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An elderly patient with a history of GERD presents to your cl inic with dysphagia and undergoes endoscopy after a barium swallow shows a ~~AI fungating mass in the lower portion of the esophagus. A biopsy specimen is taken of the mass, and an immunohistochemical stain is applied.

The antibodies used in this stain are specific for what protein?

A. Cytokeratin

B. Desmin

C. Desmoglein

0 . Tubulin

E. Vimentin

:

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The correct a nswer is A. 44°/o chos e t h is . Esophageal adenocarcinoma is the diagnosis in this pat ient. History of GERD and occurrence in t he lower esophagus are all clues to adenocaricnoma, as opposed to squamous cell carcinoma . Adenocarcinomas are neoplasias of epithelial cel ls, more specifical ly epithelial cells of glandular origin. Low-molecular-weight cytokeratin is characteristical ly present in adenocarcinomas of this t ype, as detected by an antibody to cytokeratin. Cytokeratin is expressed by cel ls of epithelial origin . Squamous-cell carcinoma Esophagus Cytokeratin Adenocarcinoma Carcinoma Epithelium Antibody Esophageal cancer Gastroesophageal reflux disease Squamous epithelial cell Gland

B is not correct. 16% chose this . Desmin is an intermediate filament found near the Z-line in sarcomeres. Thus, it is used to stain muscle t issue, specif ical ly sarcomas. Oesmin Intermediate filament Sarcomere Protein filament Sarcoma

C is not co rrect. 11% chos e this . Desmoglein is a protein expressed between adjacent cells and used to form t ight j unctions. It is not characterist ically associated with adenocarcinoma. Desmoglein Protein Tight junction Adenocarcinoma

D is not correct. 11% c hose this. Tubulin is a microtubule that helps move chromosomes during mitosis and meiosis. It is involved in ci liary and flagellar movements and in int racellular transport via motor proteins. It is a target of many drugs includ ing taxol, colchicines, and v inblast ine, but it is not highly associated with adenocarcinomas. Rather, tubulin (and other types of neurofilaments) can be used to stain neuromas. Vinblastine Microtubule Meiosis Mitosis Tubulin Paclitaxel Colchicine Chromosome Motor protein Intracellular Flagellum Adenocarcinoma Protein Neurofilament Intracellular transport

E is not correct. 18°/o chose this . Viment in is an intermediate f ilament protein t hat is expressed in mesenchymal cells and connect ive t issue. I t is used to stain for mesenchymal tumors. Intermediate filament Vimentin Protein Connective tissue Mesenchymal stem cell Mesenchyme Neoplasm

Bottom Line :

Cytokeratin is found on the epi thel ium of the gastrointest inal and genitourinary t racts and is used for tumor detect ion . Cancers in the upper two-thirds of the esophagus are most likely squamous cel l; whereas, cancers in the lower third are most likely adenocarcinoma evolved f rom Barrett esophagus. Barrett's esophagus Esophagus Adenocarcinoma Epithelium Neoplasm Genitourinary system Human gastrointestinal tract Gastrointestinal tract Squamous epithelial cell

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Ulifil·!ltl for yea r: 2017 • FIRST AID FACTS

FA17 p 447.1

Epithelial cell junctions

Apical ,.1

)>---- Teght junction (zonula occludens)-prevents par acellular E-cadherin ~ movement of solutes. composed of claudins and occludins.

Actin : e }-Adherens junction (belt desmosome. zonula adherens)-below filaments _/ tight junction. forms 'belt" connectir19 actin cytoskeletons of

Cytokeratin - :

Oesmoplakin __/ •

Connexon ( with central

channel

adjacent cells with CADhenns (Ca~· -dependent ~hesion l prote1ns). Loss of E -cadhenn promotes metastasis.

.J"-- DtsiiiOSOIM (spot desmosome. macula adherens)-structural support v1a 1ntermed1ate filament interactions. Autoantibodies - pemphigus vulgaris.

}-_ Gap junction-channel proteins called connexons permit electrical and chem1cal communication between cells.

~ ~Cell membrane Basolateral ::::::r~\= Basement membrane

lntegrins-membfane prote1ns that maintain J \_ HemideH~GSome-connects keratin 10 basal cells to integrity of basolateral membrane by binding underlyirMJ basement membfane. Autoantibodies - bullous

to collagen and laminin in basement membrane. pemphigoid. (Hemtdesmosomes are down 'bullowl



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to collagen and laminin in basement membrane. pemphigoid. (Hemidesmosomes are down "bullow").

Cytoskeletal elements

TYPE OF FILAMENT

Microfilaments

Intermediate

filaments

Microtubules

Esophageal cancer

CANCER

Squamous cell

carcinoma

Adenocarcinoma

FA17p44.1

A network of protein fibers within the cytoplasm that supports cell structure, cell and organelle movement, and cell division.

PREDOMINANT FUNCTION EXAMPLES

Muscle contraction, cytokinesis

Maintain cell structure

Actin, microvilli.

Vimentin, desmin, cytokeratin, lamins, glial fibrilla ry acid proteins (CFAP), neurofilaments.

