Download Overview of thyroid disease for psychiatrists

Overview of thyroid disease for psychiatrists Dr Simon Young FRACP Waitemata DHB Auckland Outline •  Overview of thyroid physiology •  Thyroid and the brain •  Assessment and treatment of common thyroid diseases •  Thyroid disease and mental illness •  Controversies Role of Thyroid Gland •  Produce Thyroxine (T4) and Triiodothyronine (T3) •  These hormones are important in controlling cell differenLaLon during development •  In adults they maintain thermogenic and metabolic homeostasis •  Thyroid hormone receptors widespread in brain Figure 335-­‐1 Figure 335-2
Figure 335-4
Thyroid hormone and the brain •  T4 is transported into brain by carrier mediated process (OATP1C1 transporters) •  T4 is converted to T3 by Lssue deiodinase enzymes in the brain glial cell D2 (± D3 in neurons) (cf D1 in liver and kidney) •  T3 transported into neurones by MCT8 to allow access to receptors •  Thyroid hormone receptors widely distributed in brain Thyroid hormone and brain 2 •  Complex system-­‐ incompletely understood •  D2 deiodinase in hypothalamus probably involved in feed back regulaLon of TRH and TSH •  MCT8 mutaLons described that leads to low T3 in neurones and results in severe X-­‐linked psychomotor retardaLon. •  May be polymorphisms in D2 that have effects on thyroid treatments e.g. hypothyroidism Table 1. Patterns of 880 thyroid function tests in
newly admitted psychiatric patients
Lederbogen et al Acta Psychiatr Scand 2001; 104:305-310
PaWern n % 1. TSH=thyroid-­‐sLmulaLng hormone, T4=thyroxin, FTI=free thyroxin index. ↓=Lower than reference range, ↑=higher than reference range. TSH, T4 and FTI normal 637 72 TSH normal, T4 and/or FTI ↑ 38 4.3 TSH normal, T4 and/or FTI ↓ 43 4.9 TSH ↑, FTI normal 15 1.7 TSH ↑, FTI ↓ 5 0.6 TSH ↓, FTI normal 126 14.3 TSH ↓, FTI ↑ 16 1.8 Thyroid func4on test abnormali4es in newly admi<ed psychiatric pa4ents residing in an iodine-­‐
deficient area: pa<erns and clinical significance Acta Psychiatrica Scandinavica Volume 104, Issue 4, pages 305-­‐310, 7 JUL 2008 DOI: 10.1111/j.1600-­‐0447.2001.00328.x hWp://onlinelibrary.wiley.com/doi/10.1111/j.1600-­‐0447.2001.00328.x/full#f1 Table 3. Classification of 100 patients with thyroid
disease
Lederbogen et al Acta Psychiatr Scand 2001; 104:305-310
ClassificaLon New diagnosed (n) Former known (n) Sum (n) Euthyreosis 0 0 0 Manifest hyperthyroidism 6 6 12 Subclinical hyperthyroidism 19 51 70 Manifest hypothyroidism 1 1 2 Subclinical hypothyroidism 2 5 7 Hyperthyroxinaemia 0 8 8 Hypothyroxinaemia 0 1 1 Normal morphology 2 5 7 Diffuse goitre 12 10 22 Nodular goitre 12 16 28 Former thyroid surgery 0 4 4 Small, low echogenic thyroid gland 2 1 3 Not determined 0 36 36 FuncLonal status Morphological status (based on ultrasound study) Conclusions
Lederbogen et al Acta Psychiatr Scand 2001; 104:305-310 •  Thyroid dysfuncLon mild to moderate in most and not felt to be cause for psychopathology. •  TSH reasonable screening test in this populaLon with level of ≤ 0.1 being deemed significant. •  Subclinical hyperthyroidism most common abnormality 7.9% and overt hyperthyroidism in 1.4% (half of the laWer known) •  Overt hypothyroidism rare~0.2% •  Goitre in 7.7% (68 paLents) Serum TSH-­‐screening • 
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TSH normal (0.4 – 5.0): if screening, stop TSH high (>10): FT4, autoanLbodies TSH low (<0.05): FT4, FT3, autoanLbodies TSH borderline (0.1 -­‐ <10): repeat + Ab TSH is ‘normal’ in hypopituitarism: FT4 low TSH is more precise than FT4 when monitoring replacement T4 treatment Hypothyroidism-­‐causes • 
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Autoimmune (Hashimoto’s) Iatrogenic Drugs (Lithium) Congenital (1:4000) Iodine deficiency InfiltraLve ThyroidiLs (temporary) Secondary (pituitary or hypothalamic disease) Hashimoto’s thyroidiLs •  PosiLve autoanLbodies (anL TPO and thyroglobulin anLbodies) in >95% •  Goitre-­‐ in early stages •  Raised TSH •  Low freeT4 •  Clinical hypothyroidism •  Goitre disappears TreaLng hypothyroidism • 
