• What is rT3 (reverse T3)?
o Usu ↑ in hypothyroidism
o help dx “sick thyroid” pts (who are euthyroid) from true hypothyroid cases
o in a body under stress (illness, fasting, high cortisol) T4 is deiodinized to rT3 instead of T3
o (“step down”, instead of “step up”)= (-) charge in diff spot
o Metabolic enzyme function ↓ → Stresses inhibit 5’-deiodinase → ↓ T4 to T3, ↑ rT3
o Sxs of Wilson’s (temp) syndrome: hypothyroid, ↑rT3, corrected by giving T3 (Not accepted by mainstream)
• What is significance of BBT?
o reflects metabolic rate controlled by thyroid hormones
o N = 97.6-98.2 F
o Menstruating females take BBT on d2-4 of menses
o ↓ quite common, may = hypothyroidism
o ↑ BBT less common, may = hyperthyroidism
o Look for other sxs thyroid dz
• What are thyroid antibodies? Risk factors?
o =auto-Abs
o Stimulating: a-Thyroid receptor =Thyroid stimulating Igs (TSI)
o Blocking: a-thyroperoxidase (a-TPO); Thyroglobulin (a-TGLB)
• What is Graves dz?
o MC cause hyperthyroid (80-85%)
o dt stimulation of TSHRs by TSI, over stimulate thyroid activity
o Abs arise 2nd to defect in T-suppressor cells → clone of T-helper to interact with thyroid Ags → stimulate B cells to make TSI
o a-TPO and a-TGLB often seen
• what are ssx of graves?
o → sympatho-adrenergic activity and metabolism o ↓ TSH, ↑ T3/T4 o Exophthalmos o Warm pulsating goiter o Tachycardia o Fine tremor (hand) o Pretibial myxedema
• how is Graves diagnosed?
o ↑T3, T4; ↓TSH
o gland non-palpable or smooth symmetric goiter
• Describe fetal thyroid development, and how it’s affected by Graves?
o fetus dependent on mom’s T4 until 10-12 wks
o 20 wks, responsive to its own TSH, low thyroid function
o IgG Abs in Graves cross placenta → fetal hyperthyroid after 20 wks gestation
o Antithyroid drugs (methimazole, propylthiouracil) also cross placenta → tx both maternal and fetal hyperthyroid
• What is RAIU (radioactive iodine uptake)?
o Scintillation counter measures radioactivity 6 & 24 hrs after I(123) given
o Uptake varies greatly by iodine status: Indigenous diet (normal uptake 10% vs 90%); Amiodarone, Contrast study, Topical betadine
• What causes abnormal RAIU results?
o Sx ↑: Graves, Toxic goiter
o Sx ↓: Thyroiditis (Subacute, Active Hashimoto’s), Hormone ingestion (Thyrotoxicosis factitia, Hamburger Thyrotoxicosis); Excess I- intake in Graves’ (Jod-Basedow effect); Ectopic thyroid carcinoma (Struma ovarii)
• What is hashimoto’s thyroiditis?
o MC cause acquired primary hypo o mb caused by any environmental trigger o F>M, 8:1; Onset usu 30-50 o FHx common o Early stages may present as hyper o Early labs may show normal T4 and TSH, ↑ a-TPO, and less commonly a-Tg
• How is hashimoto’s diagnosed?
o RAIU mb ↑ or ↓
o Later: hypo, ↓T4, T3RU, ↑TSH, ↓ RAIU dt gland destruction
o Ab titers much higher in thyroiditis than Grave’s
o Gland mb TTP dt inflammation
• What is Euthyroid sick syndrome?
o T4/T3 ↓ in acute & chronic illness (any severe), fasting, starvation, sepsis, surgery, MI, BM transplant
o Abn tests w acute or chronic non-thyroidal systemic illness
o Secondary to:
o ↓ peripheral conversion T4 T3
o ↓ clearance rT3
o ↓ binding T3/T4 to TBG
• What are common causes of ESS w fidnings?