Mo,·ement, cell division Cilia, flagella, mitotic spindle, axonal trafficking, centrioles.

FA17 p 361 .2

Typica lly presents with progressive dysphagia (first solids, then liqu ids) and weight loss; poor prognoSIS.

PART OF ESOPHAGUS AFFECTED RISK FACTORS PREVAlENCE

Upper 2/3

Lower l /3

Alcohol, hot liqu ids, caustic strictures, smoking, achalasia

Chronic GERD, Barrett esophagus, obesity, smoking, achalasia

More common worldwide

More common in America


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A 30-year-old woman has a history of syncopal episodes, palpitat ions, and irritable mood. Serum laboratory stud ies show t he fo llowing results:

Glucose, serum: 50 mg/dL Na+: 136 mEq/L K+: 3.2 mEq/L cl-: 100 mEq/L HC03-: 25 mEq/L C-peptide, serum: 4.5 ng/ml (normal 0.9- 3.9 ng/mL)

Which receptor class is responsible for mediating this patient's abnormal laboratory values?

:

A . a 1-Receptor

B. ~2-Receptor

C. G-protein-coupled receptor

D. Intranuclear receptor

E. Tyrosine kinase receptor



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The correct ans wer is E. 77°/o chose this . This patient has an insulinoma wit h resultant hypoglycemic syncope and irrit able mood . I nsulinomas are rare tumors that secrete insulin, result ing in the Whipple t riad of ( 1) hypoglycemia, (2) hypoglycemic symptoms such as headache and irrit able mood, and (3) relief of symptoms with caloric intake. An elevated C-pept ide level indicates that the pat ient's high serum insulin level is endogenous rather t han exogenous (ie, injected). Insulin acts via stimulation of a tyrosine kinase cel l swface receptor that autophosphorylates when act ive . Jnsulinoma Whipple's triad Hypoglycemia C-peptide syncope (medicine) Insulin Headache Cell surface receptor Neoplasm Tyrosine Blood plasma Tyrosine kinase Endogeny (biology) Exogeny

A is not correct . 1 °/o chos e this. a1-Receptors mediate vasoconst rict ion mediated by adrenergic stimulation . The metabolic effects of a1-adrenergic receptor st imulat ion include glycogenolysis and gluconeogenesis that result in increased in glucose availabilit y in the blood . Gluconeogenesis Glycogenolysis vasoconstriction Glucose Adrenergic Adrenergic receptor Receptor (biochemistry) Metabolism

B is not correct. 2% chos e this. ~2 -Receptors mediate bronchodilat ion, glucagon act ivity, and smooth muscle re laxation in response to epinephrine . Epinephrine Glucagon Bronchodilator Smooth muscle tissue

C is not correct. 13% chos e this . The low level of glucose shown in the pat ient's lab result can be explained by pathological ly high levels of insulin in the blood . I nsulin receptors belong to the tyrosine kinase fami ly of receptors and is not a G-protein coupled receptor. Tyrosine kinase G-protein coupled receptor Insulin Tyrosine Glucose G protein Kinase Receptor (biochemistry)

D is not correct. 7°/o chos e this. I nt ranuclear receptors mediate the response to steroid hormones such as testosterone, estrogen, and cort icosterone. Corticosterone Testosterone Estrogen Steroid Steroid hormone Hormone Receptor (biochemistry)

Bottom Line:

C-peptide increase, irrit ability, and syncope point to an insulinoma. I nsulin is a tyrosine kinase receptor st imulant. Jnsulinoma syncope (medicine) Insulin Stimulant Tyrosine kinase Tyrosine Receptor (biochemistry) C-peptide

l@ljl'il·1i•J for year:[2017 • J FIRST AID FACTS


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Insulin

SYNTHESIS

SOURCE

FUNCTION

Preproinsulin (synthesized in RER) - clem·age of'·presignal" - proinsulin (stored in secretory granules) - cleavage of proinsulin - exOC} tosis of insulin and C-peptide equally. Insulin and C-peptide are t in insulinoma and sulfon) I urea use, whereas exogenous insulin lacl..s C-peptide.

Released from pancreatic P cells.

Binds insulin receptors (tyrosine kinase acti\'ity 0 ), inducing glucose uptake (carriermediated transport) into insulin-dependent tissue e and gene transcription.

Anabolic effects of insulin: t glucose transport in skeletal muscle and adipose tissue

• t glycogen synthesis and storage • t triglyceride synthesis • t a+ retention (kidneys) • t protein synthesis (muscles) • t cellular uptake of K+ and amino acids

l glucagon release • l lipolysis in adipose tissue

Unlike glucose, insulin docs not cross placenta.

FA17 p 314.1

Proonsulln

I nsulin-dcpcndcnt glucose transporters: CLUT4: adipose tissue, striated muscle (exercise can also increase CLUT4 expression)

Insulin-independent transporters: • CLUTI: RBCs, brain, cornea, placenta • CLUT2 (bidirectional): P islet eel Is, liver,

kidney, small intestine • CLUT3: brain, placenta • C LUT5 (fructose): spermatocytes, C I tract

Brain utilizes glucose for metabolism normally and ketone bodies during stan·ation. RBCs utilize glucose because they lack mitochondria for aerobic metabolism.