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Wide T4 dose range 25-­‐200 mcg/day AC Young or recent onset (e.g. post 131l) > start 100 mcg/day Wait 4-­‐6 weeks for new steady-­‐state TFTs If TSH <0.05 mU/l, reduce dose else> A Fib Prescribe T4 as daily dose; can give weekly Take on empty stomach and away from other meds esp iron and calcium which can reduce absorpLon Hypothyroidism and neuropsychiatric effects •  CogniLve symptoms common in overt hypothyroidism (changes in IQ, psychomotor speed and memory) which largely resolve with treatment •  Controversy regarding subclinical hypothyroidism and cogniLve impairment •  Impact of thyroid autoimmunity on the brain in those with normal TSH also unclear. Hashimoto’s encephalopathy •  Very rare and controversial syndrome •  Subacute confusion, drowsiness, seizures and myoclonus also stroke like episodes and psychosis/hallucinaLons common •  Associated with other autoimmune diseases and thyroid autoimmunity but TFTs usually normal at Lme (assoc HLA B8 DRw3 ) •  Possibly an autoimmune vasculiLs/encephaliLs •  Steroid responsive Low free T4, normal TSH • 
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Hypopituitarism Third trimester in 10% Resolving thyroidiLs; viral or silent Phenytoin, carbamazepine Sick euthyroid syndrome T3 treatment Hyperthyroidism: causes • 
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Graves disease (~85%) Toxic Nodular Goiter (Plummers disease) Toxic adenoma Subacute thyroidiLs Post-­‐partum thyroidiLs Hyperthyroidism •  Symptoms –  Weight loss with increased appeLte –  Tremor –  Muscle weakness –  Frequent BM –  PalpitaLons –  FaLgue –  Heat intolerance –  Nervousness •  Signs – 
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Goitre Tachycardia or AF Bruit (Graves) Tremor Myopathy CHF Eye signs InvesLgaLons •  TPO anLbodies •  Thyroid sLmulaLng anLbody •  Consider thyroid scinLscan/uptake if diagnosis unclear •  Ultrasound may have role (large goitre or nodularity) Drug related hyperthyroidism • 
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Amiodarone Iodides, contrast media Lithium(rare, usually hypothyroidism) Thyroxine Interferon-­‐α Treatment of Hyperthyroidism • 
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AnLthyroid drugs (thionamides) Betablockers Occasionally steroids (thyroidiLs or storm) RadioacLve iodine treatment (curaLve) Thyroidectomy Carbimazole treatment •  Carbimazole 15-­‐30 mg daily, Ltrate (may need 60-­‐80mg in some cases) and then wean ayer a couple of months when controlled •  Treat for 12-­‐18 months •  Occasionally used with T4 (“block and replace”) •  Reasonably safe in pregnancy & breas}eeding but PTU preferred in 1st trimester •  Can use long-­‐term if paLent choice or dependent elderly •  Ref: Franklyn J A NEJM 330:1731-­‐1738, 1994 Thionamide side-­‐effects • 
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Rash ~5% (usually early) Agranulocytosis ~1/500-­‐1000 Nausea Arthralgias/myalgias→Lupus syndrome (rare) Hair loss Proteinuria (rare) Hepatotoxicity (PTU) Hyperthyroidism and Neuropsychiatry •  Anxiety disorders very common •  AgitaLon, poor concentraLon, emoLonal lability, poor sleep also widespread •  May see depression. •  May unmask psychosis •  Delerium and psychosis may be part of thyroid storm Thyroid Storm •  Rare, usually in context of severe thyrotoxicosis with intercurrent illness •  Think thyroid storm in paLent with fever, delerium, marked tachycardia, CHF or AF •  Significant mortality risk •  Intensive treatment with thionamides, steroids, betablockers, Lugol’s iodine required Subclinical hypothyroidism (raised TSH, normal T4) •  Common in general populaLon (~4-­‐15% depending on study and iodine intake) •  Treat if TSH >10 •  If TSH 4-­‐10, then treat if symptoms or goitre or if a woman contemplaLng pregnancy Subclinical Hyperthyroidism (TSH <0.1, Normal T4) ~2% populaLon Check T3 & anLbodies and feel for lump May normalise over Lme Associated with increased risk of AF and possibly CVD risk, plus adverse bone effects •  If persistent could consider radioiodine or carbimazole • 
