Uncommon Presentations of Thyroid Dysfunction. Douglas S Ross MD May 16, 2018 Copyrighted slides omitted

Transcription

1 Uncommon Presentations of Thyroid Dysfunction Douglas S Ross MD May 16, 2018 Copyrighted slides omitted

2 Case 1 53 year old woman Sees her PCP with complaints of fatigue She is sleeping poorly due to hot flashes She has no weight loss or palpitations AP 78, thyroid exam normal Free T4 2.9 (normal ), T3 342 (normal ), TSH <0.01

3 Uncommon cause of abnormal thyroid tests Biotin

4 Prescribed by Hairdressers

5 Biotin No RDA Adequate Intake (AI) 30 mcg Hair Skin and Nails 2,500 mcg tid Biotin 10,000 mcg

6 Prescribed by Neurologists Multiple Sclerosis Ataxia due to Multiple Carboxylase Deficiencies (MCD) Doses are up to 100 mg tid

7 Copyrighted slides withdrawn Figure: biotin effect of direct assays Figure: Standard curve sandwich assay Figure: biotin effect on competitive assays Figure: Standard curve competitive assay Figure: Biotin effect on TBII assay Figure: Time course of biotin effect

8 Case 1 follow up Off Biotin for 2 days Free T4 1.5 (normal ), T3 120 (normal ), TSH 1.4

9 Case 2 60 year old woman on levothyroxine TSH 30, PCP increased the dose 6 weeks later TSH 28.6, dose increased again 6 weeks later free T4 3.2 (normal ), T3 207 (normal ), TSH 29 Referred to endocrinologist

10 Case 2 continued She was taking no other medications or supplements except a multivitamin She was complaining of palpitations and insomnia Repeat blood tests: TSH <0.01, free T4 3.2 ( ), T3 212 (60 181)

11 Copyrighted slide withdrawn Figure: Effect of heterophilic antibodies on sandwich assays

12 Diagnosis of HAMA Human Anti Mouse Antibody Non linearity with dilution suggests interference Add nonimmune homologous mouse immunoglobulins Add Sepharose beads coated with Protein A or G to eliminate all IgG Reagents and detection kits commercially available

13 Rheumatoid Factors Directed against Fc fragment of human IgG Cross reactivity to mouse IgG may occur

14 Case 2 follow up Levothyroxine dose adjusted She is having her thyroid blood tests done through a national reference lab instead of the local hospital

15 Case 3 18 year old stressed out over exams, sleeping poorly, anxious Grandmother on thyroxine, prior radioiodine treatment Sister is being evaluated for a thyroid problem Free T4 2.7 (normal ), TSH 0.9

16 Differential Diagnosis Inappropriate TSH TSH producing pituitary adenoma Thyroid Hormone Resistance Binding Protein Abnormalities

17 Binding Protein Abnormalities (TBG excess) (free T4 should be normal) Familial dysalbuminemic hyperthyroxinemia Abnormal transthyretin Autoantibodies to T4 (or T3)

18 TBG excess Hereditary (x linked) Estrogens, raloxifen, tamoxifen, pregnancy Mild hepatitis 5 FU Perphenazine Clofibrate Heroin and methadone Acute intermittent porphyria

19 Case 3 continued T3 142 ng/ml (normal ) Excludes TBG excess Excludes TSH adenoma and thyroid hormone resistance

20 Differential Diagnosis Familial dysalbuminemic hyperthyroxinemia Abnormal transthyretin Autoantibodies to T4 These should all effect total T4 assays, but shouldn t free T4 assays measure only free T4?

