Pathology Revision

 

SEC TI ON I I

Pathology “The “T he begini gi ning ng of he health alth is to know the disease. ” ––S ––Spa panish Prove Proverb rb

Questions dealing with this discipline are difficult to prepare for because of sheer volume of material. Review the basic principles and hallmark characteristics of each key disease. Given the increasingly clinical orientation of Step 1, it is no longer enough to know the “trigger words” or key associations of certain diseases (e.g., café-aulait macules and neurofibromatosis); you must also know the clinical descriptions of these findings. With the increasingly clinical slant of the USMLE Step 1, it is also important to review the classic presenting signs and symptoms of diseases as well as their associated laboratory findings. Delve into the signs, symptoms, and pathophysiology of the major diseases having a hi hig gh pre prevalence valence in tthe he U US S ((e.g e.g.,., al alcohol coholiism, di diab abete etess, hype hyperrtension, heart failure, ischemic heart disease, infectious disease). Be prepared to think one step beyond the simple diagnosis to treatment or complication.  The examin ina atio tion in inc clud ludes a number of color lor photo tom micr icrographs and photographs of gross specimens, which are presented in the setting of a brief clinical history. However, read the question and the choices carefully before looking at the illustration, because the history will help you identify the pathologic process. Flip through your illustrated pathology textbook, color atlases, and appropriate web sites in order to look at the pictures in the days before the exam. Pay attention to potential clues such as age, sex, ethnicity, occupation, specialized lab tests, and activity.

High-Yield Clinical Vignettes High-Yield Glossy Material High-Yield Topics Congenital Neoplastic Hematologic Gastrointestinal Respiratory Neurologic Rheumatic Rhe umatic// Autoimmune Autoimmune Endocrine/ En docrine/ Reproductive Reproductive Vasc Vas cular/ Cardiac Renal Findings Photomicrographs

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PATH OLOGY— OGY—HIGH-YI HIGH-YI ELD CLINICAL CLINI CAL VIGNE VI GNETT TTES ES PATHOL

 These abstra  Thes tracted case vign ignett tte es are design igned to demonstra tratethe the tho thought processes necessary to answer multistep clinical reasoning questions. 

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Patient has multiple fractures, anemia, cranial nerve deficits → in which of the following cell types is there a defect? → osteoclasts (e.g., osteopetrosis). 35-year-ol 35-yearold d man hashi hig gh bl blood ood pressure iin n arm armssand llow ow pre presssure iin n leg legs→ what is the diagnosis?

→ coarctation of the aorta. Woman presents with diffuse goiter and hyperthyroidism → what are the expected values of   TSH and thy thyroid hormones? → low T TSH SH and hi hig gh th thyroid yroid horm hormone oness.  Patient exhibits an extended expiratory phase → what is th the e di dise sease process? → obstructive lung disease.  Woman presents with headache, visual disturbance, galactorrhea, and amenorrhea → what is the diagnosis? → prolactinoma.   Path1.37   Baby has foul-smelling stool and recurrent pulmonary infections → what is the diagnosis, and what tes test is used?→ cystic fibrosis, chloride sweat test.  Obese woman presents with hirsutism and increased levels of serum testosterone → what is the diagnosis? → polycystic ovarian syndrome.  Man presents with extensive destruction of knees, subcutaneous nodules, and exquisite pain in the metatarsophalangeal joint → biopsy shows needle-like crystals → what is the diagnosis? → gouty a arthr rthriitis tis.  48-year-old female with progressive lethargy and cold intolerance → what is the diagnosis? → hypothyroidism.   Path1.33  Patient with elevated serum cortisol levels undergoes dexamethasone suppression test. One milligram of dexamethasone does not decrease cortisol levels; 8 mg does → what is the diagnosis? si s?→ pituitary tumor.  During a game, a young basketball player collapses and dies immediately → what type of cardiac di disea sease?→ hypert rtrophi rophic c cardiomy cardiomyopa opath thy y.   Path1. 10  Child has been anemic since birth. Splenectomy would result in increased hematocrit in what disease?→ spherocytosis.  43-ye 43-year ar--ol old dm man an exp experi erience encess d diizziness a and nd ttiinni nnitus tus.. CT showsenl enlarg arged in internal ternal acou acousstic ti c meatus → what is the diagnosis? → schwannoma.

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Child exhibits weakness and enlarged calves → what is the disease, and how is it inherited? → Duchenne’s muscular dystrophy, X-linked recessive.  25-year-old female presents with sudden uniocular vision loss and slightly slurred speech. She has a his histo tory ry of we weaknes aknesss a and nd paresth paresthes esiasth that at h have ave resolved olved → what is the diagnosis? → MS MS..   Teenager presentswith nephritic itic syndrome and hearing ing los loss → what is i s his hi s dise disease?→ A lport’ lport’ss syndrome.   Tall, thin thin male teenager has abruptt-o onset dyspnea and lef left-s t-side ided chest pain. in. The Therre is hyperresonant percussion on the affected side, and breath sounds are diminished. → what is the diagnosis? → pneumothorax.   Yo  Young man is concerned about his wife ife’s ina inabilit ility y to conceive ive and her recurrent URIs URIs.. She has dextrocardia → which of her proteins is defective? → dynein (Kartagener’s). UCV

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55-year-old man who is a smoker and a heavy drinker presents with a new cough and flu-like symptoms → Gramstai tain n showsno or org gani anism sms; sil silver stai stain n of sputum shows gram ram--neg negati ative ve rods → what is the diagnosis? → Legionella. Patie Pati ent hasa stroke afte afterr iincurri ncurring ng mult ultiiple llong ong bonefractures in MVA trauma → what caused the infarct? → fat emboli. 25-year-old woman presents with a low-grade fever and a rash across her nose that gets worse when she is out in the sun → you are concerned concerned about wh what at di dise sease?→ SLE. 50-year-old man complains of diarrhea; on physical exam his face seems plethoric and a heart murmur is detected → what is the diagnosis? → carci carcinoi noid d syndrome. Elderly woman presents with a headache and jaw pain → labs show elevated ESR → what is the diagnosis? → temporal arteritis. Pregnant woman at 16 weeks of gestation presents with an atypically large abdomen → what abnormality might be seen on blood test, and what is the disorder? → high hCG; hydatidiform mole. 80-year-old man presents with a systolic crescendo-decrescendo murmur → what is the most likel kely y cause?→ aortic stenosis. Woman of short stature presents with shortened 4th and 5th metacarpals → what endocrine disorder comes to mind? → A lbrig bright ht’s ’s here heredi ditary tary os osteody teodysstrophy trophy, or pseu eudohyp dohypopa oparathyroi rathyroidi dissm. A fter fter a str tres essful life e event, vent, 30-ye 30-yea ar-ol r-old d man hasdi diarrhea arrheaand b bllood per rectum rectum;; int intes estinal ti nal biopsy shows transmural inflammation → what is the diagnosis? → Crohn’s.

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 Yo  Young man presentswith ith mental deterio iorratio ion n and tr tre emors. He has brown pigmentatio tion in a ring around the periphery of his cornea and altered LFTs → what treatment should he receive? → penicillamine for Wilson’s disease.  Patient presents with signs of vitamin B signs gns of  12 deficiency → why not give folate? → masks si neural neur al dam damag age.  10-year-old child “spaces out” in class (e.g., stops talking midsentence and then continues as if  nothing had happened). During spells, there is slight quivering of lips → what is is the the d diiagnosi nosiss?→ absence nce sei seizure. zure.

PAT PATHOL HOLOGY— OGY—HI HIGH-YI GH-YI ELD GLOS GLOSSY SY MATERI MATERIAL AL 

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Gross photograph of abdominal aorta with aneurysm → what is the most likely process? → atherosclerosis. Gross photograph of hydatidiform mole (“bunch of grapes”) → high levels of what substance are pres present ent?? → hCG. Gross photograph of focally hemorrhagic small intestine of weight lifter → what is the process responsible for this? → strangulation of a hernia. Chest x-ray shows collapse of middle lobe of right lung; recurrent pneumonia and growth in bronchus → what is the diagnosis? → bronchogenic carcinoma. Middle-aged woman with intermittent syncope has a mass removed from the right atrium → H& E showswispy, mucus-like ti tisssue→ what is the diagnosis? → myxoma. Chest x-ray shows pneumothorax → what are the clinical findings? → pleuritic chest pain. 1-year-old baby presents with big red splotch on face → what is the likely course of this lesion? → regression vs. Sturge–Weber.

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PATHOL OGY— HI HIGH-YI GH-YI ELD GLOS GLOSSY SY MATERI MATERIAL AL (Co u n t i n u e d ) PATHOLOGY—  

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Gross photograph of lung with caseous necrosis → what is the diagnosis? → TB. H& E of lung b biiopsy from plumb plumber er sshows howselon elong gate ated d sstr tructures ucturesin ttiissue (f (ferrug erruginous b bodi odies es) → what is the diagnosis? increased risk for what? → asbestosis; malignant mesothelioma. H& E of glom glome erulus → lookslike Ki Kim mmelsti tie el–Wi Willson nodu nodulles → lesion is indicative of what di diseas sease?→ di diab abete etess m mell elliitus tus.. H& E of granuloma→ what is activated? → macrophages. Softball player develops back pain and lost sensation in a dermatome of the leg → what is the diagnosis? → herniated lumbar disk. Karyotype with three 21 chromosomes → what features would patient have? → flat facies, simian crease, epicanthal folds. Gross photograph of polycystic kidneys in adult male → what is the mode of inheritance? → autosomal dominant. Patient with anemia, hypercalcemia, and bony pain on palpation; bone marrow biopsy shows lots of plasma cells → what is the diagnosis? → multiple myeloma.

PATHOL PATH OLOGY— OGY—HIGH-YI HIGH-YI ELD TOPICS

Congenital

1. Materna ternall complica pli cati tions ons of bir birth th ((e e.g .g.,., Sheehan’ han’ss synd yndrom rome e, puerpe rperal ral iinfecti nfection) on).. 2. Fail Failure ure to th thri rive: ve: co com mmon ca caus uses. 3. Causes of kerni kernicteru cteruss (hem (hemol olyti ytic c di dissease of tthe he ne newb wborn) orn).. Neoplasia

1. 2. 3. 4. 5. 6. 7. 8. 9. 10.

Bone and ca cart rtiilage tumors ((e.g e.g., os osteos teosarcom arcoma, g giiant cel celll tum tumor, or, Ewi Ewing’ ng’ss sarcoma). Clinica nicall features tures of llym ymphomas (Burki Burkitt tt’s ’sand other non-H non-Hodg odgki kin’s n’slymphomas). Ri Rissk ffa actors for com comm mon carcinom carcinoma as (e.g (e.g.,., lung, brea breasst) t).. Chemical cal ca carci rcinog noge ens (e.g (e.g.,., vinyl vinyl chl chlori oride de, n niitrosamines, aflatoxi toxin) n) and m me echa chani nissms of carcinogenesis (e.g., initiator vs. promoter). M alig gnanci nancies esassoci ociate ated dw pneum oconios oses es e.g .,las asbe sphom tos, silai)cos cosi A Iali DSDS-a associated ne neoplas oplas misth(K (Ka aposi’soconi sarcom rcoma a, (B-ce Bcel l lbes ym . is). Pi Pitui tuitary tary tumors (e.g .g.,., prolacti prolactinom noma a) and other sse ellar le lesions (e.g .g.,., cra crani niopha opharyngiom oma a). Tum Tumors ors of th the e mouth, pharynx, and larynx ((e.g e.g.,., v voca ocall cord tum tumors ors in ssm mokers okers)). Modes of sspre prea ad of ce certai rtain n cancers (e.g .g.,., trans transiitiona ti onall ce celll ca carci rcinom noma a). Clini nical cal fea features tures of lleu eukem kemias(e.g., demograp ographi hics cs,, pa path thol olog ogy y, prog prognosis). nosis).

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Nervous System

1. Hydrocephalus phalus:: types (e.g., com comm muni unicati cating, ng, obs obstruct tructiive), se seque quelae. 2. CNS manifestati tations onsof v viira rall infe i nfections ctions (e.g .g., ., H HII V, HSV HSV)). 3. Spin Spina al mu musscular atrophi trophie es (e.g., We Werdni rdnig g–Hoffm offma ann disease, AL A LS) S).. Rheumatic/Autoimmune

1. 2. 3. 4.

Trans Transplant plant re rejjection ction (hyp hype erac racute ute,, acute acute,, chronic) chronic).. Di fferencess betwee Difference between rh rheu eum matoi atoid da art rthri hriti tiss and graftraft-vers versus us-host dise diseas ase. Psoria Psoriassis: skin/j kin/joint oint involvement. A utoa utoanti ntibod bodiies (e.g (e.g.,., antim nti micros crosom oma al) and di dissease a asssociati ociations ons..

 V  Vascu ascular/ lar/H Hemato ematology logy

1. Com omm mon hematol atolog ogiic dise diseas ases(e.g e.g.,., thromb thrombocytope ocytopeni nia, a, clot clotti ting ng factor de defici ficiencies encies,, llym ymphoma, phom a, leukemia). 2. Val Valvular vular hea heart rt disease (e.g (e.g.,., mitral stenosis, mit mitral ral rre egurgitati tation, on, aorti aortic c sstenos tenosis, aorti ortic c regurgitati tation, on, tricus tri cuspid rre egurgitati tation) on),, incl nclud udiing cli clini nica call pre pressentati ntation, on, associated murmurs urs,, and cardiac catheterization results. 3. T horaci horacic c and abdominal aorti aortic c aneurys neurysm ms: similari ariti ties esand di difference fferencess. 4. Pol Polycy ycyth them emia: prim primary (pol polycy ycyth them emia vera vera)) and seco econdary ndary (e.g., hypoxi hypoxia) a) ca caus uses es, cl cliinical nical manifestations (e.g., pruritus, fatigue). General

1. Common cl cliinica nicall fe fea ature turess of A AII DS (e.g .g., ., CNS, pulm pulmona onary ry,, G GII , de derm rma atolog tologic m ma anife nifesstations tations)). 2. Derm Dermatol atolog ogiic ma mani nifes festations tati ons of system temiic di dissease (e.g (e.g.,., neop neopllasia, infla nflam mmatory bowel di dissease, meni eningococcem ngococcemia, sys ystem temiic lupus eryt rythem hematosu atosuss). 3. Geri eriatri atric c pa path thol olog ogy: y: diseasescomm common iin n the the elderl derly y, nor norm mal phys physiiolog ologiic changeswith with age. 4. Rena enall fail failure ure:: a acute cute vers versus uschroni chronic, c, fea features tures of ure urem mia. 5. A cid–ba cid–basse disturb disturba ance ncess, incl includ udiing renal tubu tubullar a aci cidos dosis. 6. Wou Wound nd rre epair. 7. Dehyd Dehydrati ration on ((e e.g .g.,., hyp hypona onatrem tremic vs vs.. is i sotoni otonic c vs vs.. hype hypernatre rnatrem mic) c),, incl i nclud udiing appropriate ppropriate tre trea atment. 8. Gyne ynecologic cologic pathology (e.g .g.,., mens nstrua truall diso disorde rders rs)). 9. Cell injury and death. 10. 10. Malabsorpti orption on (e.g .g.,., ce celliac spru prue e, bacterial bacterial ove overg rgrow rowth, th, disaccha cchari rida dasse de deficiency ficiency)).

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PATHOLOGY— PATHOL OGY— CONG CONGENI ENIT TAL

Common congenital 1. Heart defects (congenita ital rubell lla a) malformations 2. Hy Hypospadias 3. 4. 5. 6. 7.

Cle Cleft li lip p wit ith h or wit ith hout cleft palate Congenital hip dislocation Spina bifida An A nencephaly Pyl Pylori oric c stenosis (associated with polyhydram polyhydramni nios os)); projectile vomiting

Neural tube defects (spina bifida and anencephaly ly)) are associated wit ith h increased levels of α-FP (in the amniotic fluid and maternal serum). T heir inci ncide dence is decreased with maternal folate ingestion during pregnancy.

Congenital heart disease R-to-L shunts (early cyanosis) “blue babies”

1. T etralogy of Fallot Fall ot (most ost comm common cau causse of earl rly y cyanosis) 2. T ransposition of great vessels 3. T runcus arteriosu arteriosuss

T he 3 T’s: T etralogy T ransposition T runcus Children may squat to ↑ venous return.

L-t L-to o-R shunts

1. VSD (most common congenital ca cardia iac c anomaly) ly)

Frequency: VS VSD D > ASD > PD PDA A

2. A S SD D 3. PDA (close with indomethacin)

↑ pulmonary resistance due to arteriolar thickening. → progressive pulmonary hypertension.

(late cyanosis) “blue kids”

Tet etra ralog logy y of Fa Fallot llot

3 1 4

2

1. Pulmonary stenosis 2. RVH 3. Overriding aorta (overrides the VSD) 4. VSD  Thisle lea ads to early cyanosis from a R-to-L shunt across the VSD. On x-ray, boot-shaped heart due to RVH. Patients suffer “cyanotic spells.”  The cause of tetr tra alog logy of Fallot llot is antero rossuperio iorr

PROVe

displacement of the infundibular septum. U C V  Ana  Anat.7  t.7 

Transposition of great vessels

A orta leaves RV (ante (anteri rior) or) and pu pullmonary trunk leave leavess Without Wi thout surgi urgica call correcti correction, on, LV (posterior) → separation of systemic and pulmonary pulmonary most inf nfants ants di die e with withiin th the e cir circulations. culations. Not com compatible ti ble with life li fe unless a shunt is first months of life. Common present to all allow ow adeq adequa uate te mixi xing ng of bl blood ood (e.g e.g.,., VSD, VSD, congeni nital tal heart di dissease in PDA, or patent foramen ovale). offspring of diabetic mothers.

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Coarctation of aorta Ligamentum arteriosum

Postductal coarctation

Descending aorta

Patent ductus arteriosus Aorta Ductus arteriosus (patent) Pulmonary artery

Infanti nfantile type: type: aortic aortic ste stenosis nosis proxim proximal to inserti rtion of ductus arteriosus (preductal). A dult type: type: stenosis is di disstal to ductusarterios arteriosus us (postductal tductal). A ssociated with notching notchi ng of the ribs ribs, hypertension in upper upper extremities ti es, weak pulses pulses in lower extremities. U C V  Ana  Anat.4 t.4

In fetal fetal pe peri riod, od, shunt is RR-to-L to-L (norm (normal) al).. In ne neonata onatall peri period, od, lung resistance stance de decrea creassesand shunt becom becomes esL-to-R -to-R with with subseq eque uent nt RV hypertrophy rtrophy and fail failure (abnorma abnormall). A ssociate ociated d with with a continuous conti nuous,, “machine-l achine-liike” murmur. urmur. Patency is main aintai tained ned by PGE PG E synthes nthesis and low oxygen tension.

