Histo 10 In 10' Exam 3

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Mutation leading to precipitation of Hbg subject to hypoxia and this causes a sickle-shape instead of the biconcave disk. Erythrocytes are more rigid and more fragile and they are destroyed easier. They adhere more readily to endothelium and may pile up in capillaries.

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Sickle Cell Disease

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an autosomal dominant disorder characterized by the production of
rbcs that are sphere-shaped rather than biconcave shape (they lack central pallor). Therefore these cells are more prone to hemolysis (destruction of rbcs). Extravascular hemolysis occurs in this case. A mutation in ankyrin is the most common defect; mutations in spectrin, band 2, or band 3 account for other defects. Membrane transport activities of the rbc are also affected; rbcs are osmotically fragile; splenomegaly a result.

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Hereditary Spherocytosis

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Persistent neutrophilia due to a redistribution of neutrophils; total WBC count is over 50k/µl but not greater than 100k/µl; redistributed from marrow, microcirculation, and marginating compartment. Most frequent causes are inflammation, infection, and malignancy. Eos and Bas increase is rare; LAP is >100; no splenomegaly. total wbc is 50,000 to 100,000 cells/ul; due to a redistribution; Causes: I, I, M

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Leukemoid Reaction

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Proliferating cells are partly or completely differentiated. Myelocytes, metamyelocytes, band forms, and neutrophils appear in peripheral blood. Total WBC count is greater than 100k/ul; increased Eos and Bas; LAP is <10; splenomegaly is usually present. total wbc is greater than 100K and may be 300K/ul, a disease of the bone marrow cells

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Chronic myelogenous leukemia or chronic granulocytic leukemia

Front 5

Phospholipase B crystals that are found in diseases associated
with eosinophilia and are seen in secretions or excretions (sputum, feces) or CT.
Found in sputum of asthmatics.

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Charcot Leyden Crystals

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4 Situations or Disease:
1) Substantial dosage with glucocorticoids;
2) Substantial dosage with ACTH;
3) Stressers that cause high release of adrenal cortisol ex.Infection, burns, and trauma;
4) Cushing Disease – Part of Mnemonic – The H in Cushing stands for Hypercortisolism, Hypertension, Hyperglycemia, and Hirsutism

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Conditions that cause Eosinophenia and relations to Endocrine System

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Greater than 10% of total wbc count or greater than 800/µl; Many or just about Anything causes it- bacterial, viral, and protozoan infections; Hodgkin lymphoma and chronic myelogenous leukemia are two malignancies with extremely high monocyte counts. chronic infection (tuberculosis), autoimmune disease (RA), malignancy (HL, CML). Primary cell of chronic inflammation along with macrophage

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Monocytosis

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Less than 150K/uL of blood
A decrease in production or an increase in the destruction
Destruction – alcohol, abs against platelets or megakaryocyte (autoimmune thrombocytopenia purpura) or drugs i.e. penicillin, fulfonamides and digoxin or pathologic changes in the endothelial cells

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Thrombocytopenia (TCP)

Front 9

Calculate the normal bone marrow cellularity of Dancing With the Stars contestant Florence Henderson at 76 years. See Box 10.4.
Hypercellular marrow is characterisitic of bone marrow affected by tumors of hematopoietic cells.

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Cellularity of the Bone Marrow

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An X-linked disorder characterized by deficient
NADPH oxidase in the cell membranes of neutrophils and monocytes. The reduced production of O2 means the respiratory burst (RBP) is absent. Classic test for disease was the nitroblue tetrazolium test (NBT) where neutrophils change to a blue color if the RBP is intact. The new, more sensitive test involves oxidation of dihydrorhodamine to fluorescent rhodamine. HOCl is not synthesized because of the absence of H2O2 and thus some bacteria are not killed. Occurs in CT because the neutrophils, that can phagocytose bacteria but not kill most of them, are replaced by cells associated with chronic inflammation, mainly lymphocytes and macrophages. Macrophages fuse to create multinucleated giant cells. (Source – Goljan)

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Chronic Granulomatous disease (CGD)