21 Free T4 index direct free T4 assays Free T4 estimates

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25 Free T4 index Hyperthyroidism: high T4 x high T3R = high free T4 index TBG excess high T4 x low T3R = normal free T4 index

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27 Copyrighted slide withdrawn Figure: free T4 assays in patients with FDH

28 Evaluation of T4 binding abnormalities T4 binding panel measures the concentrations of TBG, transthyretin, and albumin and the percent binding of T4 to each protein T4 autoantibodies can be measured by adding labeled T4 and precipitating immunoglobulins with PEG

29 Case 3 follow up The patient s T4 binding panel showed excess binding to albumin consistent with familial dysalbuminemic hyperthyroxinemia More common in Hispanics His grandmother was never hyperthyroid and received RAI unnecessarily

30 Case 4 38 year old woman complains of fatigue TSH 7.4, free T4 4.2 ( ), T3 108 (60 181)

31 Differential Diagnosis? Mild hypothyroidism and Familial dysalbuminemic hyperthyroxinemia Abnormal transthyretin Autoantibodies to T4 With normal T3 a TSH producing pituitary tumor and thyroid hormone resistance are excluded

32 Case 4 continued Free T4 by equilibrium dialysis was normal Free T4 in a two step assay was normal Reduced T4 recovery with PEG precipitation of the patient s serum Anti T4 autoantibodies confirmed by immune assay

33 Copyrighted slides withdrawn Figure: two step free T4 assays Figure: one step labeled antibody free T4 assays

34 Case 4 follow up Patients with anti T4 autoantibodies usually have Hashimoto s thyroiditis TPO antibodies positive 486 The patient was treated with levothyroxine

35 Cases with assay interference Case 1 Biotin Case 2 HAMA Case 3 FDH Case 4 Anti T4 antibodies

36 Case 5 36 year old woman with relapsing remitting multiple sclerosis Treated with alemtuzumab 12 mg daily x 5 days One year later she was given alemtuzumab 12 mg daily x 3 days 18 months after her first dose of alemtuzumab: TSH <0.01, free T4 3.8 ( ), T3 432 (60 181)

37 Alemtuzumab and Immune Reconstitution Syndrome Anti CD52 antibody Depletes lymphocytes binds cells and initiates complement mediated lysis of lymphocytes Followed by reconstitution of immune function Clonal expansion of lymphocytes favors antibody over cellmediated autoimmunity ITP is among the major complications of treatment

38 Alemtuzumab and Thyroid dysfunction 22 % of patients have Graves, of which 23 % spontaneously remit and 15 % become hypothyroid 7 % of patients have hypothyroidism, of which 74 % have TBII 4 % of patients had subacute destructive thyroiditis 34% of patients have thyroid dysfunction Daniels et al JCEM 2014

39 Graves disease and alemtuzumab Treatment Considerations Overall remission rate 78% Methimazole may be more appropriate than definitive therapy with RAI

40 Copyrighted slide withdrawn Figure: Onset of thyroid dysfunction after alemtuzumab

41 Multiple episodes of immune reconstitution syndrome and thyroid dysfunction 30 percent of patients had more than one episode Most common was overt Graves disease initially, then overt hypothyroidism subsequently Some patients had painless thyroiditis followed by Graves disease or overt hypothyroidism Daniels et al JCEM 2014

42 Case 5 follow up She went into remission after 6 months of methimazole Currently euthyroid, but schedule to have her third treatment with alemtuzumab soon

43 Case 6 62 year old man with metastatic melanoma Treated with ipilimumab and nivolumab Free T4 2.2, T3 160, TSH <0.01

44 Immune Checkpoint inhibitors Cytotoxic T lymphocyte associated protein 4 (CTLA 4) Programmed cell death protein 1 inhibitor (PD 1) Programmed cell death ligand inhibitor (PD L1)

45 Copyrighted slides withdrawn Figure: mechanism of check point inhibition Figure: immune related adverse effects of checkpoint inhibitors endocrine

46 Endocrine Dysfunction after Checkpoint Inhibitors Meta analysis of 38 studies and 7551 patients Hypothyroid Hyperthyroid Hypophysitis CTLA 4 Ipilimumab 3.8 % 1.7 % 3.2 % PD 1 Nivolumab PD 1 Pembrolizumab Ipilimumab and Nivolumab PD L1 Atezolizumab <0.1 Barroso Sousa et al JAMA Oncol 2017