o NTI (MC): ↓T3; N TSH, T4; mb dt ↓ T3 →4
o 20% ICU pts: ↓T3/T4; N TSH; mb dt ↓ TBG, albumin
o severe illness: ↓TSH, T3/T4; HTH and Pit involved
o cirrhosis, hepatitis, acute psych: ↑ T4; TSH & T3 N or ↑
• what are screening recommendations for thyroid dz in adults?
o USPSTF: say insufficient evidence for or against routine screening
o AAFP: high-risk populations: F w FHx thyroid dz, F >35, prego, abd PE, DM, AI Hx
o ATA: start at a 35 (+ q5 yrs)
• What are some good and not-so-good indications to screen for hypothyroid?
o High suspicion: goiter, delayed reflexes
o Intermediate: Fatigue, wt gain/difficulty losing wt, Cold intolerance, Dry, rough, pale skin, Constipation, FHx, Hoarseness
o Low, non-specific sxs: Coarse, dry hair, Hair loss, Muscle cramps/aches, Depression, Irritability, Memory loss, Abn menstrual cycles, ↓ libido
• What are some good and not-so-good indications to screen for hyperthyroid?
o High: goiter, thyroid bruit, lid lag, proptosis
o Med: Fatigue, Wt loss despite ↑appetite, Heat intolerance/sweating, Fine tremor, FHx, ↑BMs, ↑HR/palpitations, Staring gaze
o Low: Nervousness, Insomnia, Breathlessness, Light or absent menstrual periods, Wt loss, Muscle weakness, Warm moist skin, Hair loss
• What is recommended prenatal thyroid screening?
o Universal screening before preg not recommended
o Prenatal serum TSH testing is recommended if high risk or known thyroid dysfunction
o Non-Consensus on TSH screening for all prego vs high-risk at time of first visit or by 9th wk
• What is neonatal thyroid screening for congenital hypothyroid?
o All infants screened at 2-4 d
o congenital hypo usu unaffected at birth, dt placental transfer of T4; but must get tx by 2-3wks
o otherwise → mental retardation
o if mom is hypo, significant impairment of neurointellectual development despite early tx
o 3 screening strategies: (1) primary TSH, backup T4 in infants w ↑ TSH, (2) primary T4, backup TSH w ↓T4, (3) both T4 and TSH (IDEAL)
- Total T4: ↑
- T3RU: ↑
- FTI: ↑
- TSH: ↓
- FT4: ↑
- Total T3: ↑
o Primary hyper
- Total T4: ↓
- T3RU: ↓
- FTI: ↓
- TSH: ↑
- FT4: ↓
- Total T3: ↓/N
o Primary hypo
- Total T4: ↑
- T3RU: ↓
- FTI: N
- TSH: N
- FT4: N
- Total T3: N
pregnancy
• What is viral hepatitis?
o 5 viruses, A-E
o affinity for hepatocyte, induce liver injury, usu immune-mediated mechanism
o Diff physical,chemical composition, mechanisms to replicate within infected cells
• Hx of viral hepatitis?
o Contagious jaundice, 8th century, Pope Zacharias ordered isolation of affected
o Virchow, 1865, epidemic jaundice dt mucous plug in the papilla of Vater
o early 20th century linking vaccination, blood drawing, blood transfusion and parenteral tx of syphilitic pts w contaminated needles, development of “serum hepatitis”
o WW II, >200,000 cases of jaundice in american, >5 million cases in germans
o MacCallum 1940’s, suggested both enteric (“infectious hepatitis”, “hepatitis A”) and parenteral/sexual (“serum hepatitis”, “hepatitis B”) transmission could occur
o mid-20th century, “A & B” had diff clinical courses, suggesting different etiologies
• What was the Willowbrook state school’s role in elucidating hepatitis viruses?
