• often supercedes death in an MI
• β-blockers reduce death in post-MI patients
• Class I agents: ↑ death in post-MI patients

Drugs:

Drugs:

• IV Lidocaine (IB): drug of choice
• Procainamide (IA)
• Bretylium (III)

Drugs for long-term prevention:

• β-blockers (II)
• Class IA drugs
• Class IC drugs
• Amiodarone (III)

• Stop digitalis
• Drugs:

• inflammation of the vessels

• occurs in diverse clinical settings

• many different types, and it’s very confusing

• they are grouped by

  • infectious vs non-infections

  • vessel size

  • role of immune complexes

  • presence of autoantibodies

  • several others

• there is lots of overlap between the vasculitides

Organization by vessel size

• diseases of the aorta

• medium-vessel diseases

• diseases of the capillaries

• immune complexes are globs of antibodies bound to antigen

• these deposit in vessel walls and attract complement

• examples

  • systemic lupus erythematosus (SLE)

  • hypersensitivity drug reactions

• immunologic mechanisms

• 1 immune-complex-associated vasculitis

• 2 antineutrophil cytoplasmic antibodies (ANCA)

• 3 antiendothelial cell antibodies

• affects young adults

• affects small- to medium-sized muscular arteries

• unknown cause

• most often involves renal, visceral vessels

Photo

• contrast study of the kidney. some sort of obstruction is going on in the renal vasculature

Histology

• there is fibrinoid transmural necrosis

  • fibrinoid = pink fibrin that is deposited

  • transmural = across the whole vessel

• so the whole vessel is blocked off

Clinical course

• findings are related to ischemia

  • malaise, fever, weight loss

  • renal artery involvement is common; it is one of the major causes of death

• episodic

• acute or chronic

• can be clinically puzzling

• treat with immune suppression—steroids and cyclophosphamide, a chemo agent that is pretty good at immunosuppression

• antineutrophil cytoplasmic antibodies

• these are circulating antibodies that react with constituents of the patient’s own neutrophils

• types

  • cytoplasmic ANCA

    • granular staining in the cytoplasm

    • ab against serine proteinase 3, a neutrophil granule constituent

    • the basis for Wegener’s granulomatosis

  • perinuclear ANCA

    • neutrophil cytoplasm itself does not stain

    • ab against myeloperoxidase

• pretty rare

• may be seen in systemic lupus erythematosus and Kawasaki disease

• just be aware that this third class exists

• older patients

• relatively common

• focal granulomatous inflammation of small to medium cranial arteries, often temporal artery

• present with nodular temporal arteries and sometimes blindness

Histology

• no lumen

• granulomatous inflammation—giant cell is seen

• internal elastic lamina of the artery has been fragmented

Microscopy

• lesions are focal

• classic: giant cells and lymphocytes with fragmented internal elastic lamina

Clinical features

• symptoms may be vague—fever, fatigue

• facial pain or headache

• tender nodularities in temple

• worst: abrupt onset of blindness because of ophthalmic artery involvement

• rx with steroids

Pathogenesis

• not clear

• autoimmune, most likely T-cell-mediated

• ding-dong association: “pulseless disease”

• young women, most often Asian, and typically of Japanese descent

• granulomatous inflammation of medium to large arteries—aortic arch and carotid

Grossly

• carotid artery has been occluded

Microscopy

• inflammation of the arterial adventitia and media

• can be granulomatous just like giant cell arteritis, so when comparing a case of Takayasu arteritis with giant cell arteritis, refer to the patient’s age

• later stages: collagenous fibrosis

Histology

• giant cell is seen in the media of the artery

Clinical features

• low blood pressure and weak distal pulses

• ocular disturbances

• distal aortic involvment: claudication, pain in calves

• renal artery involvement: hypertension

• variable disease course

• a necrotizing vasculitis

• triad

  • necrotizing vasculitis of small- to medium-sized vessels, particularly in the lung

  • acute necrotizing granulomas of the upper respiratory tract

  • necrotizing glomerulonephritis

• ding-dong: associated with c-ANCA, which is a sensitive and specific marker

• males > females, 40-50 years old

Clinical features

• pneumonitis

• ulcers of the nasopharynx

• renal disease

• lots of different stuff

Histology

• necrotizing vasculitis: vessel has been completely occluded and there is fibrinous necrosis of vessel wall

• granulomatous inflammation—eosinophils, neutrophils

Clinical course

• malignant disease: 80% of patients die within one year with no treatment

• rx with steroids and immunosuppressants, inc. cyclophosphamide

• aka Buerger disease

• young (usually < 35 years old) smokers (smokers is the ding-dong association)

• segmental, thrombosing, acute or chronic inflammation of medium to small arteries

• this often involves the extremities

Pathogenesis

• direct toxicity to endothelium

• idiosyncratic immune reaction?

Pathology

• segmental acute and chronic vasculitis

• affects medium-sized arteries, predominantly toward the extremities: radial, tibial arteries

• thrombosis with microabscesses

Histology

• acute: thrombus and neutrophils

• chronic: thrombi undergo organization and fibroblasts grow into them. organized thrombi result

Clinical features

• chronic ulceration of digits

• later: gangrene of fingers and toes. serial amputations are sometimes required

• cure: quit smoking

• terms are largely interchangeable: which was first: thrombosis or phlebitis?

