. However, sometimes the term is used when there is calcification of the tunica media and internal elastic lamina, or even just the internal elastic lamina; since the internal elastic lamina is part of the intima, “medial” calcific sclerosis would be a misnomer. Arteriolosclerosis is a lesion of arterioles, small arterial vessels with 1 or 2 layers of smooth muscle cells. It is most typically associated with HTN and DM. The 2 subtypes of arteriolosclerosis are the hyperplastic type and the hyaline type.

Question 2

Carney Complex. AKA (3)?

Answer 2

AKA LAMB syndrome (Lentigenes, Atrial myxomas, Mucocutaneous myxomas, Blue nevi), NAME syndrome (Nevi, Atrial myxomas, Myxoid neurofibroma, Ephelides), or Swiss syndrome. AD condition. The majority (Carney Complex type I) are caused by mutations in the PRKAR1-alpha gene on 17q24, which has been suggested to function as a tumor-suppressor gene. Carney Complex type II involves chromosome 2. 7% of all cardiac myxomas are associated with Carney complex. M=F. Mean age at Dx: 10-20 years.

Question 3

Dieulafoy disease.

Answer 3

AKA Dieulafoy lesion, Dieulafoy ulcer, caliber persistent artery, gastric aneurysm, gastric arteriosclerosis, submucosal arterial malformation, cirsoid aneurysm, and solitary exulceration simplex. Defined as an abnormally large artery that retains a large caliber as it approaches the mucosa. The mean diameter of pathogenic arteries at the level of the muscularis mucosae is ~1mm, versus normal arteries having a diameter of ~0.1mm. There is also an accompanying vein. MC location is the lesser curvature of the stomach, b/c the submucosal arteries of the lesser curvature are direct branches of the left gastric artery, whereas in the rest of the stomach, the submucosal vessels are of much smaller caliber b/c of their serial branching. The disease usually occurs in males, and there is a wide age range at time of occurrence.

Question 4

Examples of pseudoneoplastic lesions in the cardiovascular system and their related neoplastic mimes.

Answer 4

Rhabdomyomatous hamartomas of myocardium (hamartoma of mature cardiac myocytes) [true adult rhabdomyoma]. Endodermal choristoma of interatrial cardiac septum [metastatic adenocarcinoma]. Lipomatous hypertrophy of the heart (lipomatous hypertrophy of the atrial septum) [lipoma]. Mesothelial-monocytic intracardiac excrescences (mesothelial/monocytic incidental cardiac excrescences) [metastatic adenocarcinoma or mesothelioma]. Endocardial and myocardial lymphocytic infiltrates post transplant (aka quilty lesions) [lymphomas]. Florid pericardial mesothelial hyperplasia [epithelial mesothelioma]. Other pseudoneoplasms include inflammatory myofibroblastic tumor and calcified amorphous tumor.

Question 5

What are Weibel-Palade bodies?

Answer 5

Weibel-Palade bodies are characteristic inclusions of endothelium measuring up to 3 um in maximum dimension. These membrane-bound structures contain up to 25 parallel tubular arrays. These bodies are the site of storage of von Willebrand factor.

Question 6

What immunostain reacts with the endothelium of cerebral capillaries, placental vasculature, and juvenile capillary angiomas?

Answer 6

GLUT-1.

Question 7

Examples of pseudoneoplastic lesions in the mediastinum and their related neoplastic mimes.

Answer 7

Sclerosing mediastinitis (sclerosing carcinomas, lymphomas, or germ-cell tumors). Thymic dysplasia (thymoma). Benign mesothelial inclusions in mediastinal lymph nodes (metastatic carcinoma).

Question 8

Papillary endothelial hyperplasia.

Answer 8

Papillary endothelial hyperplasia is a pattern of organizing thrombus that may occur within a vessel or hematoma. It may be seen incidentally in a surgical specimen or represent a symptomatic small mass by itself, in which case it is called a Masson’s tumor. It is composed of tiny papillae made of fibrin and red blood cells (but no true fibrovascular cores) covered by thin, bland endothelial cells.

Question 9

What are the HACEK organisms?

Answer 9

Haemophilus (H. parainfluenzae, H. aphrophilus, H. paraphrophilus), Actinobacillus (A. actinomycetemcomitans, Aggregatibacter aphrophilus), Cardiobacterium hominis, Eikenella corrodens, Kingella kingae. These are all slow growing Gram negative bacteria that form part of the normal oropharyngeal flora. They account for 5-10% of infective endocarditis involving native valves, are the most common Gram negative cause of endocarditis among non-IVD users, and are a frequent cause of culture-negative endocarditis. In addition to valvular infections in the heart, they can also produce other infections such as bacteremia, abscess, peritonitis, otitis media, conjunctivitis, pneumonia, arthritis, osteomyelitis, and periodontal infections.

Question 10

What is Austrian syndrome?

Answer 10

Austrian syndrome was first described by Robert Austrian in 1957. The classical triad consists of meningitis, pneumonia, and endocarditis all caused by Streptococcus pneumoniae. It is associated with alcoholism, due to the presence of hyposplenia, and can been seen in males between 40–60 years old.

Question 11

Coxsackie A virus causes (conditions). Coxsackie B virus causes (conditions).

Answer 11

Coxsackie A virus causes hand-foot-mouth disease and herpangina. Coxsackie B virus causes myocarditis, pericarditis, and epidemic pleurodynia (the grippe).

Question 12

What are Quilty lesions?

Answer 12

QLs are collections of inflammatory cells usually found along the endocardium, but sometimes extending deeper into tissues, that can mimic acute rejection. QLs are also known as endocardial infiltrates and have been the subject of more than a dozen different studies, and there is still no consensus as to their etiology or significance. They have been associated with the use of cyclosporine and waxing and waning levels of immunosuppression. It has also been suggested that QLs represent a “benign” form of rejection, or an analogue of vascular rejection. More recent studies in experimental animals suggest that they may be sites of antigen processing and low grade immune stimulation. In human and experimental animals, QLs are comprised predominantly of T cells, with the CD4 subset predominating over CD8 cells by a ratio of 2-3:1. QLs have been subclassified on the basis of whether they infiltrate the underlying myocardium. In type A lesions, the border with the underlying myocardium is smooth. In type B lesions, the mononuclear cells infiltrate between myocytes in the underlying myocardium, but myocyte necrosis is not seen. On a practical level, QLs are generally not considered in the grading of cardiac allograft rejection, but mentioned in the diagnosis as a separate finding.

Question 13

What is Twiddler’s syndrome?

Answer 13

Twiddler’s syndrome is a rare but potentially dangerous complication of device therapy for arrythmias. It refers to the intentional or unintentional twisting of the generator within the pacemaker pocket by the patient, resulting in either lead dislodgement or fracture without damage to the generator itself. Patients are risk for this condition are usually elderly, obese and often female, presumably due to their relaxed subcutaneous tissue that facilitates the rotation. Diagnosis is often incidental but can also present as problems on device interrogation such as loss of capture or stimulation of the pectoral muscle or diaphragm. Clinically it can manifest as twitching or the pectoral or abdominal muscles, chest pain, hiccups, change in voice, dysrhythmias, syncope or pre-syncope.

Question 14

What are the 4 subtypes of hemangioendothelioma?

Answer 14

Epithelioid, spindle cell, retiform, kaposiform.

Question 15

How are podoplanin and D2-40 different?