A ffects males:fem ales:females ales3:1. Check femoral pulses on physical exam. INfantile: IN close to the heart heart.. (A ssociate ociated d with with Turner’s syndrome.) A Dult: Distal to Ductus.

I ndomethacin is used to cl clos ose ea PDA PD A . PG PGE E is used to keep a PDA PD A open, open, which which maybe necessary to sustai tain n life in conditi conditions ons such astransposition ti on of the the great reat vessels.

U C V  Ana  Anat.6 t.6

Eisenmenger’s syndrome U C V Path3. 4

Uncorrected VSD, A SD, or PDA PDA leadsto prog progres ressive pulmonary hypertension. As As pulmonary resistance increases, the shunt changes from L → R to R → L, which causes late cyanosis (clubbing and polycythemia).

 Autoso  Aut osomal mal ttriso risomie miess Down’ own’ss syndrom ndrome

(tris (tri somy 21), 21), 1:70 1:700 0

Most com common chrom chromosomal diso disord rde er and and ca caus use of Drinking age (21) co cong nge enital mental ntal reta retard rda ation. Findings Findings: mental ntal retardation, flat facial profile, prominent epicanthal folds, simian crease, duodenal atresia, congenital heart disease (most common malformation is endocardi rdial al cushion de defect) fect),, A lzheimer’s heimer’s disease in affected individuals > 35 years old, associated with an increasedri risk sk of AL ALL. Ni N inety-five perce percent nt of cases are due to meiotic nondisjunction of homologous chromosomes, 4% of cases are due to Robertsonian

translocation, and 1% of cases are due to Down mosaici osaicissm. A ssociate ociated d wi with th advance advanced d maternal age (from 1:1500 in women under 20 to 1:25 in women over 45). yndrome Finding Findingss: seve vere re mental retard retarda ati tion, on, roc rocke kerr b bottom ottomfee feet, Edwards’ syndrom (tri (t rissomy 18 18)), 1:800 1:8000 0 low-se low-set ea ears rs,, microg microgna nathi thia a, congeni nital tal hea heart disease, clenched hands (flexion of fingers), prominent occiput. Death usually occurs within 1 year of birth. tau’ u’s syndrom ndrome Findings Findings: severe vere mental ntal reta retard rda ation, microphtha icrophthalmia lmia,, Pata (tris (tri somy 13), 13), 1:6 1:600 000 0 microcepha phaly ly,, cl cle eft lip/pa l ip/palate, late, abnorm abnormal forebrain structures, polydactyly, congenital heart disease. Death usually occurs within 1 year of birth.

Election age (18)

Puberty (13)

U C V Path2. 2

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PATHOLOGY— PATHOL OGY— CONG CONGENI ENIT TAL (co n t i n u e d )

Genetic gender disorders Klinefelter’ssyndrom yndrome e [male] (XXY (X XY), ), 1:850   Path2 Path2.4, .4, Bio.23 yndrom rome Turner’ssynd [female] le] (XO), 1:3000   Path2.6 2. 6 Doub Dou ble Y males [male] le] (XYY) (XY Y),, 1:1000

Testicular ti cular atrophy, eunuchoi unuchoid d body body shape hape, tall, tall , long extrem xtremiti itie es, gyneco necom mastia, fem female ha hair ir distribu distribution. tion. Pressenc Pre nce e of inactiva inactivated ted X chro chrom mosome (Barr (Barr bod body y). Short stature tature,, ovari ovaria an dy dyssgene nessis, webb bbing ing of ne neck, ck, coarc rcta tatio tion n of the the aort rta a, most common cause of pri prim mary amenorrhea. No N o Barr body. Phe Pheno noty typ picall ically y no norm rmal, very tall tall,, severe acn cne e, antisoc ntisocial ial beha havior vior (se (seen in 1–2% of XY XYY Y male less).

One of the mos ostt common ca caus uses of hypo hypog gonadism dism in male less. “Hugs “Hugs & kisses” (XO) (X O) from TinaTurner (female). Observed with increased frequenc ncy y amon ong g inma inmates tes of penal institutions.

UCV

Pseudohermaphroditism

Fem Female pseudohermaphro herma phrodi dite te (XX) (XX)

Male pseudoMale hermap herm aphrodi hrodite te (XY)

Cri-du-chat syndrome

Di Dissagree reem ment be betwee tween the phenotypic (external external Gender ide denti ntity ty is ba bassed on genitalia) lia) and and gonadal ((te tesstes vs. ova ovarie riess) sse ex. exte xtern rna al g ge enitalia and sex o of  f  Ova Ovarie riess pre ressent, but external genitali nitalia a are viriliz virili zed or upbringing ringing.. ambigu biguous. ous. Due to excessive and inappropriate nappropri ate exposure to androgenic steroid idss durin ing g early gestatio ion n (i.e., congenital adrenal hyperplasia or exogenous administration of androgens during pregnancy). Te Tesstes present, nt, b bu ut e ext xte ern rna al ge genitalia arefemale or ambi big guous. Most com comm mon form is tes testi ticul cular ar feminization (androgen insensit nsitiivi vity ty), which results from a mutation in the androgen receptor gene (X-linked recessive); blind-end vagina. Congenital deletion of short arm of chromosome 5 C riri-du-ch -du-cha at = cry of the cat (46 XX or XY, 5p−). Findings: microcephaly, severe mental retardation, high-pitched crying/mewing, epicanthal folds, cardiac abnormalities.

X-llinkedFMR defect1 affecting the methylation thylation and expres xpression Tri Triplet plet repe repeat di disorder order (CG (C GG)n Fragile X syndrome Xof the gene. It is th the e second most common that th at may show genetic neti c

U C V Bio.61

Duchenne’s and Becker’s muscular dystrophies

U C V Bio.55

cause of geneti caus tic c mental retardati retardation on (the most ost common causeis Down’s Down’s syndrome ndrome). A ssociated ociated with macro-orchidism (enlarged testes), long face with a large jaw, large everted ears, and autism.

anti antici cipa pati tion. on.

Duchenne’s MD is an X-linked recessive muscular disease featuring a deleted dystrophin gene, leading to accelerated muscle breakdown. Onset before 5 years of age. Weakness begins in pelvic girdle muscles and progresses superiorly. Pseudohypertrophy of calf muscles due due to fibro-fatt fibro-fatty y replacement of muscle; cardiac cardi ac myopathy. The T he use of Gower’s Gower’s maneuver, requiring assistance of the upper extremities to stand up, is characteristic but not specific (indicates proximal lower limb weakness). Becker’s muscular dystrophy is due to dystrophin gene mutations (not deletions) and is less severe. Diagnosis by muscle biopsy.

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Cystic fibrosis

A utosom utosomal recessive defect in CFT FTR R gene on − chromosome ome 7. Defective Defective Cl Cl channel → secreti tion on of abnorma abnormallly thi thick ck mucusthat plugslungs, ungs, pancreas, and liver → recu recurrent rrent pu pullmonary infections (Pseudomonas species and  Sta  Staphylo ylococcus aure reu us), chronic bronchitis, bronchiectasis, pancreatic insufficiency (malabsorp-

Inferti nfertillity in males. Fat-soluble vita vitamin deficiencies ficiencies(A , D, E, K). Can present asfai faillure to thrive thri ve in infancy.

tion and steatorrhea), meconium ileus in newborns. Increased concentration of Cl− ions in sweat test is diagnostic.

U C V Path2. 1

 Autosomal  Autoso mal domin dominant ant diseases A dul dult polycys polycystic ti c kidne ki dney y Bi Billateral ateral massive enl enlarg argement of ki kidneys dneysdu due e to mul multi tiple ple larg large cys cysts. Patie Pati ents pres present with dise di sease   Path2. 84 pain, hematuria, hypertension, progressive renal failure. Ninety percent of cases are due to mutati mutation on in in APK A PKD1 D1 (chromos (chromosome ome 16). A ssociate ociated d with polycy polycyssti tic c liliver ver di disease, berry valve prolap prolapsse. Juve Juveni nille form is recessive. aneurysms, mitral valve Familial El Eleva evated LDL owing owing to defecti defective ve or abse absent LDL receptor. receptor. Heterozy eterozyg gotes(1 in 500) 500) have hy hyp percho rchole lesste tero role lem mia chole cholesstero teroll ≈ 300 mg/dL /dL.. Hom H omozy ozygote gotess (very rare) have choles cholesterol ≈ 700+ mg/dL, severe atheros athe roscleroti clerotic c dis disease early early iin n lliife, and tendon tendon xanthomas xanthomas(cl clas assica callly iin n the the A Achi chillles Marf Ma rfa an’s n’s synd ndro rom me Path2. 5

Von Reckli Recklinghaus nghausen’s dis ise ease (NFT1) (N FT1) Von Hippel–Lindau dise di sease   Path2. 28 Hunting untington’s ton’s d diisease

tendon). Myocardial infarction may develop before age 20. Fib Fibrillin rillin ge genemutatio tation n → connecti connective ve tis ti ssu sue e dis disorders. Skeletal abnormalities: tall with long extremities, hyperextensive joints, and long, tapering fingers and toes Cardiovascular: cystic medial necrosis of aorta → aortic incompetence and dissecting aortic aneurysms. Floppy mitral valve. Ocular: subluxation of lenses. Fi Findi ndings ngs: cafécafé-au-l au-lait ait spots, spots, neural neural tumors, Lis Li sch nodul nodules(pigmented pigmented iri riss hamartomas). On longarmof chr chrom omosome 17; 1 17 7 lette lettersin von von Reck Reckling lingha hau usen. Fi Findi ndings ngs: hemangioblastomasof retina/cere retina/cerebe belllum/medulla; dull a; ab about out half of affected affected individuals develop multiple bilateral renal cell carcinomas and other tumors. A ssociated with with del deletion of VH V HL gene (tumor suppres uppressor) on chrom chromos osom ome e 3 (3p). (3p). Fi Findings ndings:: depre depresssion, progressive de dementia, nti a, chorei choreiform movem ovements, cau cauda date te atrophy atrophy and

decreased levels of GA GA BA and ace cetylch tylchol oliine in the brain. Symptoms manifest anifest in affected affected individuals between the ages of 20 and 50. Gene located on chromosome 4; triplet repeat disorder. denomatous Colon olon becomescovered covered with with adenoma adenomatous polypsafter puberty puberty.. F Fe eatures atures: deleti tion on on Familial Adenoma Polyposis   Path1. 45 chromosome Five; Autosomal dominant inheritance; Positively will get colon cancer (100% without resection). Here Hereditary itary Sp Sphe heroid roid ery eryth thro roc cytes; hemolytic lytic ane anemia; ia; incre increased MCHC. MCH C. Sp Sple lene necto tom my iscurative tive. spherocytosis UCV

 Autosomal Autoso malrecessive diseases

Cystic fibrosis, albinism, α1-antitrypsin deficiency, phenylketonuria, thalassemias, sickle cell anemias, glycogen storage diseases, mucopolysaccharidoses (except Hunter’s), sphingolipidoses (except Fabry’s), infant polycystic kidney disease, hemochromatosis.

21 215 5

 

PATHOLOGY— PATHOL OGY— CONG CONGENI ENIT TAL (co n t i n u e d )

 X-linked  X-link ed rec reces essiv sive e disorders

Fragile X, Duchenne Fragi Duchenne’s ’smuscular cular dys dystrophy trophy, h hem emophi ophillia A and B, Fabry’s, G6PD G 6PD de deficiency ficiency,, Hunter’s syndrom syndrome, ocular ocul ar albi albini nism sm, Lesch–N ch–Nyhan syndrome syndrome, Bruton’s Bruton’s agammaglobuliline nem mia, Wi Wisskott–A kott–A ldri ldrich ch syndro syndrom me. Female carriers of x-linked recessive disorders are rarely affected because of random inactivation of x chromosomes in each cell.

Neural tube defects

A ssociated with low l ow folic folic aci acid intake intakedu duri ring ng preg pregnancy. Eleva Elevated α-fetoprotein in amniotic fluid. Spina bifida occulta: failure of bony spinal canal to close, but no structural herniation. Usu suall ally y seen at lowe lower vertebral leve levels. Meningocele: meninges herniate through spinal canal defect. Meningomyelocele: meninges and spinal cord herniate through spinal canal defect.

Skin

Subarachnoid space Dura Meninges

Spinal cord ;

;

;

;

;

;

;

;

;

;

Normal ;

Transverse process

;

;

;

;

;

;

;

;

;

;

;

;

;

;

;

;

;

;

;

;

;

;

Spina bifida occulta

;

;

;

;

;

;

Meningocele ;

;

;

Meningomyelocele ;

;

;

U C V  Anat.51  Anat.51

Tera erattogens og ens

Most susceptible in 3rd–8th week of pregnancy. Examples

Effects

A CE inhibitors Cocaine DES Iodide

Renal damage Ab bn normal fetal development and fetal addiction Vaginal clear cell adenocarcinoma Congenital goiter or hypothyroidism

13-cis-retin ino oic acid  Thalido  Thalid omide ide Warfarin, x-rays

Extremely high risk for bir irtth defects Limb Limb defects Multiple anomalies

Fetal infections can also caus Fetal cause congeni nital tal malformati tions ons.. (Other Other me medications dications contraindicontraindicated in pregnancy are shown in the pharmacology section.)

Fetal alcohol syndrome

U C V Pharm. 50

Newborns of mothers who consumed significant amounts of alcohol (teratogen) during pregnancy (highest risk at 3–8 weeks) have a higher incidence of congenital abnormalities, including pre- and post-natal developmental retardation, microcephaly, facial abnormalities, limb dislocation, and heart and lung fistulas. Mechanism may include inhi nhibiti bition on of cell migration. T he number one caus cause of conge congeni nital tal malformati tions ons in the United States.

21 216 6

 

PAT PATHOL HOLOGY— OGY—NEOPLAS NEOPLASTI TIC C

Neoplastic progression Epithelial cell layer • Normal cells with basal → apical differentiation Normal

Basement membrane

• Cells have ↑ in number - hyperplasia • Abnormal proliferation of cells with loss of size, sha shape, pe, and orientation - dysplasia Hyperplasia

• In situ carcinoma • Neoplastic cells have not invaded basement membran membrane e • High nuclear/cytoplasmic ratio and clumped chromatin

Carcinoma in situ/  preinvasive

• Cells have invaded basement me membrane mbrane using collagenases and hydrolases • Will metastasize if they reach reach a blood or lymphatic v vessel essel

Invasive carcinoma

Metastatic focus

Blood or lymphatic vessel

Metastasis   - spread to distant or Metastasis organ gan • Must survive immune attack • "Seed and soil" soil" theory of metastasis   • Seed = tumor embolus   • Soil = target organ––liver organ––liver,, lungs, bone, brain ...

21 217 7

 

PATHOLOGY— PATHOL OGY— NEOPLASTI TIC C ( co n t i n u e d )

-p la sia  sia  definitions

Hyperplasia = increase in number of cells (reversible). Metaplasia = one adult cell type is replaced by another (reversible). Often secondary to irritation and/or environmental exposure (e.g., squamous metaplasia in trachea and bronchi of smokers). Dysplasia = abnormal growth with loss of cellular orientation, shape, and size in comparison to normal tissue maturation, commonly preneoplastic (reversible). A napl naplasia = abnormal cells lacking differentiation; like primitive cells of same tissue, often equated with undifferentiated malignant neoplasms. Tumor giant cells may be formed. Neoplasia = a clonal proliferation of cells that is uncontrolled and excessive.

Tumor g gra rade de versus stage Gra Grade

Stage

Tumor nomenclature

His Histo tolo log gic appearance of tum tumor. Usu Usually graded I–IV based on degree of diff differenti erentiati ation on and number of mitoses per high-power field. Based on site ite and size of primary lesio ion n, spread to regiional lymph n reg nodes odes, presence presence of metastases.

Stage has more pro rog gnostic val value ue than than grade. T NM staging system: T =si size zeof Tumor N =Node involvement M = Metastases

Cell type

Benign

Malignant

Epith ithelium lium Mesenchyme Blood cells Blood vessels Smooth muscle Skeletal muscle Bone More Mor e th tha an on one cell typ type

Adenoma, papillom illoma

Ad Ade enocarcin ino oma, papillary carcin ino oma

Hemangioma Leiomyoma Rhabdomyoma Osteoma Matu Mature reterato tom ma

Leukemia, lymphoma A ngiosarcoma Leiomyosarcoma Rhabdomyosarcoma Osteosarcoma Imm Immature tureterato tom ma

21 218 8

 

Conditions associated with neoplasms

Condition 1. Down’s syndrome

Neoplasm 1. Acute Lymphoblastic Leukemia. “We will ALL go DOWN together.”

2. Xeroderma pigmentosum 3. Chronic atrophic gastri triti tiss, perni rnicious ciousane nem mia, postsurgical gastric tri c remnants 4. Tuberoussclerosi clerosis (facial angiofibrom ofibroma, a, seizures ures, mental retardation) 5. A ctinic keratosis 6. Barrett’s esophagus (ch (chronic GI re reflux) 7. Plum Pl ummer–Vi er–Vinson nson syndrom yndrome e (atrophi atrophic c glos osssitis tis, esophageal we webs bs,, anemia; all all due to iron deficiency) 8. Cirr Cirrhosis(alc (alco oholi lic c, hepatitis itisB or C) 9. U lcerative colitis 10. Paget’s disease of bone

2. Squamous cell and basal cell carcinomas of skin 3. Gas Gastri tric c adenocarcinoma rcinoma 4. A strocytoma trocytoma and ca cardiac rdiac rhabdomyoma 5. Squamous cell carcinoma of ski skin n 6. Esophageal adenocarcinoma 7. Squamousce celll ca carci rcinom noma a of esophagus 8. Hep Hepatocell llu ular carcin ino oma 9. Colonic adenocarcinoma 10. Secondary osteosarcoma

andfibrosa fibrosarcoma rcoma 11. Malignant lymphomas 12. A ggressive malignant lymphomasand Kapos K aposi’s sarcoma 13 13.. A utoimmune diseases (e.g., Hashi him moto’sthyroidit thyroiditiis, 13. 13. Benign and mali alig gnant myasthenia gravis) thymomas 14. A canthos nthosis nig nigrica ricans(hyp (hyperp rpig igm mentation and 14. Visce Viscera rall ma malig ligna nanc ncy y epidermal thickening) (stomach, lung, breast, uterus)

11. Immunodeficiency states 12. A IDS

Oncogenes

Gain of function.