• basically, venous thrombosis with inflammation

• most often seen in leg veins. deep vein thrombosis = DVT

• direct invasion of vessel wall by bacteria or fungi

• can cause

  • thrombosis and infarction

  • mycotic aneurysm—more later

Gross section of invasive aspergillus

• a ball of fungus is sitting inside the vessel

—memorize this, it’s “prime pimping material”

• alterations in normal blood flow (stasis)

• injury to the vascular endothelium

• alterations in the constitution of blood (hypercoagulability)

• CHF

• pregnancy

• obesity

• recent surgery

• prolonged immobility

• hypercoagulability

• distinctive: venous thrombi appear, disappear, and reappear elsewhere

• associated with visceral malignancies, e.g. pancreatic cancer

• can be difficult to diagnose

  • pain, swelling

  • Doppler ultrasound is the gold standard…but OS points out that angiography is the gold standard, and Doppler ultrasound is used frequently in clinical settings

  • MR points out “it’s a silver standard”

• sometimes, a pulmonary embolus is the first manifestation

Diagram

• thrombosed vein can resolve

• or embolize to lung

• or organize and become incorporated into wall

• or organize and undergo recanalization—the formation of multiple lumina through the clot

Treatment

• treat DVTs with anticoagulants

• if this doesn’t work, insert a Greenfield filter, which prevents pulmonary emboli

• transient venous thrombi are indicative of visceral cancer

• Trousseau described this phenomenon in himself

• then he died of pancreatic cancer

• brown coloration from hemosiderin

• skin is thickened, rough, brown

• abnormally dilated tortuous veins

• superficial veins of the legs, not deep veins

• more common in females

• familial disposition

• caused by prolonged elevated pressure; elevated pressure leads to venous valvular incompetence

• results: venous stasis, congestion, edema, pain, and thrombosis

• however, in contrast with DVT, there is a very low risk of embolization

• eventually: stasis dermatitis and ulceration

• thrombosis of hepatic vein

• hepatomegaly

  • ascites

  • abdominal pain

  • liver dysfunction

  • sometimes, acute liver failure

Pathology

• thrombi in large hepatic veins

• hemorrhage along the central veins

• liver necrosis

• may evolve into cirrhosis

Grossly

• thrombosed hepatic vein

Histology

• you see bleeding into the space of Disse, the sinusoidal plates

• you also see sinusoidal congestion

Pathogenesis

• most commonly, hypercoagulable states: polycythemia vera, factor V Leiden, oral contraceptives, pregnancy, systemic malignancy

• stasis or mass lesions and vascular injuries, much like Virchow’s triad

• localized abnormal dilatation of a blood vessel or the wall of the heart

• true vs false aneurysms

  • true involves all layers of the artery

  • false involves few layers but then blood goes out into extravascular connective tissue

• sacular vs fusiform aneurysms

  • fusiform looks like a spindle

  • saccule just billows out on one side

• abdominal aorta is most common site for aortic aneurysm

CT scan

• aorta shouldn’t be that big

• white is blood, but there is a thrombus around it

Grossly

• most common site: infrarenal aorta—above the iliacs

• when you open the aortas up, they are packed in with thrombus

Pathology

• destruction and thinning of aortic media

• atheromatous changes

• usually, large thrombus

Pathogennesis

• atherosclerosis and hypertension

• genetic factors (“this is sort of disturbing because my uncle had one”)

• imbalance in collagen degradation and synthesis, related to inflammation

Clinical features

• rupture: massive, often fatal hemorrhage

• obstruction of branch vessel—ischemia

• impingement of adjacent structures

Risk of rupture increases with size

• <>

• 5 cm or above: 11% per year, which is when vascular surgeons intervene

• Laplace’s law: at constant pressure, surface tension is directly related to radius, so if the blood pushes the wall out a bit, then the surface tension increases, weakening the wall; then the blood pushes the wall out a little bit more, and surface tension goes up and the wall gets even weaker, and eventually the wall rips open

Treatment

• open surgery

• endovascular stents

• treat before rupture. after rupture, mortality is 50%

• most common cerebral aneurysm

• most often occur around the circle of Willis, particularly at bifurcations

• 20-30% have multiple

Angiogram and photo

• looks like a white raspberry

Complications

• rupture and subarachnoid hemorrhage, aka “worst headache of my life”

• risk of rupture is 1.3% per year, higher with larger aneurysms

• mortality: 25-50% die after first aneurysm

Pathogenesis

• not fully understood, but does have to do with nonlaminar flow around arterial branchings

• strongly associated with polycystic kidney disease

• dissection is an intimal tear with hemorrhage into the wall of the vessel

• most often occurs in the thoracic aorta

• two main groups at risk

  • hypertensive men, 40-60 years old

  • people with connective tissue disorders (e.g. Marfan syndrome)

• hypertension is present in 94% of cases

• technically a type of false aneurysm

Grossly

• there is a little transverse tear spreading from the aortic valve

• another specimen: carotid has blood accumulating in the media and compressing the lumen

Sequence of events

• intimal tear

• hemorrhage into aortic media

• extension of hemorrhage

• rupture

Histology

• hemorrhage dissecting along lengthwise

• vessel with hemorrhage into the media

Pathogenesis

• clearly related to hypertension

• cystic medial degeneration (CMD)

  • elastic fragmentation of media

  • cystic faces are filled with amorphous proteoglycan material

• CMD is not seen in all cases of dissection and CMD is pretty commonly seen without dissection

Histological stains

• elastic stain: normal aorta: parallel fibers

• elastic stain: cystic medial degeneration: a little degeneration, a little cystic space

• mucin stain: the orifice in the elastic material really lights up

Clinical course

• classically described as abrupt onset of tearing chest pain radiating to the back

• most common cause of death is rupture

• dissection to the aortic root can cause cardiac tamponade, aortic insufficiency, MI

Classification schemes

• Stanford type A and B: ascending aortic involvement vs. descending aortic involvement

• or, Debakey I, II, III; DeBakey I is the most common (60% cases)

• Stanford A (DeBakey I and II) are more common and more dangerous; require surgery