47 Copyrighted slides withdrawn Table: destructive thyroiditis with nivolumab Figure: Graves disease from CTLA 4 inhibition

48 Current indications for checkpoint inhibition CTLA 4 Melanoma CTLA 4 + PD 1 Melanoma PD 1 PD L1 Melanoma Bladder Cancer Squamous NSCLC RCC CRC HCC Hodgkin s

49 Thyroid Cancer and Immune Checkpoint Inhibition High PD LI expression in more aggressive cancers PD LI expressed in anaplastic cancer PD LI expressed in BRAF mutated cancers Ongoing clinical trials in thyroid cancer and anaplastic thyroid cancer Nivolumab + ipilumumab Pembrolizumab + levantinib Cunha et al 2013, Ahn et al 2017, Angell et al 2014

50 Case 6 follow up One month later TSH 89, free T4 <0.4 ( ) Patient started on levothyroxine

51 Case 7 49 year old woman with nonresectable hepatocellular carcinoma Treated with sorafenib 400 mg bid 17 weeks into treatment: free T4 2.7 ( ) and TSH <0.01 After 4 months: free T4 0.1 and TSH 86 Anti TPO negative Levothyroxine started

52 Thyroid dysfunction with Tyrosine Kinase Inhibitors (TKIs) Overt hypothyroidism 32 to 85% of patients Transient hyperthyroidism (destructive thyroiditis) 0 to 24% Increased levothyroxine requirements in patients with prior hypothyroidism Onset averages 4 weeks, but reported up to 94 weeks after initial exposure Torino et al Thyroid 2013

53 Mechanism of thyroid dysfunction with TKIs Unlikely due to lymphocytic thyroiditis. Anti TPO antibodies usually negative. Hypothesis: Inhibition of angiogenic pathways: VEGF (vascular endothelial growth factor) PDGFR (platelet derived growth factor receptor) Results in reduced blood flow, ischemic thyroiditis, destruction and atrophy

54 Copyrighted slide withdrawn Figure: CT showing reduction in thyroid size with sorafenib

55 Evidence to support the angiotoxic hypothesis for TKI associated hypothyroidism TKIs that were potent inhibitors of VEGF and PDGFR (e.g. sunitinib) were more likely to cause destructive thyroiditis and hypothyroidism Thyroid vascularity measured by doppler is reduced during sunitinib treatment and increases when sunitinib is discontinued Torino et al Thyroid 2013; Makita et al Thyroid 2010

56 Other potential mechanisms of TKI associated hypothyroidism Impaired iodine uptake (related to reduced blood flow) Increased non deiodination metabolism of thyroxine Increased type 3 (DIO3) deiodination Hershman & Liwanpo Thyroid 2010; de Groot et al Clin Pharmacol Ther 2005; Schlumberger et al J Clin Oncol 2009

57 Case 7 follow up Patient remains euthyroid on levothyroxine

58 Cases of thyroid dysfunction from drug therapies Case 5 Alemtuzumab for relapsingremitting multiple sclerosis Case 6 Immune check point inhibitors Case 7 Tyrosine kinase inhibitors

59 Case 8 27 year old woman, 14 weeks pregnant Chiropractor diagnosed hypothyroidism 2 years ago On Naturethroid 2 grains TSH 0.07, free T4 0.5 (normal )

60 Free T4 in pregnancy non pregnant 1 st 2 nd 3 rd Total T Free T4 index Free T4 A Free T4 B Lee et al Am J Obstet Gynecol 2009

61 Why did the chiropractor prescribe thyroid extract?

62 Copyrighted slide withdrawn Figure: blood levels of T4 and T3 on levothyroxine

63 Normal T4:T3 ratio Approximate average daily requirements (taking into account absorption): T mcg T mcg Normal T4:T3 ratio (in humans) is 14:1

