12 Liu Common Thyroid Problems - UCSF CME Liu Common Thyroid Pr… · – TSH

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Chienying Liu MD

Common Thyroid Problems Case-‐Based Discussion

Schematic diagram of a follicular cell, illustrating the steps involved in thyroid hormone synthesis.

Park S M , and Chatterjee V K K J Med Genet 2005;42:379-389

©2005 by BMJ Publishing Group Ltd

cAMP

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Case 1 -‐ Hyperthyroidism

63 yo man not feeling himself, with unintenFonal weight loss and eyes feeling irritated •  Exam

–  Thyroid, not enlarged, somewhat firm, no nodules, no bruits

–  Subtle exophthalmos in the right eye with mild conjuncFval erythema

•  Came to us with the following labs –  TSH < 0.01 –  Free T4 1.09 (<1.8) –  Free T3 4.40 (< 4.2)

–  TPO anFbody 101 (<34) –  Tg anFbody posiFve

T3 toxicosis

(Common) Causes of Hyperthyroidism

•  Graves disease –  The most common cause of hyperthyroidism –  Caused by sFmulaFng autoanFbodies to the TSH receptor ( measured by TSI or TBII)

–  TPO and or Tg AB frequently present 70-‐90 %

•  Toxic nodule/Toxic MNG – 1.5-‐44.5% of hyperthyroidism, depending on the iodine intake – 2% in the United States

www.thyroidmanager.org

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Causes of Hyperthyroidism

•  Thyroidi8s –  Autoimmune (painless) = subacute lymphocy8c thyroidi8s (1-‐ 5%)

•  Postpartum thyroidiFs also an example •  TPO present in 50% of these paFents at the Fme of diagnosis •  Clinically, may not be differenFated from Graves disease on PE

–  InfecFous (very painful gland) •  Post-‐viral: Subacute granulomatous thyroidiFs = de Quervain's thyroidiFs ( < 1%)

–  Strongly associated with HLA-‐B35 –  ESR very elevated

•  Acute Bacterial infecFon: fevers/chills, unilateral neck pain. May have hyperthyroidism

–  Drug induced •  Interferon-‐alfa → induced autoimmunity: painless thyroidiFs or Graves disease •  Interleukin 2 (for leukemia) •  Lithium → mostly hypothyroidism but can induce autoimmune: Graves or painless thyroidiFs •  TKIs → usually hypothyroid but may also have destrucFve thyroidiFs •  Amiodarone induced type II hyperthyroidism → destrucFve thyroidiFs

–  Others •  RadiaFon , palpaFon

Iodine Scan Uptake 0 or very low

Causes of Hyperthyroidism •  Exogenous thyroid hormone

•  Rare –  TSH mediated (TSH secre8ng pituitary adenoma)

–  Struma Ovarii •  Autonomous funcFoning thyroid Fssue in the teratoma

–  Trophoblas8c disease •  HydaFdiform mole or choriocarcinoma (↑𝐻𝐶𝐺)

–  Metasta8c thyroid cancer

–  Familial non-‐autoimmune hyperthyroidism •  Due to a gain of funcFon in the TSHR •  AutoanFbodies negaFve •  Neonatal hyperthyroidism

–  Thyroid hormone resistance

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DiagnosFc Test of Choice •  TSH receptor anFbody tesFng

–  TSI 433 (< 140 %)

•  Iodine Uptake scan –  Diffuse uptake –  4h 10% and 24 h 21%

–  TSH < 0.01 –  Free T4 1.09 (<1.8) –  Free T3 4.40 (< 4.2)

–  TPO anFbody 101 (<34) –  Thyroglobulin anFbody posiFve

Course

Started on Methimazole Euthyroid on 5mg 5 months later

T3 toxicosis

Case 2 -‐ Hyperthyroidism •  60 yo presented with apparent exophthalmos and chemosis and atrial fibrillaFon –  TSH < 0.01 –  Free T4 20 (9-‐24) –  Free T3 436 (145-‐348) –  TPO and TgAB negaFve –  TSI negaFve

•  Thyroid gland mildly enlarged 2-‐3 x, firm

AddiFonal Test(s)? •  TBII PosiFve

•  Iodine scan Not done (not needed)

T3 toxicosis

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TSH Receptor AutoanFbodies

•  TSH receptor is the major auto-‐anFgen in Graves’ disease (GD) AnFbodies include:

– SFmulaFng, most common –  Inhibitory/blocking

•  Thyroid atrophy and hypothyroidism

– Neutral –  In GD hyperthyroidism, the sFmulaFng type predominates

Best PracFce & Research Clinical Endocrinology & Metabolism Vol. 19, No. 1, pp. 33–52, 2005