• previously almost uniformly fatal, better now

• require immediate antihypertensives

• syphilitic aneurysm

• manifestation of 3^o syphilis

• thoracic aorta, arch

• caused by obliterative endarteritis in vasa vasorum

Grossly

• dilation of the aortic root

• ding-dong: looks like tree bark from continual scarring and healing

Histology

• wall is invaded by inflammatory cells

• micrograph of spirochetes

Pathology

• gross: massive dilatation of aorta and tree-barking

• micro: vasa vasorum are surrounded by inflammatory cells

Clinical features

• pretty rare in the US today because syphilis doesn’t often get to the tertiary stage

• involvement of the aortic root causes aortic insufficiency

• large size leads to respiratory and swallowing difficulties, cough, and pain

• usually bacterial, not fungal, in origin, as we would have guessed from the name

• occur in patients with endocarditis and sepsis

• usually occur at an arterial bifurcation after a bacterial embolus has lodged

• Salmonella is commonly isolated from the lesion

• have facilitated treatment of end-stage disease by allografts

• have rescued patients who have autoimmune and inflammatory diseases

• have side effects and limitations that provide the impetus for continued drug discovery

• Pharmacology

  • oral or IV

  • binds extensively to serum albumin, so increased bioavailability with low serum albumin

• Mechanisms of action

  • binds glucocorticoid receptor and regulates transcription of a multitude of genes for the initiation, implementation of immune responses

  • glucocorticoids enhance IκB expression (i.e., decrease NF-κB); impairs expression of a number of cytokines (decreases IL-1, 2, 3, 6, TNFα, IFN-γ)

  • lympholytic; causes redistribution of lymphocytes into nodes; decreases activation of cytotoxic T lymphocytes (CTLs)

• Common side effects, which generally are associated with high doses of systemic glucocorticoids and not inhaled agents
  

  • hypertension

  • glucose intolerance

  • dyslipidemia

  • osteoporosis; avascular necrosis of femoral head

  • decreased wound healing

  • cataracts

  • enhanced risk of infection; decreased signs of infection. “patients smile all the way to the morgue”

• we use it early, at the time of transplantation; it is a mainstay of treatment for autoimmune diseases and a variety of inflammatory diseases

• Tolypocladium inflatum: Sandos (now Novartis) told employees to bring plastic bags and collect soil samples while on vacation so that they could test it for compounds that had antibiotic activity

• soil collected from Hardanger Vidda, Norway, grew fungi. these fungi produced cyclosporine

• it was tested for antibiotic activity and found to have none; it was almost thrown away when someone from the new drug development unit decided to screen it as a new drug because it had a novel structure

• the immunosuppressive assay was positive

  • inject sheep RBC into mice

  • concurrently inject cyclosporine and look at mice antibody response. cyclosporine inhibited anti-sheep-RBC antibody production in mice

  • nothing bad happened if you injected the animals only cyclosporine and not sheep RBCs

  • however, the animals that they injected developed renal insufficiency

• Cyclosporine

  • lipid-soluble, variable absorption; microemulsion is more predictable

• Tacrolimus (FK506)

  • macrolide; well-absorbed

  • came from a bag of dirt from Mt. Tsukuba

• Mechanism of action

  • cyclosporine/tacrolimus bind to cyclophilin/FKBP, impairing ability to activate calcineurin

  • NFAT (nuclear factor of activated T cells) doesn’t get dephosphorylated, so it does not go into the nucleus to upregulate transcription

  • this is easy to use with transplantation because you know when the patient’s immune response will be turned on. it will be turned on after you transplant the graft. it is harder to use in chronic inflammation because when you intervene, the immune response is already turned on

  • markedly diminishes IL-2 production

  • augments TGF-β

• Uses

  • cyclosporine: 1980s

  • Tacrolimus: 1994

  • solid-organ transplants

  • not typically used together because of their similar mechanisms of action

• Side effects
  

  • both drugs demonstrate dose-dependent nephrotoxicity, hypertension, dyslipidemia (also caused by prednisone), glucose intolerance (also caused by prednisone), hirsutism/hyperplasia of gums

  • with tacrolimus, hirsutism/gum hyperplasia is less common and diabetes is more common

• Nephrotoxicity of calcineurin inhibitors
  

  • after 72 months, 25% of intestinal allograft recipients have chronic renal failure

  • in someone with a heart-lung transplant, you have to keep their immunosuppression very high because it can be their only hope. you can be more cavalier in kidney transplants because there is anyway always the option of dialysis

• Drug interactions
  

  • they are metabolized by CYP3A system

  • drug inhibiting this enzyme augment blood concentrations of calcineurin inhibitor

    • Ca channel blockers

    • ketoconazole

    • erythromicin

    • HIV-protease inhibitors

    • glucocorticoids

    • grapefruit juice

  • drugs inducing CYP3A can decrease blood concentrations

    • nafcillin

    • rifampin

    • phenobarbital

• at the time of transplantation

  • use some combination of immunosuppressive drugs with antilymphocyte treatment (monoclonal or polyclonal Ab)

• maintenance immunosuppression

  • glucocorticoids, calcineurin inhibitor, antimetabolite

  • sirolimus used to limit exposure to nephrotoxic calcineurin inhibitors

• treatment of rejection

  • tailored to the organ transplanted

• important for induction (at the time of allograft) as well as for acute rejection episodes

• they are not chronically used for outpatient

• “what does it sound like on the podcast when you swallow?”

• antithymocyte globulin

  • mix of antibodies of many specificities

  • targets are CD2, 3, 4, 8, 11a, 25, 44, 45, etc.