Answer 15

Basically, podoplanin is the protein, and D2-40 is the antibody against that protein. Podoplanin is a mucin-type transmembrane glycoprotein that is expressed in lymphatic endothelial cells (and several other cell types). The mouse monoclonal antibody D2-40 was originally raised against an oncofetal antigen, M2A antigen, which is an O-linked sialoglycoprotein with a simple mucin-type carbohydrate epitope associated with germ cell neoplasms, but then this antibody clone was found to be reactive with other antigens/cell types as well. D2-40: = anti-podoplanin.

Question 16

In what clinical situations may endomyocardial biopsies be taken, and for each clinical situation, should light microscopy (LM), electron microscopy (EM), immunofluorescence (IF), and viral nucleic acid studies (NuAc) be done?

Answer 16

New-onset heart failure 3-month duration (LM, EM). Heart failure with dilated cardiomyopathy (LM, EM). Heart failure associated with anthracycline use (LM, EM). Heart failure associated with restrictive cardiomyopathy (LM, EM, IF). Suspected cardiac tumors (LM, EM). Cardiomyopathy in children (LM, EM, NuAc). Heart failure associated with hypertrophic cardiomyopathy (LM, EM). Suspected arrhythmogenic right ventricular dysplasia/cardiomyopathy (LM). Plasma cell dyscrasia and cardiac symptoms (LM, EM, IF). Surveillance for cardiac rejection after transplantation (LM, IF).

Question 17

Grossing and processing of endomyocardial biopsies.

Answer 17

For light microscopy, an adequate specimen for diagnostic interpretation usually consists of three or more pieces of endomyocardium, each measuring at least 1-2 mm^3. Specimens for light microscopy evaluation should be placed in room temperature 10% buffered formalin. EM, IF, and nucleic acid studies can be accomplished with a single piece of myocardium for each study. The one exception is to increase the number of pieces for EM evaluation of anthracycline toxicity. Tissue for EM should be placed in glutaraldehyde fixative; tissue for IF should be frozen in Optimal Cutting Temperature compound or placed in Zeus solution, and tissue for viral nucleic acid studies should be frozen or placed in RNAlater RNA stabilizing solution. Specimens taken for EM should be processed to generate thick sections at which time the pathologist can determine if EM will add additional information to the case. If tissue was not originally submitted for EM processing and EM is desired, formalin-fixed tissue can be processed for EM, or paraffin-embedded tissue can be reprocessed for EM. Tissue taken for IF can be held and used when appropriate. IF can be useful for subtyping amyloid deposits and in the determination of cardiac nonamyloidotic Ig deposition disease. When viral myocarditis is suspected, tissue may be frozen or placed in RNAlater and then sent to a laboratory that has expertise in viral genome detection by assessment of nucleic acids.

Question 18

What sectioning methods and stains are used for endomyocardial biopsies?

Answer 18

A general consensus is that multiple sections (three or more) should be stained with H&E at different levels through the biopsy. For diseases that have a patchy distribution (sarcoidosis, myocarditis, etc.), even further sectioning can be performed if the entity is not seen on the initial slides. Intervening sections between H&E stains should be used for HC or IHC staining. A typical panel includes a collagen stain (Masson trichrome, Azan-Mallory, or Sirius red) for fibrosis, an elastic stain (Movat pentachrome, Verhoeff-Van Gieson) for endocardial fibroelastosis, a lymphocyte marker (CD3, CD8) for myocarditis, a macrophage marker (CD68) for myocarditis/myocyte injury, a glycogen stain (PAS) for glycogen storage disease, an amyloid stain (Congo red, thioflavin T, methyl violet, modified sulfated Alcian blue) for amyloid deposition, and an iron stain (Prussian blue) for hemochromatosis.

Question 19

What is the rationale for why ventricular myectomy specimens are taken?

Answer 19

Myectomy specimens are taken from the left ventricular septum for relieve outflow obstruction. Traditionally, these specimens are taken from patients with hypertrophic cardiomyopathy, although additional reasons for this resection include age-related angulation of the ventricular septum, sigmoid septum, and discrete subaortic stenosis. While these specimens are removed primarily for structural reasons to improve left ventricular outflow, they may be utilized to diagnose cardiac disorders.

Question 20

What is the rationale for why cardiac apical core segment specimens are taken?

Answer 20

Apical cores of ventricular myocardium are obtained at the time of ventricular assist device (VAD) placement. With the advent of smaller and simpler VADs, their use as either a bridge to transplantation or as destination therapy in heart failure patients is increasing. Apical core tissue is removed when a device cannula is placed in the ventricular apex. While this material is not taken specifically for diagnostic purposes, useful information can be obtained from pathologic evaluation.

Question 21

What is the rationale for why cardiac papillary muscle specimens are taken?

Answer 21

The most important cause of papillary muscle dysfunction is myocardial ischemia. Rupture of papillary muscle as a complication of acute myocardial infarction results in abrupt onset of severe mitral regurgitation and CHF. Rarely, papillary muscle avulsion has been reported as a consequence of blunt chest trauma. Distortion of the normal spatial relations of the papillary muscles may also be seen in left ventricuar dilatation and hypertrophic cardiomyopathy and can result in mitral regurgitation. In some instances, mitral valve mobility is restricted by anomalous direct insertion of the papillary muscle to the leaflet or via shortened chordae. The gross specimen usually consists of the papillary muscle tip with attached segment of mitral valve leaflet and chordae.

Question 22

What is the rationale for why atrial appendage specimens are taken?

Answer 22

Atrial appendages from either the right of left atrium may be surgically resected from patients with atrial fibrillation or atrial dilation to prevent embolic episodes, or from patients with congenital atrial aneurysms. The routine histology of the atrial myocardium in these patients differs from the ventricular myocardium. The myocardium in resected atrial appendages frequently displays profound myocyte hypertrophy and vacuolization, interstitial fibrosis, and not uncommonly amyloid deposition.

Question 23

What is the rationale for why pericardial biopsies/resections are done?

Answer 23

Parietal pericardium may be removed as a diagnostic biopsy particularly in cases of suspected purulent, tuberculous or malignant pericarditis, or as a partial or radical pericardiectomy in cases of constrictive pericarditis. In the specimen, the degree of calcification and fibrosis should be assessed as well as the presence of purulent exudates and fibrin. If purulent infective pericarditis is suspected, sterile portions should be sent for culture.

Question 24

What is the rationale for why aortic resections are done?

Answer 24

Segments of aorta are typically resected during the surgical repair of an aortic aneurysm, an aortic dissection, or a congenital anomaly such as coarctation. Such aortic resection specimens may contain diagnostic pathologic features that impact patient care, such as infectious or noninfectious artitis, or may show features suggesting an inherited connective tissue disease. Less commonly, segments of aorta may be surgically removed due to the presence of a neoplasm.

Question 25

Temporal artery biopsy rationale, processing, sectioning, and staining.