o 1950s and 60s: 1000s of intellectually disabled children, mostly w trisomy 21 →jaundice freq, ↑ LFTs; Newly admitted children exposed to infectious material, w parental consent → criticism
o found diff filterable infx agents caused 2 clinical patterns of hepatitis
o One inoculum of serum (MS1, initials of infected child) → illness, short inc, like epidemic hepatitis (A)
o Another, MS2 (same child who later developed the 2nd form of jaundice) →illness, longer inc, like B
o Boggs used MS1 in Marmoset monkeys (1967), Humans incarcerated at Joliet State Penitentiary (US Army 1970)
• How was hepatitis B discovered?
o 1963, Dr. Baruch Blumberg (nobel prize 1976), identified a protein (“Australia Ag” reacted to Abs from pts w hemophilia and leukemia
o Assoc w infx hepatitis 1966
o virus specifically seen by electron microscopy in 1970
• how was hepatitis A discovered?
o 1973, NIH, in fecal samples from ppl inoculated w MS1 serum from Willowbrook
o Electron microscopy: 27 nm spherical viral particles, aggregates after incubation of fecal samples w convalescent serum
o successfully adapted to grow in culture by end of 1970’s
• how was hepatitis D discovered?
o 1977, Rizetto in Turin, identitied new Ag in both liver and serum in carriers of HBsAg
o HDV= defective virus, genome is negative circular ssRNA, encodes single nucleocapsid protein (delta Ag)
o To replicate, Requires envelope of HBV w HBsAg
• How was hepatitis C discovered?
o End of 1970’s, found most cases of post-transfusion hepatitis were not dt A, B, D (20% dt cardiac surgery w blood transfusion)
o known as non-A, non-B hepatitis (NANBH)
o identified by Houghton, 1989, Chiron Corporation
o Retrospective testing showed 90% of non-A, non-B hepatitis was HVC
• What is hepatitis E?
o epidemic waterborne, similar to A
o first recognized in India in 1980
o Causative agent identified in Uzbekistan in 1983
o Genome cloned in 1990 and fully sequenced shortly after
• What are “infectious” and “serum” viral hepatitis? NANB?
o Infectious: became known as HAV
o Serum: B, D
o NANB: E (enterically transmitted), C (parenterally transmitted), F, G?
• What are sources of virus for the 5 hep viruses? Route of transmission?
o A, E: feces
o B, C, D: blood/blood-derived body fluids
o A, E: fecal, oral
o B, C, D: percutaneous, permucosal
• Which of the 5 hep viruses can be chronic infx? How are they prevented?
o Chronic: B, C, D
o A, B: pre/post-exposure immunization
o C: blood donor-screening; risk behavior modification
o D: pre/post-exposure immunization; risk behavior modification
o E: ensure safe drinking water
• What is the hepatitis A virus?
o Naked RNA virus
o Related to enteroviruses, formerly known as enterovirus 72, now put in its own family: heptovirus
o One stable serotype only
o Difficult to culture: primary marmoset cell culture, also in vivo in chimpanzees and marmosets
o 4 genotypes exist, but in practice most of them are group 1
• How is hepatitis A spread?
o Close personal contact household, sexual, day care)
o Contaminated food, water (infx food handlers, raw shellfish)
o Blood exposure (rare) ( IV drugs, transfusion)
• What is the geographic distribution of HABV infx?
o High: S and Central America, Africa, Greenland, Middle East, South Asia
o Med: S and E Europe, North Eurasia
o Low: N America, Australia
o Very low: N Europe
• What are clinical features of hepatitis A?
o Inc: avg 30 d (r 15-50)
o Jaundice: 10% < 6, 40-50% 6-14, 70-80% > 14
o Comp: fulminant, cholestatic, relapsing hepatitis
o Chronic sequelae: none
• How is HAV diagnosed?