  • used in induction/rejection

• anti-CD3 monoclonal antibody

  • directed against epsilon chain of CD3; leads to receptor internalization and cell death/marginalization

  • therapy is limited because it is a mouse monoclonal antibody and humans mount an immune response against the drug

  • cytokine release syndrome leads to very sick patients (hypotension, pulmonary edema)

• anti-IL-2-receptor antibodies (anti-CD25)

  • targets α chain of IL-2 receptor

  • used for induction as well as rejection

• azathioprine
  

  • has been used for longer than the other antiproliferative agents—40, 50 years

  • mercaptopurine analog; inhibits purine synthesis and decreases cell proliferation

  • formerly used in conjunction with prednisone for solid organ transplants; also used for rheumatoid arthritis

  • no longer a first-line drug for organ transplants

  • major side effect = bone marrow suppression (white cells > red cells > platelets)

• Mycophenolate mofetil
  

  • newer drug; is a prodrug

  • metabolized to mycophenolic acid, the active drug

  • inhibits inosine monophosphate dehydrogenase, part of guanine nucleotide synthesis

  • in B and T cells, there is no salvage pathway for guanine nucleotides. this is why mcophenolate mofetil is relatively selective as an immunosuppressive

  • decreases lymphocyte proliferation

  • used to prevent organ transplant rejection in conjunction with glucocorticoids and calcineurin inhibitors

  • cardinal side effects: diarrhea, bone marrow suppression

• Sirolimus

  • isolated from a handful of dirt from Easter Island

  • binds to FKBP-12; blocks mTOR (mammalian target of rapamycin), a kinase that promotes the cell cycle

  • this blocks the effects of IL-2

  • so you can use it in conjunction with calcineurin inhibitors as a double-whammy against lymphocytes

  • also, spares the side effects of calcineurin inhibitors, including nephrotoxicity

  • cardinal side effect = bone marrow suppression

• nephrotoxicity is part of the risk-benefit ratio for calcineurin inhibitors

• there is a long list of long-term risks of malignancies—cervical cell carcinoma; squamous cell carcinoma of the skin in both genders

• availability of alternate therapies. dialysis is an option for patients with chronic renal failure, but there is no similar option for heart or liver transplant patients

• clinical experience helps to guide decisions re intensification vs. taper of drug therapy

Other uses of these agents

• autoimmune disease

  • drugs: cyclosporine, azathioprine, glucocorticoids

  • diseases: rheumatoid arthritis, multiple sclerosis, type 1 diabetes, autoimmune kidney diseases

• inflammatory diseases

  • drugs: glucocorticoids

Inhibition of factors that stimulate T cell growth—inhibits IL-2 production, increases TGF-β production

You should at least know the general class of a chemotherapeutic agent, you don’t need to memorize the mechanisms of action.

Alkylating Agents: include Nitrogen mustard derivatives

Antimetabolites: (massive side effects; loss of hair, loss of weight)

Methotrexate (MTX) – not only an anti cancer drug (interferes with metabolism of cancer cells) but suppresses immune system, so is given in autoimmune disease. Low doses still pose a problem, especially when treating dental pain

Fluorouracil (5-FU)

Antibiotics:

Doxorubicin (Adriamycin) is the only one consistently used

Hormonal Agents:

Tamoxifen – acts on the estrogen receptor of the breast

Flutamine – acts on the prostate

Prednisone – not a hormone, the hormone circulating in the body is hydrocortisone, from the adrenal cortex.. Prednisone has immunosuppressant activities and is widely used.

Plant Alkaloids: very powerful agents

Vincristine

Taxol (paclitaxel) – derived from special tree bark

The oral complications of chemotherapy depend upon the drugs used, the dosages, the degree of dental disease, and adjuvant radiation therapy.

Before Chemotherapy:

-conduct pretreatment oral health exam

-schedule dental tx in consultation with oncologist

-schedule oral surgery 7-10 days before pt becomes myelosuppressed (suppression of the bone marrow)

-in pts with hematologic cancers (i.e., leukemia), consult the oncologist before conducting any oral procedures; do not conduct procedures in pts who are immunosuppressed or have thrombocytopenia.

During Chemotherapy

-consult oncologist prior to any dental procedure, including prophylaxis

-ask oncologist to torder blood work 24 hours before oral surgery or other invasive procedures. Postpone them when: 1.) platelet count < 50,000/ mm3 or abnormal clotting factors are present, 2.) neutrophil count is less than 1,000/ mm3

-in pts with fever of unknown origin, check for oral source of viral, bacterial, or fungal infection

-encourage consistent oral hygiene measures

-consult oncologist about implementing the AHA endocarditis prophylactic AB regimen in pts with indwelling central venous catheters before any invasive or prophylactic dental procedures.

Mucositis/ stomatitis: culture lesions to identify secondary infection. Prescribe topical anesthetics and systemic analgesics. Consult oncologist about prescribing antimicrobial for known infections. Have pt aboid rough-textured foods and report oral problems early.

Xerostomia/ salivary gland dysfunction: advise pt to soften or thin foods with liquid, chew sugarless gum, or suck ice chips or sugar-free hard candies. Suggest using commercial saliva substitutes or prescribe saliva stimulant drugs

Taste changes: refer to dietician, but generally speaking its just something that the pt will have to get used to.

Etched enamel: to protect enamel, advise pt to rinse mouth with water and baking soda solution after vomiting.

Dental demineralization: instruct pt in daily application of fluoride gel.

Complications Specific to Chemotherapy

Neurotoxicity: provide analgesics or systemic pain relief

Bleeding: advise pt to clean teeth thoroughly with a toothbrush softened in warm water. Instruct pt to avoid flossing the areas that are bleeding but to keep flossing the other teeth.

Severe dental problems should be tx’d and corrected before chemotherapy or radiation is started, if possible. During cancer tx, dental/oral tx is palliative (not going to reverse the disease, just manage the condition). Dental hygiene is crucial, include fluoride treatment. If dental tx is needed, avoid subgingival scaling. Be aware of emergence of new or recurrence of oral cancer.

Most common problems are bleeding gums, oral ulcerations, xerostomia, mucositis. Manage with:

Oral pain secondary to oral lesions: 5% viscous Lidocaine

Oral Fungal Infections: Nystatin, Mycelex troches (0.12% chlorhexidine rinses also recommended)

Mucositis: oral rinses; Triamcinolone, Sucralfate (Carafate – mucosal barrier, protects from acid attacks. Has iron and sugar base and can be used as a mouth rinse.