Answer 25

Superficial temporal arteries are biopsied to evaluate for vasculitis, particularly giant cell arteritis. Since this disorder affects arteries in a discontinuous fashion with skip lesions, it is essential to extensively sample cross-sections of the specimen. Although classified as medium-sized arteries, the superficial temporal artery is small enough to pose difficulty with tissue orientation if it is sectioned prior to processing. Thus, sectioning and embedding of the artery are typically performed by the histotechnologist after routine processing. After processing, the artery is serially sectioned at 1- to 2-mm intervals and embedded as cross-sections. All of the artery cross-sections can be embedded in the same paraffin block. Multiple H&E-stained slides should be evaluated. For each 1-mm cross-section of artery, it is recommended that a minimum of five levels (slides) be obtained, which may be serial sections or step sections. Each slide may contain a ribbon of 8 sections, to alow for the evaluation of 40 sections per artery cross-section. In borderline cases with inflammation limited to the adventitia, additional levels should be considered. An elastic stain should be evaluated to assess for fragmentation of the internal elastic lamina. CD68 and CD3 stains are helpful to deliniate subtle involvement of the arterial wall by inflammation. Temporal arteries may be involved by systemic amyloidosis, which can mimic the clinical presentation of giant cell arteritis, so if amyloid is suspected on the H&E stain, an amyloid stain such as Congo red should be assessed.

Question 26

What are the 2 most widely used synthetic vascular grafts made of?

Answer 26

Polyethylene terephthalate (PET; Dacron) and polytetrafluoroethylene (PTFE; Gore-Tex). Synthetic grafts are used in aortic and large diameter peripheral arterial bypass surgeries. Dacron is a type of polyester that is manufactured in either woven or knitted form, and it often has a crimped pattern for greater flexibility. Gore-Tex is made from fluorocarbon polymer sheets and has a smooth surface.

Question 27

How should vascular grafts and stents be grossed and processed?

Answer 27

Grafts and stents should be examined for integrity of the wall and stenosis or thrombosis of lumen. The soft tissue around the graft may be included in the specimen and should be sampled. In infected grafts or stents, cultures are ideally obtained by the clinical team preoperatively or intraoperatively from blood, wound, sinus tract or perigraft fluid. Explanted stent grafts are examined grossly for evidence of structural graft failure such as fabric tears, fractures, kinks, or collapse. Synthetic vascular grafts can be sectioned easily with a surgical blade and submitted for microscopic evaluation along with its luminal contents and soft tissue.

Question 28

What is the rationale for why microscopic examination of blood clots is done?

Answer 28

Blood clots located inside cardiac chambers or blood vessels (thrombi and emboli) may be removed as either part of an open procedure or by catheter embolectomy. Blood clots outside cardiac chambers and blood vessels (hematomas) may also be evacuated surgically. Blood clots in general and thrombi in particular should be evvaluated to assess for organization as an indication of the age of the clot and to exclude infection and embolic neoplasm. Clinicians also on occasion request verification if a thrombus is a platelet-rich thrombus, so-called "white clot," consistent with heparin-induced thrombocytopenia.

Question 29

Several named syndromes are associated with eosinophilia and eosinophilic infiltration of specific organs: eosinophilic cellulitis (__ syndrome), eosinophilic pneumonia (__ syndrome), eosinophilic fasciitis (__ syndrome), and eosinophilic vasculitis (__ syndrome).

Answer 29

Several named syndromes are associated with eosinophilia and eosinophilic infiltration of specific organs: eosinophilic cellulitis (Well syndrome), eosinophilic pneumonia (Loeffler syndrome), eosinophilic fasciitis (Shulman syndrome), and eosinophilic vasculitis (Churg-Strauss syndrome).

Question 30

The gene that encodes troponin __ is expressed in both cardiac and skeletal muscle, whereas troponin __ and troponin __ have separate cardiac and skeletal muscle genes.

Answer 30

The gene that encodes troponin C is expressed in both cardiac and skeletal muscle, whereas troponin T and troponin I have separate cardiac and skeletal muscle genes. cTnI is marginally more cardiac-specific than cTnT.

Question 31

Hypovolemic hyponatremia is often due to ___. Euvolemic hyponatremia is often due to ___. Hypervolemic hyponatremia is often due to ___.

Answer 31

Hypovolemic hyponatremia is often due to water loss either through the kidneys or GI tract. Euvolemic hyponatremia is often due to drugs. Hypervolemic hyponatremia is often due to CHF, nephrotic syndrome, or cirrhosis.

Question 32

The differential diagnosis of hypertrophic cardiomyopathy includes several syndromes that typically manifest with multiorgan involvement but that can also present with isolated or predominant left ventricular hypertrophy. What syndromes are in the DDx?

Answer 32

Metabolic (storage) cardiomyopathies such as Danon disease and Wolff-Parkinson-White syndrome, and the lysosomal storage disorder Fabry disease. LVH in these conditions is not accompanied by myocyte disarray or fibrosis but by a characteristic accumulation of glycogen or glycospingolipids in cellular vacuoles. LVH is also part of the phenotypic spectrum of Noonan syndrome and Friedreich ataxia.

Question 33

Pathogenic variants for hypertrophic cardiomyopathy have been described in eight genes encoding sarcomere proteins, with most (∼80%) present in the ___ and ___ genes. As is typical for structural proteins, most sarcomere variants are believed to act in a dominant negative manner (ie, by adversely affecting the normal gene product). Loss-of-function variants leading to haploinsufficiency occur less frequently but are prevalent in the ___ gene. Collectively, sarcomere variants are identified in up to 60% of patients with HCM who also have a family history and in ∼40% of patients with sporadic HCM.

Answer 33

Pathogenic variants for HCM have been described in eight genes encoding sarcomere proteins, with most (∼80%) present in the MYH7 and MYBPC3 genes. As is typical for structural proteins, most sarcomere variants are believed to act in a dominant negative manner (ie, by adversely affecting the normal gene product). Loss-of-function variants leading to haploinsufficiency occur less frequently but are prevalent in the MYBPC3 gene. Collectively, sarcomere variants are identified in up to 60% of patients with HCM who also have a family history and in ∼40% of patients with sporadic HCM.

Question 34

Pathogenic variants for hypertrophic cardiomyopathy have been described in eight genes encoding sarcomere proteins, with most (∼80%) present in the ___ and ___ genes. Storage cardiomyopathies masquerading as HCM are caused by mutations in ___ (Danon disease), ___ (Wolff-Parkinson-White syndrome), and ___ (Fabry disase).

Answer 34

Pathogenic variants for HCM have been described in eight genes encoding sarcomere proteins, with most (∼80%) present in the MYH7 and MYBPC3 genes. Storage cardiomyopathies masquerading as HCM are caused by mutations in LAMP2 (Danon disease), PRKAG2 (Wolff-Parkinson-White syndrome), and GLA (Fabry disase).

Question 35

2011 clinical guidelines for hypertrophic cardiomyopathy recommend comprehensive testing for what five HCM genes?

Answer 35

2011 clinical guidelines for hypertrophic cardiomyopathy recommend comprehensive testing for five HCM genes (MYBPC3, MYH7, TNNI3, TNNT2, and TPM1).

Question 36

Dilated cardiomyopathy is defined by LV dilatation and systolic dysfunction (a reduction in myocardial force generation characterized by an ejection fraction of

Answer 36

DCM is defined by LV dilatation and systolic dysfunction (a reduction in myocardial force generation characterized by an ejection fraction of

Question 37

Compared with hypertrophic cardiomyopathy, which is mainly a disease of the sarcomere, dilated cardiomyopathy shows a considerably higher degree of locus heterogeneity with a steadily growing number of genes implicated (currently ∼40, with HCM

Answer 37

Compared with HCM, which is mainly a disease of the sarcomere, DCM shows a considerably higher degree of locus heterogeneity with a steadily growing number of genes implicated (currently ∼40, with HCM

Question 38

Overview of arrhythmogenic right ventricular cardiomyopathy.