TSH Receptor AutoanFbodies-‐ Clinical Use •  DifferenFate GD from other causes of hyperthyroidism

•  Predict risk of fetal or neonate hyperthyroidism

•  ?? Predict remission or relapse in GD aner anFthyroid medicaFons –  In a meta-‐analysis from 1994**:

•  AB+ pts 3 Fmes more likely to relapse •  But 25% of AB-‐ pts relapsed 25% of AB+ pts stayed in remission

–  Recent studies: uFlity in predicFon is yet to be proven* •  heterogeneous populaFons, different assays, Fming, duraFon of follow up, different cut offs to define posiFvity

* Kamath et al J of Thyroid Research 2012 **Feldt-‐Rasmussen et al JCEM 1994

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Kamath et al J of Thyroid Research 2012

Graves’ Disease Assessment of TSH Receptor AutoanFbodies (TRAb)

TSI = Thyroid SFmulaFng Immunoglobulin Bioassay

TBII = Thyroid Binding Inhibitory Immunoglobulin

Immunoassay

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Graves’ Disease Assessment -‐TSI

•  Bioassay detecFng cAMP producFon (Measures the final balance of all TRAb)

–  2nd generaFon (2 steps), cumbersome •  Detect cAMP using RIA •  SensiFvity 85-‐90%, Specificity 99%

–  3rd generaFon •  Employing luciferase reporter gene •  Higher sensiFve •  Quest/Labcorp: 92% sensiFve and 99.3% specific

– Advocates of this test: reflect clinical phenotype beser

J Clin Endocrinol Metab 98 (2013): 2247–2255 Lyson et al. Autoimmunity Review 2010

Graves’ Disease Assessment-‐ TBII

•  CompeFFve Immunoassay (Measures TRAb of all types)

–  1st generaFon – poor sensiFvity –  2nd generaFon

•  Used labeled TSH to TSH receptor from CHO or a recombinant TSH receptor protein preparaFon

•  SensiFvity 97.1%, Specificity 97.4% (meta-‐analysis)* –  3rd generaFon

•  Replaced labeled TSH with specific TSH human monoclonal sFmulaFng anFbody M22 •  SensiFvity 98.3%, Specificity 99.2% (meta-‐analysis)* Quest: SensiFvity 92%, specificity 100% (kronus) Mayo Clinic: SensiFvity 95%, specificity 97% (Roche) •  There can be between method variability and subopFmal inter-‐assay precision

*Autoimmunity Reviews 12 (2012): 107–113

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Case 2 -‐ Hyperthyroidism •  60 yo women presented with

apparent exophthalmos and chemosis and atrial fibrillaFon –  TSH < 0.01 –  Free T4 20 (9-‐24) –  Free T3 436 (145-‐348) –  TPO and TgAB negaFve –  TSI negaFve

•  Thyroid exam – mildly enlarged, firm

AddiFonal Test(s)? •  TBII posiFve 81% (<16%) inhibiFon

Clinical Course •  On methimazole •  Eye disease improved •  On MMI 10-‐15mg 2-‐3 years later

–  No side effects –  Wants to conFnue MMI


•  47 yo woman presented with palpitaFons and some weight loss •  Maybe some URI symptoms 1-‐2 months prior to presentaFon

–  TSH 0.03 –  Free T4 18 (10-‐18) –  Free T3 6.5 (<5.7)

•  Came to us for a consultaFon, 2.5 weeks later •  Exam

– Non-‐tender gland, palpable but not grossly enlarged, no nodules – No ophthalmopathy, not grossly hyperthyroid

Another case of T3 toxicosis

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Case 3 -‐ Hyperthyroidism •  Repeat labs + TSHR Ab at the Fme of the visit

–  TSI negaFve –  TSH 0.38 –  Free T4 9 –  Free T3 3.6

3/4/2015 3/30/2015 TSH 18.90 (H) 4.58 (H)

Free T4 10 -‐ 18 pmol/L 7 (L) 8 (L) Free T3 2.6 -‐ 5.7 pmol/L 3.7 2.8

TPO >850

Ø  Acute Lymphocy8c Thyroidi8s = Silent Thyroidi8s §  If uptake scan were to performed early on

when hyperthyroid, uptake = very low

Ø Monitor TFT – at risk for hypothyroidism

Course •  Not symptoma8c of hypothyroidism •  Feeling be]er with 8me •  Wants to be monitored