Systemic Infections: 22% of leukemia pts develop infection

Cancer Pain: most pts already on potent analgesics (oxycontin was over Rx’d as once a day sustained release, but began to be diverted. If oxycontin is prescribed now it’s a red flag to the FDA/ DEA… Remember, you can always use Tramadol (Ultram)!!! )

Xerostomia: orabase, artifical saliva, pilocarpine (muscarinic agonist… systemic effects)

Mucositis, Oral lesions, Oral mucosal inflammation…

Prescribe mouth rinses using sucralfate (Carafate). This drug is approved as an anti-ulcer agent (Gastric- Duodenal). It does not act systemically. It provides a chemical mucosal barrier allowing tissues (mucosa) to heal. It is a sugar- aluminum complex molecule. There are no contraindications for its use. The drug is available as a solution-suspension. Contains 1.0 g/ 10 mL (dissolved in glycerin, methylcellulose, water, simethacone).

Remember: If the pt swallows the rinse, aluminum ions in the gut may chelate with certain medications (eg, tetracyclines, ciprofloxin, etc.) administered concurrently. Advise the pt to avoid swallowing the rinse.

It is recognized that estrogens play a key role in initiating and maintaining breast cancer development in susceptible women. These women should aboid estrogen containing meds. At tx modality is to block the estrogen receptors with oral administration of the agent Tamoxifen (Tamofen, Tamone). This agent inhibits cell division by binding to the intracellular estrogen receptor, with the net effect that DNA synthesis is impaired. Used only in documented estrogen-dependent breast cancer.

Oral manifestations: Dysgeusia; variable effect on oral mucosa

Systemic problems: Blood dyscrasia (leukopenia, thrombocytopenia)

Potential concerns associated with long-term Tamoxifen

Premenopausal pts: Teratogenesis, Ovarian stimulation

Pre- and post-menopausal pts

1.) Antiestrogenic effects: Osteoporosis, Atherosclerosis

2.) Estrogenic effects: Endometrial carcinoma, Thromboembolic disorders,

Hepatocellular carcinoma

3.) Ophthalmic changes

Prostate Cancer Therapy (Hormonal Agents)

Estrogenic agents (studies at USC using these drugs resulted in feminization – not tolerated well by male pts… surprise!): Conjugated estrogens (Premarin); Dietrhylstilbesterol (DES); Ehthinyl estradiol

Antiandrogens (androgen receptor antagonists): Futamine (Eulexin, hepatic injury); Bicalutamide (Casodex, 2-5% incidence of dry mouth, dysphagia, periodontal abscess)

Tissue Effect

Bone Marrow Leukopenia and resulting infections, Immunosuppression,

Thrombocytopenia, Anemia

GI Tract Oral or intestinal ulceration, diarrhea

Hair follicles Alopecia (hair loss)

Gonads Menstrual irregularities including premature menarche, impaired

Spermatogenesis

Wounds Impaired healing

Fetus Teratogenesis (especially during first trimester)

Very effective, largely developed to give chemotherapeutics a way to manage nausea associated with chemotherapy. May be Rx’d for pts who are refractory to or have severe adverse rxns to std antiemetic tx. Ondansetron may be rx’d for young pts(<45yo who are more likely to develop extrapyramidal rxns to high-dose metoclopramide) who are to receive h ighly emetogenic chemotherapeutic agents.

Baby Oragel: active ingredient = 7.5% benzocaine (with glycerin, polyethylene glycol, purified water, sodium saccharin, sorbic acid, sorbitol)

Maximum strength Oragel: active ingredients = 20% benzocaine and clove oil (active ingredient of eugenol) (with polyethylene glycols, sodium saccharin, sorbic acid, “may contain citric acid”)

Oragel Mouth-Aid: 20% benzocaine, benzalkonium chloride 0.02%, zinc chloride 0.1%, Allantoin, EDTA, Polyethylene glycol, Povidone.

Fast Facts:

• Introduced in 1950, hepatotoxicity recognized in 1966
• Accounts for more overdoses and overdose-related deaths than any other drug. (~23%)
• Most common cause of acute liver failure in alcoholics
• Generally good outcome if N-acetyl cysteine is given

Effects and mechanism:

Has analgesic and antipyretic (fever-reducing) effects. The mechanism is not really known but it acts centrally to inhibit prostaglandin synthesis. Some theories say it might inhibit a third version of cyclo-oxygenase (COX-3) but that has not been proven. Its antipyretic effects are a result of its effect on the temperature regulating region of the hypothalamus.

Toxicity!

Normally, 90% of acetaminophen is conjugated to sulfate or glucuronide. This conjugate is then excreted in urine. 5% is excreted unchanged the remaining 5% is metabolized by the p450 to NAPQI. NAPQI is hepatotoxic (oxidative injury and necrosis) and is conjugated to glutathione and excreted.

Excess NAPQI occurs for these reasons:

• Excess acetaminophen intake overloads livers ability to conjugate to sulfate or glucuronide

• Decreased ability to glucuonidate or sulfate

• Induction of p450 enzymes (Occurs in chronic alcoholism)

• Depletion stores of glutathione (Chronic alcoholism)

Hepatic injury is caused mainly when glutathione stores are depleted by 70%. To eliminate NAPQI, N-acetyl-cysteine is given which is a precursor to glutathione. With this new glutathione the NAPQI can be excreted.