Gene

Associated tumor

c-myc  bcl-2

Burkitt’s lymphoma Folli lic cular and undifferentiated lymphomas (inhib ibiits apoptosis) Breast, ovarian, and gastric carcinomas Colon carcinom carcinoma a

erb-B2 ra rass

Tumor supp suppress ressor or genes

Loss of function; both alleles must be lost for expression of disease.

Gene

Chromosome

Associated tumor

Rb BRCA -1& 2 p53

13q 17q, 13q 17p

Retinoblastoma, osteosarcoma Breast and ovarian cancer Most human cancers, Li–Fraumeni syndrome

21 219 9

 

PATHOLOGY— PATHOL OGY— NEOPLASTI TIC C ( co n t i n u e d )

Tumor ma mark rkers ers PSA , prostatic acid acid phosphatas phosphatase e CE CEA A

Prostatic carcinoma Car Carcin ino oembryonic antige igen. Very nonspecifi ific c but produced by 70% of colorectal colorectal and pa pancreati ncreatic c cance ncers; als lso o by gastric and breast ca carc rcinom inomas. Normally made by fetu fetuss. Hepa Hepatoce tocellular llular carc rcinom inomas. Nonseminomatous germ cel celll tumors of th the e testis testis (e.g., yolk sac tumor). Hydatidiform moles, Choriocarcinomas, and Gestational trophoblastic tumors. Live Liver and yolk sac tumors. Ovarian, malignant epithelial ttu umors. Melanoma, neural ttu umors, astrocytomas. Metastasesto bo bone, ne, obstructive tructi ve bil biliiary disease, Paget’s disease of bone. ,

α-fe -feto top prote rotein in

β-hCG α1-antitr itrypsin CA-1 CA125 S-100 A lkali kaline ne phosphatas phatase

Oncogenic viruses

Chemical Carcinogens

Tumor markers should not be used asth the e pri prim mary tool tool for cancer dia iag gnosis. is. They may be used to confirm diagnosis, to monitor onitor for for ttu umor recu currre renc nce e, and to monitor onitor response response to th therapy erapy.

Virus

Associated cancer

HT LV-1 HBV, HCV EBV HPV HHV 8 (Kaposi’s aposi’s sarcoma–associated herpesvirus)

A dult T-cell leukemia Hepatocellular carcinoma Burkitt’s lymphoma, nasopharyngeal carcinoma Cervical carcinoma, penile/anal carcinoma Kaposi’ssarcoma

Toxin

AffectedOrgan

A flatoxins, vinyl chloride Nitrosamines A sbestos A rsenic

Liver Esophagus, stomach Lung(mesothelioma) Skin (squamous cell)

22 220 0

 

Local effects of tumors

Local effect

Cause

Mass Nonhe Nonh ealing ulcer

Tissue lump or tumor. Desstru De truct ction ion of epithelial ithelial surfaces (e (e.g .g., ., sto tom mach ch,, c colo olon, n, mouth, bronchus). From ulc lce erated area or eroded vessel. Any Any site with sensory nerve endin ing gs. Tumors in brain are initiall nitially y painl inle ess.

Hemorrhage Hem Pain Seizures Obstruction

Perforation Bonedestr tru uction tion In Infl flammation Space-occu ce-occupy pyiing lesion Localiz ocali zed loss oss of sensory or motor otor func function tion Edema

Prostatic adenocarcinoma

U C V Path2. 95

Tumor mass in brain. Of bronchus → pneumonia. Of biliary tree → jau  jaundic ice e. Of left colon → constipation. Of ulcer in viscera → peritonitis, free air. Path Patho olo log gic ffra racture ture, c co olla llap pse of b bo one. Of serosal surface → pleural effusion, pericardial effusion, ascites. Raised intracranial pressurewith brain brain neopl neoplasms. A ne nem mia due to bone marrow replacement. Compres ompression or de destructi struction on of nerve (e.g e.g.,., recurrent laryngeal nerv rve e by lung lung or thyro roid id canc nce er, with with hoa hoarseness). Venous or lymphatic obstruction.

Comm ommon iin n men over age 50. A ri rissesmost ost often often from fromthe posteri posterior or llobe obe(peri riphera pheral zone) zone) of the prostate gland and is most frequently diagnosed by digital rectal examination (hard nodule) and prostate biopsy. Prostatic acid phosphatase and prostate-specific antigen (PSA PSA ) are us useful tumor tumor markers. markers. Oste Osteoblasti oblastic c metastas tastases esin bone may develop in i n llate ate stages, as indicated ndi cated byan incr increa ease sein serum alkali kaline phosphatase and PSA PSA .

Skin cancer Squamouscell Squam carcino rcinom ma

Very comm common. A ssociate ociated d with with excessive exposu exposure re to sunlight nlight.. Commonly appear on hand ndss and fac face. Locally invasive, but rarely metastasizes.   A nnaat. 32

A cti ctini nic c keratosi keratosis is a precursor precursor to squamous cell carc rcino inom ma. Path1. 2 20 0

Keratin “pearls.” A rseni nic c exposure. Ba Bassal ce cell ca carcinoma rcinoma Mela Me lano nom ma

UCV

Most common in sun-expo un-expossed are rea as of body body. Localllly y inva inv asive, b bu ut alm almo ost never metas tastas tasiz ize es. Gros Gross pathology: pearly papules.   Path1.21 Common tu tum mor with sig ignifi nific cant risk of meta tassta tassis. is. A ssociated with with sunli unlight expos exposure. ure. Incide nci dence nce increasing. Depth of tumor correlates correlateswith with ri rissk of metastasis.   Path1.2 Path1.23 3

Metastasis to brain Primary tumors that metastasize to brain: Lung,

Ba Bassal ce cell tumorsha have ve “palis lisa ading” nu nuc cle lei. i. Incre Increased risk in fa fairir-sskinne kinned pe persons rsons.. Dyspl Dysplastic ti c nevusis a precursor precursor to melano elanom ma. lls Glia Lots of Bad Stuff K iills

Breast, Skin (melanoma), K idney idney (renal cell carcinoma), GI. Overall, approximately 50% U C V Path2. 19

of brain tumors are from metastases.

22 221 1

 

PATHOLOGY— PATHOL OGY— NEOPLASTI TIC C ( co n t i n u e d )

Metastasis to liver

U C V Path1.65

 Thelive liver and lu lun ngare the most common site itesof metastasis after the regional lymph nodes. Primary tumors that metastasize to the liver: Colon > Stomach > Panc ancreas reas >Breast > Lung.

Metastasis to bone  These pri rim mary tu tum morsmetastasiz ize e to bone: K idney, idney, Thyroid, T estes, Lung, Prostate, Breast.

Metastasis fr from om breast and prostate prostate a are re most common. Metastatic bone tumors are far more common than 1° bone tumors.

Meta Metastases >> 1° liver tumors. Cancer Someti ometime mes Penetrates Benign Liver.

K iller iller T umors T hat Love Penetrating Bone Lun ung g =Lytic

Prostate = blastic Breast = Both lytic and blastic

Paraneoplastic effects of tumors Neoplasm

Small cell lung carcinoma Small cell lung carcinoma and intracranial neoplasms Sq Squ uamou ouss cell lu l ungcarc rcinom inoma, renal cell carcinoma, breast ca carci rcinom noma, a, mul multiple ti ple myel eloma oma, and and bone metastasi tasiss (lyse (l ysed bon bone) e) Renal cell carcinoma  Thym  Thy moma, bronchogenic carcinoma Vario rious neoplas lasms

Causes

Effect

AC CT T H or A CT CT H-like peptide. A DH or A NP.

Cushing’s syndrome SI A DH

PTHPT H-re relate lated peptide, TGFTG F-α, TNF-α, IIL L-2.

Hypercalcemia

Erythropoietin. A nti tib bodie iess again insst presynaptic Ca2+channels at N MJ . Hyp Hyperurice icemia due to excess nucle leic ic acid tu turrnover (i.e., cytotoxic therapy).

Polycythemia Lambe bert rt––Eaton syndrome Gou Gout

Cancer epidemiology Incidence

Mortality

Male

Female

Prostate (32%) Lung (16%) Colon Colo n and rectum tum (1 (12 2%) Lung (33%) Prostate (13%)

Breast (32%) Lung (13%) Colon Colon andrectum tum (13 (13%) Lung (23%) Breast (18%)

22 222 2

Deaths from lung cancer have plateaued in males, but deaths continue to increase in ffe emale less. Cancer is the second leading cause of death in the U.S. (heart disease is first).

 

PAT PATHOL HOLOGY— OGY—HEMA HEMATOL TOLOGI OGIC C

 Anemia  Ane mia Type

Etiology

Microcytic, crocytic, hypochromic

Iron defic ficiency iency:: ↑ TI  TIB BC, ↓ ferritin, ↓ serum iron   Bio.89 T halassemias Lead poisoning Megaloblastic: Vitamin B12/folate deficiency Dr Drug ugs that that block DNA DN A synthes nthesis (e.g e.g.,., sul ulfa fa drugs, A ZT) ZT) Marked reticulocytosis Hemorrhage En Enzzyme defects(e.g (e.g., G6PD G6PD de deficie ienc ncy y, PK de deficie ienc ncy y) RBC membrane brane defects fects (e.g., (e.g., here hereditary ditary spherocytos rocytosis) is) Bone marrow di disorde orders (e.g (e.g.,., aplasti tic c ane anem mia, le l eukemia) Hem Hemoglo lob binop inopath thie iess (e.g (e.g., sic ickle klecell dis dise ease) A utoimmune hemolytic anemia A nemia of chronic chronic diseas disease: ↓ TI  TIB BC, ↑ ferritin, ↓ serum iron, ↑ storage iron in marrow macrophages

Macrocytic

Normocytic, no norm rmochro hromic

UCV

 Aplastic  Aplast ic anem anemia ia

Cau Causes

Sy Sym mpto tom ms Pathologic Patholog ic fea features tures  Tr  Tre eatment U C V Path1. 77 

Vit. B12 and folate deficiencies are associated with hypersegmented PMNs. Unlike folate deficiency, vit. B12 de defici ficiency ency is associate ociated d with with neurol neu rolog ogiic probl problems. Serumhaptoglobin and serum LDH are used to determine RBC hemolys lysis. is. Dire Direc ct Coombs’ tes test iiss used to disti disting nguis uish h betwe between iim mmune vs. no nonimmunemedia iate ted RBC hemolysis.

Pancytopenia characterized by severe anemia, neutropenia, and thrombocytopenia caused by failure or destruction of multipotent myeloid stem cells, with inadequate production or release of differentiated cell lines. Rad Radia iatio tion, n, be benzene, chlo chlora ramphenico nicol, alky alkyla latin ting g agent ntss, a ant ntim ime etabolites, vira viral agent ntss (HCV, CMV, EBV, herpes zoster-varicella), Fanconi’s anemia, idiopathic (immune-mediated, primary stem-cell defect). Fatigu tigue, ma malais laise e, pa pallor, llor, pu purp rpu ura ra,, mu mucosal ble lee eding, pe petechiae hiae, infection. tion. Pancyto Pancytope peni nia a with normal cell cell morpholog orphology; y; hypoce hypocellllular ular bo bone ne marrow with fatty fatty infiltration. With Withdrawal of of offendin ing g agent, allog llogenic bone marr rro ow tra transpla lan ntation tion, RB RBC C an and pla late tele lett transfusion, G-CSF or GM-CSF.

22 223 3

 

PATHOLOGY— HEMATO PATHOLOGY— HEMATOLOGI LOGIC C (co n t i n u e d )

Blood dyscrasias Sickle ce cellll anem nemia

α-thalassemia

β-thalassemia

UCV

HbS mutation is a single ingle amino acid re repla place cement in β-chai -chain n (subs ubsti tituti tution on of normal normal glutam utamic ac aciid with valine). Low O2 or dehydrati dehydration on precipitates precipitatessickl ckliing. Heterozygotes(sickl ckle ecell trait) trait) arerelatively malariare ressistant (balance (balanced polymorphism) polymorphism). Compl ompliications cations in homozygotes (sickle cell disease) include aplastic crisis (due to B19 parvovirus infection), autosplenectomy, ↑ risk of encapsulated organism infection, Sa  Sallmonella lla osteomyelitis, painful crisis (vaso-occlusive), and splenic sequestration crisis. HbC defect is a different β chain mutation; pa pati tie ents with c s c Hb or Hb (1 of each mutant gene) have milder dise disease th than an Hb Hbss patients. New therapies for sickle cell anemia include hydroxyurea ( ↑ HbF) and bone marrow transplantation.   Bio.94, Path Path3.43 Th The ere are four α-globin genes. In α-thal -thalas assemia, the α-globin -globin chain is underproduce underproduced d (asa functi function of numbe num berr of ba bad d genes, one to four) four).. T here is no compe com pensa nsatory tory increas i ncrease of any other chains. chains. HbH HbH (β4tetramers, lacks three α-globin genes). Hb Barts (γ 4 -tetramers, lacks all four α-globin genes) results in hydrops fetalis and intrauterine fetal death. In β-minor thalassemia (heterozygote), the β-chain is underproduced; in β-ma -majjor (homozygote), the β-chain -chain is abs absent. I n both cases, fetal hemogl oglobi obin n production producti on is compe compensa nsatori torily increased but is inadequate. HbS/β-th thalass alassemia heterozygot ote e has mil mild d to moderate di dise sease.   Bio.95, Pa Path th3.37

Eight Eight percent of A fricanfricanA meri rica cans ns ca carry rry the HbS trait tr ait.. 0.2% have the di dissease. Si Sickl ckled ed cell cellss are crescent nt-shape shaped d RBC BCss.

T halassemia is prevalent in Med ediiterranean popul populati ations ons (thalassa = sea). T hi hink nk of thalaSEAmia.

β-thalassemia major results in severe anem anemia requi requiri ring ng bl blood ood trans transfusions. Cardiac fai faillure dueto secondary hemochr hemochroma omatosis. tosis.

Diagnosis of hematologic defects

Heinz bodies are seen in G6PD deficiency. Ham’s test is used to diagnose paroxysmal nocturnal hemoglobinuria (PNH). Osmotic fragility test is used to diagnose hereditary spherocytosis (treat with splenectomy).

DIC

A ctivation ctivation of coagulati ulation on casca cascade de, lead adiing to microthrom microthrombi bi and global obal consum consumption ption of platelets, fibrin, and coagulation factors. Causes: septicemia, pregnancy, transfusion, trauma, malignancy, acute pancreatitis, nephrotic syndrome. Lab findings: ↑ PT, PTT, fibrin split products; ↓ platelet count.

U C V Path1.82

22 224 4

 

Bleeding disorders Platelet abnormaliti ities (microhemorrhage)

Mu Muc cous membrane bleedin ing g Petechiae Purpura Prolonged bleeding time

Coa Coagulatio ion n factor

Hemarthroses (ble (bleedin ing g in intto jo join intts)

defects (macrohemorrhage)

Leukemias

Causesinclude IT ITP P (antiplatelet antibodies and ↑ megakaryocytes), T T P (schistocytes), drugs, and DIC (↑ fibrin split products). Co Coa agulo lop pathies in inc clu lud de hemo-

Easy bruising Prolonged PT and/or aPT T

philia A (factor VII I deficiency), hemophilia B (factor IX deficiency), and von Willebrand’s disease (deficiencyof von Wil Wi llebrand’s antigen), the most common bleeding disorder.

General considerations: ↑ number of circulating leukocytes in blood; bone marrow infiltrates of leukemic cells; marrow failure can cause anemia (↓ RBCs), infections (↓ WBCs), and hemorrhage (↓ platelets); leukemic cell infiltrates in liver, spleen, and lymph nodes are common. A LL––chil children; dren; lymphobl phoblasts; mos mostt responsive to therapy therapy. A ML––A uer rods; myeloblasts; ad adults. ults. CLL––older adults; lymphadenopathy; hepatosplenomegaly; few symptoms; indolent course; ↑ smudge cell cellss in peripheral peripheral blood bl ood smear; warm Ab Ab auto toiimmune mune hemol olyti ytic c anemia; very similar to SLL (small lymphocytic lymphoma). CML––most ost commonly only associated wi with Phil Phi lad ade elphia chrom chromos osom ome e [t(9;22), bcr-abl]; myeloid stem stem cell cell prolifera proli ferati tion; on; may a acce ccellerate to AM A ML (“b “bllast cris cri sis”). LEUKEMIA

↑ Leukocytes Full bone marrow

ACUTE LEUKEMIAS

CHRONIC LEUKEMIAS

Blasts predominate Children or elderly Short and drastic course

More Mo re mature cells cells Midlife age range Longer, less devastating course

ALL ALL

AML AM L

CLL

CML CM L

Lymphoblasts (pre–B or pre–T)

Myeloblasts

Lymphocytes Non–Ab-producing   B cells

Myeloid stem cells

U C V Pa Path th1.75, 76, 80, 81

Chromosomal translocations

t(9;22), or the Philadelphia chromosome, is associated with CML ( bcr-abl hybrid). t(8;14) is associated with Burkitt’s lymphoma (c-myc activation). t(14;18) is associated with follicular lymphomas (bcl-2 activation).

22 225 5

 

PATHOLOGY— HEMATO PATHOLOGY— HEMATOLOGI LOGIC C (co n t i n u e d )

Multiple myeloma M-spike

Albumin

α1  α2  β 

γ 

Monoclonal plasma cell (“fried-egg” appearance) cancer that arises in the marrow and produces produc eslarge amounts of IIg gG (55%) 55%) or IIg gA (25%) 25%). Mos M ostt common 1° tumor arising within bone in adults. Destructive bone lesions and consequent hypercalcemia. Renal insufficiency, ↑ susceptibi ceptibillity to infection, infection, and anemia. Ig Ig light chains chains in urine urine (BenceJ ones ones protein) protei n).. A Asssociate ociated d with prim pri mary amyloi yloidos dosis and punched-out punched-out lyti l ytic c bone lesions on x-ray. Characterized by monoclonal immunoglobulin spike (M protein) on serum protein electrophoresis. Blood smear shows RBCs stacked like poker chips (rouleau formation).