o Acute: serum HAV-IgM by EIA
o Immunity: HAV-IgG by EIA.
o Cell culture: difficult, up to 4 wks, not routine
o Direct Detection: EM, RT-PCR of feces. detect earlier than serology but rarely done
• What is the typical serological course of hepatitis A?
o Fecal HAV peaks @ 1-3 mos (correlated w sxs)
o ↑ ALT 1-3 mos?
o IgM a-HAV present 1-5 mos
o Total a-HAV plateaus after 1 ye (IgG)
• What does CDC say about HAV prevention?
o Vaccine is primary o 2006: Universal infant vaccination o 1996, Adults w ↑ risk infx or its adverse consequences: o Traveler to HAV endemic country o MSM o Illegal drugs o chronic liver dz o clotting factor dos
• what is the hepatitis B virus?
o dsDNA virus (+ strand not complete)
o Replication involves a reverse transcriptase
o Complete Dane particle 42 nm, 28 nm electron dense core, w HBcAg and HBeAg. coat and 22 nm free particles contain HBsAg
o At least 4 phenotypes of HBsAg: adw, adr, ayw and ayr.
o HBcAg is single serotype
o HBV has 8 genotypes (A-H): A and C predominate in US, B and D also present. Genotype F in S America and Alaska. A, D, E in Africa. D in Russia (USSR), B and C in Asia
o Can’t culture
• What are the relative concentrations of HBV in diff body fluids?
o High: blood, serum, wound exudates
o Mod: semen, vaginal fluid, saliva
o Low/not detectable: urine, feces, sweat, tears, breast milk
• What is the geographic distribution of chronic HBV infection?
o High: Alaska, N Canada, S Greenland, N Brazil, Africa, Asia
o Med: Brazil, N Africa, E Europe, Middle East
o Low: N America, Argentina, N Greenland, N Europe, Australia
• Describe the structure of the hepatitis viruses:
o A: ssRNA → capsid
o B: (elongated or spherical) dsDNA (partial ss) →HBeAg →HBcAg →nucleocapsid →envelope (lipid from host cell) → HBsAg
o C: ssRNA →nucleocapsid →envelope → glycoproteins
o D: tiny ssRNA → small and large delta Ag → HBsAg
o E: ssRNA → unenveloped, 32-34nM
• What are clinical features of hepatitis B?
o Inc: avg 60-90 d (r 45-180) o Jaundice: 10% < 5, 30-50% > 5 o Acute fatalitiy: 0.5-1% o Chronic: 30-90% < 5, 2-10% > 5 o mortality dt chronic liver dz: 15-25%
• what is typical serologic course of acute HBV w/o chronic progression?
o HBsAG 4-24 wks (correlated w sxs) o IgM a-HBc 6-32 wks o a-HBs after 32 wks o HbeAg: 4-12 wks o a-HBe: after 12 wks o total a-HBc plateaus at 16 wks
• what is typical serologic course of chronic HBV?
o HBsAg plateaus at 12 wks o Total a-HBc plateaus at 16 wks o IgM a-HBc 6-36 wks o HBeAg: 6wks – yrs o a-HBe mb seen yrs later
• how is hepatitis B diagnosed?
o HBsAg: general marker of infx
o HBsAb: document recovery/immunity
o a-HBc IgM: marker of acute
o a-HBc IgG: past or chronic
o HBeAg: indicates active replication = infectiveness
o a-Hbe: virus no longer replicating. Mb (+) for HBsAg, made by integrated HBV
o HBV-DNA: indicates active replication, more accurate than HBeAg esp in cases of escape mutants. monitoring response to tx
- HBsAG: (-)
- Total a-HBc: (-)
- IgM a-HBc: (-)
- a-HBs: (-)
o never infected
- HBsAG: (+)
- Total a-HBc: (-)
- IgM a-HBc: (-)
- a-HBs: (-)
o early acute, or transient after vaccine
- HBsAG: (+)
- Total a-HBc: (+)
- IgM a-HBc: (+)
- a-HBs: (-)
o acute
- HBsAG: (-)
- Total a-HBc: (+)
- IgM a-HBc: (+)
- a-HBs: (-)
o acute resolving
- HBsAG: (-)
- Total a-HBc: (+)
- IgM a-HBc: (-)
- a-HBs: (+)
o recovered from past infx and immune
- HBsAG: (+)
- Total a-HBc: (+)
- IgM a-HBc: (-)
- a-HBs: (-)
o chronic infx
- HBsAG: (-)
- Total a-HBc: (-)
- IgM a-HBc: (-)
- a-HBs: (+)
o vaccine immunity
• what are possible outcomes HBV infx?