Note: Acute alcohol intoxication may actually have a slight protective effect by the competition of alcohol for p450 enzymes

• it is something that happens at different rates in different organs

• heart attacks, Alzheimer’s disease are both consequences of senescence

• sometimes senescence is abnormally accelerated: some people have progeria and die of old age when they are 16 or 20

• a lot of cell division is normal

• your bone marrow divides a lot every day; you make about 10 pounds of WBCs every year

• in retrospect, leukemia is a very rare disease, afflicting 1 in 5000 children. this is very low considering how much division occurs in bone marrow

• similarly, you redo your epidermis every two weeks—when you vacuum, you are vacuuming up your dead skin cells

• you shed 70 pounds of GI epithelium a year

• the female breast is an example of something that goes from milligrams of epithelial cells to grams of epithelial cells during puberty; in pregnancy, this goes up even more and undergoes differentiation

• after pregnancy and after nursing has stopped, breast tissue involutes and those cells go away

• so there are normal cycles of proliferation, differentiation, and regression

Differentiation

• there is a lot of differentiation in a developing fetus, for example

• a female breast starts with ducts only and develops lobules at puberty

• a male breast starts with ducts only and never develops lobules, not even in gynecomastia

• one of the most important environmental changes that causes cell injury is lack of oxygen

• heart attacks are the number one cause of death in this society and they are caused by lack of oxygen supply to the myocardium

• lack of oxygen will ultimately cause cell injury because the cell can’t produce ATP anymore

• normally, in oxidative phosphorylation, you make about 30 ATPs per glucose molecule. when you cut that off, you get two ATPs, a reduction in energy production by a factor of 15

• so, cutting off oxygen leads to a big decrease in ATP production

• on the other hand, if injury is mediated by radiation, chemicals (including drugs), or reperfusion, many activated oxygen species are created (O₂⁺, H₂O₂, OH^.)

• ischemia is important for heart attacks and strokes; activated oxygen species are important in a variety of inflammatory diseases

• when a cell is injured (alcohol, starvation, radiation, viral infection, autoimmunity), cell function (which can be measured biochemically) decreases rapidly

• as function decreases, cell death or adaptation occurs

• the rate of loss of ability to grow (i.e., the rate of death) occurs faster than any other changes

• after a cell has died, you see ultrastructural changes (nuclear chromatin, lysosomes, polyribosomes)

• then, you see light microscopic changes

• so when a cell is dead, you won’t see any evidence with light microscopy until about six hours after death

• gross morphologic changes occur only, say, after two days

• hypertrophy means increase in size

• hyperplasia means increase in cell number

• this can be confusing because a common disease that aging men get is prostatic hypertrophy

• example of cellular hyperplasia

  • prostatic hypertrophy (an increase in the size of the organ) is caused by hyperplasia (increase in the number of prostate cells)

• pure examples of cellular hypertrophy (of which, he implied, there are only two)

  • if you take steroids, you get hypertrophy of muscle due to hypertrophy of muscle cells

  • adipose tissue gets bigger because the cells get bigger because more fat is stored in each adipocyte. when you gain weight, adipocytes get bigger, and when you lose weight, adipocytes get smaller

• more examples: if we all move to Cusco, we will get hyperplasia of bone marrow that will lead to increased production of RBCs that will ultimately help us get enough oxygen. this is mediated by cytokines

• if you take erythropoietin, hematocrit is increased via hyperplasia of bone marrow

• lymph nodes get big because of hyperplasia—immune cells proliferate. they also trap cells, which is neither hyperplasia or hypertrophy

• cellular hyperplasia: the prostate gets bigger under the influence of androgens; the breast gets bigger under the influence of estrogens

• involution, e.g. a female breast post pregnancy: hyperplastic glandular cells undergo apoptosis and lobules shrink back down. cells are gobbled up by macrophages

Hypertrophic ventricle

• increase in size of muscle cells leads to thickening of heart chamber walls

• oxygen can’t diffuse as easily as the walls get bigger; this ischemia eventually leads to irreversible fibrosis

• so don’t let your patients have high blood pressure…there are many good medications to treat it

Normal-sized vs. pregnant uterus

• look at the difference between the distance between nuclei. a large uterus is due to hypertrophy of uterine smooth muscle cells, a fact we conclude because the nuclei are so much farther apart

• this also involutes after delivery

Epithelium

• normal ciliated columnar epithelial cells are depicted (normally found in cervix, lung)

• due to a variety of injuries, these cells may undergo metaplasia, meaning that they change to a different differentiated form; hyperplasia can also occur

• density of nuclei increases as hyperplasia proceeds, and indeed the nuclear-to-cytoplasmic ratio has increased as hyperplasia progresses

• so the normal epithelium which has cilia and makes mucus turns into an epithelium which is pretty much just dividing

• eventually these cells look flat, like epidermis; this is squamous metaplasia

• so now this is both hyperplasia and metaplasia at the same time

• the most common cause of squamous metaplasia and hyperplasia is cigarette smoking

• then, you notice that the cells don’t flatten off at the top anymore like squamous cells should. all the nuclei look the same, and this is called dysplasia

• meta- refers to a change, dys- means something’s wrong with it

• then you see carcinoma in situ. this is a malignant proliferation that hasn’t invaded through the basement membrane

• this happens to cigarette smokers over the course of years

Brains and atrophy

• normal brain has thinner sulci and thicker gyri than the atrophied brain

• metaplasia: change from one differentiated form to another

  • bronchial epithelium can undergo squamous metaplasia after exposure to polycyclic hydrocarbons

  • esophageal epithelium can undergo glandular metaplasia (Barrett’s esophagus), a consequence of acid reflux

  • cervical epithelium can undergo squamous metaplasia; this is due to papilloma viruses

  • the third way to get squamous cancer is via radiation from the sun

  • so squamous cancers don’t tell you how the cells got there

• dysplasia: change to an abnormal differentiated form

• anaplasia: loss of differentiation. neoplasia: new growth (usually sloppily used to mean “cancer”)