U C V Path1.90

PATHOL OGY— GAS GASTROINTEST TROINTESTII NAL PATHOLOGY—

 Achala  Ac halasia sia

U C V Path1.40

Failure of relaxation of lower esophageal sphincter dueto loss oss of myenteric nteri c (A ue uerbach’s rbach’s) plexus. plexus. Causesprogressive dysphagi phagia. Barium Bari umswal alllow showsdil dilated esophagus ophagus wi with th an areaof di distal stal stenosis. A ssociated with with an increasedri rissk of esophageal carcinoma.

Barrett’s esophagus Glandular (columnar epithelial) metaplasia— U C V Path3.29

replacement of strati replace stratifie fied squamousepithel epitheliiumwi with th gastric (columnar) epithelium in the distal esophagus.

 A -ch -chalasia = absence of

relaxation. relaxation. 2° achalasia may arise from Chagas’ di dise sease. “Bird “Bird be beak” ak” on ba bari rium umswal wallow.

BARRett ett’s ’s =Becomes Adenocarcinoma, carcinoma, Resul ults ts from from Reflux.

Esophageal cancer Risk factors for esophageal cancer are:

U C V Path1.54

Achalasia Barrett’s esophagus Corrosive esophagitis Diverticuli Esophageal web Familial

ABCDEF

Chronic ga st stritis ritis  Typ  Ty pe A  Typ  Ty pe B

Autoimmune disorder characterized by Autoantibodies Type A = 4 A’s to parietal cells, pernicious Anemia, and Achlorhydria. ylori infection ylori  Ca Cau used by H . pylo Type B =a Bug, H . pylo

U C V Path3.31

22 226 6

 

Peptic ulcer disease Gastric ulcer

Duodenal ul ulcer

U C V  Anat.25,  Anat.25, Path1.42, 69

Inflammatory bowel disease Lo Loc catio ion n

Gross mor orp pholog hology

Pain Greater with meals: weight loss H . pylori infe infection iin n 70%; 70%; NSA NSAIID use use also iim mpli plica cate ted d Due to ↓ mucosal protection against gastric acid Pain Decreases with meals: weight gain A lmost ost 100% have H . pylori infection Due to ↑ gastric acid secretion or ↓ mucosal protection Potential complications include bleeding, penetration, perforation, and obstruction. H . pylori  infection can be treated with “triple therapy” (metronidazole, bismuth salicylate, and either amoxicillin or tetracycline) with or without a proton pump inhibitor. Incide ncidence nce of pe pepti ptic c ulcer ulcer dise disease iiss twice as great reat in smokers smokers..

Crohn’s disease   Ma May y in inv volv lve e any portio ion n of the GI tr tract, usuall lly y the the terminal ileu ileum, ssm mall intestine tine, and andcolo lon n. Skip lesions, rectal sparing. Transmura rall infla inflammation. tion. Cobblestonemucosa, creeping fat, bowel wall thi thickeni ckening ng (“stri tring sign”

on x-ray), linear ulcers, fissures. Microscopic morphology Complica lications tions

Ulcerative colitis C olitis = colon inflammation.

Con Contin tinu uous le lessio ions nswith rectal involvement. Mucosal ucosal inflamm nflammati ation. on. Fri Friab able mucosal pseu eudopolyps dopolyps

Noncaseating granulomas.

with freely hanging mesentery. Crypt abcesses and ulcers.

Stric Strictu ture res, fi fisstu tula lass, p pe erianal disease, ma malab labsorp rptio tion– n– nutritional depletion.

Severestenos nosis is,, tox toxic megacolon, colorectal carcinoma.

Extraint intestina inal manifestations U C V Path3.32, 3. 32, 35

Migratory poly lya arthritis itis, erythema nodosum.

Pyoderma gangrenosum, sclerosing cholangitis.

For Crohn’s, think of a fat old crone skipp skippingdown a cobblestone road.

Diverticular disease Diverticu Dive rticulum lum

Diverticu Dive rticulos losis is

Diverticu rticulitis liti s U C V Path1. 53

Blind pou pouch ch leading off off thealilim mentary ntary tra tract, ct, lined lined by muco cossa, mu muscu cular laris is,, a and nd sero rossa, that that communicates with the lumen of the gut. Most diverticula (esophagus, stomach, duodenum, colon) are acquired and are termed “false” in that they lack or have an attenuated muscularis propria. T hepr pre evalen valence ceof diverticulos rticulosis is (m (ma any diverticula) rticula) in pa patients tientsove over age 60approaches50%. Caused by increased intraluminal pressure and focal weakness in the colonic wall. Most freque freq uently ntl y iinvol nvolve vess the sigmoid colon. A ssociated wi with low-fibe ow-fiber di die ets. Mos M ostt often asymptomatic or associated with vague discomfort. Inflammation of of dive divertic rticu ula cla classsically ically c ca ausing LLQ pain. May be co com mplicate licated d by by perfora rfora-tion, peritonitis, abscess formation, or bowel stenosis.

22 227 7

 

PATHOLOGY— PATHOL OGY— GAS GASTROINTEST TROINTESTII NAL (co n t i n u e d )

Hirschsprung’s disease Transition

Congeni nital tal megacolon characterized characterized by ab abssence of paras pa rasym ympa patheti thetic c ganglion cells cell s (A ue uerbach’s rbach’sand Meissner’s plexuses) on intestinal biopsy. Due to failure of neural crest cell migration. Presents as chronic constipation early in life. Dilated portion of the colon proximal to the the ag aganglionic onic segment, resulti ulting ngiin a “transition ti on zone.” one.”

zone

Dilated megacolon Constricted aganglionic segment

T hi hink nk of a giant spri pring ng that hassprungin the colon.

U C V  Anat.21  Anat.21

Colorectal cancer risk factors

Risk factors for carcinoma of colon: colorectal villous adenomas, chronic inflammatory bowel bow el dis disease, llow-fibe ow-fiberr di diet, et, increas increasing age, familial adenomatous pol polypos yposis (FAP) FA P),, hereditary nonpolyposis colorectal cancer (HNPCC), personal and family history of colon cancer. Screen patients > 50 years old with stool occult blood test.

U C V Path1.50

Cirrhosis/ portal hypertension

 

Effects of portal hypertension • Esophageal varices  

Hematemesis Peptic ulcer

• Melena • Splenomegaly • Caput medusae • Ascites • Testicular atrophy • Hemorrhoids

Effects of liver cell failure • Coma • Scleral icterus • Fetor hepaticus (breath   smells like a freshly   opened corpse) • Spider nevi • Gynecomastia • Jaundice • Loss of sexual hair • Liver "flap" = asterixis   (coarse hand tremor) • Bleeding tendency   (decreased prothrombin)

 

• Anemia • Ankle edema

Cirrho (Greek) = tawny yellow.

Diffuse fibrosis of liver, destroys normal architecture. Nodular regeneration. Micronodular:nodules< 3mm, uniform size. Due to metabolic insult (e.g., alcohol). Macronodular: nodules > 3mm, varied vari ed size. Usu U suall ally y due due to significant liver injury leading to hepatic necrosis (e.g., postinfectious or druginduced hepatitis). I ncreased ri rissk of  hepatocellular carcinoma.

U C V  Anat.26,  Anat.26, Path1.60

 Alcoho  Alc oholic lic h hepat epatit itis is

U C V Path3.28

Budd–Chiari syndrome U C V Path3.30

Swollen and necrotic hepatocytes, neutrophil infiltration, A Scotch and T onic: Mall allory ory bodies(hyal hyaline), fatty change, and sclerosi clerosis vated (>A (>A LT LT)) AST elevated AST arou round nd central ntral vein. vein. SGOT SGOT (A ST ST)) to SGPT (ALT (A LT)) with alcoholic hepa hepatitis titi s. ratio is usually greater than 1.5. Occlusion of IVC or hepatic veins with centrilobular congestion and necrosis, leading to congestive liver disease (hepatomegaly, ascites, abdominal pain, and eventual liver fail failure). A ssociated ociatedwith with polycy polycythem themiia vera, pregnancy, hepatocell hepatocellular ular carcinoma carcinoma.

22 228 8

 

Wilson’s disease

Due to fai failure of copp coppe er to enter cir circulati culation on in the form of ceruloplasmin. Leads to copper accumulation, especi ciall ally y in liver, ver, brain, cornea. A lso known as hepatolenticular degeneration. Wilson’s disease is characterized by: Asterixis Basal ganglia degeneration

Treat Treat wi with pe peni nicil cilllamine.

ABCD

Ceruloplasmin ↓, Cirrhosis, Corneal deposits (Kayser–Fleischer rings), Copper accumulation, Carcinoma (hepatocellular), Choreiform

U C V Bio.83, Path1 Path1.72 .72

Hemochromatosis

UCV

movements Dementia Increas ncreasediron deposition ti on in m many any organs. Classic triad triad Total Total body body iron mayreach reach 50 50 g, of micronodular cronodular pigment pigment ci cirrh rrhos osiis, “bronze” di diab abete etes, s, enough to set off the metal ski kin n pigmentati pigmentation. on. Result ultss in CHF and an increased de detectors tectors at air airports. ports. ri risk sk of hepatocell tocellular carcinoma carcinoma. Di Dise sease may be a Tr Trea eat with with repeated ated phl phleeprima prim ary (autos (autosomal rec rece essive ve)) disorde disorder or seconda condary bo botom tomy y, d de eferoxa feroxam mine ne.. to chronic transfusion therapy. ↑ ferritin, ↑ trans transferrin ferrin saturation. aturation.

Path1.59, 1. 59, Path3.42 3. 42

Hereditary hyperbilirubinemias Cri rig gler–N r–Najjar ajjar synd ndro rom me, typ type I

Gilbe Gilb ert’s syndrome

Dubin–JJohnson Dubin– syndrome

A bsent UDPDP-g glucuronyl ucuronyl transfera transferasse. Presents early in life; life; p pa atient tientss die within ithin a few years.   Bio.46 Findings: jaundice, kernicterus (bilirubin deposition in brain), ↑ unconjugated bilirubin.  Tre  Treatment: plas lasmapheresis and phototh tothe erapy. Mild Mildly ly ↓ UDP DP--glucuronyl transferase transferase. A symptomati tic, c, but unconjug unconjugated ated bil biliirubin rubin is elevated elevated without without overt hem hemol olys ysis. A ssociate ociated d wit with h stress stress.   Bio.48 Conjug onj ugated ated hyperbi rbillirubinem rubinemia dueto de defecti fective ve liver excretion. Grossly black liver.   Bio.47 

U C V Path1. 61

Reye’s syndrome

U C V Pharm. 95

Gilbe bert’s rt’s may repres represent a milder form form.. Rotor’s Rotor’ssyndrom yndrome is similar but less severe and doesnot not cause black liver.

UCV

Hepatocellular carcinoma

Cri rig gler– r–N Najj ajjar ar typeI is a severe vere di dise sease.

A lso call called ed hepatoma. toma. Most comm common pri prim mary mali alig gnant Hep epatoce atocelllul ular ar carcinoma carcinoma, lilike ke tumor tum or of the liver in adult adultss. Increas ncreasedincide ncidence nce of renal renal ce celll carcinoma, carcinoma, is comcomhepatocell tocellul ular ar carcinoma carcinomais associate ociated d with with hepati titi tiss monl only y spread by hematoB and C, Wilson’sdise disease, hemochrom ochromatosis, atosis, genousdi diss ssemination. nati on. α1-anti -antitryps trypsin deficiency ficiency, alcoholi alcoholic cirrhos cirrhosiis, and carcinogens (e.g., aflatoxin B1). Rare, often fata fatall childh chil dhoo ood d he hepatoencepha phalopathy lopathy. “Don’t “Don’t give you ourr b ba abya baby Findingss: fatty lilive Finding verr (microve (microvesicular icular fatty fatty chang nge e), hypohypoaspirin.” glycemia, coma. As A ssociated with viral vi ral infection i nfection (especi peciall ally y VZV and influenza nfluenzaB) and sali alicylates cylates;; thus thus aspirin is no longer recommended for children (use ace acetaminophen, nophen, with cauti caution) on)..

22 229 9

 

PATHOLOGY— PATHOL OGY— GAS GASTROINTEST TROINTESTII NAL (co n t i n u e d )

Gallstones

Cystic duct

Hepatic duct Stone in the common bile duct

Pancreatic Fibrosed gallbladder duct with gallstones

 Acut  Ac ute e pancre pancreati atittis

U C V Path1.44

Pancreatic adenocarcinoma

Formwhen hen ssolub olubililizing izingbile acids acidsand lecithi lecithin n are are o ove verrwhelm lme ed by inc incre reased ch chole olesstero teroll a and nd/o /orr bili biliru rub bin.  Thre  Thr ee typ types of ston tones: 1. Chole holesterol stones: associated with obesity, ty, Crohn Cro hn’’s dise isease, cystic fibro rossis, is, advanc nce ed age, cl clofibra ofibrate, te, estr trog ogens ens, mul ulti tipa pari rity, ty, rapid weight loss, and Native Ame American origin. 2. Mixed stones: tones: have both choles cholesterol and pigment components. Most common type. 3. Pig Pi gment stones stones: sse een iin n pati patients entswith chroni chronic c RBC hemolysis, alcoholic cirrhosis, advanced age, and bil biliary iary infection. Diagnose with ultrasound. Treat with cholecystectomy.

Ri Rissk factors factors(4 F’s): 1. Femal ale e 2. Fat 3. Fertile 4. Forty Maypresent with with “Charcot’s “Charcot’s triad” of epigastric/RUQ pa paiin, feve fever, r, nausea/emesis.

Causes: Gallstones, Ethanol, Trauma, Steroids, GET SMASHe MASHeD D Mumps, Autoi utoimm mmune dise disease; Scorpion sting, Hyperlipidemia, Drugs. Clinical presentation: epigastric abdominal pain radiating to back. Labs: elevated amylase, lipase. Can lle ead to DIC DI C, A RDS, diffuse fat necros necrosis, hypocalcemia, and pseudocyst formation. Chronic hronic pancre pancreatit atitiis is strongly strongly associated with alcoholis alcoholi sm. Pr Prognosis ognosis averages 6 months onths or less; very aggressive; usually usuall y already already metastasized at presentation; tumors more common in pancreatic head (obstructive jaundice). Often presents with: 1. A bd bdom omina nall pain radiating radiating to bac back k 2. Weig Weight ht loss 3. A no nore rexia 4. Migratory throm thrombophlebit bophlebitiis (Trous Trousseau’ssyndrome) yndrome) 5. Pancreatic Pancreatic duct obstruction tructi on (m (malabs alabsorption orption with pa pallpa pable ble gall allbladd bladde er)

U C V Path1.66

23 230 0

 

PAT PATHOL HOLOGY— OGY—RES RESPI PIRAT RATORY  ORY 

Obstructive lung disease

U C V Path2. 55

Restrictive lung disease

UCV

Pulmonary flow volume loops

 Asbes  Asb esttos osis is

U C V Path2. 58

Obstruction of air flow, resulting in air trapping in the lungs. Pulmonary function tests: decreased FEV 1/FVC ratio (hallmark).  Typ  Ty pes: 1. Chronic Bronchiti itis s (“Blue Bloater”)—productive cough for greater than 3 consecutive months in two or more years. Hypertrophy of mucus-secreting glands in the bronchioles (Reid index > 50%). Leading cause is smoking. Findings: wheezing, crackles crackl es, cyanosis. cyanosis.   Path2. 54 2. Emphy ys sema(“pink puffer”)—enlargement of air spaces and decreased recoil resulting from destruction of alveolar walls. Caused by smoking (centriacinar emphysema) and α1-antitrypsin deficiency (panacinar emphysema and liver cirrhosis) → ↑ elastase activity. Findings: dyspnea, ↓ breath sounds, tachycardia, ↓ I/E ratio.   Path2 Path2.54, .54, 3.91 3. Asthma—bronchial hyper-responsiveness causes reversible bronchoconstriction. Can betri trig ggered by viral U RI s, all allergens, and stress. F Fiindi ndings ngs: cough, cough, wheez wheezing, dyspnea, tachypnea, hypoxemia, ↓ I/E rati ratio, o, puls pulsuspa paradoxus radoxus.   Path2. 53 4. Bronchiectasis—chroni —chronic c necrotizing necrotizing infecti infection on of bronchi → dilated airways, purulent sputum sputum,, recurrent infecti infections, ons, hem hemoptysi optysis. As Associated with with bronchial bronchi al obstruction, cystic fibrosis, poor ciliary motility. Restricted lung Restricted lung expansion causesdecrea decreassed lung volum volumes(de decrea crease sed VC V C and TL TLC). PFTs: FEV/FVC ratio > 80%.  Typ  Ty pes: 1. Poor breathing thi ng mechanics (extrapu (extrapullmonary) onary): a. Poor mus muscular effort effort:: poli polio, o, myasthenia g gravis. ravis. b. Poor appa apparatus ratus: scolios coli osiis. 2. Poor lung expansi nsion (pulmona (pulmonary): ry): a. Defecti Defective ve alveol veolar ar fil filling: ng: pneum pneumonia, onia, ARD A RDS, S, pulmonary pulmonary ede dem ma.   Bio97, Path2.52 2. 52 b. Intersti nterstiti tial al fibrosi fibrosis: caus causesincreased recoi recoill (decreasedcompli pliance ance), tthere hereby lim limiti ting ng alv alveol eolar ar expansi nsion. on. Compli plica cati tions onsinclude ncludecor pulmona pulmonale. C Can an be seen in diffuse interstitial pulmonary fibrosis and bleomycin toxicity. Symptoms incl clude ude gradual progressiv sive e dyspnea and cough.   Path3.93

Normal Restrictive Obstructive

Resistance

FVC

– ↓ ↑

– ↓ ↓

FEV1 (FEV1/FVC) × 100

– ↓ ↓↓

>80% >80% <80%

Di Diffuse ffusepulmonary interstiti nterstitial al fibrosis fibrosis caus caused by inhaled nhaled asbestosfib fibe ers. rs. IIncre ncreased risk risk of pleu pleura rall mesotheli otheliom oma and b bronc ronchog hogenic carcinom carcinoma. L Long onglatency latency. Ferru Ferru-gin ginous ous bodies bodiesin lung (asbestos fibe fibers rs coated with with hemosiderin). Ivory-white pleural plaques.

Smokers Smokers have synergi nergisticall ti cally y higher ri rissk of cance cancer. See Seen iin n ship ship buil builde ders and pl plum umbers. bers.