Answer 38

ARVC is defined by myocyte loss and fibrofatty infiltration of the myocardium is associated with an increased susceptibility to arrhythmias and sudden death and accounts for a significant portion of sudden deaths in athletes and young adults. Initially thought to affect only the right ventricle, LV involvement is now becoming increasingly recognized. The prevalence of ARVC is estimated to be 1 in 2000 to 5000 individuals, with 30% to 50% of cases being familial. ARVC is typically inherited in an autosomal dominant pattern with reduced penetrance and variable expressivity and affects men more frequently than women. ARVC is commonly described as a disease of the desmosome. Molecular mechanisms of ARVC include impaired cell-cell adhesion and defective transmission of the contractile force.

Question 39

Most pathogenic arrhythmogenic right ventricular cardiomyopathy variants are present in what five genes?

Answer 39

Most pathogenic ARVC variants are present in five genes encoding desmosomal proteins [plakoglobin (JUP), desmoplakin (DSP), desmocollin-2 (DSC2), desmoglein-2 (DSG2), and plakophilin-2 (PKP2)].

Question 40

Overview of left ventricular noncompaction.

Answer 40

Isolated LVNC is characterized by a heavily trabeculated or spongy appearance of the LV myocardium. An arrest of myocardial compaction during the first trimester of embryonic development is widely believed to be a cause. The left ventricle is typically affected, but 50% of patients with LVNC also have right ventricular involvement. There is a suggestion that LVNC is frequently associated with mitochondrial disorders, followed by Barth syndrome. Because LVNC is rare, its genetic etiology is not well understood. Variants have been described in known DCM and HCM genes encoding components of the sarcomere (ACTC1, MYH7, MYBPC3, and TNNT2), the Z-disk (LDB3), the nuclear lamina (LMNA), the dystrophin-associated glycoprotein complex (DTNA), as well as the Barth syndrome gene tafazzin (TAZ), a nuclear-encoded mitochondrial protein.

Question 41

Aorta - large to medium-sized artery - small artery - arteriole - capillary - venule - vein. What parts of the vessel do these entities affect: Giant cell (temporal) arteritis and Takayasu arteritis. Polyarteritis nodosa and Kawasaki disease. Cutaneous leukocytoclastic angiitis. Henoch-Schonlein purpura and essential cryoglobulinemic vasculitis. Microscopic polyangiitis (microscopic polyarteritis). Wegener's granulomatosis and Chrug-Strauss syndrome.

Answer 41

Giant cell (temporal) arteritis and Takayasu arteritis: aorta and large to medium-sized artery. Polyarteritis nodosa and Kawasaki disease: Large to medium-sized artery and small artery. Cutaneous leukocytoclastic angiitis: capillary and venule. Henoch-Schonlein purpura and essential cryoglobulinemic vasculitis: arteriole, capillary, and venule. Microscopic polyangiitis (microscopic polyarteritis): small artery, arteriole, capillary, and venule. Wegener's granulomatosis and Chrug-Strauss syndrome: small artery, arteriole, capillary, venule, and vein.

Question 42

Movat's stain is a pentachrome stain originally developed to highlight the varous constituents of connective tissue, especially cardiovascular tissue. What are the 5 colors and the 5 tissue types stained by them?

Answer 42

Black: nuclei, elastic fibers. Yellow: collagen fibers, reticular fibers. Blue: ground substance, mucin. Red: fibrin. Bright red: muscle.

Question 43

Does sarcoidosis cause restrictive or dilated cardiomyopathy?

Answer 43

Either.

Question 44

Is cardiac involvement by sarcoid diffuse or patchy?

Answer 44

Patchy; endomyocardial biopsy makes the diagnosis in fewer than half of patients and a negative biopsy does not exclude the disease.

Question 45

True or false. Arrhythmogenic cardiomyopathy involves only the right ventricle.

Answer 45

False. Arrhythmogenic cardiomyopathy typically involves the right ventricle (pulmonary infundibulum, apex, inferior wall) but may also involve the left ventricle and septum.

Question 46

At least 12 genes encoding sarcomeric proteins, involving thick and thin filaments, with over 400 mutations have been implicated in the pathogenesis of hypertrophic cardiomyopathy. Of these mutations, those involving the (protein) are most commonly involved and account for 35% of all cases of HCM.

Answer 46

At least 12 genes encoding sarcomeric proteins, involving thick and thin filaments, with over 400 mutations have been implicated in the pathogenesis of hypertrophic cardiomyopathy. Of these mutations, those involving the beta-myosin heavy chain are most commonly involved and account for 35% of all cases of HCM. Other common mutations involve genes encoding myosin binding protein C (20%) and cardiac troponin T (15%).

Question 47

VSDs account for __% of congenital cardiac defects, and ASDs account for __%.

Answer 47

VSDs account for 40% of congenital cardiac defects, and ASDs account for 10%.

Question 48

Which type(s) of Streptococcus cause rheumatic heart disease, and which cause infective endocarditis?

Answer 48

Streptococcus pyogenes (group A or beta-hemolytic streptococcus) is the causative agent of rheumatic heart disease. Viridans streptococci are a common cause of infective endocarditis.

Question 49

What is the most common cause of mitral stenosis?

Answer 49

Rheumatic heart disease. In 65-70% of cases, the mitral valve is the only valve affected. The mitral and aortic valves are affected in ~25% of cases.

Question 50

Why is "arrythmogenic right ventricular cardiomyopathy" a misnomer?

Answer 50

Because it is not only the right ventricle that can be affected - left ventricle and septum can be affected too. The preferred term is "arrhythmogenic cardiomyopathy."

Question 51

Of the 3 CK isoenzymes, which is the fastest migrating and which is the slowest migrating?

Answer 51

The fastest is CK-BB (CK1). The slowest is CK-MM (CK3).

Question 52

CK-MM is found in skeletal and cardiac muscle. Skeletal muscle is ~__% MM, and cardiac muscle is ~__% MM.

Answer 52

CK-MM is found in skeletal and cardiac muscle. Skeletal muscle is ~99% MM, and cardiac muscle is ~70% MM.

Question 53

CK-MB is found in skeletal and cardiac muscle. Skeletal muscle is ~__% MB, and cardiac muscle is ~__% MB.

Answer 53

CK-MB is found in skeletal and cardiac muscle. Skeletal muscle is ~1% MB, and cardiac muscle is ~30% MB.

Question 54

The ratio of CK-MB to total CK is called the "relative index." What is its utility?

Answer 54

The relative index adds to the ability of either assay alone to distinguish myocardial infarction. A relative index of about 2% is often the chosen cut-off.

Question 55

What are CK isoforms AKA CK subforms?

Answer 55

Metabolic breakdown products of CK. With high-resolution electrophoresis, CK-MB resolves into 2 bands and CK-MM resolves into 3 bands. CK-MB2 and CK-MM3 are the tissue forms that are released from damaged myocardium. CK-MB1 is the plasma form and arises as a result of cleavage of a terminal lysine from the M peptide. CK-MM1and CK-MM2 are also cleavage products. A relative increase of tissue forms indicates a recent enzyme leak.

Question 56

What are troponins?

Answer 56

Troponins are a group of enzymes consisting of TnT, TnI, and TnC that are involved in mediating the actin-myosin interactions that result in muscle contraction.

Question 57

TnT, TnI, and TnC all have cardiac and skeletal muscle forms. Which are encoded by the same genes and which are encoded by different genes?