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Mediated by RNA retrovirus called Human Immunodeficiency Virus (HIV)
2. HIV utilizes a glycoprotein (gp120) on its surface to bind to CD4 protein on the surface of T helper cells  allows virus to fuse with CD4+ T cells  release of HIV contents including reverse transcriptase & its RNA-encoded genome.
3. Reverse transcriptase converts the RNA  DNA  incorporated into genome of T cell.
4. Transcription & translation machinery of T cell now generates more copies of HIV.
5. HIV replicates inside T cell  lyzes T cell  release of thousands of new copies of HIV  infect more T cells.
6. Result is a  in number of CD4+ T cells  persistent re-occurring infections by opportunistic pathogens (pneumonia, toxoplasmosis) & development of malignancies (Kaposi sarcoma & non-Hodgkin lymphoma).
7. Immune system responds by generating CD8+ CTL & Ab
8. Diagnosis via PCR to detect virus RNA sequence and/or counts of CD4+ T cells.
9. Treatment includes a cocktail of chemotherapeutic agents including AZT – an inhibitor of reverse transcriptase

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AIDS

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abnormal swelling of arm/leg
1. Symptoms include: swelling; restricted range of movement; reoccurring infections in affected limb; hardening and thickening of skin
Causes:
A. Primary lymphedema – rare, inherited disorders causing improper development of lymphatic vessels

1. Milroy’s disease – begins in infancy; malformation of lymph nodes leads to this condition

2. Meige disease –condition occurs in childhood or at puberty; lack of valves in lymphatic vessels results backward flow and leads to this condition

B. Secondary: causes include surgery (removal of lymph nodes and/or vessels – breast cancer); radiation treatment for cancer (scarring and damage to lymph nodes and/or vessels); obstruction by cancerous mass; infection

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Lymphedema

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benign tumors of lymphatic vessels; affects ~ 1:6000; arise due to incomplete development & obstruction; failure to connect with venous system -> obstruction of lymph flow -> formation of cysts; impairment of breathing; treat with experimental drug OK-432 (Grp A strep + pencillin -> stimulates inflammatory response ->neutrophils, macrophages, & NK cells -> endothelium becomes permeable -> lymphatic fluid drains

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Lymphangiomas

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symmetrical accumulation of fluid around neck and head region; ~ 5% of stillbirths (Wisconsin); often associated with chromosomal abnormalities (Turner, Trisomies 21, 18 and 13); continued swelling of lymphatic vessels -> decease in intravascular volume leads to cardiac failure

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Cystic hygromas

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1. Affects 120 X 106 people worldwide in 80 different countries ranging from asia to S. American with infection rates increasing
2. Caused by nematode worms, which infect people by multiple bites from mosquitoes
3. Male and female larveal worms enter thru bite and circulate in bloodstream at night.
4. Adults live in lymphatic vessels and cause blockage of lymphatic vessels and lymph nodes
5. Symptoms: swollen limbs (elephantiasis)
6. Cure: Cannot kill adults so must kill larvae; adults mate for 6 years; treatment must continue for 6 years; treatment is a combination of albendazole, mectizan (heartgard for dogs), and diethylcarbamazine; China eradicated disease by adding drugs to salt

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Lymphatic filariasis

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1. Inflammation of tonsils leads sore throat & fever.
2. Severe cases, tonsils swolling impairs swallowing and/or breathing.
3. Usually caused by Group A streptococcal bacteria
4. Treatment – antibiotics
5. If re-occurring, abscess formed; hypertrophic tonsils, a tonsillectomy is performed.

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Tonsilitis

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1. Infection caused activation & migration of B cells to nodules in the cortex of lymph nodes
2. Activated B cells proliferate rapidly leads to increasing node size several times normal.
3. Node may become hard and palpable to touch; diagnostic for upper respiratory infection

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Enlarged Lymph Nodes

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1. Malfunction of immune system the body can no longer distinguish self from non-self.
2. Lymphocytes see Ags derived from self as foreign and destroy healthy tissue
3. Examples: rheumatoid arthritis, Graves disease, & lupus
4. Treatment generally consists of immunosuppressive drugs

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Autoimmune disease:

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Genetic disorder due to deletion of 22q11 (30 genes); one of most frequent chromosome defects in newborns. autosomal dominant

Characterized by: congenital absence of thymus & parathyroid glands
heart defects
affects on facial appearance
absent or malformed kidneys
mental retardation(IQ 70-90);
adults: psychiatric disorders

Associated with ABNORMAL CELL-MEDIATED immunity but relatively normal humoral immunity

Treatment: bone marrow transplant (thymus)
Usually results in death from tetany or uncontrollable infection

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DiGeorge syndrome
(Congenital thymic aplasia)