23 231 1

 

PATHOLOGY— PATHOL OGY— RES RESPI PIRAT RATORY ORY ( co n t i n u e d )

Neonatal respiratory distress syndrome

Surfactant deficiency leading to ↑ surface tension, resulting in alveolar coll collaps apse. Surf Surfactant actant is i s made ade by type type IIII pneum pneumocytesmost abundantl abundantly y after 35th wk of gestation. tation. T he lecithi lecithin-t n-to-sp o-sphi hing ngom omyelin ratio rati o iin n tthe he am amni nioti otic c fluid, a measure of of llung ung maturity, is usually less than 1.5 in neonatal respiratory distress syndrome. Surfactant: dipalmitoyl phosphatidylcholine. Prevention: maternal steroids before birth; artificial surfactant for infant.

U C V Bio.101

Kartagener’s syndrome U C V Bio.68

Immotil oti le cili cil ia due due to a dynein dynein armde defect. fect. Res Resul ults ts in situs situs invers inversus us,, sterili steril ity (s (spe perm rm also immotile), and bronchiectasis and recurrent sinusitis (bacteria and particles not pushed out).

Lung cancer Bronchogenic carcinoma

Tumors that arise centrally: 1. Squ quam amouscel cell carci carcinom noma—cl a—cle ear lliink to Smoking king 2. Small cell carcinoma—clear link to Smokin king g; associate iated with with ec ectop topic ho horm rmonepro rod duction tion  Tum  Tu mors th tha at ari risse periph ipherally: lly: 1. Ad A denocarcinoma 2. Bronchioalveolar Bronchioalveolar carcinom carcinoma a (thought (thought not to be related to smoking) 3. Larg rge e cel cell carcinom carcinoma a—undifferentia ntiated ted Can Can c ca ause carc rcino inoid id syndro ndrom me. Verycommon. Brain (ep (epilep ilepsy), bone (p (pa ath tho olo log gic fracture), and liver (jaundice, hepatomegaly).

Lung cancer is the leading cause of canc nce er death. th. Pr Pre esenta ntation: tion: cough, hemoptytysis, is, b bro ronc nchia hiall obstr tru uction, tion, wheezin ing g, pneumonic “coin in”” lesion on x-ray. SPHERE of complications: Superi rior or vena vena caval syndrome Pancoast’s tumor Horner’s syndrome Endocrine (paraneoplastic) Recurrent laryngeal symptoms (hoarseness) Effusions (pleural or pericardial)

Type

Organism(s)

Characteristics

Lobar

Pneumococcus most frequently

I ntra-alveolar exudate →

Carc Carcino inoid id tu tumor Meta Me tastases

U C V Path2.57 

Pneumonia

aureu reus, s, H. H . flu, K Kle leb bsiella siella,, S. pyogene geness Bronchopneumonia   S. au

 Myco oplasma, Leg Legio ion nella lla Inters nterstitia titi al pne neu umonia onia Viruses, Myc

Pancoast’s tumor

Carcinoma arcinomathat occurs occurs in apex apex of lung and may affect cervical cervi cal sympa patheti thetic c pl plexu exuss, causing causing Horner’s syndrome.

23 232 2

consolidation; may involve entire lung A cute inflammatory infiltr infil trate atess from bronchioles into adjacent alveoli; patchy distribution invo i nvolvi lving ng≥ 1 lobes. Diffuse patchy inflammation localized to interstitial areas at alveolar walls; distribution invo i nvolvi lving ng≥ 1 lobes Horner’s syndrome: yndrome: ptosis, miosis, anhidros anhidrosiis.

 

PATHOL HOLOGY— OGY—NEUROL NEUROLOGI OGIC C PAT

Degenerative diseases Cerebral cortex

Basal ganglia and brains instem

Spinocerebellar Motor neuron

comm mon caus cause of de dem mentia entia Alzheimer’s disease: most com

Mul ulti ti-i-infarct nfarct de dem mentia entia is the second most c co ommon ca cause of dementia in the elderly lderly..

in the the eld lde erly. A Asssocia iate ted d with senile plaq laques (β amyloi loid d co core re)) and and neur neurofi ofibr brilillary lary tang tangles les(abnor (abnor-mally phosphorylated tau protein). Familial form (10%) associated with genes on chromosomes 1, 14, 19 (A po po-E4 -E4 alle all ele), and 21 (p-App (p-A pp gene ne). ).   Path3.45 Pi Pick’s ck’s disease: associated with Pick bodies and is specific for the frontal and temporal lobes. Hunting untington’s disease: autosomal dominant inheritance, chorea, de dementia. ia. At Atrrophy of caudatenucle leu us.   Pat Path3.5 h3.52 2 Parkiinson’s disease: associated with Lewy bodies and Park TRAP =Tremor (at rest), depigmentation entati on of th the e su subs bstant tantiia ni nigra. gra. Rare cases cogwheel Rigidity, Akinesia, have been been linked to exp expos osure ure to MPTP PT P, a contami contaminant and Postural instability (you in illicit street drugs.   A na nat.50, t.50, Path2.23 Path2.23 are TRAPped in your body). Olivopontocerebellar ellar atrophy Fri Frie edreich’sataxi xia a   Path2. 14 Amyotrophic lateral sclerosis (A (AL LS): is associate ociated d with both lower and upper motor neuron signs.   Path2. 8 Werdnig–H Werdnig– Hoffm offmann disease: presents at birth as a

Comm ommonl only y known asLou Gehrig’s disease.

“floppy baby”; tongue fasciculations. Polio: lower motor neuron signs.

UCV

Brain tumors Adult Adu lt

Child Chil dhood

Seventypercent above tentor toriu ium m (e.g (e.g., cerebral hemispheres). Incidence: nci dence: metastases> astrocytoma(including ncluding glioblastoma) > meningioma. Seventypercent below low tentor toriu ium m (e.g (e.g., cerebellu llum m). Incide ncidence: nce: astrocytom trocytoma a > medulloblastoma > ependymoma.

Gliob Gliobla lassto tom ma multi ltifo forrme: necrosis, hemorrhage, and pseudo-pal udo-palisad adiing; “butt “butterfl erfly” y” glioma; very poor prognosis.

UCV  Anat.35,  Anat.35, Path2.15, 18, 18, 19, Path3.56

Intracranial hemorrhage Epidu Epidura rall hematoma Subdura Subd urall hematoma Subarachnoid Subarachnoi d hemorrha rrhage Parenchymal hematoma

Rupture Ruptureof middle iddle meninge ningeal artery, often often 2° to fracture of temporal bone. Lucid interval. Rupture of bridgi bridging vei veins. ns. Venousbleeding bleeding (le (l ess pres pressure) ure) with delaye delayed onset of symptoms. Seen in elderly individuals, alcoholics, blunt trauma. Rupture of an aneurys aneurysm (usua uallly be berry rry aneurys aneurysm) or an AV AVM M. Patients Pati ents complai complain n of “worst headacheof my my life.” Bloo Bloody or xa xant ntho hoc chr hro omic spinal tap tap. Cause aused by hypertension, rtension, amyloi yloid d angiopathy, opathy, diabetes diabetes mell elliitus, and tumor. tumor.

U C V Pa Path th2.13, 25, 26

Berry aneurysms

U C V Path2. 9

Berry aneurysms occur at the bifurcations in the circle of Willis. Most common site is bifurcation of the anterior communicating artery. Rupture (most common complication) leadsto h he emorrhag orrhagic strok stroke. e. As A ssociate ociated d with with adu adullt polycy polycysstic ti c kidne ki dney y disease, Ehlers Ehlers– Danlos Danl os syndrome syndrome a and nd Marfan’s M arfan’s dise disease.

23 233 3

 

PATHOL OGY— NEURO NEUROLOGIC LOGIC (co n t i n u e d ) PATHOLOGY—

Demyelinating and 1. Mul hig gher prevalence prevalence with with Multi tip plesclerosis (MS)—hi dysmyelinating greater distance from the equator; periventricular diseases plaques, preservation of axons, loss of oligodendrocytes, reactive oli ctive astrocytic trocytic glios osiis; ↑ protein (IgG) in CSF. Many patients have a relapsing– remitting course. Patients can present with optic neuritis (loss of vision), MLF syndrome (internuclear ophthalmoplegia), hemiparesis, hemisensory symptoms ptoms, or bl bladde adder/bowel r/bowel incontinence.   Path2.20 2. 20

UCV

Guillain–Barré syndrome (acute idiopathic polyneuritis)

U C V Path2.16

Poliomyelitis

UCV

Classic tri triad ad of MS is a SIN: Scanning speech Intention tremor Nystagmus

2. Prog Progressivemulti ultifocal focal lleukoe eukoencephalopathy ((PML PML))— associatedwith J C virus virusand seen iin n 2–4% of A IDS pati tie ents (reactivation of la latent viral infection) nfection)..   Micro2.87  3. Postinfecti Postinfectious ousencephalomyeliti tis s 4. Metachromatic leukodystrophy (a sphingolipidosis)   Bio.72 5. Guil uillain– lain–Barré Barré syndrome—inflammation and demyelination of peripheral nerves; ascending muscle weakness and paralysis beginning in distal lower extremitiies. IIn extremit n some casesit fo folllowsherpesvi virus rus or C . jejun jejuni i infection. CSF shows ↑ protein and normal cells.   Path2.16 2. 16 Sensory and motor neuron loss Sensory oss at the level of th the e peri periphera pherall nervesand motor fibers of th the e ventral roots (sensory effect less severe than motor) otor), caus causing symmetric etri c we weaknes aknesss wi with th variable variable paresth thes esia or dysesthes thesiia. Facial di dipleg plegiia in 50% of cases. A utonomic function may be severely affected (e.g., cardiac cardiac irreg i rregulariti ularitie es, hype hypertensi rtension, or hyp hypotens otension). on). Findings: elevated CSF protein with normal cell count.

A ssociatedwith vi viral ral infections, inoculati noculations, ons, and str tres ess, but no de defini finiti tive ve link to pathogens. pathogens.

Caused by poliovirus, which is transmitted by the fecal-oral route. Replicates in the oropharynx and small intestine ntestine before before spreadi ding ng through the bloodstream bloodstream to the the CN CNS, where it leads to the destruction of cells in the anterior horn of the spinal cord, leading in turn to LMN destruction. Symptoms: mal malaise, aise, heada headache, che, feve fever, n nau ause sea, abdom abdomiinal pa paiin, sorethroat. throat. Si Sig gns of LM L MN lesions: muscle weakness and atrophy, fasciculations, fibrillation, and hyporeflexia. Findings: CSF with lymphocytic pleocytosis with slight elevation of protein. Virus recovered from stool or throat.

23 234 4

 

Seizures

Partia iall seizures: one area of the brain in.. 1. Si Sim mple pa part rtiial (aware awarenes ness intact): ntact) : motor, sensory, autonomic, psychic. 2. Comple lex x pa part rtia iall (imp (impaired awareness). Generalized seizures: diffuse. 1. Ab Abssence: blan lank stare (pe (petit mal). l). 2. Myo Myoclo lon nic ic:: quic ick k, repetit itiv ive e jerks. 3. Tonic-cl Toni c-cloni onic: c: alternating stiffenin tiffening g and movem ovement (grand mal). 4. Tonic: stiffening. 5. A tonic: “drop” seizures.

Broca’s versus Wernicke’s aphasia UCV

Broca’s is nonfluent aphasia with intact comprehension (expressive aphasia). Wernicke’s is fluent aphasia with im i mpaire ired d com compre rehe hens nsion (rece (receptive apha hassia). Broca’s area = inferior frontal gyrus. Wernicke’s area = superior temporal gyrus.

Epil ile epsy isa disorder of recurrent seizures eizures (febrile febril e seizures are not epilepsy). Part Partia iall sse eizu izures can seconda ndarily generalize. Ca Cau uses of seizures by age: Chil Child dren: genetic ic,, in inffectio ion n, trauma, conge congeni nital, tal, metabolic. A dults: tumors, trauma, stroke, infection. Elderly: stroke, tumor, trauma, metabolic, infection. BROca’s is BROken speech; Wernicke’s is Wordy but

makes kes no sens nse e.

Path3. 47 

Horner’s syndrome Sympathectomy of face: 1. Ptosis Ptosis (sli (slig ght drooping drooping of eye eyelilid) d) 2. Miosis iosis (pupil (pupil constriction) triction) 3. A nhi nhidros drosis (abs (absence of sswe weating) and flus flushi hing ng (rubor) of affected affected sideof face A ssociated wi with Pancoast’s tumor. tumor.

Syringomyelia

U C V Path2. 27 

Ta bes dorsa dorsalis lis U C V  Anat.53  Anat.53

 Syrinx (Greek) = tube, as in Softening and cavitation around central canal of spinal  Syrinx cord. Crossing fibers of spin pinothal othalam amic tract are syri ringe nge. dam damaged ed.. Bi Billateral ateral lossof pain and tempe perature rature Often presents in pa pati tients ents with with sensation ation in upper upper extremiti ties eswith with preservation of A rnold–C rnold–Chi hiari ari malformation. alformation. touch sensation.

Degeneration rati on of dorsal colum columns and dorsa dorsal roots roots dueto 3° syphili yphil is, res resul ulti ting ng in iim mpa paiired propri prop rioce oception and locom locomotor ata ataxia. xia. A ssociated ociated wi with Charcot harcot jjoint ointss, shooting (l (lightni ning) ng) pain, pain, A rgyl rgyll–Robertson obertson pupils pupil s, and absence of deep tendon reflexes.

23 235 5

 

PATHOL OGY— RHEU RHEUMAT MATII C/ AUTOIMMUNE AUTOI MMUNE PATHOLOGY—

Osteoarthritis

Mechanical: wear and tear of joints leads to destruction of articular cartilage, subchondral bone formati formation, on, sclerosi sclerosis, osteophyte osteophytess, eburnation, eburnation, and Heb Heberde erden’s nodes (DI (DIP) P).. Common in older patients. Classic presentation: pain in weight-bearing joints after use (e.g., at the end of the day), improving with rest. No systemic symptoms. Normal

Osteoarthritis

Thickened capsule

Capsule

Slight synovial hypertrophy Osteophyte

Synovium

Ulcerated, narrowed cartilage

Cartilage

Sclerotic bone Bone U C V Path3.98

Rheumatoid arthritis

U C V Path2.80

Gout

U C V Bio.13, Path3 Path3.96 .96

Pseudogout

U C V Path3.102

Celiac sprue U C V Path1.51

A utoim utoimmune: inflammatory di disorder affecting affecting synovial ynovial joi joints, nts, with with pa pannus nnus formati formation on in in  join  joints ts(MCP, (MCP, PIP), PIP), subcutaneous rheumato toid id nodule less, uln lna ar devia iatio tion n, sublu lux xati tio on. Comm ommon in in females. ales. Ei Eig ghty percent percent of RA RA patients patients have positive ti ve rheum rheumatoid atoid factor (anti-I (an ti-Ig gG Ab A b). Classic presentation: morning stiffness improving with use, symmetric joint involvement and systemic symptoms: fever, fatigue, pleuritis, pericarditis. Precipitation of monosodium urate crystals into joints due to hyperuricemia, which can be caused by Lesch–Nyhan disease, PRPP excess, decreased excretion of uric acid, or glucose -6-phosphatas e de defici A lso sociated sociated with withacid. the the of thi tm hiaz icdejjoin di diureti uretics, bebe-caus cause the they y competiti ti tive vel lyficiency inhi inhency ibit.the se seas cretion of uric aci d.us As Aesym eaz tri tric oint t di disscs, tri tribu bution. ti on. Favored Favored manifestation tation is is pai painful MT P jjoin ointt iin n the bi big toe (podagra). Tophu Tophuss formation (often on external ear). Crystals are needle-shaped and negatively birefringent.  Tr  Tre eatment isallop llopurin ino ol, probenecid id,, colc lch hic icin ine e, and NSAIDs. Mor More common in men. Caused by deposition of calcium pyrophosphate crystals within the joint space. Forms basophilic, rhomboid crystals (as opposed to the birefringent, needle-shaped crystals in gout). out). Us U sua uallly affects affects large joi oint ntss (cl clas assicall sically the knee) knee). >50 >50 yearsol old; d; both sexes sexes affected equally. No treatment. A utoimmune-me une-mediated int intolerance oleranceof gliad gli adiin ((whe wheat). A ssociated wi with people of northern European descent, blunting of villi, lymphocytes in the lamina propria, and abnormal D-xylose test. Steatorrhea.

23 236 6

 

Systemic lupus erythematosus

U C V Path2.82, 2. 82, Path3.107  3. 107 

Sarcoidosis

U C V Path3. 94

Reiter’s syndrome

90% are female and between ages 14 and 45. Fever, fatigue, weight loss oss. J oin ointt pai pain, malar rash, photosensi nsitivi ti vity ty,, pleuritis pleuriti s, peri ricard cardiitis ti s, nonbacterial nonbacterial verrucous endocarditi endocarditis, s, Raynaud’s aynaud’sphenomenon. non. Wire Wir e looplesions in ki kidne dney y with immune com comple lex x deposition (w (with ith ne nephrotic hrotic syndro ndrom me); death from renal fail failure ure and infections. False positive ti vess on syphi yphillis tests (RPR/ RPR/V VDRL DRL). Labtests detect presence of: 1. A ntinuclea ntinuclearr antibod antibodies ies(A NA ): sensiti nsitive ve,, but but not specific for SLE 2. A ntibodies ntibodiesto double-s ble-stra trand nde ed DNA DNA (anti-ds DNA DN A ): ve very ry specific 3. A nti-Smith nti-Smith anti antibod bodies ies(anti-Sm): (anti-Sm): very specific A ssociated with restri tricti ctive ve lung di disease, bilate bil ateral ral h hiilar lymphadenopathy, erythema nodosum, Bell’s palsy, epitheli pithelial al granul ranulomas omas containi containing ng mi microscopic croscopic Schaumann and asteroid bodies, uveoparotitis, and hypercalcemia (due to elevated conversion of vit. D to iits ts acti active ve formin epi epithelioid theli oid macrophag crophages). A lso associated with immune-mediated, widespread noncas non caseati ting ng granuloma ranul omas and elevated serum AC A CE levels. Common in black females.

SLE causes LSE (Libman– Sacks Endocarditis).