64 Thyroid Extract 1 grain = 38 mcg T4 and 9 mcg T3 T4:T3 ratio 4.2:1 T4:T3 ratio in rats 4:1 T4:T3 ratio in humans 14:1

65 Extract versus L T4 Extract does NOT mimic normal physiology extract L T4 normal mg mcg Free T T TSH Hoang et al JCEM 2013

66 T3 containing thyroid medications Cytomel (liothyronine) Thyroid extract Armour Westhroid Naturethroid W P thyroid Thyrolar (liotrix)

67 Thyroid Extract Probable Harm to Fetus Fetal type 2 deiodinase converts maternal T4 to T3, the primary source of thyroid hormone through week 16 of gestation Maternal T3 does not appear to correlate with fetal T3 levels Thus maternal hypothyroxinemia seen in mothers taking extract may have adverse effects on fetal development

68 Maternal Thyroid Function during Early Pregnancy and Cognitive Functioning in Early Childhood: The Generation R Study Odds Ratio for non verbal cognitive delay Free T4 <10 percentile 1.37 ( ) Free T4 < 5 percentile 2.03 ( ) * Henrichs et al JCEM 2010

69 Low maternal free T4 and IQ in offspring 3727 mother child pairs Thyroid tests before 18 weeks gestation; Non verbal IQ at 6 years Free T4 in lowest 5% ile with normal TSH IQ was 4.3 points lower (CI 6.7 to 1.8, P<0.001) Ghassabian et al JCEM 2014

70 Case 8 follow up Patient refused to take levothyroxine alone Patient is unable to function at work on T4 alone (brain fog) Agreed to levothyroxine and liothyronine at 14:1 ratio She had a non eventful pregnancy

71 Case 9 62 year old woman with a thyroid nodule

72 Toxic adenoma 10 years after radioiodine

73 Radiology report Heterogeneous hypoechoic nodule with macroand microcalcifications, and possible extrathyroidal extension highly suspicious for malignancy.

74 Case 9 14 years earlier Free T4 2.8 ( ), T3 336 (60 181), TSH <0.01 Palpable right nodule Scan 30% uptake, toxic adenoma

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76 Which Treatment? Surgery Radioiodine Hypothyroid: 20% Hypothyroid: 8% 1 yr, 60% at 20 yrs Re treatment: 1% (Rapid) control of hyperthyroidism: 99% Nerve palsy 1% Hypoparathyroidism 2% Re treatment: 20% Control of hyperthyroidism, 6 mos: 80% Graves disease: 4% PERSISTENT NODULE

77 Treatment of toxic adenoma RAI 75% of patients were no longer hyperthyroid at 3 months, with nodule volume decreased by 35% at 3 months, 45% at 2 years. Risk of an ugly nodule on ultrasound 10 years later Ceccarelli et al Clin Endocrinol. 62:

78 Use of Ultrasound by ATA members in the year 1999 Only 34 % would obtain an ultrasound to evaluate a patient with a solitary nodule. Bennedbaek & Hegedos JCEM 2000

79 Case 9 follow up FNA was read as FLUS due to the presence of microfollicles The patient, at the insistence of her PCP underwent surgery The pathology was a benign adenoma with mixed macro and microfolicular architecture The patient expressed satisfaction with her outcome. She did not want a scar on her neck in her 40s, but this concerns her less in her 60s.

80 Case year old woman Graves diagnosed during her first pregnancy T4 13, T3 292, TSH <0.01 She was managed without ATD Post partum free T4 2.2, T3 320 and methimazole started Rash on methimazole after 4 weeks Off methimazole free T4 1.8, T3 187, TSH <0.01 She is unwilling to take PTU, radioiodine, or have surgery

81 Iodine as Primary Therapy for Graves Disease 44 Japanese patients 66 % controlled for 9 28 years (mean 18 yrs) 39 % achieved a remission after mean 7 years 10% no benefit 25% only transient benefit Okamura et al JCEM 2014

82 Iodine as Primary Therapy 2016 ATA Hyperthyroid Guidelines Potassium iodide may be of benefit in select patients with hyperthyroidism due to GD, who have had adverse reactions to ATD, and have a contraindication or aversion to RAI (or additional RAI) or surgery. Treatment may be more suitable for patients with mild hyperthyroidism, or a prior history of RAI. Insufficient evidence to determine net benefits or risks.