BRICK L (insulin-independent glucose uptake): Brain, RBCs, Intestine, Cornea, Kidney, Liver.

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REGUlATION Glucose is the major regulator of insulin release. t insulin response with oral \ 'S IV glucose because of incretins such as glucagon-like peptide 1 (C I .P-1) and glucose-dependent insulinotropic polypeptide (GIP), which are released after meals and t P cell sensitivity to glucose. Release l by~. t by ~ (2 = regulates insulin)

Glucose enters p cells €) - t ATP generated from glucose metabolism e closes K~ channels (target of sulfonylureas) 0 and depolarizes P cell membrane 0 . Voltage-gated Ca1- channels open

•

- Ca2+ influx fl and stimulation of insulin exoc) tosis 0 .

Tyrostne 0 phospholylaltoo

,----.JA'----..,

f l Phosphotnosttlde· 3

kinase pathway

Glu~~;4 -1~ c:::::::> Glycogen. lipid, prote1n

syntheSIS 0

Ves1ctes conta n1119

GlUT4

RASJMAP k1nase

pathway

Cell growth. DNA

synthes1s

0 ATP·5ellSillve

K' channels dose

ATP

"' 0 _. ATP/AOPrat10

~yeo lysis GlUT? Glucose

u,e

Voltage-gated Cal· channels

0 open

Oepo; nzatton 0' 0~

f Intracellular Ca'' ~

• • • • / e

lr ' • • •

Blood vessel

Insulin-dependent glucose uptake lnsuUn se<retion by pancreatic I} cells


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lnsulinoma

FA17 p 338.3

Tumor of pancreatic~ cells ..... overproduction of insulin ..... hypoglycemia . .\ lay see Whipple triad: low blood glucose, symptoms of hypoglycemia (eg, lethargy, syncope, diplopia), and resolution of symptoms after normalization of glucose levels. Symptomatic patients have 1 blood glucose and t C-peptide levels (vs exogenous insulin use).- 10% of cases associated with MEN 1 syndrome. Treatment: surgical resection.

FA17 p 81 .2

Glycogen regulation by insulin and glucagon/epinephrine

Ep1nephnne (liver and muscle)

lnsutin (liver and muscle)

Glucago\:1 (11verl :-..+ Men~\a\e ..-~ --.. c.~c.\a

Glucagon ~ . , receptor / cAMP ~alc1um·cal~odulln

ATP m muscle dunng

EndoplasmiC ret1culum

~ t contraction

~---~Calcium Protein kinase A/ \ + Protein kinase A

~ // -~ Glycogen \ j / + Glycogen ~

phosphorylase k1nase '-..... __.. Glycogen

phosphorylase

Tyrosine kinase dimer receptor

8 s ~

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- ..... ~ ~ - - - ·- · - .. -Treatment: surgica I resect ion.

Glycogen regulation by insulin and glucagon/epinephrine

Glucagon (liverl

Epinephrine (liver and muscle) -

~ ) Receptor _____ _

~ (>.def\'1\a\t .,-

Insulin (liver and muscle)

-+~c.\ast Glucagon . receptor cAMP ~alc1um·calmodulln EndoplasmiC

ret1culum

~ ------~ Calcium

ATP )_ m muscle dunng i contraction

Protein kinase A/

\ +

~ I/ Glycogen

phosphorylase kinase

'-- -.

Protein kinase A

;·~M\ ~ I Glycogen Glycogen

phosphorylase synthase

~~l "' •• ,,. J ~.!~''""~ _______ /

FA17 p 81 .2

Tyrosine k1nase dimer receptor

•



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A 53-year-old man is t reated for Helicobacter pylori- related peptic ulcer disease with a 2-week course of tri ple therapy including IAAI · amoxicilli n, clarithromycin, and lansoprazole. One week later t he patient experiences fatigue and a temperature of 38.5°C (101.3°F). This is fol lowed by the appearance of diffuse, generalized erythematous macules and patches, which are tender to the touch and accompanied by a burning sensation of the skin. These lesions are observed on both the skin and the mucus membranes as seen in the image.

Image courtesy Balasundaram et al., J Oral Maxillofac Pathol. 2011

Based on the history and cl inical presentat ion, what is t he most likely diagnosis?