Answer 57

While the same gene encodes cardiac and skeletal TnC, separate genes encode TnI and TnT in cardiac and skeletal muscle.

Question 58

Is cardiac muscle troponin present mostly as a free or a bound form in the cell?

Answer 58

A small proportion of cardiac muscle troponin is free in the cytoplasm but the vast majority of it is bound to actin and myosin. Thus, there is both an immediate release of cytoplasmic troponin by infarcted cardiac muscle (within 4-8 hours) and a sustained release of bound troponin (over 10-14 days).

Question 59

What is the Altered Cobalt Binding (ACB) assay?

Answer 59

A measured quantity of cobalt is added to patient plasma and the amount of unbound cobalt is measured. The quantity of unbound cobalt is a measure of ischemia-modified albumin (rises within minutes of myocardial ischemia and returns to baseline within 6 hours due to rapid hepatic clearance).

Question 60

In what locations are the natriuretic peptides ANP, BNP, and CNP produced?

Answer 60

ANP is synthesized mainly by atrial myocytes (but synthesis of ANP also takes place in the ventricles, brain, kidney, and adrenals). ANP is stored in granules and stimulation results in a rapid response. BNP is synthesized by ventricular myocytes (predominantly) and brain, as well as atrial myocytes under some conditions. BNP is secreted by a constitutive mechanism; only small amounts are stored and cells are dependent upon activation of the BNP gene when secretion is needed. CNP is synthesized by brain and endothelium.

Question 61

Serial measurements improve the sensitivity of both troponin and CK-MB for AMI to almost 100%. How do the 2 compare for specificity?

Answer 61

The specificity of CK-MB cannot equal that of troponin, because of false-positives from non-ischemic cardiac injury (pericarditis, myocarditis) and skeletal muscle disease (rhabdomyolysis, exercise). However, troponin is not useful to determine temporal stage of the MI (it remains elevated for up to 2 weeks following AMI), so serial CK-MB is still useful to see if the infarct is acute or resolving, or if there is a complication of MI such as extension of the infarct.

Question 62

What is the "washout phenomenon" in cardiac reperfusion?

Answer 62

An indication of successful reperfusion following thrombolysis is the washout phenomenon. In successful reperfusion, all of the cardiac markers peak earlier than normal; although, their sequence of peaks parallels that of normal MI. In addition, their peak concentrations may be higher than they would have been with unreperfused MI.

Question 63

What tumors are seen commonly in tuberous sclerosis (the "major features" as set forth in a consensus statement from the Diagnostic Criteria Committee of the National Tuberous Sclerosis Association)?

Answer 63

Facial angiofibromas (adenoma sebaceum) or forehead plaque. Nontraumatic ungual or periungual fibroma. >3 hypomelanotic macules. Shagreen patch (connective tissue nevus). Multiple retinal nodular hamartomas. Cortical tuber. Subependymal nodule. SEGA. Cardiac rhabdomyoma, single or multiple. LAM. Renal AML. Definite TSC is either 2 major features or one major plus 2 minor features.

Question 64

What tumors occur in Carney complex?

Answer 64

Cutaneous lentigenes (simple lentigos). Blue nevi, particularly the cellular blue nevus. Cardiac myxomas (as well as myxomas of breast, female genital tract, and skin (especially on eyelid and external ear)). Endocrine tumors including thyroid follicular adenomas, pituitary adenomas (GH-secreting), and the so-called primary pigmented nodular adrenocortical disease (a form of multinodular hyperplasia of the adrenal cortex that causes Cushing syndrome). Large-cell calcifying Sertoli cell tumor. Psammomatous melanotic schwannoma.

Question 65

About 2% of atrial myxomas can have heterologous elements such as glands or extramedullary hematopoiesis. What is the prognostic significance of this?

Answer 65

There is no reported prognostic significance of the presence of heterologous elements. It is just important not to confuse a benign myxoma with a metastatic adenocarcinoma.

Question 66

The exact pathogenesis of idiopathic giant cell myocarditis is unknown, but what disorder(s) has it been associated with?

Answer 66

Autoimmune disorders (IBD, hyperthyroidism, hypothyroidism).

Question 67

For the following clinical syndrome(s), give the causative agent(s) (list most common first): viral myocarditis.

Answer 67

Coxsackie B.

Question 68

What are the 3 possible haptoglobin phenotypes? Is there a disease association with any particular phenotype?

Answer 68

The haptoglobin genetic locus at 16q22 is polymorphic with two classes of alleles: type 1 and type 2. Based on these 2 alleles, the 3 haptoglobin phenotypes/protein products are: Hp 1-1, Hp 2-1, and Hp 2-2. The 2-2 phenotype is an independent risk factor for CV disease in DM.

Question 69

Formerly, assays for CRP had an analytical sensitivity of ~5mg/L. This was appropriate, as the CRP test then was used to support such diagnoses as bacterial endocarditis, appendicitis, active collagen vascular disease, etc, in which the CRP tended to be well over 10mg/L. Now, high-sensitivity CRP assays are available, that have an analytical sensitivity of ___.

Question 70

What is Dirofilariasis?

Answer 70

Dirofilariais is caused by filarial nematodes (roundworms) of the genus Dirofilaria. The three species most commonly reported to cause disease in humans are D. immitis (the dog heartworm), D. repens, and D. tenuis. Dogs and wild canids are the main natural hosts for D. immitis and D. repens and raccoons for D. tenuis.

Question 71

What is the vector for Dirofilaria immitis?

Answer 71

Mosquito (Aedes, Culex, Anopheles, Mansonia).

Question 72

Commotio cordis is a sudden death due to a cardiac arrhythmia caused by a blunt impact to the chest. The impact must occur at what very narrow part of the cardiac cycle for the ventricular fibrillation to occur?

Answer 72

15 ms before the peak of the T-wave.

Question 73

What is the histologic appearance of cardiac allograft vasculopathy AKA transplant coronary arteriopathy?

Answer 73

Histologically, CAV is associated with concentric intimal thickening with or without foamy macrophages, subendothelial clusters of lymphocytes, and perivascular fibrosis. It diffusely affects vessels of different size and function, including coronary arteries, epicardial vessels, intramyocardial arteries, arterioles, and capillaries. Evidence of myocardial ischemia is sometimes present.

Question 74

Can cardiac allograft vasculopathy AKA transplant coronary arteriopathy be diagnosed on endomyocardial biopsy?

Answer 74

CAV can be difficult to diagnose on endomyocardial biopsy as the arteries typically involved are not present; however, other findings such as myocytolysis in the absence of inflammation and hypertrophic myocytes may suggest concurrent ischemia. Intravascular ultrasound is useful; the presence of CAV has been reported to be as high as 75% at 1 year after transplant using IVUS, whereas angiography detects disease in only 10-20% of patients at the same time interval.

Question 75

In Alagille syndrome, abnormalities in which organ system causes the most mortality?

Answer 75

Hepatic complications do contribute significantly to the morbidity of AGS but it is the cardiovascular sequelae that are most directly responsible for the early mortality. Specifically, intracardiac anomalies, which affect ~25% of AGS patients (most commonly tetralogy of Fallot).

Question 76

What is Alagille syndrome (AGS) AKA syndromic paucity of interlobular bile ducts AKA arteriohepatic dysplasia?