Mos ostt common and severe vere in bl black ack femal females es. Drugs Drugs (procai procainamide, INH, phenyto nytoin, in, hy hydra rala lazzine) ine) can produce produce an SL SLE-l E-liike syndrom yndrome e that is commonl only y reversible.   Pharm. 77 

GRAIN: Gammaglobulinemia Rheumatoid arthritis ACE ↑ Interstitial fibrosis Noncaseating granulomas

A seronegative spondyloarthropa pondyloarthropathy thy.. Strong HLA -B27 link. Classic triad: 1. Ur U rethritis 2. Co Con njunctiv iviitis and anterior ior uveitis itis 3. A rthritis Has a strong predilection for males.

“C “Can’t an’t see (anteri anterior or uveiti tiss/ conjunctivitis), can’t pee (urethritis), can’t climb a tree (arthritis).” Post-GI or chlamydia infections.

Sjögren’s syndrome Classic tri triad ad:: dry eyes (conjunctivi conjuncti viti tiss, xerophthalmia), xerophthalmia),

A ssociated with rheum rheumatoid

U C V Path2. 79

dry mouth (dys dyspha phag gia, xeros xerostom tomiia), arthriti arthritiss. Parotid Parotid enlargement, ↑ ri rissk of B-cell B-cell lymphoma. phoma. Predominantly affects females alesbetwe between en 40 and 60 years of age. U C V Path2. 81

Scleroderma (progressive systemic sclerosis–PSS)

U C V Path2. 78

arthriti arthritiss. Si Sicca cca syndrome: dry eyes, dry mouth, nasal and vagi vaginal dryness, chronic bronchitis, reflux esophagitis.

Excessive fibrosis a and nd coll col lagen depos deposiition ti on tthroughout hroughout the the body. 75% female. Com C omm monl only y scl cleros erosis of ski skin n but als also of cardiovascul cardiovascular and GI systems and kidney ki dney. T Two wo major categories: 1. Diffuse scleroderma: widespread skin involvement, rapid progression, early visceral involve nvolvem ment. A ssociated with anti-Scl anti- Scl-70 -70 anti antibod body y. 2. CREST syndrome: Calcinosis, Raynau aynaud’s d’sphenomenon, Esop sophag hageal dysmoti otillity, Limited ski kin n involve nvolvem ment, often confined confined to Sclerodactyly, and Telangiectasia. Li fingersand face. fingers face. More M ore benign benign cli clini nical cal course. A ssociate ociated dw wiith anticentrome anti centromere antibody.

23 237 7

 

PATHOL OGY— RHEU RHEUMAT MATII C/ AUTOIMMUNE AUTOI MMUNE (co n t i n u e d ) PATHOLOGY—

Goodpasture’s syndrome

Fi Findi ndings ngs: pulmonary hemorrhag orrhages, renal lesions, hemoptysis, optysis, hematuria, aturi a, anemia, crescenti ntic glomerulonephritis. A nti nti-gl -glom omerular erular bas basement membrane anti antibodies bodies pr prod oduc uce e liline nea ar sta staini ining ng on imm immun unofl ofluo uore resscence.

T here are two Good Pastures for th thiis di dise sease: Glomerulus and Pul ulm monary onary.. A lso, a type II hypersensitivity disease. Most co com mmon in men 20–40yo.

U C V Path2.67 

PAT PATHOL HOLOGY— OGY— ENDO ENDOCRI CRINE/ NE/ REPRODUCTIVE

Cushing’s syndrome

Increased cortis corti sol dueto a variety variety of causes causes. Etiologies include: 1. Cushi hing’ ng’ss disease (1˚ pituit pituitary ary ad adenom enoma); ↑ ACTH 2. 1˚ ad adrena renall ((hyp hype erplasi rplasia/neoplas a/neoplasia); ↓ ACTH 3. Ectopic Ectopic ACT AC T H produc production tion (eg, carcinoid); ↑ ACTH 4. I atrog trogenic; ↓ ACTH  The clin linic ica al pic pictu ture rein inc clu lud des hypertensio ion n, weig igh ht gain in,, moon facie iess, tr tru uncal ob obesity, buffalo hump, hyperglycemia (insulin resistance), skin changes (thinning, striae), osteoporosis, and immune suppression.

Hyperaldosteronism Pri Primary (Conn’s synd ndro rom me) Secondary Seconda ry

U C V Bio.8, Path Path3.35

 Addiso  Addi son’ n’ss disease U C V Bio.5, Path Path3.23

Tumors of the adrenal medulla

Cause aused by an aldosterone-secre aldosterone-secreti ting ng tumor, tumor, resul ulti ting ng in hy hyp pert rte ension, ion, hy hyp pokale lem mia, ia, meta tab bolic alkalosis, and low plasma renin. Due to renal artery stenosis, chroni chronic renal fai faillure, CHF, cirrhosis, or nephrotic syndrome. Kidney perception of low intravascular volume results in an overactive racti ve reninrenin-ang angiotens otensiin ssys ystem. T Therefore, herefore, it is associated with high pl plas asma renin. renin.

Tr Trea eatment include ncludes spiro irono nola lac cto tone ne, a diu iure retic that works by acting as an aldosterone antagoni onisst.

Deficiency of aldosterone and cortisol due to adrenal atrophy, causing hypotension (hyponatremic volume contraction) and skin hyperpigmentation ( ↑ MSH). SH). Characterized by three c cortical ortical Adrenal Atrophy and Absence of hormone production; involves All three divisions. Pheochromocytomais th the e most common tumor of th the e

adrenal medulla in adults. Neuroblastomais th the e most common tumor of th the e adrena nall medu dulllla a in childre chil dren, bu butt it ca can n occur occur anywhere along the sympathetic chain.

23 238 8

Ph Pheochromocytomas eochromocytomasmay be associated with neurofibromatosis, tosis, MEN type I I, and MEN typ type e I II.

 

Pheochromocytoma Most of th thes ese neoplas neoplasms secrete a combinati combination on of

U C V Bio.30

Rul ule e of 10s: norepiinephri norep nephrine ne and epinephrine. Uri Urinary nary V MA level vels 10% malignant and plasma catecho catechollamines are elevated. Ass A ssoci ociated ated 10% bilateral with MEN type II and type III. Treated with α 10% extraadrenal antagonists, especially phenoxybenzamine, 10% calcify a nonselective, irreversibleα blocker. 10% kids Episodic hyperadrenergic symptoms (5 P’s): 10% familial Pressure (elevated blood pressure) Pain (headache) Perspiration Palpitations Pallor/diaphoresis

Hypothyroidism and hyperthyroidism Hypot Hyp othy hyro roidis idism

Hype Hyp erthyro rthyroidis idism m

Grave Gra ves’ dise isease

Cold intole intolera ranc nce e, h hy ypoactivity ctivity, w we eig ight ht gain, fa fatig tigu ue, lethargy, ↓ appetite ite, constipa ipation ion, weakness, ↓ reflexes, myxedema (facial/periorbital), dry, cool skin, and coarse, brittle hair.   Path1.33 Heat intole intolera ranc nce e, hyperactivity ractivity, w we eig ight ht los loss, c che hesst pa pain/ pal palpitations, pitations, arrhythmias, diarrhea, ↑ reflexes, warm, moist skin, and fine hair.   Path1.30 Oph Ophtha thalm lmop opa athy (prop (proptosis, is, EOM swelllling ing), ), pre retibia tibiall myxedema, diff diffuse use goiter. oiter.   Bio.14, Pa Path th3.25

↑ TSH (s (se ensiti itiv ve test for 1° hypothyroid idis ism m), ↓ total T4, ↓ freeT 4, ↓ T3 uptake.

Endemic cretini cretinissm occurs whereve whereverr endemic goi oiter ter is prevalent pre valent (lack ack of dietaryiodine); sporadic poradic cretini creti nism smis caus caused by de defect fect in T 4 formati formation on or develo lop pment nta al failu ilure rein thy thyroid roid form formation. tion. Fi Findings ndings:: pot-bel pot-bellied, pal pale, pu puffy-face ffy-faced d chil child with protr rotru udingumbilicu ilicus and pro rotu tub berant tong tongue.

Creti retin n means Chri hrisst-l t-like (French chrétien). Those affectedwere considered considered so menta ntally retard rde ed as to be incapab ncapablle of sinni nning ng.. Stil Sti ll common in China China.

UCV

Cretinism

U C V Path1. 25

↓ TSH (if 1°), ↑ total T4, ↑ freeT 4, ↑ T3 uptake. A n autoimmune hy hyp perthyrthyroidism with thyroid stimulati ting ng/T /TSH SH re rece ceptor ptor antibodies.

23 239 9

 

PATHOLOGY— PATHOL OGY— ENDO ENDOCRI CRINE/ NE/ REPRODUCTI REPRODUCTI VE (co n t i n u e d )

Diabetes mellitus A cute cute manifestations Polydips Polydipsia, ia, polyuria, polypha polyphagia, weight loss loss, DKA DK A (I (IDDM DDM), ), hy hype perosmolar com coma (NI (NIDDM), DDM ), unopposed secretion of GH and epinephrine (exacerbating hyperglycemia). Insulin deficiency (and glucagon excess)

Decreased glucose uptake

Increased protein catabolism

Increased lipolysis

Hyperglycemia, glycosuria, osmotic diuresis, electrolyte depletion

Increased plasma amino acids, nitrogen loss in urine

Increased plasma FFAs, ketogenesis, ketonuria, ketonemia

Dehydration, acidosis

Coma, death

Chronic hroni c manife nifessta tations tions

 Tests

Nonenz onenzym ymatic glycos ycosylati ylation on 1. Small vessel dise disease (diffus (diffuse thickening of BM) BM),, retinop retinopa athy (hem (hemor orrha rhage, e exu xud dates tes, microaneurysms), nephropathy (nodular sclerosis, progressive proteinuria, chronic renal fail failure ure,, arteri arterios oscleros clerosiis lead adiing to HT HT N) 2. Large arge vessel atherosclerosis, coronary artery diseas disease, peri riphera pherall vascular occlus occl usive dise di seaseand gangrene, cerebrov cerebrovas ascular cul ar dise disease 3. Neu europathy ropathy (motor, sens sensory ory,, and autonomic degenerati ration) on) 4. Cataracts, cts, glauc ucom oma Fastin ting serum glu luc cose, glu luc cose tole tolerrance test, Hb HbA A lc (measures long-term diabetic control)

U C V Path1.27, 1. 27, 28

24 240 0

 

Type I vs. type II diabetes mellitus

Incidence Insulin necessary in treatment A ge (exceptions commonly occur) A ssociation with obesity Genetic predisposition A ssociation with HLA system Glucose intolerance Ketoacidosis Beta cell numbers in the islets Serum insulin level Classic symptoms of polyuria, polydipsia, thirst, weight loss Basic cause

Diabet ia betes es iinsipidus nsipidus

Find inding ings  Tr  Tre eatment U C V Bio.10

SIADH

U C V Bio.38

Carcinoid syndrome

U C V Bio.45, Path3 Path3.49 .49

TypeI––juvenileonset (IDDM)

Type II––adult onset (NIDDM)

15% A lways Under 30 No Weak, polygenic Yes (HLA DR 3 & 4) Severe Common Reduced Reduced Common

85% Sometimes Over 40 Yes Strong, polygenic No Mild to moderate Rare Variable Variable Sometimes

?Vir ira al or or immune destructio ion n of beta cells lls

?In Inc creased resistance to in inssuli lin n

Characterized by intensive thirst and polyuria together with an inability to conce conc entrateurine wi with fluid res restri triction ction owing to lack of ADH A DH (central (central DI) DI ) or to a lack of renal renal response to A ADH DH (nephroge nephrogeni nic c DI) DI ). Cau C aussed bylithium thi umor dem demeclocycline. clocycli ne. Urin Urine e specifi ific c gravity<1.0 .00 06; seru rum m osmola lalit lity y >290 mOsm/L. Adequatefluid in inta take. For centr tra al DI: in intr tra anasal d de esmopressin (ADH an analo log g) o on nce or twice daily. For nephroge nephrogeni nic c DI: DI : hydrochlorothiaz hydrochlorothi azide, iindom ndomethacin, or amilori oride de. Syndrome of inappropri Syndrome nappropriate ate antidi antidiureti uretic c hormone secretion: Excessive water retention Hyponatremia Serumhypo-osmolari olarity ty with with uri urine ne osmol olarit arity y> serum osmolarity Very low serum sodium levels can lead to seizures.

Cau aussesinclude ncl ude: Ectopic A DH (small cell lung cancer) CNS disorders/head trauma Pulm Pul monary disease Drugs

Rule of 1/3s: 1/3s: Rare syndrome caused by carcinoid tumors, especially those of the small bowel; the tumors secrete high 1/3 metastasize levels of serotoni serotonin n (5H (5HT T ) that that does not get metab metabol oliized 1/3 present with second by theliver liver d du ue to liver me metas tastas tases. Re Ressults in re recu currmalig ligna nanc ncy y rent diarr diarrhea hea, cutaneous flushing, asthmatic 1/3 multiple wheezing, and carcinoid heart disease. ↑ 5-HI 5-HIA A A in Trea Treat with oc octre treotide otide. urine.

24 241 1

 

PATHOLOGY— PATHOL OGY— ENDO ENDOCRI CRINE/ NE/ REPRODUCTI REPRODUCTI VE (co n t i n u e d )

Zollinger–Ellison syndrome

Gastrin-secreting tumor that is usually located in the pancreas. Causes recurrent ulcers. May be be associated ociatedwith with MEN M EN syndrometype I.

U C V Path1.73

Multiple endocrine

MEN typeI (Wermer’ssyndrom yndrome e)–pa pancrea ncreas (e.g., ZE

neoplasias (MEN)

spituitary yndrome, yndrome, insulinoma nsulinomas, V IPomas Pomas), pa parathyroi rathyroid d and (PParathyroid). ancreas, Pituitary, and tumors. MEN typeII (Si Sipp pplle’ssyndrom yndrome e)–medu dulllary A ll MEN syndrom yndrome es areau autotocarc rcino inom ma of the the thy thyro roid id,, p phe heochro chrom mocytom toma, somal dom dominant inantly ly inhe inherited. parathyroid tumor or adenoma. MEN type III (formerly MEN IIb)–medullary carcinoma of the thyroid, pheochromocytoma, and oral and intestinal ganglioneuromatosis (mucosal neuromas).

Osteoporosis

Reduction of bone mass in spite Reduction pite of normal normal bone mineralization.

A ffects whites whites>blacks >A sians.

 Typ  Ty pe I

Po Posstmenopausal ((1 10–15 –15 years afte fter menopause);

Vertebral cr crush fractur tures: acute

 Typ  Ty pe II

trogen levels. Tr Trea eated ba back pai osss of height, ↑ ibone w th estresorption rogen repladue cemto en↓t. estrogen kyck phopa siisn, . los Senile osteoporo rossis is—a —afffectsmen and women >70 years. Distal rra adiu iuss (Colle (Colless’) ffrractu ture res, vertebral wedge fractures.

U C V Path3.100

Benign prostatic hypertrophy

U C V Path2. 86

MEN I = 3 “P” organs

Common in men over age 50. May be due to an age-related increase in estradiol with possible sensitization of the prostate to the growth-promoting effects of DHT. Characterized by a nodular enlargement of the periurethral (lateral and middle) lobes of the prostate gland, compressing the urethra into a vertical slit. Often presents with increased frequency of urination, nocturia, difficulty starting and stopping the stream of urine, and dysuria. May lead to distention and hypertrophy of the bladder, hydronephrosis, and urinary tract infections. Not conside considered a premali alig gnant lles esion.

pathol patholog ogiicvil ovum “e mlife pty etion gg ”—ovum withc no DNA DN Aum ) res ult ingblas in cys tiM cost sswe we llingmof oon f Hydatidiform mole A chorionic vill li and(“em proli pro fera rati on of chorionic chorioni e epitheli pithelium (tropho (tulti rophoblas t). t).tic Mos t comm com precursor of choriocarcinoma. High β-HCG. “Honeycombed uterus,” “cluster of grapes” appearance. Genotype of a completemol ole eis 46, XX and is purel purely y paternal in origin (no maternal chromosomes); no associated fetus. Parti Partia al moleis commonly triploid or U C V Path2.40

tetraploid.

24 242 2

 

Breast disease Type Fibrocysti Fi brocystic c disease

Characteristics

Presents with diffuse breast pain and multiple lesions, often bilateral. Biopsy showsfibrocystic ti c elements elements.. U sual ually does not indi indicate cate increa increased risk of carci carcinom noma. a. Hi H istolog tologiic typ type es: Fluid-filled. Inc ncre rea ase in num number of of e ep pitheli ithelia al cell cell layers in term terminal inal duct duct lobu lobule. Increased risk risk of carcinom carcinomawith atypical cells. Occurs >30 yrs. Hyperplasia of breast stroma. In Inc creased acin inii and in inttralob lobular fibrosis.

Cystic Ep Epithe ithelilia al hype hyperplas rplasia Fibrosis Sclerosing Benig Beni gn tu tum mors

Cystosarcom tosarcoma phyl phyllodes Fibro Fib roa adeno nom ma Intraductal pa pap pillom il loma a

Large, bul bulky mass of connecti connective ve tis ti ssueand cysts. Breas Breast ssurfac urface e has“leaflike” “leaflike” appearance. Most c co ommon tum tumor <25 years. Small, mo mobile ile,, fi firm rmmass with sharp edges. ↑ si size ze and tenderness with pregnancy. Tum Tumor of of lactife lactifero rou us ducts; p pre ressentswith nipple nipple dis disch cha arge.

Come Com edoca ocarcinom rcinoma

Common postmenopause. nopause. A Ari rise sefr from om mammary duct duct epithel epitheliiumor llobul obular ar glands. ands. Examples of histologic types: Chee Cheesy cons consis iste tenc ncy y of tu tumor tis tisssue due to ce centr ntra al necr necros osis is..

Infiltra Infiltr ating ting ductal Infl Inflammatory Paget’s disease

Most co common carc rcino inom ma. Firm Firm, fi fib bro rou us mass. Lymphatic in inv volve lvement; poor prognosis. Eczematous patches on nip nipp ple.

Malignant tumors Mali (carcinoma):

PAT PATHOL HOLOGY— OGY— VASCULAR/ CARDIAC

Hypertension Risk factors Features Fea tures Pred Pre disp isposes to Patholog Pathol ogy y

↑ age, obe obessity, diab diabete etess, smoking, oking, genetics netics,, Bl Black ack >Whi hite te >A sian. 90% of HT N is pri prim mary (essenti ential) al) and related to↑ CO or ↑ TPR; remain inin ing g 10% mostly 2˚ to renal disease. Coron Corona ary he hea art dis dise ease, cere reb brova rovascular cular accide ccidents, C CH HF, rena renall failure, a and nd aortic ortic dissection. Hyaline thickening thi ckening and atheros atheroscleros clerosiis.