:

A. Cutaneous flushing

B. Drug- induced acute urticaria

C. Erythema nodosum

D. Pyoderma gangrenosum

E. Stevens-Johnson syndrome



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The correct a nswer is E. 78°/o chose this . Stevens-Johnson syndrome lies on the urticaria-erythema mult iforme-toxic epidermal necrolysis spectrum of acute epidermal disorders. I t is most commonly associated with drug exposures, especially to penicillins, sulfonamides, ethosuximide, and lamotrigine. The quest ion stem presents a t ypical clinica l picture, including the prodrome of fever and fat igue, fo llowed by skin and mucocutaneous lesions. Skin lesions begin as erythematous macules, progress to form bullae, and subsequent ly slough. Mucus membrane involvement is required for the diagnosis of Stevens-Johnson syndrome. Ethosuximide Lamotrigine Stevens-Johnson syndrome Prodrome Sulfonamide (medicine) Epidermis Fatigue (medical) Cutaneous condition Erythema Penicillin Blister Fever Sulfonamide

A is not correct . 3°/o chose t his. Cutaneous flush ing can be induced by drug exposure, includ ing niacin, adenosine and vancomycin. Fevers, fatigue, and pain on palpation are more characteristic of Stevens-Johnson syndrome. Niacin vancomycin Fatigue (medical) Flushing (physiology) Adenosine Palpation

B is not correct. 8% chose t his . An allergic drug reaction could present as urticaria, or hives, which are raised lesions (transient edematous papules and plaques) . Angioedema is a larger edematous area that involves the dermis and subcutaneous t issues. While many ant ibiotics, includ ing amoxicill in, can cause acute urticaria, the cl inical description is more consistent with the much more severe Stevens-Johnson syndrome. Stevens-Johnson syndrome Amoxicillin Urticaria Dermis Angioedema Edema Antibiotics Papule Subcutaneous tissue Allergy Subcutaneous injection

C is not co rrect. 5 °/o chose this . Erythema nodosum is characterized by the appea rance of painful erythematous nodules on the lower legs. Like Stevens-Johnson syndrome, fever and malaise are common symptoms. Drugs, infect ions, and inflammatory diseases are some of the diverse et iolog ic associations with this condit ion. Stevens-Johnson syndrome Erythema nodosum Erythema Malaise Etiology Inflammation Fever Nodule (medicine)

D is not correct. 6°/o chose t his. Pyoderma gangrenosum, seen commonly in associat ion with ulcerat ive colit is, is not related to medication use and is characterized by boggy, red ulcers with purulent , necrot ic bases. Both pyoderma gangrenosum and Stevens-Johnson syndrome are painful to the touch. Ulcerative colitis Pyoderma gangrenosum Colitis Pyoderma Necrosis Pus Ulcer (dermatology) Peptic ulcer Pharmaceutical drug

Bottom Line :

Stevens-Johnson syndrome, a urticaria-erythema mult iforme-toxic epiderma l necrolysis disorder, is associated with exposure to penici llins, sulfonamides, ethosuximide, and lamot rigine. •



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Blistering skin disorders

Pemphigus vulgaris

Bullous pemphigoid

Dermatitis herpetiform is

Erythema multiforme

Stevens-Johnson syndrome

FA17 p452.1

Potentially fatal autoimmune skin disorder with lgG antibody aga inst desmoglein (component of desmosomes, which connect keratinocytes in the stratum spinosum) .

Flaccid intraepidermal bu llae · caused by acantholysis (separation ofkeratinocytes, resembling a "row of tombstones"); ora l mucosa is also involved. Type II hypersensitivity reaction .

lmmunoAuorescence reveals antibodies around epidermal cells in a reticular (net-like) pattern rn. Nikolsky sign EEl (separation of epidermis upon manual stroking of skin).

Less severe than pemphigus vulgaris. Involves lgG antibody against hem idesmosomes (epiderma l basement membrane; antibodies are "bullow" the epidermis).

Tense blisters mJ containing eosinophils affect skin but spa re oral mucosa. lmmunoAuorescence reveals linear pattern at epidermal-dermal junction (!].

ikolsky sign e. Pruritic papules, ,·esicles, and bullae (often found on elbows) 1]. Deposits of lgA at tips of dermal

papillae. Associated with celiac disease. Treatment: dapsone, gluten-free diet.

Associated with infections (eg, Mycoplasma pneumoniae, HSV), drugs (eg, sulfa drugs, P-lactams, phenytoin), cancers, autoimmune disease. Presents with multiple types of lcsions-maculcs, papules, vesicles, target lesions (look like targets with multiple rings and dusky center showing epithelial disruption)(].

Characterized by fever, bullae formation and necrosis, sloughing of skin at dermal-epidermal junction, high mortality rate. Typically 2 mucous membranes arc involved [!I Cl, and targetoid skin lesions may appear, as seen in erythema multi forme. Usually associated with adverse drug reaction. A more severe form of Stevens-Johnson syndrome (SJS) with > 30% of the body surface <>rP<> i n ,.nl""rl i< trwir onirlorrn::>l norrnl\/ck 0 0 fTI= I\l\ 1 (\_~(\o/n in•·nl""""' "t riPnntP< ,T,_Tf<' i



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~ ~ - . . . . . •

Erythema multiforme Associated \\·ith infections (eg, Mrcoplasma pneumoniae, HSV), drugs (eg, sulfa drugs, ~-lactams,

Stevens-Johnson syndrome

phenytoin), cancers, autoimmune disease. Presents with multiple types of lesions-maculcs, papules, \·esicles, target lesions (look like targets with multiple rings and dusky center showing epithelial disruption)

Characterized by fever, bullae formation and necrosis, sloughing of skin at dermal-epidem1al junction, high mortality rate. 'l)•pically 2 mucous membranes arc involved [!J , and largctoid skin lesions may appear, as seen in erythema multiforme. Usually associated with adverse drug reaction. A more severe form of Sic\ ens-Johnson syndrome (SJS) with > 30% of the bod} surface area im·oh-ed is toxic epidermal necrolysis (TEN). 10-30% im·oh-ement denotes SJS-TE~.