Case 4 -‐ Thyroid Nodule •  32 yo woman presented with right neck pain that turned out to be musculoskeletal

•  Found to have a 2.5 cm hypoechoic nodule

•  Exam not remarkable other than the palpable nodule

•  Work up: –  TSH 0.11, then 0.39 –  TSH 0.46 (0.4-‐4.0) –  Free T4 11 (9-‐24) –  Free T3 284 (145-‐384)

–  TPO 119 (<60) –  TSI negaFve

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Case 4 – Thyroid Nodule

•  Biopsy = follicular neoplasm

•  Iodine uptake scan showed a hot nodule in the right with suppression of the rest of the gland

Treatment OpFons •  Monitor given normal TFT •  RAI •  Surgery •  ATD •  New strategies

–  Ethanol injecFon –  Percutaneous laser thermal ablaFon

Hyper-‐funcFoning Thyroid Nodule •  Usually a follicular adenoma

–  57% of 75 toxic adenomas found to have TSHR mutaFons, 3%-‐ Gsα mutaFons in a study –  When biopsied – FNA shows either a benign nodule or follicular lesion/neoplasm

•  DefiniFve diagnosis of follicular adenoma cannot be made on biopsy •  Surgical resecFon needed to exam the capsule

•  Risk of malignancy is said to be very low, biopsy not needed in most paFents –  Not completely free of cancer . –  Case reports of malignancy, especially in children

•  Progression from a hyperfuncFoning nodule to a toxic nodule -‐ 4% year –  Risk higher in older pts, nodules > 3 cm, in areas of low iodine intake

•  Heterogeneity in clinical behavior of hyperfuncFoning nodules –  Thyrotoxicosis is usually not common < 2.5 cm – there are excepFons –  Only about 30-‐40% of hyperfuncFoning nodules > 3-‐4.5 cm are toxic

Krohn et al. Endocrine Reviews 26(4):504–524 2005; Corvilain Ann. Endocrinol 2003 (217 pts in Belgium)

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Treatment ModaliFes & Risk of Hypothyroidism •  RadioacFve Iodine Treatment

–  Risk of hypothyroidism, variably reported –  Incidence of hypothyroidism may increase with Fme

•  11% at 1 year, 33% at 5 years, and 49% at 10 years in a study of 105 paFent –  Euthyroidism ( 9.7% vs 1.5% with hyperthyroid hot nodule) is a risk factor –  Presence of thyroid anFbody status is a risk factor –  Pretreatment with ATD (raise TSH) is a risk factor –  No correlaFon demonstrated with nodule size and radioiodine dose, or iodine uptake, or degree of adjacent suppression on scans

•  Surgery –  Risk of hypothyroidism, 4.4% in one study, 14% in another –  May also depend on anFbody status

•  ATD –  Not curaFve, but may be considered in selected cases

Thyrotoxicosis of Other EFology. ThyroidManager.org

Case 4 – Thyroid Nodule •  Biopsy = follicular neoplasm

•  Uptake scan showed a hot nodule in the right with suppression of the rest of the gland

Treatment OpFons •  Monitor given normal TFTs •  RAI •  Surgery •  ATD?

•  Newer strategies

–  Ethanol injecFon –  Percutaneous laser thermal ablaFon

•  Course

•  Elected surgery – Lobectomy •  Path-‐ Benign adenoma •  On T4 25 mcg

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Case 5 – Hyperthyroidism + Nodule

•  30 yo woman presented with nausea, headaches, and malaise

•  Exam – right thyroid fullness •  TFT

–  TSH 0.01 –  Free T4 17

•  US showed a 2.9 cm ill defined right nodule

•  Uptake scan showed a hyperfuncFoning nodule

Papillary Thyroid Cancer

Mirfakhraee et al. Thyroid Research 2013 Review of cases 1950-‐2012

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Hyperthyroidism Work UP-‐ Take Home Messages •  Given that Graves disease is the most common in the iodine replete areas,

obtaining a TSH receptor anFbody tesFng ie either TSI or TBII is most cost effecFve

•  TPO and Tg anFbodies usually not every helpful in the work up of hyperthyroidism in most cases

•  Uptake scan should be considered as the next step –  If TSH receptor anFbody tesFng is negaFve and thyroid funcFon results are not improving

–  If a nodule is present (> 1 cm) •  Especially if negaFve TSH receptor anFbodies

–  T4 and T3 profile can be helpful but is an overall relaFvely insensiFve assessment of eFologies for hyperthyroidism

•  Risk of malignancy is low in hyperfuncFoning nodules but not zero –  Biopsy is not needed in most cases