Pregnancy-induced Preeclampsia is the triad of hypertension, proteinuria, and edema; eclampsia is the addition hypertension of sei seizures zures to the the tri triad. ad. Aff A ffects ects 7% 7% of pregnant women women from from 20 wee weeks’ ges gestation tati on to to 6 (preeclampsiaweekspostpartum. tpartum. Increased incide inci dence in in patients patients with preexi xissti ting ng hypertension, rtension, diabetes diabetes, eclampsia) chronic renal disease, and autoimmune disorders. Clilinica nicall fea featur ture es

 Tr  Tre eatment U C V Path2. 49

Headache, blurre blurred d vision, vision, abd abdom ominal pain, ede edema of face and extrem xtremiti itie es, altered mentation, hyperreflexia; lab findings may include thrombocytopenia, hyperuricemia. Delive liveryof fetu tuss as soon as viab iable le.. Ot Oth herwis ise e bed rest, salt restr tric ictio tion n, and monitor itorin ing g and treatment of hypertens hypertensiion. For eclampsia, a medical emerg ergency ency, IIV V magnesi nesium sulfate sulf ate and diazepam.

24 243 3

 

PATHOLOGY— PATHOL OGY— VASCULAR/ CARDIAC CARDI AC ( co n t i n u e d )

 Athe  At heros rosccler lerosi osiss

U C V Path1. 5

Ischemic heart disease

Disease of elastic arteries and large and medium-sized muscular arteries. Risk factors: smoking, hypertension, diabetes mellitus, hyperlipidemia. Prog Pr ogres ression: fatt fatty y strea streaks ks → proli prolifera ferati tive ve plaq plaque ue → complex atheromas. Complications: aneurysms, ischemia, infarcts, peripheral vascular disease, thrombus, emboli. Locati ocation: on: abdom abd ominalclaudication, aorta > coronary artery poplliteal teal artery artery > carotid artery. > pop Symptoms: angina, but can be asymptomatic. Possible manifestations: 1. Angina– Stable: mostly 2° to atherosclerosis (retrosternal chest pain with exertion) Prinzmetal’s variant: occurs at rest, 2° to coronary artery spasm U nstabl nstable/crescendo: thrombosis in a branch (wors (worsenin ening g chest pain) pain) 2. Myocardial infarction rction—mo —mosst often occurs occursin CA C A D iinvolvi nvolving ng theleft anterior anterior descending artery 3. Sudden cardiac cardiac death—death from cardiac causes within 1 hour of onset of symptoms, most commonly due to a lethal arrhythmia 4. Chroni hronic c ischemic heart disease—progressive onset of congestive heart failure over many years due to chronic ischemic myocardial damage

Infarcts: red versus pale

Red (hemorrhagic) infarcts occur in loose tissues with collaterals, such as lungs, intestine, or following reperfusion. Pale infarcts occur in solid tissues with single blood supply, such as brain, heart, kidney, and spleen.

24 244 4

REd = REperfusion.

 

Evolution of MI

Coronary oronary artery artery occlus occlusion: LA D > RCA > circumflex. Symptoms: severe retrosternal pain, pain in left arm and/or jaw, shortness of breath, fatigue, adrenergic symptoms.

A. First day Occluded artery Infarct Pallor

Coagulative necrosis leads to release of contents of necrotic cells into bloodstream with the beginning of neutrophil emigration

B. 2 to 4 days Tissue surrounding infarct shows acute inflammation Dilated vessels (hyperemia) Pallor ±  hyperemia

Neutrophil emigration Muscle shows extensive coagulative necrosis

C. 5 C. 5 to 10 days Hyperemic border; central yellow-brown softening ––  maximally yellow and soft by 10 days

Outer zone (ingrowth of granulation tissue) Macrophages Neutrophils

D. 7 D. 7 weeks

Recanalized artery Gray-white

Contracted scar complete

U C V Path1. 14

24 245 5

 

PATHOLOGY— PATHOL OGY— VASCULAR/ CARDIAC CARDI AC ( co n t i n u e d )

Diagnosis of MI

In the first six hours, EKG is the gold standard. Cardiac troponin I is used within the first 8 hours up to 7 to 10 days; more specific than other protein markers. CK-MB is test of choice in the first 24 hours post-MI. LDH1 (former test of choice) is also elevated from 2 to 7 days da pos t-M t-eM I . and can A ST isysnonsp no nspe cific can be found found in in cardiac, li liver, ver, and skeletal muscle cells. EKG EKG changes can iincl nclud ude e ST elevation (transm transmural ural ischemia) and Q waves (transmural infarct).

MI complications

CK-MB LDH1 AST   LDH

Pain

1

2

3Days4

 

ES ESR R

5

6

7

1. 2. 3. 4. 5.

Cardiac arrhythmia (90%) (90%) LV fail failure ure and pul pulmonary edema (60%) T hromboe hromboembolis boli sm: mura murall thrombus thrombus Cardioge rdiogenic shock (la (l arg rge e infarct: infarct: hig hi gh ri rissk of mortali mortality) ty) Rupture of of ventricular ventricular free wall, iinterve nterventri ntricular cular sep septum tum, pap papiillary muscl cle e (4–10 (4–10 day days post-MI), cardiac tamponade 6. Fi Fibrinous brinousperi rica carditi rditiss: fri friction ction rub (3–5 dayspo posst-MI t-M I)

7. Dr Dres essral ler’swe syndrome: yndrom autoi utoim phenomenon result ultiing in fibrinous fibri nous pe peri ricardit carditiis (seve ekspostpose: t-M M I) mmune phenom

Cardiomyopathies Dil Dila ate ted d (cong (congestive) tive) cardiom iomyopath thy y Path1. 9

Hypertrophi rtrophic c cardiom rdiomyopa opathy (fo (form rmerly IHSS IH SS))

Most Most com common card rdiom iomy yop opa athy (90% (90% of cases). Eti tio olog logie iess inc inclu lud de chronic Alcohol abuse, Beriberi, postviral myocarditis by Coxsackievirus B, chronic Cocaine use, Doxorubicin toxicity, peripartum cardiomyopathy. Heart dilates and looks like a balloon on chest x-ray. Hypert rtrophy rophy often often asymmetric etric and involvi nvol ving ng th the e intraventr ntricu icula larr sse eptu tum m. 50% 50% of ca cases arefam famili ilia al and areinhe inherited as an AD A D tra trait. Cau Cause of su sudden

Sy Sysstolic dysfunc function tion ens nsu ues. Alcohol Beriberi (wet) Coxsackievirus B, Cocaine Doxorubicin Di Dias astol toliic dysfuncti function ensue uess.

death de ath iam n young athlete athletes. s. Walls Wall sshaped of LV are thicke ckened ned and chin cham ber becomes banana-shaped bananaon thi echocardiogram. Restri Res tricti ctive ve/obli /oblitera terati tive ve Major caus causes includ nclude e sarcoi arcoidosis, a am myloidos yloidosis, cardiom rdiomy yop opa athy end ndoc oca ard rdial ial fib fibro roe elastosis, is, a and nd end ndom omyoc oca ard rdial ial fibros fibrosis (Löffler’s). Path1. 10

U C V Path3. 3

Heart murmurs A ortic ste tenos nosis A ortic ortic re reg gurgitat rgitation ion Mi Mitra tral sste teno nossis Mi Mitra tral reg regurgitation itation Mi Mitra tral prola prolap pse

Cre resscendo-d ndo-de ecrescendo ndo systolic ejec ejection tion murmur, with LV >>aortic pre resssure during systole. tole. Hig Hi gh-pitche h-pitched ““b blowing lowing”” dias diastolic m mu urmur. Wide Wide puls lse ep pre resssure re.. Rum Rumbling la late te dia iasstolic tolic mu murmurs. LA >>LV pre resssure duringdia iassto tole le.. Openingsnap nap. Hig Hi gh-pitch h-pitche ed “blowing lowing”” holo holossystolic tolic m mu urmur. Sys Systolic tolic mu murmur with with mids midsystolic tolic click. click. Most Most frequent va valvula lvularr les lesion, ion, e esspecia cially lly in you young ng

VSD PDA

Howomen. losystolic murmur. Continuous machine-like murmur.

U C V  Anat.2,  Anat.2, 8, Path1.4, 12, 1 13 3

24 246 6

 

Cardiac tumors U C V Path3. 1

Myxomas a are re the the most common 1° cardiac tumor in adults. Ninety percent occur in the atria atria (mostl ostly y LA ). Myxom M yxomasare usua uallly des descri cribe bed d as as a ““ba balll-valve” obstr tructi uction on in in the the LA . R Rhabdom habdomyomas yomasare the most frequ frequent ent 1° cardiac tumor in children.

CHF Abnormality

Cause

A nkle nkle,, sacral ed edema

RV failu failure re→ increased venous pressure → fluid trans transudati tion. on. Inc Incre reased cent ntra ral veno nou us pressure → increased resistance to portal flow. Rarely, leads to “cardiac cirrhosis.” LV fa faililu ure→ increasedpulm pulmonary venous pressure → pulmonary venous distention and transudation of fluid. Presence of hemosiderinosiderin-lladen aden macrophages (“hea “heart fa faiilure” cells cells). Fail Failu ure of left left ventricular ntricular ou outpu tputt to increase during exercise. Fail Failur ure e of left left hea heart outpu outputt to kee keep up with with ri right ght heart heart output → acute rise in pulmonary venous and capillary pressure → transudation of fluid. Pooli Pooling of blood in lungs ungs in supine positi tion on adds volum volume e to congested pulmonary vascular system; increased venous return not put out by left ventricle ventricl e. Gre Greater v ve entric tricu ula larr e end nd-dia -diasstolic tolic volume.

Hep Hepato tom megaly (nutmeg liver)

Pu Pulm lmon ona ary con cong gestion

Dy Dysspn pne ea on exe xertion rtion Pa Paroxy roxysmal nocturna nocturnal dyspnea, pul pulm monary edema

Orth rthopne opnea a (shortnes hortness of breath when supine)

Car Cardia iac c dila dilatio tion n

Decreased myocardial contractility

Decreased cardiac output

Effective arterial blood volum vol ume e

Sympathetic nervous outflow

Venous pressure

Renin release

Maintains blood pressure

Angiotensin Angioten sin II II

Renal vasconstriction

Aldosterone secretion

GFR

Tubular reabsorption of Na+ and H2O Urinary excretion of Na+ and H2O

 T  Tot otal al body body Na+ and H2O

Edema

UCV Path1. 7 

Embolus types

Fat, Air, T hrombus, Bacteria, Amniotic nioti c fluid, T umor or..

Fat emboli are associated with long bone fractures and liposuction. uction. A mni nioti otic c fluid emboli boli can lead to DIC, DIC , e esspeciall cially y pos postpa tpartu rtum m. Pulmon Pulmona ary embolus olus: chest pain, tachypnea, dyspnea.

Deep venous thrombosis

Predisposed by Virchow’s triad: 1. Sta Stasis 2. Hypercoa rcoagulabili ulability ty 3. Endothe Endothellial damage

A n embolus olus move oves like a FAT pproximately tely 95% of BAT. A pproxima pulmonary embol bolii ari arisse from deep leg leg veins. ins.

24 247 7

 

PATHOLOGY— PATHOL OGY— VASCULAR/ CARDIAC CARDI AC ( co n t i n u e d )

Bacterial endocarditis

U C V  Micro.1. 2

New murmur ur,, anemia, feve fever, r, Osler nodes (tende tender raised Mitral valve is mos ostt freque frequently ntl y lesionson fing finger or toepads), Roth’s Roth’sspo pots ts(round (round white involved. nvolved. Tricu Tri cusspid val valve spo pots ts on reti retina na surround urrounde ed by by he hem morrhag orrhage), JJa ane newa way endoca ndocarditi rditiss is as associated lesions (small ery rythe them matous tous lesions on pa palm or or ssole ole), ), with IV I V dr drug ugabus buse. splinter hemorrhages on nailbed. Multiple blood cultures necessary for bacteremia). 1. A cute: Sta  Stap hylo yldiagnosis ococcus au(continuous re reu us (high virulence). Large vegetations on previously normal valves. Rapid onset.  Strep ptococcus viridans (low virulence). 2. Suba Subacu cute te:: Stre Smaller vegetations on congenitally abnormal or diseased valves. Sequela of dental procedures. More in inssidious onset. Endocarditis may also be nonbacterial secondary to metastasis or renal failure (marantic/thrombotic endocarditis).   Path3. 5

Rheumatic fever/

Rheumatic fever is a consequence of pharyngeal

FEVERSS:

rheumatic heart disease

infe infection withincludes grou group p A, Arheumatic , β-hemolytic olytic streptococci. treptococ Late sequelae heart disease, ci. which affects heart valves: mitral > aortic >> tricuspid (high-pressure valves affected most). A ssociated wi with A schoff bodi bodies, migratory polyarthritis, erythema marginatum, elevated A SO tite ti ters rs.. Due to cross-reactivity, not direct effect of bacteria

F Eever rythema marginatum Valvular damage ESR ↑ joints (po (polyarthriti lyarthritiss) Red-hot joints Subcutaneous nodules St. Vitus’ dance (chorea)

U C V  Micro.1. 23

Pericarditis

U C V  Micro1.1, Path Path3.3

Syphilitic heart disease

U C V Path1.17 

Buerger’s disease

U C V Path1.19

Cause auses: iinfecti nfection on (vi (viruse ruses, T TB, B, pyogenic pyogenic bacteria; bacteria; often by dir direct ect sprea spread from lung or mediastinal lymph nodes), ischemic heart disease, chronic renal failure → uremia, and connective tissue disease. Eff Effus usions are usua uallly serous; hemorrhag orrhagic effusions effusions a are re associate ociated d wi with th T B and malignancy. Renalpain, failurefriction causes serous fibrinouspulsus effusions. Findings: pericardial rub, EKGor changes, paradoxus. Can resolve without scarring or lead to chronic adhesive or chronic constrictive pericarditis.  Tertiary syphilisdis isrruptsth the e vasa vasorum of aorta via vi a endarteriti rteri tiss obliterans obli teransand disrupts elasti elastica ca (with with conse cons equ que ent dil dilation ation of aorta aorta and valve ri ring ng)). Often Often affects the aortic aortic root and ascending aorta. A ssociated ociated with a tree-bark tree-bark appe appeara arance nce of tthe he aorta.

Ca Can n result in aneurysm of ascending aorta or aortic aortic arch and ao aorti rtic c valve incompete ncompetence. nce.

Known as smoker’s oker’s di disea seaseand thromboangiitis obliterans; idiopathic, segmental, thrombosing vasculitis of intermediate and small peripheral arteries and veins. Findings: intermittent claudication, nodular sensitivity (Raynaud’s phenomenon), severesuperficial pain in affected part;phlebitis, may leadcold to gangrene.  Tr  Tre eatment: quit smokin ing g.

24 248 8

 

Ta kaya ka yasu’s su’s a arterit rteritis is Known as “pul pulse seless di dise sease”: thickeni thi ckening ng of aortic aortic arch and/or proxim proxi mal great vessels, causing we weak ak pul pulse ses in upper extremiti extremitiesand ocular disturbances disturbances. A Ass ssoci ociated ated with an el elevated ESR ESR.. P Pri rim maril arily ya affects ffectsyou young ng As A sian females. Fever, Arthritis, Night sweats, MY algia, algia, SKIN nodules.

Tempora emporall arteritis a rteritis

U C V Path1. 18

Polyarteritis nodosa Sympto tom ms Fin ind ding ings

 Tr  Tre eatment

Most common vasculiti vasculi tiss that affects affects medium and small arteries arteri es, usua uallly branchesof carotid carotid artery. Fi Findi ndings ngs includ nclude e unilate unil ateral headache dache,, jawclaudi claudicati cation, on, impai paired vi vission (occlusi occlusion of ophthalmi ophthalmic artery artery,, which can lead to bli blindnes ndness). Half of pa pati tients entshave have systemic involvement and syndrome of polymyalgia rheumatica. atica. As A ssociated with with elevate elevated d ESR. ESR.

A ffects med ediiumand large arteries arteri es. FAN MY SKIN.

Temporal = signs near Temples.

ESR is markedl arkedly elevated. elevated. A lso known asgiant ce celll arteri arteriti tiss. A ffectselderl rly y females. ales.

Characterized by necrotizing immune complex PAN =P-ANca inflammation of small or medium-sized muscular arteries, typically involving renal and visceral vessels. Fever, we weig igh ht lo losss, ma malais laise e, a ab bdominal pa pain, headache, myalgia, hypertension. Cot Cotton-wool spots, mic icrroaneurysms, perica icarditis itis, myocardi rditi tiss, pa pallpa pable ble purpura. purpura. Increas ncreased ESR. ESR. A ssociated ociated wi with hepatiti ti tiss B infection infection in in 30% of pati tie ents. P-ANCA (peri rinuclea nuclear pattern of antine nti neutrophil utrophil cytoplasmic antibodies) is often present in the serum and correlates with disease activity, primarily in small vessel di disea sease. Cor Cortico icosteroid idss, azath thio iop prin ine e, and/or /or cyclop lophosphamid ide e.

U C V Path2. 76

Wegener’s granulomatosis Sym Sympto tom ms Find Fin dings  Tr  Tre eatment U C V Path2. 66

Characterized by focal necrotizing vasculitis and necrotizing granulomas in the lung and upper airway and by necrotizing glomerulonephritis. Perf Perfor ora ation of nas nasal sse eptu tum m, chro chronic nic sinus inusitis, itis, o otitis titis media ia,, masto toiditis iditis,, c cou oug gh, dy dyspnea, hemoptysis. C-A NCA NC A is a stro trongmark rke er of of dis dise ease; CXR may reveal la larg rge no nod dula larr de densities ities; he hematuria turia and red cell casts. Cyc Cyclop lophosphamide ide, cortico ticosteroids ids, and/or /or meth tho otr tre exate.

24 249 9

 

PATHOLOGY— PATHOL OGY— RENAL

Glomerular pathology

Nephriti phritic c syndrome: hematuria, hypertension, oliguria.

1. A cu cute te poststre tstreptoco tococc cca al g glom lomeru rulone lonephr hritis itis LM: glomeruli enl nlarg arged and hype hypercellular; rcellular; neutrophills; “l neutrophi “lum umpy-bumpy.” EM: EM : su sube bepit pitheli helial al humps. IF: granular pattern.