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Controversies •  Use of T3/T4 combinaLon in hypothyroidism •  Role of thyroid autoimmunity with normal TFTs in anxiety and depression •  Subclinical thyroid disorders-­‐ treat vs observe •  Importance of deiodinase gene polymorphisms in thyroid homeostasis Mental Illness and Metabolic Syndrome/Diabetes Dr Simon Young FRACP WDHB Outline •  The size of the problem •  Metabolic screening: what and when? •  Management issues Severe Mental Illness (SMI) and Mortality •  SMI paLents have 2-­‐3 fold increased mortality and ~15 year shorter life span •  The mortality gap may have widened over Lme •  Increased CVD risk is a significant contributor to excess mortality (similar increase shown in schizophrenia, BPAD and major depression) Diabetes Prevalence in Schizophrenia Patients With Schizophrenia
% of Patients With Diabetes
General Population vs Schizophrenia Patients
20
18
16
20
16
12
14
10
12
8
10
6
8
4
6
2
4
NHIS (1994)
Pre-atypicals (1991)
1
Ages 45-64
Ages 45-641
(General Population) (Schizophrenia
Patients)
Atypicals
18
14
0
Conventionals
2
0
Post-atypicals (1999)
Ages 40-602*
*Values are arithmetic means of 2 different age groups
(40-50, 50-60) and assume comparable exposure times.
1. Dixon L, et al. Schizophr Bull. 2000;26(4):903-912. 20
2. Sernyak MJ, et al. Am J Psychiatry. 2002;159(4):561-566.
Type 2 Diabetes Is More Prevalent Among SMI PaLents Compared to the General PopulaLon EsLmated Prevalence of Type 2 Diabetes Schizophrenia Bipolar disorder 2-­‐4 x the general populaLon 2-­‐3 x the general populaLon Impact of Screening: the True Prevalence Known cases Newly diagnosed cases as a result of screening Diabetes 4.9% 16% IGT N/A 31% Bushe & Holt 2004
Diabetes and Depression • 
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Depression 2x more common in diabetes Associated with poorer glycaemic control Associated with higher risk of CVD Possible “vicious cycle” effect SMI PaLents have a Worse Lifestyle Compared to the General PopulaLon ü  Poor diet q  Less dietary fibre q  Less anLoxidant vitamins (C&E) q  Fewer porLons of fruit and vegetables q  High fat and sugar consumpLon q  Lower socio economic class ü  Inac4vity ü  Smoking Ø Poor lifestyle can increase diabetes suscep4bility in SMI pa4ents. Ø Lifestyle interven4ons are key to improving physical health of SMI pa4ents. Peet 2004
A GeneLc Link between DM and SZ? Alkelai A, etal PLoS ONE 2012 7;1: e29228
•  Emerging evidence to support a geneLc link between schizophrenia and diabetes risk •  Drug naïve 1st episode paLents had higher DM risk and higher glucose levels than matched controls •  SZ paLents had much stronger family history of T2 DM than controls •  TCF7L2 diabetes suscepLbility gene on Chromosome 10 now linked to schizophrenia in 4 different studies The Metabolic Syndrome (Syndrome X) Reaven Diabetes 1988 37:1595 Holt BJDVD 2006 •  A cluster of risk factors (hyperglycaemia, dyslipidaemia, hypertension, pro-­‐thromboLc state, central obesity) linked to insulin resistance and predisposing to DM and CVD •  Prevalence increased 2 fold in those with SMI especially SZ •  Some surveys around 50% prevalence in SMI Insulin Resistance: Causes and Associated CondiLons Hyperinsulinemia Increases Risk for Other Metabolic Disorders Insulin Resistance Syndrome: DiagnosLc Criteria Mortality Associated With Metabolic Syndrome © 2003 PPS® Metabolic syndrome-­‐ is it more than the sum of its parts? Kahn et al Diabete Care 2005 28(9):2289 •  Varying definiLons of syndrome in varying cohorts and resultant significant variaLons in CVD risk •  Some studies showed most excess CVD risk explained solely by presence of diabetes •  Measurement of “insulin