•  Look at ultrasound characterisFcs and biopsy suspicious appearing nodules

32 yo woman not responding to LT4

•  Graves disease, status post RAI ablaFon in 2013

•  Started on LT4 one month later •  Never had normal TSH levels by report •  02/13/2015: TSH 38.8 when on 75 mcg •  02/25/2015: TSH 72 (0.5-‐4.8) on 150mcg

–  FT4 0.92 (0.8-‐1.7) –  T3 48 (55-‐170)

•  03/12/2015: on 225mcg •  Exam

–  Weight 51 kg –  Mildly tachycardic –  Mild tremors and warmth on the outstretched

hands

DifferenFal Diagnoses 1.  Noncompliance 2.  Interfering drugs or supplements 3.  MalabsorpFon 4.  Lab error/issues

Heterophile anFbodies MacroTSH (anF TSH IgG-‐TSH complex)

5.  Conversion? 6.  Others?

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Levothyroxine (l-‐thyroxine) •  SyntheFc form of thyroid hormone, structurally idenFcal to human thyroxine secreted

by the thyroid gland –  Various brands have slightly different preparaFons and fillers, but with the same acFve

ingredient –  ½ life is 7 days

•  AbsorpFon takes place in the small intesFne –  45% upper jejunum, 34% lower jejunum and ileum, 21% duodenum (End Rev 2014)

•  Gastric acid (acidic PH) important for its subsequent absorpFon –  Best absorbed when fasFng

•  70-‐80% of the given dose is absorbed → IV conversion

•  Metabolized in liver, eliminated by kidneys

Endocrine Reviews 2014

Food and beverages Interfering L-‐thyroxine AbsorpFon

•  Best absorpFon to poorest absorpFon 60 min prior to breakfast BedFme (3 hours aner last meal)

30 min prior to breakfast With breakfast – Most consistent TSH levels achieved at fasFng states

•  Coffee, especially espresso coffee – Probably by sequestering LT4 in the small intesFne

•  Fiber •  Soy products

–  ProblemaFc for infants with CH, fed with soy formula

•  Others –  Coson seed meal – Walnuts

ATA guidelines on Treatment of Hypothyroidism Thyroid 2014 Endocrine Reviews 2014

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Supplements/Drugs Interfering AbsorpFon •  Calcium supplements •  Ferrous iron •  MVI that has calcium and/or iron •  Phosphate binders (sevelamer) •  Aluminum antacids •  PPI and H2 blocker

–  Short term co-‐administraFon PPI -‐> no change in absorpFon

•  Sucralfate (mixed results) •  Orlistat •  Rolaxifene (decreased absorpFon) •  Cholestyramine •  Colesevelam

•  Chromium picolinate •  Charcoal •  Ciprofloxacin •  Kayexelate

•  Synthroid package insert: –  Iron, calcium supplements and antacids should not be

administered within 4 hours –  Has a cauFon statement on soy regarding its effects on

absorpFon –  Other food cauFons: coson seed meal, walnuts, fibers

•  Soy ? 4 hours

ATA 2014 Hypothyroid Guidelines

ATA guidelines on Treatment of Hypothyroidism Thyroid 2014

Gastro-‐IntesFnal Disease AffecFng AbsorpFon •  Diseases affect gastric acid producFon

– H-‐Pylori – Autoimmune atrophic gastriFs

•  AnF-‐parietal cell anFbody or IF anFbody •  Disease affecFng the small intesFne

–  Celiac disease •  IgA anFendomysial anFbody or Fssue transgluaminase IgA anFbody

– GI surgeries affecFng the small bowel •  (there are also data showing L-‐thyroxine absorp6on preserved in Roux-‐en-‐Y pa6ents)

–  Lactose intolerance •  Case reports of 900mcg requirement to 150ug aner lactose free diet

–  IntesFnal giardiasis

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32 yo woman not responding to LT4 •  Her husband vouched for her compliance

•  We lowered her T4 dose empirically to 150mcg and repeat blood tests and obtained addiFonal work up:

•  4/6/2015 on 150mcg

Take Home Message

•  Consider various causes of high T4 requirement –  ? Lab issue or error in this case –  Autoimmune gastriFs in this case

3/12/2015 TSH (0.45 -‐ 4.12 mIU/L) 0.26 (L) Free T4 (10 -‐ 18 pmol/L) 25 (H) T3, Total (0.9 -‐ 2.4 nmol/L) 1.7