Answer 76

AGS is a multisystem disorder with AD inheritance and variable penetrance and expressivity. The traditional diagnostic criteria have consisted of paucity of the interlobular bile ducts in association with 3 of 5 major findings, including chronic cholestasis, cardiac disease (most frequently peripheral pulmonary artery stenosis), skeletal manifestations (short stature, butterfly vertebrae), ocular abnormalities (most commonly posterior embryotoxon, a circular opacity of the posterior peripheral cornea), and characteristic facial features (triangular face with a prominent forehead, deep-set eyes, a pointed chin, and a straight nose with a bulbous tip). Mutations are in the JAGGED1 (JAG1) gene.

Question 77

In addition to an increased incidence of IUGR and preterm labor, neonates born to mothers with SLE have a risk of congenital heart block. Why?

Answer 77

Antibodies to SS-A and SS-B (Ro and La) are thought to mediate this complication.

Question 78

What is in the differential diagnosis of cocaine-associated chest pain?

Answer 78

MI (due to cocaine-induced vasoconstriction). Pneumothorax (due to inhalation barotraumas). Aortic dissection (due to HTN). PE (due to clotting activation). Endocarditis (due to injection of cocaine).

Question 79

How are the specificities of myoglobin, CK-MB, and troponin I different in cocaine-induced AMI vs. non-cocaine-induced AMI?

Answer 79

Due to skeletal muscle effects, the specificity of both myoglobin and CK-MB is lower in cocaine-induced AMI, but the specificity of troponin I is equally good.

Question 80

What 3 major categories of small vessel vasculitis can cause the pulmonary-renal syndrome?

Answer 80

Anti-GBM disease, ANCA disease, and immune complex-mediated diseases (such as SLE).

Question 81

The Chapel Hill consensus conference recommendation on the nomenclature of systemic vasculitides is based primarily based on what?

Answer 81

It is based on the caliber of the most inflamed/affected vessels (the system does additionally incorporate IF findings and selected clinical/lab parameters). Small vessel vasculitis refers to changes found in distal vascular branches including arterioles, capillaries and venules. Medium vessel vasculitis is found in the main muscular arterial segments with multiple medial smooth muscle layers. Large vessel vasculitis is seen in the aorta and its largest branches.

Question 82

What is the most common form of vasculitis in patients older than 50?

Answer 82

Giant cell arteritis (formerly termed temporal arteritis).

Question 83

Giant cell arteritis (formerly termed temporal arteritis) is a granulomatous form of ANCA-negative large vessel vasculitis. What vessels does it tend to affect?

Answer 83

The aorta and its major branches, especially the extracranial arteries.

Question 84

Giant cell arteritis (formerly termed temporal arteritis) tends to affect the aorta and its major branches, especially the extracranial arteries. Histologic appearance?

Answer 84

The inflammatory process, composed of mononuclear cells with a predominance of macrophages and lymphocytes, originates in the media and extends into the intima and adventitia. Multinucleated giant cells, of either the Langerhans or foreign body type, are found in about half of cases, often adjacent to the fragmented internal elastic lamina. Fibrinoid vascular wall necrosis is an infrequent observation and, when present, it patchy in distribution. GCA involves arteries in a segmental fashion, so a minimum of a 3 cm long segment should be obtained for an adequate histologic examination.

Question 85

Giant cell arteritis is an ANCA-negative large vessel vasculitis. Is extensive fibrinoid necrosis consistent with giant cell arteritis?

Answer 85

No. In GCA, fibrinoid vascular wall necrosis is an infrequent observation and, when present, is patchy in distribution. The presence of extensive fibrinoid necrosis should raise the possibility of another type of systemic ANCA-negative vasculitis found in medium-sized vessels, such as polyarteritis nodosa.

Question 86

In antiphospholipid antibody syndrome, venous thrombosis is typically seen in deep leg veins (__%), as well as renal, hepatic, and retinal veins. Arterial thrombosis is typically seen in cerebrovascular (__%), coronary (__%), as well as ocular, mesenteric, deep leg, and renal arteries.

Answer 86

In antiphospholipid antibody syndrome, venous thrombosis is typically seen in deep leg veins (55%), as well as renal, hepatic, and retinal veins. Arterial thrombosis is typically seen in cerebrovascular (50%), coronary (25%), as well as ocular, mesenteric, deep leg, and renal arteries.

Question 87

Thrombotic microangiopathy -a descriptive term- characterizes stenosing and/or thrombotic changes in small vessels (capillaries, arterioles, pre-arterioles, and small arteries). Veins and larger arteries with multiple layers of medial smooth muscle cells are characteristically spared. What are histologic features of the acute phase of a TMA?

Answer 87

The acute phase of a TMA is characterized by various changes that can be seen individually or in combination: (1) endothelial cell swelling and "mucoid" intimal widening with severe narrowing of vascular lumens; (2) intraluminal fibrin thrombi and/or fragmented RBCs in the intima and media; (3) necrosis of individual endothelial or medial smooth muscle cells; (4) PAS-positive nodular proteinaceous deposits replacing single necrotic arteriolar smooth muscle cells. Note: fibrin thrombi may sometimes be detected but they are not essential for establishing the diagnosis of a TMA.

Question 88

Why is the "thrombotic" in thrombotic microangiopathy sometimes a misnomer?

Answer 88

Fibrin thrombi may sometimes be detected but they are not essential for establishing the diagnosis of a TMA.

Question 89

The thrombotic microangiopathies are microvascular occlusive disorders characterized by systemic or intrarenal aggregation of platelets, thrombocytopenia, and mechanical injury to erythrocytes. TTP and HUS are both TMAs; What distinguishes them?

Answer 89

TTP affects mainly adults, with systemic microvascular aggregation of platelets affecting primarily the brain. HUS affects mainly children, with platelet–fibrin thrombi occluding predominantly the renal circulation.

Question 90

The initial common event in the pathogenesis of all forms of thrombotic microangiopathy is severe endothelial cell injury that is caused by a wide variety of different agents. How reliably can the pathologist identify the underlying causative agent or event?

Answer 90

The pathologist generally cannot reliably identify the underlying causative agent or event and can often render only a descriptive diagnosis of TMA. The clinical distinction is not always clear-cut either and they are often clinically referred to as TTP-HUS.

Question 91

Initially, arterial hypertension results in hypertrophy of the medial smooth muscle cell layer. Why is there atrophy of the smooth muscle cells in later stages?

Answer 91

Once fibroelastic intimal thickening impairs the diffusion of nutrients from the vascular lumen to the media, smooth muscle cells undergo atrophy.

Question 92

What histologic changes are seen in renal arterioles in calcineurin inhibitor-induced toxicity?

Answer 92

Calcineurin inhibitors include cyclosporin A and tacrolimus. The afferent arterioles show nodular, PAS-positive, protein (hyaline) deposits deep in the medial smooth muscle layers replacing individual (necrotic) myocytes. Hyaline nodules are often seen in a necklace-like pattern along the adventitial aspect of afferent arterioles. The most serious toxic side effect is a fully developed thrombotic microangiopathy.

Question 93

The major adverse consequences of tricyclic overdose take place within the CNS and cardiac systems. Describe.

Answer 93

CNS: sedation, coma, seizures. Cardiac: tachycardia, hypotension, conduction abnormalities (V tach and V fib, particularly when QRS prolongation is present). A QRS interval longer than 0.16 sec is strongly associated with arrhythmia, while a QRS interval longer than 0.1 sec is associated with a high risk of seizures.