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Drug reactions- musculoskeletal/skin/connective tissue

DRUG REACTION CAUSAL AGENTS

Fat redistribution

Gingival hyperplasia

Hyperuricemia (gout)

Myopathy

Osteoporosis

Photosensitivity

Rash (StevensJohnson syndrome)

SLE-Iike syndrome

Teeth discoloration

Tendonitis, tendon rupture, and cartilage damage

P rotease inhibitors, Glucocorticoids

Phenytoin, Ca2+ channel blockers, C)closporine

Pyrazinamide, T hiazides, Furosemide, '\ iacin, Cyclosporine

Statins, fibrates, niacin, colchicine, daptomycin, hydroxychJoroquine, interferon-a,

penicillamine, glucocorticoids

Corticosteroids, depot medroxyprogesterone acetate, GnRH agonists, aromatase inhibitors,

anticonvulsa nts, heparin

Sulfonamides, Amioclaronc, Tetracyclines, 5-F U

Anti-epileptic drugs (especially lamotrigine),

allopuri nol, sulfa dmgs, penicillin

Sulfa drugs, Hydralazine, Isoniazid,

P rocainamide, Phenytoin, Etancrcept

Tetracyclines

F'luoroqui nolones

FA17 p 241.2

NOTES

Fat PiG

Painful Tophi and Feet '\eed Care

SAT For Photo

Ste\en Johnson has epileptic allergy to sulfa dmgs and penicillin

llaving lupus is "SIIIPP-E"

Tcethracrclines

•



1 FA17 p 514.1 •

2 Epilepsy drugs 3 GENERALIZED

• 4 -~ · 5 < '-' '-' c:> z "' ~ c:> ::::>

'-' ~ ~ ... .,;::: c '-' '-' ;::: ..:.. z ::::> ...

z ... _ ... a: "' ..., ::: c c:> "" _.._

MECHANISM SIDE EFFECTS NOTES ... - c "' ... Ethosuximide • Blocks thalamic T-trpe Ca!• 1.1 G IIIJ- l .thosuximidc Sucks to ha,·e Silent

./ channels causes Fatigue, Gl distress, llead.Jche, llching (and

{absence) Seizures

urticaria), and Ste,·ens-Johnson syndrome

Benzodiazepines •• t GABAA action Sedation, tolerance, Also for eclampsia seizures (1st (eg, diazepam, ./ dependence, respiratory line is 1\ lgS04)

lorazepam, clepre~~ion midazolam)

Phenobarbital ./ ./ t GABAA action Sedation, tolerance, I st line in neonates dependence, induction of cytochrome P-450, cardiorespiratory depression

Phenytoin, ./ • uo Blocks a+ channels; zero- eurologic: nystagmus, diplopia, ataxia, sedation, peripheral fosphenytoin ./ ./ order kinetics neuropathy. Dermatologic: hirsutism, Ste, ens-)ohnson

syndrome, gingival hyperplasia, DRESS syndrome. Mu~cu lo~keleta l: osteopenia, SLE-Iike syndrome. llematologic: megaloblastic anemia. Reproducti,e: teratogenesis (fetal hydantoin syndrome). Other: cytochrome P-450 induction

Carbamaze pine • ./ Blocks a+ channels Diplopi.l, atnxia, blood 1st line for trigeminal neuralgia ./ dyscrnsias (agranulocytosis,

...... 1.~~ · :- ..... , ...... "'; ... \ 1:._ ..



1 Carbamazepine • ./ Blocks a• channels Diplopia, atnxia, blood 1st line for trigeminal neuralgin •

2 ./ dyscrasias (agranulocytosis, 3 apl a~lic anemia), li1er

• 4 toxicit), teratogenesis, induction of c1·tochrome

· 5 P-450, SIADI i, Slelens-Johnson syndrome

Valproic acid ./ ./ I 'a• channel inaclil alion, Cl di~lre~. rare but fatal Also used for myoclonic sci.wres, ./ I GA BA concentration hepatotoxicit} (measure bipolar disorder, migraine

by inhibiting GABA LFTs). pancreatitis, neural prophylaxis transaminase lube defects, tremor, "eight

gain, contraindicated in pregnancy

Vigabatrin ./ I GABA by irreversibly Permanent visual loss (black inhibiting CABA bo' "arning) transaminase

Gabapentin Primarily inhibits high-1 ollage- Sedation, ata\ia Also used for peripheral ~lclil':l led Ca2+ channels; neuropathy, post herpetic designed as CABA analog neuralgia

Topiramate ./ ./ Blocks a• channels, I CABA Sedation, ll lt:nlal dulling, Also used for migraine action kidney stones, weight loss, prevention

glaucoma

Lamotrigine ./ ./ ./ Blocks voltage-gated \Ja+ Stevens-Johnson syndrome channels, inhibits the release (must be titrated slowly) of glutamate