• aplasia: failure to develop normal tissue

  • often, hypoplasia is incorrectly termed aplasia. aplastic anemia is more precisely hypoplastic anemia, not completely aplastic anemia

  • lots of cancer drugs that we give people lead to bone marrow hypoplasia. many people who undergo chemotherapy die of bleeding, infection, or anemia

  • lymphoid tissue can undergo aplasia (SCID, drugs)

  • a hypoplastic left ventricle is one of the most common congenital abnormalities that you will see in the neonatal nursery

• necrosis: death of tissue due to a disease process

  • distinguish this from apoptosis, which is not necessarily due to a disease process

  • infarction: death due to lack of blood supply, as in myocardial infarction, stroke (cerebral infarction), renal infarction, bone infarction

• cellular inclusions

  • these indicate that a cell has been damaged somehow

  • fatty change is most commonly seen in this society as a consequence of alcoholic liver disease. increased production of lipids and decreased secretion of lipids leads to this fatty change

  • metabolic products: hemochromatosis or hemosiderosis leads to excess uptake of iron by cells. lipofuscin is a general wear-and-tear pigment seen with age

• this person had thickened ventricle walls

• the white scarred tissues are remnants of old myocardial infarctions

• the new, yellower tissue is a recent result of degradation of dead myocardial cells. substances from inside these dead cells leak out and blood tests can reveal that the person has had a MI

• fatty change is one of the common changes that causes cells to increase what they have in them

• Wilson’s disease is a disease where you synthesize a copper transport protein but you can’t get it out; it fills up the Golgi apparatus and it just sits there. there are a whole bunch of diseases like this (gene to make protein is there but gene to make the transporter isn’t there)

• Tay-Sachs disease: liposomal storage disease due to lack of enzyme

• iron overload: exogenous material accumulates in cells

Fatty liver

• too much fatty acid synthesis occurs and not enough export of lipoproteins happens

• you can also see alcoholic hyalin, a condensation of proteins in dying cells

• the two together are almost pathognomonic of alcoholic liver disease

Hemosiderosis

• iron on H&E stain looks like brown granules

• on Prussian blue stain, it turns blue

• so these cells have accumulated iron

Lipofuscin

• a collection of yellowish stuff in cells, staining black in the bottom images

• we’ll see this in the laboratory

Alcoholic hyalin

• normally, from the preparation process, lipids turn into empty space; hepatocytes containing a lot of lipids therefore look mostly empty under light microscopy

• in this cell, there isn’t complete empty space, rather, there is cloudy swelling, which is illustrative of cells that have lost their ability to pump ions and water out of the cell

• this is a nonspecific form of cell injury

• so, a lot of these things can happen all at once

Microorganism-induced changes

• these changes are an inflammatory response to an infection or to some toxin that you can’t get rid of

• cells undergo a form of necrosis termed caseous (cheesy) necrosis

Sickle-cell disease

• hypoxic changes lead to deformation of red blood cells; this is ultimately a consequence of an amino acid mutation

• Hypoxia, ischemia

  • brain; heart: atherosclerosis, a process that advances as you get older

• Nutrition

  • too little (developing countries) or too much (developed countries)

• Genetic disease

  • sickle-cell disease, the molecular basis of which was defined when Dr. Baird was in medical school

  • Tay-Sachs, for which screening can now be performed

  • Gaucher’s disease, of which there are three different forms

Ischemic changes in cells

• Ca leaks into cells, uncoupling ox phos and causing further damage

• you basically need to know it at the level of this diagram, which is found in the book

• leukocyte recruitment further damages cells because leukocytes excrete hyperactive oxygen radicals

• Physical agents

  • heat

  • cold

  • bullets

  • sports

• Infections agents

  • viruses

  • bacteria

  • fungi

  • prions, which are alternative folding patterns of proteins

• Autoimmunity

  • antibodies

    • autoimmune hemolytic anemia

    • erythroblastosis fetalis: Rh antigen and maternal anti-Rh, anti-fetus antibodies

    • lupus erythematosus: antibodies against DNA; potential exposure was in bone marrow (10% of RBCs are defective and are turned over; nuclear material leaks out)

  • T cells

    • involved in graft rejection

    • also play a role in polio, where most of the destruction of neurons is via the polio virus; however, if T cells are turned on, they kill the virus-producing factories—namely, the neurons, which can’t regenerate

    • hepatitis B: hepatocytes are destroyed

• coagulative necrosis: cell outlines survive for several days. you can see the cell progres from a normal healthy cell to a sickle-cell-appearing cell (infarcts in heart, liver)

• caseous necrosis: seen in granulomas

• liquefactive necrosis: characteristic of brain and pancreas, the latter of which makes digestive enzymes

• germ cells stay relatively young forever

• however, babies’ eggs do age, and sperm do age, but not quite as fast as eggs

• bone marrow stem cell can make all the blood cells plus bone marrow stromal cells, but they can’t make heart cells. however, if you tickle a committed skin cell with genes, it can start making blood cells

• you gradually use up all your stem cells, which is why Dr. Baird has 40% cellularity and we have 70%

• the best source of any type of stem cell is still a fetal stem cell because they, although not immortal, are still very young

• normal cells are fully differentiated and they die and are replenished by stem cells

• note that some organs (skin, bone marrow, pancreas) replenish their own cells via division of committed stem cells

• most cancers come from committed stem cells of the organ in question, not from normal, differentiated cells

• this is a type of cell death associated with metabolism of DNA and the cell in a certain way

• the result is nice packages that macrophages can eat

• necrosis is just a cell going “blphhhhhh,” leaving crap all over the place

• in your thymus, you make cells that potentially have autoimmune capability. these inappropriate T cells die via apoptosis

• there are many distincctions between coagulation necrosis and apoptosis

• in apoptosis, DNA is broken up into specific lengths

• in necrosis, the DNA of the cell is one smear upon electrophoresis, meaning there is no specificity to the degradation of cell DNA