resistance” variable and inaccurate •  Underlying pathophysiology not clear Metabolic syndrome: conclusions •  Kahn et al (Diabetes Care 2005) argue: –  Adults with one major CVD risk factor should have the others sought –  If RF above normal then lifestyle advice, if frank disease then treatment as per guidelines. –  CVD risk factors should be individually aggressively managed –  Using the label “metabolic syndrome” should be avoided Atypical AnLpsychoLcs •  Fewer neurological side-­‐effects •  Fewer negaLve symptoms •  BeWer compliance with fewer relapses and hospitalisaLons •  Less hyperprolacLnaemia •  But…. More weight gain! •  Used for more indicaLons? Mean Change in Weight With AnLpsychoLcs 6
5
4
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2
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0
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do
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ne
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ly
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Ch pe
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on
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Th m
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or z i
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la
nz
ap
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*4-6 week pooled data (Marder et al. Schizophr Res. 2003. In press).
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Extrapolated from 6-week data.
Adapted from: Allison et al. Am J Psychiatry. 1999;156:1686.
13.2
11.0
8.8
6.6
4.4
2.2
0
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-4.4
-6.6
Weight change (lb)
Weight change (kg)
Estimated Weight Change at 10 Weeks on “Standard” Dose
Weight Gain with anLpsychoLcs •  Obesity more common in schizophrenia but the drugs appear to worsen the problem-­‐exact mechanism unclear •  Large inter-­‐individual variaLon in weight gain with the drugs-­‐ some very large indeed! •  CATIE study of olanzapine showed 30% gained >7% bodyweight over 18 months •  Hagg et al (2006) showed a doubling of the diagnosis of “metabolic syndrome” with the use of atypical anLpsychoLcs Who to metabolically s
creen?
Diabetes Care 2004 27(2):596
•  ADA recommend need structured metabolic/CVD screening programme for all paLents with SMI treated with anLpsychoLcs perhaps in liaison with primary care •  Evidence suggests this is erraLcally and inconsistently done and aWendance at primary care may be erraLc •  Occasional cases of hyperglycaemic crises associated with these drugs Diabetes Cases Have Been Reported With Atypicals ü  Review of all case reports published 1980-­‐2001: q  45 cases on new-­‐onset diabetes and diabeLc ketoacidosis q  20 Clozapine, 19 Olanzapine, 3 QueLapine, 3 Risperidone q  Mean age: 40 years q  Mean drug exposure: 19 weeks q  59% presented within 3 months q  47% were of African-­‐American origin q  84% were overweight at baseline q  42% had family history of diabetes q  77% were taking adjuncLve medicaLon(s) q  50% had no weight gain on therapy Jin et al 2002
High Risk Groups for Diabetes • 
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Maori, Pacific, South Asian, Asian Obese at baseline Prior GDM or large babies Family history of DM PCOS Age >40 Acanthosis nigricans Metabolic Screening for paLents on anLpsychoLcs De Hert et al BJ Psych 2011 199:99-­‐105 Baseline Medical hx 6 weeks? 12 weeks Annually + + + Wgt/waist/BMI + + + BP + + + FG/HBA1C + + + Lipids + + + Lifestyle advice esp smoking + and exercise + + What to do about weight gain? •  If weight gain >5% then consider another agent with less propensity to weight gain? •  Avoid these agents for first aWack or in high risk people? Lifestyle •  Smoking cessaLon criLcal •  Structured diet and exercise programmes for people with chronic mental illness •  Perhaps mental health services should have more robust links with diabetes and cardiac services. Diagnosing Diabetes 2014 •  NZSSD guidelines –  SymptomaLc: HBA1C ≥ 50mmol/mol and/or FG ≥ 7 mmol/l or random G ≥ 11.1 –  AsymptomaLc: need two separate tests as above –  HbA1C 41-­‐49 mmol/mol = “prediabetes” or “IFG”-­‐ for lifestyle advice –  HBA1C ≤ 40 =normal (and if measured FG≤ 6.0)-­‐ retest at interval –  NB These are slightly different to ADA guidelines which use a cut-­‐off of 48 (or 6.5%) for HBA1C to diagnose diabetes HBA1C and DM diagnosis • 