Levetiracetam ./ ./ Unknown; may modulate F'atigue. dro" siness, CABA and glutamate release headache, neuropsychiatric

S) mploms (eg, personality changes)

Ti: s - -s h :"' ft ./ t r A Jli\ h. :n i,. :J,:t :,..,,.. .-A .. , , • .,. I n



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A baby girl is born to a 38-year-old mother wit h litt le prenatal care. Physical evaluation of the infant is notable for low bi1th weight, small head size, small right orbit, cleft lip and palate, and an extra right-sided digit coming off the thumb. A holosystolic murmur is appreciated over the precordium, and severe hypotonia is noted. The attending physician remarks that the diagnosis could have been made before birth by amniocentesis and chorionic villus sampling.

What is the mechanism for the disease producing this constellation of physical findings?

:

A. Defect in degradation of branched -chain amino acids

B. Deletion of the short arm of chromosome 5

C. Intracellular glycogen accumulation

D. Maternal nondisjunction

E. Microdeletion on chromosome 22

F. Nonenzymatic glycosylat ion



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The correct a nswer is 0. 56°/o chose t his. The physical find ings described in this patient are those of t risomy 13 or Patau syndrome, including microcephaly, micropht halmia, polydact yly, hypotonia suggest ive of cent ral nervous system defects, and congenital heart disease suggested by a heart murmur. Advanced maternal age is a risk factor for nondisjunct ion, the primary mechanism for chromosomal aneu ploid ies. Maternal nondisjunct ion results when sister chromatids fa il to separate during meiosis I ( rare) or II, respectively, leading to daughter cells with abnormal chromosome numbers or aneuploidy. I n t risomy 13, each cell contains an ext ra copy of chromosome 13 due to nondisjunct ion, which occurs during meiosis. Nondisjunction Meiosis Aneuploidy Advanced maternal age Microcephaly Polydactyly Hypotonia Patau syndrome Chromosome 13 (human) Microphthalmia Congenital heart defect Chromosome Trisomy

Congenital disorder Heart murmur Central nervous system Sister chromatids Chromatid Meiosis I Nervous system

A is not correct . 5°/o chose this. This describes maple syrup urine disease, in which decreased act ivit y of a-ketoacid dehydrogenase causes manifestat ions of cent ral nervous system defects, intellectual disabilit y, and death. Maple syrup urine disease Central nervous system Maple syrup Intellectual disability Urine Nervous system

B is not correct. 14% chose this . This describes cri -du-chat syndrome, which shares features of growth retardation, microcephaly, and congenital heart disease with Patau syndrome. Other features of cri -du-chat include the unusual cat -like cry for which t he syndrome is named, dist inctive facial features including epicanthal folds, and commonly visceral anomalies. Microcephaly Cri du chat Patau syndrome Congenital heart defect Congenital disorder Delayed milestone Epicanthic fold Cardiovascular disease

C is not co rrect. 6 °/o chose this . Glycogen storage diseases are t he result of abnormal glycogen metabolism and subsequent int racellu lar accumulat ion of glycogen. Presentation of the 12 types vary, but include von Gierke disease, Pompe disease, and McArdle disease. Glycogen storage disease type I Glycogen Glycogen storage disease type II Glycogen storage disease type V Metabolism Glycogen storage disease

E is not correct. 1 6°/o chose this. This describes 22qll syndrome, or DiGeorge syndrome, common features of which include clefting, abnormal facies, and congenital heart disease. Other features of 22qll syndrome are t hymic aplasia leading to immunodef iciency and parathyroid aplasia leading to hypocalcemia. Hypocalcaemia DiGeorge syndrome Congenital heart defect Parathyroid gland Cleft lip and palate Thymus Immunodeficiency Aplasia Congenital disorder Cardiovascular disease

F is not correct . 3°/o chose this. I nfants of diabetic mothers have an increased risk of congenital anomalies, includ ing well known associations such as caudal dysgenesis and t ransposit ion of the great vessels. The congenital abnormalit ies in t his case do not exclude maternal diabetes as a possible cause . However, amniocentesis and chorionic villus sampling are not used for diagnosis of diabetes during pregnancy.



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Bottom Line: Trisomy 13 manifests wit h microcephaly, microphthalmia, polydacty ly, hypotonia, and heart defects. It is caused by materna l nondisj unction, for which advanced materna l age is a risk factor. Nondisjunction Patau syndrome Advanced maternal age Microcephaly Hypotonia Polydactyly Microphthalmia Trisomy Congenital heart defect

l@ljl'il·1i•J for yea r:[ 2017 • J FIRST AID FACTS

Autosomal trisomies

Down syndrome (trisomy 21)

Findings: intellectual disability, Rat facies, prominent epicanthal folds, single palmar crease, gap between 1st 2 toes, duodenal atresia, Hirschsprung disease, congenital heart disease (eg, atrioventricular septal defect), Brush field spots. Associated with early-onset Alzheimer disease (chromosome 21 codes for amyloid precursor protein) and f risk of ALL and AML.