• RBC = 120 days

• Neutrophils = 6-12 hours (longer in marginated pool)

• Platelets = 7-10 days

• Stem cell factors (c-kit ligand, flt3-ligand) – stimulate production of pluripotent stem cells

• EPO (erythropoietin)

  • Made by kidneys and liver

  • Stimulates erythropoiesis and megakaryocytopoiesis (problems with EPO will be manifested as RBC and platelet changes)

• GM-CSF (granulocyte/monocyte colony stimulating factor)

  • Made by T cells and stimulated by fibroblasts, monocytes, and endothelial cells

  • Stimulates formation of granulocytes and monocytes from G/M-CFU

• Interleukins

  • Hematopoietic cofactors from monocytes, lymphocytes, fibroblasts, and endothelial cells

  • IL-3 stimulates CFU-S (the myeloid stem cell)

  • IL-5 stimulates CFU-Eo (eosinophil stem cells)

• Thrombopoietin – regulates megakaryocytopoiesis

• The volume of hematopoietic cells is expressed as a percentage, which can be roughly figured by [(100-age) ⁺/_- 10]%

• The myeloid to erythroid ratio should normally be about 1.5-3:1

• Storage iron (hemosiderin)

  • Stored in 30-40% of RBC precursors (called sideroblasts)

  • Present in macrophages

• Anatomy

  • Bony trabeculae

  • Network of thin-walled sinusoids lined by endothelial cells, through which differentiated cells enter the blood stream

  • Clusters of fat cells (yellow marrow) and hematopoietic cells (red marrow) are supported by a reticulin meshwork (red marrow is everywhere in a newborn’s skeleton, but is only found in the axial skeleton of adults)

  • The release of mature blood cells into the bloodstream is regulated by endothelial cells lining the marrow sinusoids (this isn’t found in extramedullary hematopoiesis, so immature cells will be found in the peripheral blood if that is going on)

• Morphology

  • There should be progressive maturation of all blood cell lines

  • Non-hematopoietic bone marrow elements

    • Osteoblasts – look like plasma cells, but plasma cells don’t have nuclei, granular pink cytoplasm, or line up next to the trabeculae

    • Osteoclasts – multinucleated (that’s how you can tell them from megakaryocytes)

• Intravascular

  • From normal RBCs being damaged by mechanical injury, complement fixation, or exogenous toxins

  • See anemia, jaundice, increased LDH, decreased serum haptoglobin (which binds up the toxic free Hb…decreased serum haptoglobin is pretty specific for anemia), hemoglobinemia, hemoglobinuria, and hemosiderinuria

  • Free Hb and metHb will be seen in serum and urine when haptoglobin is depleted

• Extravascular

  • Occurs when RBCs are rendered “foreign” or become less deformable

  • RBC destruction occurs in the mononuclear phagocyte system (mostly spleen, some liver)

  • See anemia, jaundice, increased LDH, and normal to mildly decreased serum haptoglobin (since hemolysis is occurring outside of circulation, free Hb is not released in great amounts)

  • Hemoglobinemia or hemoglobinuria are absent or minimal

  • Splenomegaly may occur due to hypertrophy of the RES

• RBC count – normally 4.1 – 5.3 X 10⁶ per mm³

• Hb – normally 12.0 – 17.5 ^g/_dL

• HCT

  • Normally 36 – 53

  • May be measured directly (“spun crit”) or calculated (MCV X RBC ÷ 10)

• Mean corpuscular volume

  • This is the average size of the RBCs (normal = 80 – 100)

  • Microcytic = decreased MCV

  • Normocytic = normal MCV

  • Macrocytic = increased MCV

• Mean corpuscular Hb – normal = 26 – 34

• Mean corpuscular [Hb]

  • MCHC = (Hb ÷ HCT) X 100 (normal = 30 – 36

  • Hypochromic = decreased MCHC

  • Normochromic = normal MCHC

  • Hyperchromic = artifactual

• RBC distribution width – variation in RBC size (i.e., anisocytosis)

• The rule of 3’s

  • RBC X 3 = Hb ± 3

  • Hb X 3 = HCT ± 3

• Hereditary spherocytosis

  • Most frequent; due to decreased RBC deformability due to abnormalities of the cytoskeletal protein spectrin (and/or ankyrin)

  • AD inheritance in 75% of cases; AR inheritance associated with more severe disease (may come from a spontaneous mutation, so don’t rely on family history)

  • C/S: jaundice, splenomegaly, pigment gallstone formation, and mild to moderate chronic hemolysis which may be worsened by infection, resulting in a hemolytic or aplastic crisis

  • May be confirmed with an osmotic fragility test (lysis in hypotonic saline), but this is not specific…the diagnosis is one of exclusion

  • Splenectomy may be beneficial if hemolysis is severe

• Hereditary elliptocytosis – similar to spherocytosis and is also due to an abnormal RBC structural protein

• Rare and acquired

• Unknown etiology; comes from a somatic mutation of affecting a pluripotent stem cell

• RBCs, granulocytes, and platelets are very sensitive to complement-mediated lysis due to a lack of 3 normal membrane proteins: decay accelerating factor (CD55), membrane inhibitor of reactive lysis (CD59) and a C8-binding protein; hemolysis may worsen at night

• Chronic hemosiderinuria may lead to iron deficiency

• Nonlytic complement interactions with granulocyte and platelet membranes predispose to infections and thrombosis (especially in the hepatic, portal, and cerebral veins)

• There is an increased risk for aplastic anemia and acute leukemia because this is a stem cell d/o

• Diagnosis can be suggested by a (+) sucrose hemolysis test and confirmed by performing an acidified serum test (Ham’s test) – flow cytometry of WBC and RBC levels of CD55 and CD59 is currently the gold standard

• Median survival is 10 years