83 Case 10 Patient was started on SSKI one drop daily One month later: free T4 1.2, T3 160, TSH 0.02 Two months later: free T4 0.8, T3 90, TSH 7.23 Dose reduced to one drop every other day One month later: free T4 1.1, T3 148, TSH 2.1 She wants to get pregnant again

84 Use of Iodine during pregnancy 2017 ATA Pregnancy Guidelines Excessive doses of iodine exposure during pregnancy should be avoided, except in preparation for the surgical treatment of GD. Clinicians should carefully weigh the risks and benefits when ordering medications or diagnostic tests that will result in high iodine exposure. Strong recommendation, moderate quality evidence. Excessive = >500 mcg / day 1 drop SSKI = 50 mg

85 2016 ATA Hyperthyroid Guidelines Women with Graves hyperthyroidism who are planning a pregnancy could consider: 1) Changing to PTU prior to conception 2) Changing to PTU when hcg positive 3) Stopping ATD when hcg positive 4) Definitive therapy before conceiving Weak recommendation; low quality evidence. Stopping iodine when hcg positive? Continuing iodine during first trimester?

86 Iodine treatment during pregnancy 283 Japanese woman who stopped methimazole and shifted to iodine first trimester Hyperthyroidism was not as well controlled, but Fewer birth defects 1.53 versus 4.14 % More live births 92 versus 85% Yoshihara et al 2015 Thyroid

87 Iodine treatment during pregnancy 35 Japanese patients taking 6 to 40 mg of iodine daily Only one infant was born with subclinical hypothyroidism Momotani et al 1992 JCEM

88 Case 10 follow up Uneventful pregnancy Iodine was discontinued when she got pregnant Peak T3 343, T4 14, TSH <0.01, TSI 2.56 end of first trimester Then slowly normalized tests: TSH 1.26 by third trimester Post partum T3 228, T4 13 TSH<0.01 T3/T4 ratio suggests post partum thyroiditis

89 Case year old woman with a 70 g nodular goiter She has noted increased dysphagia, and her gland bothers her when she lies on the couch while watching television TSH 0.06, free T4 1.0 ( ), T3 110 (60 181) Ultrasound Multiple spongiform appearing nodules, as large as 3.6 cm Scan 15% uptake, with areas of both increased and reduced isotope concentration

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92 Case 11 continued Surgery discussed with the patient who refuses to consider surgery. Is her RAIU too low to effectively treat her with radioiodine?

93 Low iodine diet rhtsh methimazole Strategies to increase RAIU in patients with nodular goiter

94 rhtsh and radioiodine treatment of nodular goiter 0.3 mg rhtsh versus placebo OFF LABEL RAIU 35 % versus 26 % Goiter size reduced 62 % versus 41 % Hypothyroidism in 62 % versus 11 % Nielsen et al Arch Int Med 2006

95 Methimazole pretreatment to increase RAIU Preliminary Study of 5 women Methimazole 10 to 15 mg given for 2 to 4 months Mean TSH increased from 0.32 to 2.6 RAIU increase from 26 to 49 % Thyroid Volume reduced 46% at 12 months after 30 mci 100 % became hypothyroid Flores Rebollar J Clin Med Res 2013

96 Case 11 follow up Patient received methimazole 20 mg for 3.5 months TSH increased to 7.8 RAIU increased to 48% Patient received 24 mci radioidine Her goiter has regressed by about 40% She is taking levothyroxine for hypothyroidism

97 Questions or Comments Biotin HAMA FDH Anti T4 antibodies Alemtuzumab Immune checkpoint inhibitors Tyrosine kinase inhibitors Thyroid extract in pregnancy Toxic adenoma s/p radioiodine Iodine as primary therapy for Graves Toxic MNG with low RAIU