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1. Malignant growth of cells
2. Characterized by Reed-Sternberg cells (most likely B-cell derived)
3. 40 – 50% of cases also associated with Epstein-Barr virus
4. More common in ages 15-40 & > 55; rare in < 5 years of age
5. 2007: 4330 men & 3550 women diagnosed
6. Symptoms include: painless enlargement of lymph nodes; splenomegaly; heptamegaly; petechia due to decrease in platelet number; weight loss; fatigue
7. Diagnosed by biopsy
8. Treatments include: chemotherapy, bone marrow &/or peripheral blood transplants, immunotherapy (mAbs) &/or radiation therapy

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Hodgkin’s Lymphoma

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Absence or reduction in ADH
(lesion of hypothalamus or
posterior lobe of pituitary gland)

ADH increases permeability of
distal region of nephron via ADH-
regulated water channels

ADH increases rapid resorption of water across tubule epithelium

Reduced levels or absence of ADH
results in production of large
volumes of dilute urine
(up to 20L/day) and extreme thirst

Diagnosed: determining urine and/or blood concentration

Treatments include: synthetic ADH

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Diabetes insipidus

Front 22

Tumors of anterior pituitary; PRL tumors account for ~50% of all tumors

Enlarge and often suppress secretions by remaining cells of pars distalis

Frequently destroy surrounding bone & neuronal tissues

Treated by surgical removal

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Pituitary adenoma

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essential in fetal development:

T3 and T4 cross placental barrier; critical in early stages of brain development leads deficiency during fetal development results in irreversible damage to CNS including decreased numbers of neurons, defective myelination, and mental retardation.

T3 and T4 also stimulate gene expresson for GH in somatotropes cause stunted growth

Congenital hypothyroidism (cretinism) combination of CNS damage and stunted growth

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Thyroid hormones

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1. Diffuse enlargement of thyroid gland and protrusion of eyeballs (exophthalmic goiter)

2. Histology: columnar-shaped thyroid follicular cells,increased production of thyroid hormones, and decreased amounts of follicular colloid

3. Caused by binding of autoimmune IgG Abs to TSH receptors which leads to stimulation of thyroid follicular cells & increase thyroid hormone secretion

4. Normal negative feedback so TSH levels in circulation usually normal.

5. Abnormal levels of secretion of thryoid hormones leads to increase in metabolism & increase in sympathetic activity

6. Treatment: surgical removal of thyroid gland or radiotherapy (labeled iodine) to destroy most active follicular cells; immunosuppression

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Graves disease:

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1. Most common symptom of thyroid disease

2. Enlargement of thyroid gland due to excessive release of TSH from anterior pituitary

3. Due to insufficient iodine in diet (< 10 μg/day) or autoimmune – Hashimoto’s thyroiditis

4. Diagnosis: analysis of TSH and T3/T4 levels;
US of thyroid

5. Treatment: increase iodine in diet or synthetic thyroid supplement

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Simple goiter:

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Overactivity of parathyroid glands results in excess secretion of PTH which can cause bone resorption.

Associated w/high blood calcium levels that leads to deposition of calcium salts in kidneys (kidney stones – leading to recurrent UTI) & bv walls

Causes: benign tumor of parathyroid glands

4. Diagnosis: bone x-rays; determination of blood calcium levels; determination of PTH levels

5. Treatment in minor cases: i intake of Ca2+-rich foods; severe cases: surgical removal of portion of parathyroid glands.

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Hyperparathyroidism

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1. Characterized by secretion of inadequate amounts of adrenocortical hormones

2. Usually due to destruction of adrenal cortex via autoimmune disease or TB

3. Most often caused by autoimmune disease or tuberculosis

4. Symptoms include: weight loss, muscle weakness, fatigue, low BP, skin hyperpigmentation

5. Life-threatening & requires steroid treatment

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Addison disease:

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1. Tumor within pineal gland can disrupt melatonin production leads to insomnia

2. Other symptoms (Parinaud syndrome esp.) include paralysis of upward gaze due to compression of vertical gaze center in midbrain tectum at level of superior colliculus and CN III.

3. Also can result in disruption of hypothalamic inhibitory pathways --> b-hCG secretion --> Leydig cell stimulation of testosterone; hydrocephalus; gait disturbance and precocious puberty.

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Pinealoma with Parinaud syndome:

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1. Decrease in or total absence of plasma insulin leads to an increased elevated blood glucose levels and the loss of glucose in urine.

2.Type I (insulin-dependent; juvenile-onset)
a. Results from low levels of insulin in blood
b. Characterized by insatiable hunger, unquenchable thirst, and excessive urination.
c. Usually has sudden onset before age 20
d. Distinguished by damage to and destruction of β cells of islets
e. Treated with combination of diet and insulin therapy.