o Acute
o → chronic: 3-5% of adult-acquired, 95% infant-acquired
o → chronic hepatitis: 12-25% in 5 yrs
o HCC 6-15% in 5 yrs → death or transplant
o Liver failure, 20-23% in 5 yrs → death or transplant
• What is HBV infx?
o >200 million carriers worldwide
o Established cause of chronic hepatitis and cirrhosis
o Human carcinogen: cause up to 80% HCC
• Who gets chronic HBV dz?
o Rule of thumb, the younger the age, the more likely to become chronic
o Neonates: 95% chronic, most asx
o Infant-6 yrs: 30% chronic
o >6: 3-5% chronic
• What is HBV perinatal transmission?
o *in the absence of postexposure prophylaxis
o If mother (+) HBsAg and HBeAg: 70%-90% of infants infx → 90% become chronic
o If (+) HBsAg only: 20% of infants infected → 90% become chronic
• What is the strategy to eliminate HBV transmission?
o (Advisory Committee on Immunization Practices CDC)
o Prevent perinatal HBV transmission
o Universal infant vaccination
o Catch-up vaccination of all children and adolescents <19 years
o Vaccination of adults in high risk groups
• What is the HDV?
o delta agent = defective virus, like viroids in plants
o 35 nm particle w delta antigen surrounded by outer coat of HBsAg
o tiny ssRNA genome
• what are clinical features of HDV infx (w HBV)? How is it spread?
o Co-infection: severe acute dz, low risk chronic
o Super-infection: usu chronic, high risk severe chronic liver dz, may present as acute
o Spread: percutaneous exposure (IV drugs), per-mucosal (sex)
• What is the typical serologic course of HBV-HDV co-infx?
o Weeks after exposure: HBsAg, HDV RNA, IgM-HDV (+total) peak then drop (assoc w sxs, ↑ ALT)
o anti-HBs then rises and plateaus
• what is typical serologic course of HBV-HDV superinfx?
o Similar to co-infx o Esp jaundice as sx o HDV RNA and HBsAg persist o total a-HDV persists (IgM never disappears, IgG rises and plateaus) o ALT oscillates
• What are sequelae of HBV-HDV infxs?
o Co (in healthy ppl): 3-4% fulminant, death; 90% recovery w immunity; rare chronic HBV/HDV hepatitis, cirrhosis o Super (HBV carrier): 7-10% fulminant, death; 10-15% acute, severe, recovery; 80% chronic HBV/HDV, cirrhosis
• What is geographic distribution of HDV infx?
o High: brazil, some Africa, some Europe
o Med: some Africa, middle east
o Low: N America, argentina, some Africa, Europe, india, Australia
o Very low: Alaska, brazil, South Africa, china
o Lots of “no data”
• What are recommendations for HDV prevention?
o Co: Pre or post-exposure prophylaxis to prevent HBV
o Super: Education to reduce risk behaviors in chronic HBV pts
• What is the HCV?