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No need to fast Reduced biological variaLon Good relaLonship to complicaLons risk But: can be inaccurate with increased RBC turnover, post transfusion, some haemoglobinoapathies. May be some ethnic differences in glycosylaLon therefore OGTT sLll has a role in some cases. Prevalence of DM i
n N
Z Coppell K et al 2013 NZMJ 126(1370):23-­‐42
•  Survey of 4721 NZ people › 15 across NZ using 2010 ADA HBA1C criteria •  Prevalence of diabetes 7.0% and prediabetes 25.5% overall •  Obese had 14.2% prevalence of DM cf 2.5% in normal weight people •  Undiagnosed diabetes in 6.4% Pacific people Management of CVD risk •  Suggest apply NZGG CVD risk assessment guideline-­‐ but some say conservaLve •  If established CVD or 5 year risk >20% then intensive lifestyle and medicaLon approach •  If risk 10-­‐20% then lifestyle and probably medicaLons with follow-­‐up annually •  If <10% lifestyle advice or and re-­‐evaluate 5 years?? •  The field is evolving Diabetes Management •  Suggest use NZGG guidelines •  Me}ormin sLll 1st line drug therapy for T2 DM. Start if HBA1C≥ 50. Weight neutral, no hypos, may reduce CVD risk •  In NZ sulfonylureas (low cost, efficacy) second line but in some countries trend to GLP-­‐1 system modulaLng drugs because of weight advantage and lack of hypoglycaemia. Pioglitazone a small role •  Many progress to insulin within 10 years Type 2 DM is a Progressive Disease ß-cell function and insulin secretion progressively
decline in type 2 diabetes
Diagnosis of type 2 diabetes
IGT = impaired glucose tolerance. PPH = postprandial hyperglycaemia
DeWitt DE & Hirsch IB. JAMA 2003; 289:2254–2264. RACGP Diabetes Management in General Practice. Seventeenth edition 2011/12
CVD Risk Assessment hWp://www.nzssd.org.nz/cvd/ Blood Pressure •  Treat if persistent BP >140/90 or if combined CVD risk ≥10-­‐20% over five years •  First line usually ACE inhibitor especially if microalbuminuria •  Second line calcium blocker or thiazide diureLc •  Target BP ~130/80 Microalbuminuria •  Persistent microalbuminuria is marker of increased CVD risk (~2X) •  Microalbuminuria should be treated with ACE-­‐I or ARB (if s/e with ACE-­‐I) regardless of BP. •  Treat hypertension to target: SBP<130 mmHg, DBP ≤ 80 mmHg •  Treat hyperglycaemia Lipids •  Drug treatment decision based on risk calculator •  StaLns in most as good evidence for risk reducLon •  Fibrates lower triglycerides but weak evidence for CVD lowering effect and only used in selected cases •  InternaLonal guidelines becoming more aggressive and creaLng controversy Aspirin NZGG Primary Care handbook 2012 A B C ss A
B
C
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BP
Cholest
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< 7.0%
=<53
130/80
LDL < 2.5
TG < 2.0
Quit
75-100g
If á
CV risk
Smoking Salicylate
Conclusions •  SMI paLents have increased risk of both diabetes and CVD even in younger age groups. Hard to sort effect of disease from effect of drugs •  Contact with primary care oyen irregular and with cost barriers •  Mental health services should consider having systemaLc programme for monitoring cardiometabolic risk factors in paLents with SMI •  If significant CVD risk (>10-­‐15% over 5 years) then plan for managing this in liaison with primary care. Some useful websites www.nzssd.org.nz www.diabetes.org www.nice.org.uk www.idf.org www.easd.org www.dtu.ox.ac.uk/ukpds •  hWp://
www.nzgg.org.nz/ •  hWp://
www.diabetes.org.uk/ •  hWp://
www.racp.edu.au/ads •  hWp://www.idi.org.au/