Most Most fre frequently seen in chil childre dren. n. Peripheral Peripheral, peri ri-orbital orbital ed edem ema. Resol olves ves spontaneously.

2. nephri Rap Rapidly rog gressive (crescentic) ntic) g glom lomeru rulolonephriti tisspro LM and IF: IF: crescentcrescent-m moon shape shape.. 3. Goodpasture’s syndrome IF: linear pattern; anti-GBM antibodies. 4. Membrano ranop pro rolife lifera rative tive glomeru rulone lonephr hritis itis EM: subendothelial hu humps; “tramtrack.” 5. Ig IgA A ne nephropathy (B (Be erger’s disease) I F and EM: EM: mesangial depos deposiits of Ig I gA .

Rap Rafr pid cours rseoftoma reny nal nalcaus failure failure from omcou one es. Hemoptysis, hematuria. Slowly pro rog gresses to re rena nall failur ilure. Mild Mild disease.

Nephroti hrotic c syndrome: massive proteinuria,

U C V Path Path2.87-92, 3.107 

Kidney stones Calc Calciu ium m

A mmonium onium magnesium phosphate Uric ac acid

Cys Cystine U C V Path2.98

hypoalbuminemia, generalized edema, hyperlipidemia. 1. Mem Membranous glo lom merulon lonephrit itis is Ac co ommon cause of adult LM: diff diffus use capil capilllary thicke thi ckeni ning ng.. IF: granul ranular nephroti nephrotic c syndrom yndrome e. pattern. 2. Minima Minimal c cha hange dise isease (lipoid (lipoid nephr hro osis) is) Most c co ommon cause of LM: normal normal glome omeruli ruli.. EM: EM: foot process chil childhood nephroti nephrotic c effacement. syndrome. 3. Focal segmental glomerular omerular sclerosi sclerosis More severe disease in HIV LM: segmental sclerosisand hyali lin nosis. patients. 4. Dia Diabeti tic c ne nephro phropa pathy LM: Kimmelstiel–Wilson lesions. 5. SL SLE E (5 (5 pa patternsof rena renall involvem nvolvement) LM: Wire loop appearance with extensive granular subendothelial basement-membrane deposits in membranous glomerulonephritis pattern. (LM =light mi microscopy; EM =electron microscopy microscopy; IIF F = immunofluoresce unofluorescence) Can lead to severe complications such as hydronephrosis and pyelonephritis. Four major types: Comprises th the e majo jorit rity y of kidn kidney sto tone nes (8 (80 0-85 -85%). Calc Calciu ium m oxala late teor calc lciu ium m phosphate or both. Stones are radiopaque. Disorders or conditions that cause hype hyp ercalcemia (e.g., (e.g., cance cancer, r, iincrea ncreased PTH PT H, iincrea ncreasedvi vitam tamin D, D, milk-al mil k-alkali kali syndrome) can all lead to hypercalciuria and stones. Second most ost comm common ki kidney dneystone. Rad adiiol oluce ucent nt and formed formed in alkali alkaline uri urine ne by ureasepositi itive bugs such as Pr Pro oteus teus vulgaris vulgaris or Sta  Staphylo ylococcus. Can form large struvite calc lcu uli that can be a nid idu us for UTIs. Stro Strong ngassociation tion with with hy hyperu ruric rice emia (e.g., gout). Ofte Often se seen as as a result of dis dise eases with increased cell proliferation and turnover, such as leukemia and myeloproliferative disorders. Mo Mosst often secondary to cystinuria.

25 250 0

 

 Acid-base  Acidbase physiology

pH

Metabolic acidosis

↓

Respiratory acidosis Respiratory Res piratory alkalosis alkalosis

↓ ↑

Metaboli tabolic c alkalosi alkalosis

↑

PCO2 [HCO3–] Cause

↓

↑ ↓ ↑

Compensatory response

Dia Diabeti tic c ketoa ketoacidos cidosis; diarrhea; Hyp ype erventi rventillati tion on lactic acidosis; salicylate OD; acetazolamide OD COPD; COP D; air irw way obstructio ion n Renal [HCO [HCO3–] reabsorption Hig igh h alti altitu tud de; hyp hyperventilation Re Rena nall [HCO [HC O3–] secretion Vomiting

Hypoventilation

Henderson–Hasselbalch equation: ti on: pH = pKa + lo log g

Key:

[HCO3] 0.03 Pco2

= pri prim marydisturba disturbance; ↓ ↑ = compensatory response.

 Acidos  Ac idosis/a is/alkalos lkalosis is

Check arterial pH

pH <7.4 Acidosis

pH >7.4 Alkalosis Check PCO2

PCO 2 > 40 mmHg

PCO 2 < 40 mmHg

Respiratory acidosis

Metabolic acidosis with compensation

Hypoventilation  –Acute lung disease  –Chronic lung disease

PCO2 < 40 mmHg Respiratory alkalosis  –Hyperventilation  –Aspirin ingestion (early)

PCO2 > 40 mmHg Metabolic alkalosis with compensation  –V  –Vomiting omiting  –Diuretic use  –Antacid use  –Hyperaldosteronism

Check anion gap

Anion gap  –Renal failure  –Lactic acidosis  –Ketoacidosis  –Ketoacido sis (DM)  –Aspirin ingestion

Normal anion gap (5–15 mEq/L)  –Diarrhea  –Glue sniffing  –Renal tubular acidosis –Hyperchloremia

U C V Bio.9, 11, 25, 34, Path2.99

 Anion ga p  Anion acidosis

Gap is Na+ − (Cl– + HCO–3) = 8 to 12 mEq/L. If elevated, elevated, m may ay bedue to: Methanol Uremia Diab abe etic ti c k ke etoacidosis Paraldehyde or Phenformin Iron tablets or I(CN NH −, CO, shock) actic acidosis L Ethanol or Ethylene glycol Salicylates

MUD PI PILES

25 251 1

 

PATHOLOGY— PATHOL OGY— RENAL (co n t i n u e d )

Renal failure

Failure to make urine and excrete nitrogenouswastes. Failure Consequences: 1. A nemia (failu ilure reof e ery ryth thro rop poietin ietin p pro rod ductio tion) n) 2. Rena Renall osteodystrophy (failure failureof acti ctive ve vi vitam tamin D production)

Two forms of renal fail failure ure: acute renal failure (often due to hypoxia ia)) a and nd chro hronic renal fai failure.

3. H yperkal rkalemia, whi which ch can can le l ead to cardiac arrhythmias 4. M etab taboli olic c acidosis due due to ↓ acid secretion and ↓ generation of HCO3– 5. U re rem mia (incre (i ncreased BUN BUN,, crea creati tinine) nine) 6. Sod Sodium ium and H2O excess → CHF and pul ulm monary edema

Electrolytes Electrolyte Ca2+

Causes andsigns signs

of deficiency

of toxicity

Functions M uscle contraction

Kids– rickets

Neurotransmitter release Bones, teeth

Adu Adults–o –ossteomalaci cia a Contributes to osteoporosis

Delirium

 Tet  Tetan any y

Bio.15, Bio.15, 17 

PO43−

Causes andsigns signs

ATP

Kids– rickets

Low serum Ca2+

Nucleic acids

Adults– osteomalacia

Can cause bone loss

Phosphorylation Phos phorylation

Renal stones

Bones, teeth Na+

Extracellular fluid

2° to injury or illness

Delirium

2° to injury, illness, or

EKG changes

Maintains plasma volume Bio.20

Nerve/muscle function

K +

Intracellular fluid Nerve/muscle function

diuretics

Arrhythmia

Causes weakness, paralysis, confusion

Bio.18

Cl−

Fluid/electrolyte balance Gastric acid HC HCO O–3/Cl /Cl–

2° to em emesis esis,, diuretic diuretics, s, renal disease

clinically significant

shift in RBC

Mg2+

Bones, teeth

2° to malabsorption

Bio.19

Enzyme cofactor

Diarrhea, alcoholism

UCV

None that are

↓ Reflexes ↓ Respiration

25 252 2

 

PATHO PATHOLOGY— LOGY— ALCOHOLISM

 Alcoho  Alc oholis lism m

Physiologic tolerance and dependence with symptoms of withdrawal (tremor, tachycardia, hypertension, malai alais se, nausea, deliri rium um tremens) when when intake is is in interrupted terrupted. Continued drinking despite medical and social contraindications and life disruptions.  Tr  Tre eatment nt:: disu isulfiram to condition the patient negatively against alcohol use. Supportive treatme trea tment of other other systemic mani nifes festations tati ons.. A lcoholi coholics Anonym Anonymousand other peer peer support groups are most successful in su sus stai taini ning ng absti tinence. nence. Ethanol Alcohol dehydrogenase MEOS Acetaldehyde

Interpolates into membranes

Increased membrane fluidity

Forms adducts with proteins and nucleic acids

Converted to acetate

Increased NADH/NAD:   Increases lactate/pyruvate   Inhibits gluconeogenesis   Inhibits fatty acid oxidation   Inhibits glycerophosphate   dehydrogenase, leading   to elevated glycerophosphate

Converted to acetyl-CoA Toxic effects, particularly in the brain Increased fatty acid synthesis

U C V Path1. 46

Long-term consequences of alcohol use A lco coholi holic c cirrhosis

Fatty liver

A lcoholic coholi c hep hepa atiti ti tis s and ci cirrhosis, pancreatiti ti tis s, di dillated cardiomyopathy, periphe ripheral neuropathy, cerebellar degeneration, Wernicke–Korsakoff syndrome, testi ticul cular ar atrophy trophy and hyperestrinism, and Mallory–Weiss eisssyndr ndrome ome. Long Long-term -termalcohol use use le lea adsto m micronod icronodular ular ci cirrhosis w wit ith h acco accom mpany nying ing symptom ptoms of  jau  jaundice ice, hypoalbu lbuminemia ia,, coagula latio tion n facto torr deficiencies, and portal hypertension, leading to peripheral edema and ascites, encephalopathy, and neurologic manifestations (e.g., asterixis, flapping tremor of the hands).

Wernicke–Korsakoff syndrome

Mallory–Wei Weis ss syndrome UCV

  Path3.5 Path3.51 1

Caus aused by vitam vitamin B1 (thiamine) deficiency in alcoholics. Classically may present with triad of psychosis, is, op ophth tha almopleg legia ia,, and ataxia (Wernick icke’s encephalopa phalopath thy). y). May progress to memory loss, confabulation, confusion (Korsakoff ’s syndrome; irreversible). A ssociated wit with h peri periventri ventricular cular hem hemorrhage/necros e/necrosiis, especi ciall ally y in in mamillary b bodies odies..  Tr  Tre eatment nt:: IV vita vitamin B1 (thiamine).   Path2.29, Path2.29, Path th3.61 3.61 Longitudi ongitudinal nal lacerations rati ons at th the e gastr troes oesophageal junct unctiion caused by excessive vomiti vomiting with ffa ailu ilurre of LES LES re rela lax xatio tion n tth hat c co ould le lea ad to fatal hematemesis is..

25 253 3

 

PATHOLOGY— PATHOL OGY— FI FINDINGS NDINGS

 Argyll–Robe  Argyll–R obert rtson son pupil

A rg rgy yll –Robertson pupil constricts with accommodation but is not reactive to light. Pathognomonic for 3° syphilis.

Argyll–Robertson Pupil ARP: Accommodation Response Present.

 Amylo  Am yloidos idosis is

Primary (lig (li ght c cha hain de deposition ition)) s se een w with ith multiple

A lz lzhe heim ime er’s dise disease associated sociated

myeloma or W Waldenstr aldenström’s macroglobulinemia; secondary (amyl yloi oid-ass d-associ ociated) ated) can cause nephrotic syndrome in kid kidne ney. Ap App ple le-g -green birefringence on Congo red stain.

with β-amyloid deposition in th the e cerebral cort cortex; ex; isle lett ce cell am amylo loid id deposition ition characteristic of diabetes mellitus type type I I.

 Aschof  Asc hofff bod body y

A schoff bodies (granu ranulloma with giant cells) and A ni nits tschko chkow w’s cells (activated histiocytes) are found in rheumatic heart disease.

T hi hink nk of twoRHussians with atic heart di dise sease RHeumatic (A schoff and A n niitschkow).

 Auerr bodies (ro  Aue (rods) ds)

A uer rrods odsare c cytoplas ytoplasmic iincl nclus usions in granulocytesand myeloblasts. P Pri rim marily aril y see seen in acute promyelocytic leukemia.

U C V Path2.94

Casts

Casts of nephron: RBC RBC cas casts = glomerular inflammation, tion, is isc chemia ia,, o orr malignant hypertension. WBC casts = inflammati tion on in i n renal renal intersti titi tium um, tubules, and glomeruli eruli.. Hyaline casts often seen in normal urine. Waxy casts seen in chronic renal failure.

Presence of casts indicates tha that h he ematu turia ria/py /pyuriais of renal origin.

Erythrocyte sedimentation rate

Very nons nonspecific test th that at measures acuteacute-phase phase reactants. Dramatical Dramaticallly increased wit with h infection, nfection, malignancy, conne connective ctive tis tiss suedis dise ease. Al A lso increased with pregnancy, inflammatory dise disease, anemia. Decreased with with sickl ckle e cell anemia, pol polycy ycyth them emia,

Si Simp mple, cheap, but nonspe nonspecific. Should Should not beused for asymptomati tic c screeni ning ng;; can be used to di diag agnose and monitor onitor temporal arteriti rteritisand

congestive heart failure.

polymyalgia rheumatica.

Ghon complex

 TB granu nulo lom mas with lob lobar or perihilar lym lymph no nod de inv invo olv lve ement (Gho (Ghon n fo foc cus and lym lymph node involvement). Reflects prim primary iinfecti nfection on or exposure.

Hyperlipidemia signs

A therom theromata ata= plaques in blood vessel walls. Xantheloma = plaques or nodules composed of lipid-laden histiocytes in the skin, especially the eyelids.  Tendino inou us xant ntho hom ma= lipid depos posit iin n tendo tendon, n, especiall cially yA Achil chillles. Corneal arcu arcus s = lipid deposit in cornea, nonspecific (arcus senilis).

25 254 4

 

Psammoma bodies

Laminated, concentric, calcific spherules pherul esseen iin: n: 1. Pap Papiillary adenocarcinomaof thyroi thyroid 2. Serou Serous sp pap apillary cys cystadenocarcinomaof ovary 3. Men Mening ingiom ioma 4. Malig li gna nant nt mesothelioma ioma

RBC forms

Papillary (thyroid) Serous (ovary) a Meningioma Mesothelioma

Biconcave = normal. Spherocytes = hereditary spherocytosis, autoimmune hemolysis. Elliptocyte = hereditary elliptocytosis. Macro-ovalocyte = megaloblastic anemia, marrow failure. Helmet cell, schistocyte = DI DIC C, traumati atic c hemol olys ysis. Sickle cell = sickle cell anemia.  Teardrop cell = myeloid metaplasia with myelofibrosis. A canthocyte= spiny appearance in abetalipoproteinemia.  Target cell = th thalas alassemia, lliiver diseas disease, HbC H bC.. Poikilocytes = nonuni nonuniform form shapes hapesin T TT T P/H P/HU S, microvas crovascular damage, DI DIC C. Burr cell = TT P/HUS. P/HUS.

HLA-B27

A ssociated wit with h Psoriasis, Ankylosing spondylitis, tory ry bowel dise disease, Reiter’s syndrome syndrome. Inflammato Ninety-fol nety-fold d grea greater chance of developing veloping ankyl nkylos osing spondylit itis is w wit ith h HLA H LA -B27.

PAIR

Reed–Sternberg cells

Distinctive tumor giant cell seen in Hodgkin’s di dis sease; large cel cell that is bin binucleate ucleate or bil bilobe obed with with the 2 halves halves asmir mirror ror images (“owl’s eyes”). N ecessary but not suf ficient cient for a diagnosi nosis of Hodg H odgki kin n’s dis ise ease.

T here are 4 typesof H odgki kin n’s disease; nodular scleros clerosis vari variant ant is th the e only onl y one seen in wo women >men (excellent prognosis).

 V  Virc irchow how’s ’s (se (sent ntine inel) l) node

A firm supraclavicular lymph node, often on left side, easily palpable (can be detected by medical students), also known as “ jug  jugula larr gland land.” Presumptive evidence of malignant visceral neoplasm (classically stomach).

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PATHOL HOLOGY— OGY— FI FINDINGS NDINGS (co n t i n u e d ) PAT

Peripheral blood smears Normal

—normal

Microcytic hypochromic anemia

—normally 2° to iron defici ciency ency —low serum ferritin —elevated serum iron binding capacity

Megaloblastic anemia

—2° to fol folate ateor B12 deficiency —hypersegment ented ed (5 (5–7 lobes) PM PMN Ns blood cell cells s (M CV >100) 100) —large red bl —never give folate to a patient who is deficient in B12 autoimm mmune di dise sease which which causesB12 deficiency by depleting —perni rnici cious ous anemia—autoi intrins ntrinsic factor, which is needed to absorb B12 in terminal il ileum  Target cells

halas assemia —thal oglobin obin C dis disease —hemogl —liver disease

Hemoglobin SS with sickle cells

-globin in G GLU LU → VA L at #6; 8 8% % of US US blacks areHbS carriers rri ers —HbS—β-glob —cells will sickle 2° to hypoxia, dehydration, and ↑ blood viscosity —anemia o-occl occlus usive cris cri ses +/– chest pain —vaso—aplastic crises (B19 virus) —splenic sequestration crises —strokes

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Enzyme markers

Serumenzyme

Major diagnostic use

Amin Am ino otransferases (AST (AST a an nd ALT) ALT)

Myocardial infarction (AST AST only) Vi Vira rall hep hepa atitis titi s (A LT > A ST ST)) A lco lcoho holilic ch he epatiti titis s(A ST >A >A LT) A cute pancreatitis, mumps Wilson’s diseas disease Muscle disorders (e.g., DMD)

A mylase Ceruloplasmin (decreased) CPK (creatine phosphokinase)

GGT (γ -glutamyl transpeptidase) LDH-1 LDH-1 (lactate dehydrogenase fractio ion n 1) Lipase A lkaline phosphatase

and myocardial infarction (CPK-MB) Various liver diseases My Myo ocardia iall in inffarctio ion n (LDH1 > LDH2) A cute pancreatitis Bone disease, obstructive liver dise di sease

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NOTES

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NOTES

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NOTES