o Genome like a flavivirus, (+) ssRNA, 10,000 bases, enveloped, 30-60nm
o 1 single reading frame, structural genes at 5’ end, non-structural genes at 3’ end
o morphological structure remains unknown
o 6 genotypes (1-6) on basis of phylogenetic analysis
o 1 and 4 have poorer px and response to interferon tx
o In Hong Kong, 1 is 67%, 6 is 25%
• How does HCV infect a cell?
o Binds receptor (also for LDL and VLDL)
o Enters in endosome → uncoated → genome replicated in cytoplasm
o → translated and produced in ER → golgi → combo w genome
o → exocytosis
• What is geographic prevalence of HCV in blood donors?
o High (>5%): N African country
o Med: N Asia, brazil
o Low: N America, argentina, china, australia, S Africa, W Europe
o Very low: N Europe
• What are risk factors assoc w HCV transmission?
o Transfusion or transplant from infx donor
o IV drugs
o Hemodialysis (yrs of tx)
o needles/sharps accidents
o Sex/household exposure to anti-HCV-positive contact
o Multiple sex partners
o Birth of HCV-infx mother
• What are clinical features of HCV?
o spectrum similar to chronic HBV, but w lower freq o Inc: avg 6-7 wks (r 2-26 wks) o Jaundice: r 20-40% o Chronic hepatitis: 70-85% o Persistent infx: 85-100% o Cirrhosis: 17% o HCC: 2% o Immunity: no known protective Ab response
• what is typical serologic course of chronic HCV?
o ↑ALT (correlate w sxs) 1-5 mos, then oscillates for years
o a-HCV rises and plateaus at 1 yr
• how is HCV infx diagnosed?
o 1) a-HCV: Not useful in acute phase, appears after 4 wks
o 2) HCV-RNA (qual or quant): via PCR and branched DNA. Mb dx in acute phase. Mainly to monitor response to antiviral tx
o HCV-Ag: EIA. Easiest for monitoring
• What are prognostic tests for HCV infx?
o Genotyping: 1 & 4 have worse px, respond poorly to interferon tx (DNA sequencing, PCR-hybridization e.g. INNO-LIPA.)
o Serotyping: useful when no detectable RNA
o Viral Load: ↑ → poorer px; also monitor IFN tx
• What is prevalence of a-HCV in US? Screening?
o Overall: 1.6%
o M»F, esp born 1945-65
o 76% of infected ppl are baby boomers → birth cohort screening by CDC
o Also higher in blacks
• What is CDCs Hep C prevention strategy?
o Prevent new infxs: Risk-reduction education and awareness; Review and update infx control practices; Screen and test donors; Virus inactivation of plasma-derived products
o Reduce risk of liver dz w chronic: Identify and test persons at risk for HCV infx, Counseling, medical evaluation, management of infected ppl
• What is HEV?
o Calicivirus-like viruses
o Unenveloped RNA virus, 32-34nm in diameter
o Single stranded RNA genome, 7.6 kb in size.
o Very labile and sensitive
o Can only be cultured recently
• What are clinical features of HepE infx?
o Inc: avg 40 d (r 15-60)
o Fatality: 1-3% (if prego: 15-25%)
o Illness severity: ↑ w age
o Chronic sequelae: none
• What is typical serologic course f HEV infx?
o Feval HEV, ALT, IgM-HEV 3-10 wks (correlate w sxs)
o IgG-HEV rises at 3 wks, plateaus at 10 wks
• What are epidemiologic features of HEV?
o outbreaks usu assoc w fecal in water
o Several large epidemics in India, USSR, China, Africa, Mexico
o US and other nonendemic areas, no documented outbreaks, low prevalence of a-HEV (<2%) → unknown source of infx
o Minimal person-to-person transmission
• What are prevention and control measures for travelers to HEV-endemic regions?
o Avoid drinking water (and beverages w ice) of unknown purity, uncooked shellfish, uncooked fruit/vegetables not peeled or prepared by self
o Igs prepared from donors in Western countries does not prevent infx
o Unknown efficacy of Ig prepared from donors in endemic areas