Question 94

What symptoms are seen in acrodynia (AKA hydrargyria, mercurialism, erythredema, erythredema polyneuropathy, Pink's disease, Bilderbeck's disease, Selter's disease, Swift's disease, Swift-Feer disease, and Feer syndrome)?

Answer 94

Acrodynia results from chronic exposure to mercury and occurs most often in infants and young children. Symptoms include irritability, photophobia, polyneuritis, autonomic manifestations (sweating, hemodynamic instability), and a desquamative erythematous rash on the palms and soles. It is associated with increased urinary catecholamines and can in many ways mimic pheochromocytoma. The presentation may also be similar to Kawasaki disease.

Question 95

What are typical manifestations of quinidine toxicity?

Answer 95

Cinchonism (tinnitus, hearing loss, vertigo, blurred vision), AMS, widening of the QRS complex, prolonged QT interval, and hypotension (without compensatory tachycardia).

Question 96

How is quinidine cleared from the body? What test is used to predict toxicity?

Answer 96

Quinidine is cleared by the liver. Quinidine levels are not routinely used to predict toxicity; the ECG is more reliable in this regard. It is important to check and correct electrolyte levels.

Question 97

What are early manifestations of phenytoin toxicity, and manifestations associated with severe toxicity?

Answer 97

Early manifestations: ocular dysmotility (particularly horizontal gaze nystagmus), ataxia, and incoordination. Severe toxicity: AMS and cardiac conduction disturbances.

Question 98

Oral phenytoin overdose has not been associated with significant cardiac conduction abnormalities, while IV overdose often produces a prolonged PR interval (AV block), hypotension, and a risk of arrhythmia. What is thought to be the reason for this discrepancy?

Answer 98

It is thought that this discrepancy and the arrhythmogenic effects of IV intoxication are due to the propylene glycol diluent instead of phenytoin.

Question 99

Is calcineurin inhibitor-induced toxicity seen in arteries or arterioles?

Answer 99

Arterioles.

Question 100

What is the histologic appearance of transplant endarteritis? What is the treatment for it?

Answer 100

Transplant endarteritis shows infiltration of lymphocytes through an activated endothelial cell layer into the subendothelial compartment/intima. The media of the vessels is unaltered. Transplant endarteritis is a common type of acute allograft rejection. Patients usually do not benefit from conventional anti-rejection therapy with bolus steroids, but rather require potent treatment with anti-lymphocytic preparations (ATG or OKT3).

Question 101

What is the definition of sclerosing transplant vasculopathy ("chronic vascular rejection")?

Answer 101

A rejection-induced arterial intimal thickening due to de novo deposition of collagens I and III without associated intimal elastosis. During intimal remodeling, myofibroblasts may occasionally form a new rudimentary media under the endothelial layer; Such a (so-called) neo-media formation is almost pathognomonic for "chronic vascular rejection."

Question 102

Systemic forms of amyloidosis, most frequently caused by the deposition of AA, AL, or sometimes ATTR amyloid variants, typically (do/do not) affect cerebral arteries.

Answer 102

Systemic forms of amyloidosis, most frequently caused by the deposition of AA, AL, or sometimes ATTR amyloid variants, typically do not affect cerebral arteries. Cerebral amyloid deposits are characteristically of the "beta" type and limited to the brain.

Question 103

Is the most common cause of the pulmonary-renal vasculitic syndrome ANCA disease or anti-GBM disease?

Answer 103

ANCA disease accounts for ~55% of cases, anti-GBM for 7%, and both ANCA and anti-GBM present in 8% of cases.

Question 104

Into what 5 morphologic forms is fibromuscular dysplasia classified, and what are their frequencies?

Answer 104

Intimal fibroplasia - <1%. There are 3 types of medial dysplasia: Medial fibroplasia - 75-80%. Perimedial fibroplasia - 10-15%. Medial hyperplasia - 1-2%.

Question 105

In the past, polyarteritis nodosa and what is now termed microscopic polyangiitis were used synonymously. What are the current definitions according to the Chapel Hill nomenclature system?

Answer 105

PAN is defined as an "ANCA-negative" necrotizing arteritis without immune complex deposits that primarily affects medium-sized arteries. Microscopic polyangiitis is defined as a (commonly) ANCA-positive necrotizing vasculitis without immune deposits that affects small vessels including capillaries.

Question 106

What are the 3 major ANCA-associated, necrotizing small vessel vasculitides not associated with the deposition of immune complex deposits?

Answer 106

Wegener's granulomatosis, microscopic polyangiitis, and Churg-Strauss syndrome.

Question 107

The 3 major ANCA-associated, necrotizing small vessel vasculitides not associated with the deposition of immune complex deposits are Wegener's granulomatosis, microscopic polyangiitis, and Churg-Strauss syndrome. How are these 3 differentiated?

Answer 107

Clinical features. Patient's lacking signs of asthma, lung and sinus inflammation, or peripheral blood eosinophilia are best classified as having microscopic polyangiitis. Necrotizing inflammatory lesions involving the lungs, nasal sinuses and kidneys are typically seen in cases of Wegener's granulomatosis. Peripheral blood eosinophilia and asthma are defining features of Churg-Strauss syndrome.

Question 108

The morphologic changes of calcineurin inhibitor-induced toxicity are almost exclusively seen in what organ?

Answer 108

The kidney (either native or transplanted).

Question 109

What are the 2 types of ANCA assays used?

Answer 109

Indirect immunofluorescence assay (IIA), using alcohol fixed buffy coat leukocytes, and enzyme-linked immunosorbent assay (ELISA), using purified specific antigens. The IIA is more sensitive and the ELISA more specific. The optimal approach to clinical testing for ANCA is therefore to screen with IIF assays, if available, and to confirm all positive results with ELISAs directed against the vasculitis-specific target antigens (PR3 and MPO).

Question 110

In vasculitis, the two relevant target antigens are proteinase 3 (PR3) and myeloperoxidase (MPO). Where are these antigens located?

Answer 110

Both PR3 and MPO are located in the azurophilic granules of neutrophils and the peroxidase-positive lysosomes of monocytes. Antibodies with target specificities for PR3 and MPO are called PR3-ANCA (c-ANCA) and MPO-ANCA (p-ANCA), respectively.

Question 111

When the sera of patients with ANCA-associated vasculitis are incubated with ethanol-fixed human neutrophils, what are the two major immunofluorescence patterns observed?

Answer 111

With the C-ANCA pattern, the staining is diffuse throughout the cytoplasm. In most cases, antibodies directed against PR3 cause this pattern, but MPO-ANCA can occasionally be responsible. The perinuclear or P-ANCA pattern results from a staining pattern around the nucleus, which represents an artifact of ethanol fixation. Among vasculitis patients, the antibody responsible for this pattern is usually directed against MPO (and only occasionally PR3).

Question 112

In generalized granulomatosis with polyangiitis (GPA) (Wegener's granulomatosis), what % of patients are ANCA positive? And what type of ANCA do they have?

Answer 112

~90% of patients with active, generalized GPA are ANCA-positive. There is a small subset of patients with active, generalized GPA who do not have ANCA. Furthermore, in limited forms of the disease (such as subsets in which upper respiratory tract disease predominates and renal involvement is absent), up to 40% of patients may be ANCA-negative. Thus, the absence of ANCA does not exclude the diagnosis of GPA. Among GPA patients with ANCA, 80-90% have PR3-ANCA.

Question 113

In Churg-Strauss syndrome, what % of patients are ANCA positive? And what type of ANCA do they have?