3/12/2015 Tissue Transglutaminase An8body, IgA <20.0 CU

<10.0

Vitamin B12 211 -‐ 911 ng/L 245 Intrinsic Factor Blocking An8body

POSITIVE

4/6/2015 TSH 3.83 Free T4 10 -‐ 18 pmol/L 15 T3, Total 0.9 -‐ 2.4 nmol/L 1.3

20 yo woman TSH high normal, feeling Fred

•  Healthy otherwise •  FH posiFve for hypothyroidism •  Exam -‐ small goiter (right>len), firm by palpitaFon

•  Ultrasound –  Prominent thyroid with diffuse heterogeneous echo-‐texture with minimal increase in vascularity

•  1/10/2014: TSH 3.01 •  8/22/2014: TSH 5.43, FT4 1.08 (0.89-‐1.76) •  TPO negaFve, Tg AB posiFve •  1/05/2015: TSH 3.96, FT4 0.81

Do you treat?

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TSH Targets No known thyroid disease/goiter and AnFbodies NegaFve

NHANES III

NHANES III Distribu8on by Age

Hollowel J Clin Endocrinol Metab 2002 Surks J Clin Endocrinol Metab 2007

TSH 0.45 – 4.12 mIU/L = 2.5 to 97.5 percenFle

Age Specific DistribuFon of TSH

Surks J Clin Endocrinol Metab 2007

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Age Specific TSH Reference Range

Boucai et al THYROID 2011

TSH -‐ 97.5 cenFle by Age Group

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Subclinical Hypothyroidism

•  TSH ≥10 → Treat – Meta-‐analyses

•  Increased HF (Gencer et al CirculaFon 2012) –  Also some increase with TSH >7 -‐9.9 but more significant when TSH ≥ 10 –  80 yo or older, risk not increased

•  Increased CV events and CV mortality (Rondondi JAMA 2010)

– One meta-‐analysis suggested significance in younger paFents only (<65 yo) (Razvi JCEM 2008)

– No randomized studies to evaluate benefits of treatment


•  TSH 4.5-‐10 →Mixed data/treatment is controversial (studies were in older individuals) – Not as clearly associated with adverse CV events from observaFonal studies – No clear CV benefits, inconsistent LDL benefits with tx *

•  Possible benefits of tx in CV events in paFents 40-‐70 yo but not older than 70 yo (Razi Arch Intern Med 2012, retrospecFve study )

– No demonstrated improvement in quality of life or cogniFve funcFon in older paFents with tx (50s-‐70s yo)*

– ATA 2012 guidelines: Consider anFbody status, symptoms before treatment – DO NOT OVERTREAT older individuals

•  Older individuals (>70 yo) may have TSH in this range, because of normal aging

*Rugge Ann Intern Med 2015

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•  TSH 2.5-‐4.5 – Small studies showed benefits of tx in lipids, endothelial funcFon, inFma media thickness

– But no clinical outcome data – ExcepFon: women considering pregnancy

•  Increased pregnancy loss for TSH 2.5-‐5.0 during 1st trimester (Negro R JCEM 2010) •  Keep TSH < 2.5 prior to concepFon (Endocrine Society guidelines 2012) •  During pregnancy: TSH goal: 1st Trimester 0.1-‐2.5; 2nd trimester 0.2-‐3; 3rd trimester 0.3-‐3.

Treatment of Subclinical Hypothyroidism •  Full replacement dose 1.6mcg/kg body weight (more lean body weight dependent) – Older paFents require less, lower lean body weight

•  PaFents with subclinical hypothyroidism do not need full replacement –  25-‐50mcg if TSH ≤10 * –  Consider age and risk for CAD when dosing, use lower dose

•  Monitor TSH, 4-‐6 weeks aner iniFaFon or a dose change* –  Target range depending on ‘age and comorbidiFes’ , typically 0.5-‐3.5 to 4 mIU/L *

–  Target range 4-‐6 mIU/L for persons >70-‐80 yo* *ATA guidelines Thyroid 2014

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20 yo woman TSH high normal, feeling Fred •  High normal TSH •  FH of hypothyroidism, evidence

of thyroidiFs (exam)

•  What could be the ‘proven’ benefit of treatment? –  A reducFon in goiter size (Romaldini Thyroid 1996)

•  What could be the potenFal harm of treatment? –  Likely minimal in this young pt

•  May consider a trial of LT4

•  TSH goal -‐ the lower half of the normal range for this young paFent

•  Also work up other causes of faFgue

•  If she were to consider pregnancy → keep TSH < 2.5 mIU/L

THANK YOU

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12 Liu Common Thyroid Problems - UCSF CME Liu Common Thyroid Pr… · – TSH