95% of cases due to meiotic nondisjunction (t with adva nced maternal age; from 1:1500 in women< 20 to 1:25 in women > 45 years old).

4% of cases due to unbalanced Robertson ian translocation, most typically between chromosomes 14 and 21. 1% of cases clue

Incidence 1:700. Drinking age (21).

FA17 p 59.1

Most common viable chromosomal disorder and most common cause of genetic intellectual disability.

First-trimester ultrasound commonly shows t nuchal translucency and h)'poplastic nasal bone; l serum PAPP-A, f free ~-hCC.

Second-trimester quad screen shows l o:-fetoprotein, t ~-hCC, l estriol, t inhibin .



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Edwards syndrome (trisomy 18)

Patau syndrome (trisomy 13)

Findings: PRII\CE Edward- Prominent occiput, Rocker-bottom feet, Intellectual disability, '\'ondisjunction, Clenched fi sts (" ith o,·erlapping fingers), low-set l',ars, micrognathia (small jaw), congenital heart disease. Death usually occurs by age I.

Findings: severe intellectual disability, rockerbottom feet, microphthalmia, microcephaly, cleft liP/Palate, holoProsencephaly, Polydactyly, cutis aPlasia, congenital heart disease. Death usually occurs by age I.

Nondisjunction in meiosis I

Meiosis I

Meiosis II

I

Incidence 1:8000. Election age (18). 2nd most common autosomal trisomy resulting

in Ji,e birth (most common is Do" n S) ndrome). PAPP- and free f3-hCG are l in fi rst trimester.

Quad screen shows l a-fetoprotcin, l f3-hCC, l estriol, l or normal inhibin A.

Incidence 1:15,000. Puberty (13). First-trimester pregnancy screen shows l free

f3-hCC, l P. PP-A.

Nondisjunction in meiosis II

' :>

' :> I

'' ' v I Nondisjunction

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Patau syndrome (trisomy 13)

Findings: severe intellectual disabil ity, rockerbottom feet, microphthalmia, microcephaly, cleft liP/Palate, holoProsencephaly, Polydactyly, cutis aPlasia, congenital heart disease. Death usuall) occurs by age I.

Nondisjunction in meiosis I

Meiosis I

c :> Meiosis II

A A Ill Ill I I Gametes

n+ 1 n+1 n-1 n-1

Trisomy Monosomy

Incidence 1:15,000. Puberty (1 3). First-trimester pregnancy screen shows ! free P-hCG, l PAPP- .

Nondi.sjunction in meiosis II

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A ,,,;,;"""'" A II II I Ill n n n - 1 n+1

I Normal Monosomy Trisomy Ill

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A 28-year-old African-American woman comes to t he clinic because she has had fevers and painfu l j oint s for the past month. Her temperature is 37.8°C (100°F). Physical examinat ion reveals an erythematous rash bi laterally on her cheeks. Laboratory studies show a creatinine level of 4.0 mg/dL, a posit ive Venereal Disease Research Laboratory test for syphilis, and a posit ive ant inuclear antibody test with a t iter of 1:2560.

This patient is most likely to have which additional physical examination finding?

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A. Painful erythema of the first metatarsophalangeal joint

B. Painless erythematous oropharyngeal ulcers

C. Painless purple striae on the abdomen

D. Painless reddish-brown wart-like lesions in the groin and perineum

E. Painless ulcer with raised margins on the labia majora


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The correct a nswer is B. 46% chos e t his . This patient has SLE. Oral or nasopharyngeal ulcerations occur f requently in SLE and are 1 of the 11 classif ication crit eria for SLE. White plaques can also be present in the oral cavity. The ulcerat ions and plaques seen in SLE are often painless. Mouth systemic lupus erythematosus Human mouth Peptic ulcer Mouth ulcer Pharynx Ulcer (dermatology)

A is not correct . 2 1 % chos e this . This describes podagra, t he sudden onset of severe pain in the great toe associated with gout. Although polyarthralgias or arthrit is are common manifestations of SLE, the arthrit is is usually symmetric, resembling rheumatoid arthri tis. I nvolvement of exclusively the great t oe would be very rare . Rheumatoid arthritis Gout Toe Arthritis Systemic lupus erythematosus Hallux

C is not co rrect. 7 °/o chose this . This describes a cutaneous finding in Cushing syndrome. It may be seen in patients with SLE who have been t reated with long-term high -dose steroids, but it is not characterist ic of SLE itself. Cushing's syndrome systemic lupus erythematosus Anabolic steroid Steroid

D is not correct. 9°/o chose t his. This describes a classic secondary syphilis rash : condyloma lata. These lesions are rapid in onset , appearing in a matter of weeks. As mentioned above, SLE pat ients often have false-posit ive VORL due to the presence of ant iphospholipid ant ibody. Syphilis Antibody Systemic lupus erythematosus Antiphospholipid syndrome Venereal Disease Research Laboratory test Secondary syphilis Rash Genital wart Type I and type II errors