Answer 113

~50% of CSS patients overall are ANCA positive, with the percentage being somewhat higher in those with active, untreated disease. There appears to be a moderate predilection for MPO-ANCA among those patients with CSS who have ANCA.

Question 114

In microscopic polyangiitis, what % of patients are ANCA positive? And what type of ANCA do they have?

Answer 114

~70% of patients with MPA are ANCA positive. Most ANCA-positive MPA patients have MPO-ANCA.

Question 115

~90% of patients with active generalized granulomatosis with polyangiitis (GPA) (Wegener's granulomatosis) are ANCA-positive, and ~70% of patients with microscopic polyangiitis are ANCA positive. Can the type of ANCA (PR3-ANCA/c-ANCA or MPO-ANCA/p-ANCA) distinguish the 2 diseases?

Answer 115

Among GPA patients with ANCA, 80-90% have PR3-ANCA. This is in contrast to microscopic polyangiitis, where the majority of patients have MPO-ANCA. But, the 2 diseases cannot be distinguished based on ANCA specificity.

Question 116

A negative ANCA assay does not rule out a vasculitis. On the other hand, elevated ANCA titers (often p-ANCA and generally low titer levels) have also been reported in many inflammatory conditions such as ___. ANCA positivity is seen in __% of patients with UC and PSC, and in __% of patients with Crohn's disease.

Answer 116

A negative ANCA assay does not rule out a vasculitis. On the other hand, elevated ANCA titers (often p-ANCA and generally low titer levels) have also been reported in many inflammatory conditions such as RA, SLE, Sjogren's syndrome, scleroderma and antiphospholipid syndrome. ANCA positivity is seen in 60-80% of patients with UC and PSC, and in 10-30% of patients with Crohn's disease. Elevated ANCA titers can also be found in some healthy individuals.

Question 117

Rubella virus causes German measles, which is only really consequential in pregnancy. Which trimester infections have the most serious fetal implications?

Answer 117

First trimester infections have the most serious fetal implications. Defects in neonates infected in the first trimester include hearing impairment (60%), heart defects (45%) (PDA in 20% and peripheral pulmonic stenosis in 12%), microcephaly (27%), cataracts (25%), low birth weight (<2500 g) (23%), hepatosplenomegaly (19%).

Question 118

Premature atherosclerosis is a consequence of hyperlipidemia. Specifically, what lipid types?

Answer 118

It is seen when there is abnormally high LDL or IDL; that is, whenever the cholesterol is too high. It is not a prominent feature when only the TG is elevated.

Question 119

A low level of HDL cholesterol, defined as less than ___ mg/dL, is an independent risk factor for premature atherosclerosis. A high HDL, greater than ___ mg/dL, is protective.

Answer 119

A low level of HDL cholesterol, defined as less than 35 mg/dL, is an independent risk factor for premature atherosclerosis. A high HDL, greater than 70 mg/dL, is protective.

Question 120

Tangier disease is an autosomal recessive disorder of lipid metabolism characterized by what lipid values?

Answer 120

Low cholesterol, normal to increased TG, absent HDL, and absence of APO-A1. Cholesterol esters deposit in the tonsils, lymph nodes, vasculature, and spleen, and corneal opacities develop.

Question 121

What is the clinical utility of cANCA antibodies?

Answer 121

High specificity for Wegener syndrome; cANCA is anti-proteinase 3 (PR3).

Question 122

Antibodies to mitochondrial antigens M1 to M9 are associated with various diseases. List.

Answer 122

M1, M2, and M7 are on inner mitochondrial membranes, while M3, M4, M5, M6, M8, and M9 are on outer mitochondrial membranes. Anti-M1: syphilis. Anti-M2, anti-M4, anti-M8, anti-M9: primary biliary cirrhosis (anti-M2 is a specific marker for the diagnosis of PBC). Anti-M3: phenopyrazon-induced pseudolupus syndrome. Anti-M5: undefined collagen diseases. Anti-M6: iproniazid-induced hepatitis. Anti-M7: cardiomyopathy.

Question 123

Anti-centromere antibody strongly suggests ___ and is occasionally seen in ___ and ___.

Answer 123

Anti-centromere antibody strongly suggests CREST syndrome and is occasionally seen in progressive systemic sclerosis and Raynaud syndrome.

Question 124

c-ANCA is positive in __% of Wegener granulomatosis. Does its presence correlates with activity? Specificity?

Answer 124

c-ANCA is positive in 90% of Wegener granulomatosis. Its presence does correlate with activity, and c-ANCA titers can be monitored to follow disease activity. It is highly (95-99%) specific for Wegener granulomatosis.

Question 125

p-ANCA is less specific than c-ANCA but still has clinical utility, since it is seen in a small number of disorders. List.

Answer 125

Primary sclerosing cholangitis. Ulcerative colitis. Microscopic polyangiitis. Also, RA and Churg-Strauss syndrome.

Question 126

What autoimmune condition are each of the following triggering exposures correlated with: Coxsackie B virus infection; HBV infection; K. pneumoniae infection; aldomet; penicillamine; procainamide, hydralazine, and isoniazid.

Answer 126

Coxsackie B virus infection - development of IDDM. HBV infection - polyarteritis nodosum. K. pneumoniae infection - onset of ankylosing spondylitis. Aldomet - WAIHA. Penicillamine - systemic vasculitis. Procainamide, hydralazine, and isoniazid - drug-induced SLE.

Question 127

What are the 4 (plus one) types of hypersensvitiity reactions, their mediators, and associated diseases?

Answer 127

Type I (allergic, immediate-type): IgE; atopy, asthma, anaphylaxis. Type II (antibody-dependent, cytotoxic, antibody-mediated cellular cytotoxicity): IgM or IgG, complement, MAC; Goodpasture syndrome, autoimmune hemolytic anemia, erythroblastosis fetalis, rheumatic heart disease (also Graves disease and myasthenia gravis, but some classify these as type V). Type III (immune complex): IgG, complement, neutrophils; SLE, serum sickness, Arthus reaction, PSGN. Type IV (delayed-type, cell-mediated immune memory response, antibody-independent): T cells; tuberculin skin test, contact dermatitis, MS. Type V (an additional subtype sometimes used as a distinction from type II) (receptor mediated autoimmune disease): IgM or IgG, complement; Graves disease, myasthenia gravis.

Question 128

Scleroderma (progressive systemic sclerosis) is associated with obliterative vasculopathy, dermal sclerosis, epidermal atrophy, tenosynovitis, esophageal sclerosis, interstitial lung disease, pulmonary hypertension, telangiectasia, calcinosis, and renal hypertension. What auto-antibodies are associated with scleroderma, and how are they detected?

Answer 128

ANA, anti-nucleolar, anti-Scl-70 (anti-topoisomeraseI). IIF on C. luciliae or HEp-2 cells; ELISA.

Question 129

What are the 5 mechanisms for increased vascular permeability?

Answer 129

1. Gaps due to endothelial contraction (venules; vasoactive mediators such as histamine and leukotrienes; fast and short-lived (minutes)). 2. Direct injury (arterioles, capillaries, and venules; toxins, burns, chemicals; fast and may be long-lived (hours to days)). 3. Leukocyte-dependent injury (mostly venules; pulmonary capillaries; late response; long-lived (hours)). 4. Increased transcytosis (venules; vascular endothelium-derived growth factor). 5. New blood vessel formation (sites of angiogenesis; persists until intercellular junctions form).