3. Type II (non-insulin-dependent)
a. DOES NOT result from low levels of insulin in blood
b. Is INSULIN-RESISTANT (due to decrease binding of insulin to its receptor and defects in induction of signal transduction pathway).
c.Commonly occurs in overweight individuals over 40 years of age
d. Usually controlled by diet.

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Diabetes mellitus:

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1. Defined in patients who have 2 or more tumors of endocrine glands
2. 1st described in 1903 in patient with acromegaly, pituitary adenoma, enlargement of 3 out of 4 parathyroid glands

3. MEN1: prevalence 1:35,000 associated w/ pituitary adenoma, parathyroid hyperplasia, pancreatic tumors

4. MEN2: parathyroid hyperplasia, medullary pheochromocytoma, and thyroid carcinoma

5. Lincoln originally thought to have Marfan Syndrome, however, not reported to have any CV or visual issues

6. In 2007, Lincoln proposed to suffer from MEN type 2B. Marfan-like body shape; large bumpy lips; history compatible w/ cancer

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Multiple endocrine neoplasia (MEN)

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typically categorized as tyrosinase positive or negative. In cases of tyrosinase positive albinism, the tyrosinase is present but is unable to enter melanocytes to produce melanin. In tyrosinase negative cases, this enzyme is not produced.

Note-Melanin is found in melansoomes

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Albinism

Front 32

Initial phase of invasion
Melanocytes proliferate
Laterally within the epidermis
Along dermoepidermal junction
Within the papillary dermis
No metastatic potential in this
No tumor cell nodules This is the leading cause of death due to skin cancer, the most rapidly increasing cancer worldwide

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Malignant Melanoma Radial Growth Phase

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excessive production of collagen in the dermis; systemic sclerosis can occur in other organs (kidney, GI tract, lungs) but when it occurs in the skin it is called scleroderma; characterized by tightening of skin (skin becomes parchment like), radial furrowing around lips; Raynaud’s phenomena is a clinical finding; Type I and Type II collagen are extensively deposited in papillary layer and then eventually the reticular layer; Histologically see a lot of enlarged collagen bundles, occluded or disappearance of vasculature/appendages in dermis. T cells accumulate at some point, secrete cytokines and this results in increased collagen synthesis—this points to an autoimmune disorder

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Scleroderma

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Hair follicle becomes plugged with keratin or dead cells/debris, sebaceous gland becomes over productive and distends, bacteria are involved and inflammation can occur. Affects the areas of skin with the densest population of sebaceous follicles; these areas include the face, the upper part of the chest, and the back.

4 factors: Epidermal hyperproliferation with subsequent plugging of the follicle, excess sebum, the presence and activity of Propionibacterium acnes, and inflammation.


neutrophils accumulate, treatment is antibiotics and topical steroids; males tend have more severe disease.

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Acne Vulgaris

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pemphix=bubble; a chronic, blistering skin disorder caused by the action of IgG antibodies to surface antigens (desmoglein & plakin family) on keratinocytes, an autoimmune disorder


A Type II Hypersensitivity Reaction

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Pemphigus vulgaris (PV)

Front 36

Sweat Test, an indicator of this disorder, see Box 15.4;

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Cystic Fibrosis

Front 37

1. Keratin filament disorder - Keratin Molecular Defect

2.Cleavage in the Lamina Lucida -- Laminin Molecular Defect

3. Entire basal lamina and epidermis split - Type VII Collagen (Anchoring Fibril) Defect

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1. Epidermolytic

2. Junctional

3. Dermolytic

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Skin Repair – See Fig. 15.5;

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Skin Repair

Front 39

A noncontagious skin disorder that most commonly appears as inflamed, edematous skin lesions covered with a silvery white scale. Cells reach apical layers in a short time. The most common type of this disorder is most common on the extensor surfaces of the knees, elbows, scalp, and trunk. Another form appears as erythematous raised plaques with silvery white scales on the scalp.

associated with an increase activity of T cells and thus significant evidence has accumulated that is an autoimmune disease. T cells accumulate in the skin and release tumor necrosis factor (TNF).

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Psoriasis

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associated with partial albinism of hair and skin, results from mutation in myosin Va gene. Myosin Va is a molecular motor protein that binds to actin and the melanosome when it is released from the microtubule in dendrite. The binding helps transfer or transport melanosome to melanocyte dendrite cell membrane.

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Griscelli Syndrome