E is not correct. 1 7°/o chose this. This describes the rash t hat often accompanies primary syphilis. The Venereal Disease Research Laboratory (VORL) test for syphilis is not specif ic, and systemic lupus erythematosus (SLE) can produce a false-posit ive VORL due to the presence of ant iphospholipid ant ibody. There are several causes of a fa lse-posit ive VORL. Acute causes include many febrile illnesses and some drugs, and chronic causes include SLE, leprosy, and rheumatoid art hrit is. Systemic lupus erythematosus Rheumatoid arthritis Syphilis Leprosy Antibody Fever Arthritis Antiphospholipid syndrome Sexually transmitted infection Lupus erythematosus Type I and type II errors Rash

Venereal Disease Research Laboratory test

Bottom Line :

Systemic lupus erythematosus (SLE) often manifests with mucosal ulcerations that are usually painless. Patients with SLE often have a fa lseposit ive VORL. Systemic lupus erythematosus Lupus erythematosus Peptic ulcer Mouth ulcer Type I and type II errors Ulcer (dermatology) Mucous membrane


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Systemic lupus erythematosus

SYMPTOMS

FINDINGS

C lassic presentation: rash, joint pain, and fever, most commonly in a female of reproducti'e age and frican- merican descent.

Libman-Sacks Endocarditis-nonbacterial, ,·errucous thrombi usually on mitral or aortic vah-c and can be present on either surface of the \'a h-e (but usually on undersurface) (LSI': in SLE).

Lupus nephritis (glomerular deposition of antiDNA immune complexes) can be nephritic or nephrotic (hematuria or proteinuria). Most common and severe type is diffuse pro! i ferative.

Common causes of death in SLF:: Cardiovascular disease Infections Renal disease

Antinuclear antibodies (A 'A)

Anti-dsD1 antibodies

Anti-Smith antibodies

RASI I OR PAll\: Rash (malar rJ or discoid : ) Arthritis (nonerosive) Serositis

FA17 p 443.1

llematologic disorders (eg, crtopenias) Oral/nasopharyngeal ulcers Renal disease Photosensitivity \ ntinuclear antibodies Immunologic disorder (anti-dsD lA, anti-Sm,

ant iphospholipid) t\eurologic disorders (eg, seizures, psychosis)

Sensitive, not specific

Specific, poor prognosis (renal disease)

Specific, not prognostic (directed against snR ' Ps)

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VORL false positives

Cushing syndrome

ETIOLOGY

FINDINGS

DIAGNOSIS

VORL detects nonspecific antibod) that reacts with beef cardiolipin. Quantitative, inexpensive, and widely available test for syphilis (sensiti,·e but not specific).

f cortisol due to a variet} of camcs:

FA17 p 143.2

False-positive results on VORL with: Viral infection (eg, EBV, hepatitis) Drugs Rheumatic fe,·er Lupus and leprosy

FA17 p 323.1

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• Exogenous corticosteroids-result in l ACT! I, bilateral adrenal atrophy. Most common cause. Primary adrenal adenoma, hyperplasia, or carcinoma- result in l CTII, atrophy of unim·olvecl adrenal gland. Can also present with pseudohypcraldosteronism. ACTH-sccreting pituitary adenoma (Cushing cli sca~c); parancoplastic ACTH secretion (eg, small cell lung cancer, bronchial ce:1rcinoicls)- result in t ACTH, bilateral adrena l hyperplasia. Cushing disease is responsible for the majority of endogenous cases of Cushing syndrome.

Hypertension, weight gain, moon facies Fl. abdominal striae I}] and truncal obesity, buffalo hump, skin changes (eg, th inning, striae), osteoporosis, hyperglycemia (insulin resistance), amenorrhea, . . 1mmunosuppress1on.

Screening tests include: t free cortisol on 24-hr urinalysis, f midnight salivary cortisol, and no suppression with overnight low-close dexamethasone test. Measure serum CTI I. If l, suspect adrenal tumor or exogenous glucocorticoids. Iff, distinguish between Cushing disease and ectopic CT II secretion (cg, from Slll<lll cell lung cancer) with a high-dose dexamethasone

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Lode. Suspe-nd End Bloc:k


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suppression test and CRII stimulation lest. Ectopic secretion will not decrease with dexamethasone because the source is resistant lo negative feedback; ectopic secretion " ill not increase with CRI-1 because pituitarr ACTII is suppressed.

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Suppressed

ACTH-rndependent Cusllrng syndrome

l Exogenous glucocorticoids

or adrenal tumor (consider adrenal CT to confirm)

i 24-hr unne free cortisol. i late mght salivary cOrtisol. and/or rnadequate suppresSion on 1 mg overnoght dexamethasone test

Measure ACTH

Hrgh-dose dexamethasone suppression test

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Elevated

ACTH-dependent Cushrng syndrome

l CRH stimulatron test

No suppressron Ectopic ACTH

secretion

Adequate suppressron

Cushing dist'st

i ACTH and cortrsol Cushing disease

No i mACTH and cortrsol Ectopic ACTH

secretion

CT of the chestlabdomen/pelvrs MRI of the prturtary CT of the chestlabdomen/pelvrs

c.


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