Download Thyroid Autoimmunity : The once and future questions

Endocrine Updates
Dr Malcolm Prentice
Consultant in Endocrinology and
Diabetes
Croydon University Hospital
St George’s Hospital for ARSAC
1. Management of Hypothyroidism
2. Subclinical Hyperthyroid – Treat?
3. Thyroid nodules -? cancer
4. Polycystic Ovarian Syndromes
5. Odd General Medical presentations
6. Calcium and Vitamin D
Thyroid hormone replacement –
the issues
• Optimising thyroid hormone replacement
• How to take thyroxine
• Trials of T3 and T4; Armour Tablets
• Patients with normal thyroid function tests
Normal physiology
Hypothyroid
Hypothyroidism Standard Guideline
Diagnosis
• Raised TSH and Low FT4 = overt hypothyroidism
Treatment
• Start 50-100 mcg levothyroxine
• Only 12.5 -25 mcg in the elderly or cardiac patients
• Re assess after 8 weeks (exceptions)
• Aim of treatment is TSH within reference range;
once normal then annual follow up
Optimising Therapy
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Remember to take it - time place
Before meal 1 hour, Morning?
Not with iron, calcium, aluminium (4 hrs)
Decide dosing and testing strategy ,
• age , heart dis , AF, post menopause TSH >0.1
• Reassess after other diagnoses,
» drug changes, Sertraline, phenytoin, carbamazepine
Coeliac disease
Higher doses needed if athyrotic , less T3
conversion.
Problems with variable TSH
• Restrict interval testing to 2/12 max
• Compliance, bathroom, dosebox,
• Absorption Iron/Calcium?Al, Coeliac,
gastritis, achlorhydria, PPI, Metformin,
GLP-1 ??
What about those who feel unwell
despite a normal (Ideal)TSH?
GHQ-12 and thyroid symptom
questionnaire given to 961 patients
on thyroxine for >4 months
62% response rate: significantly
worse scores in patients on thyroxine
(e.g. score >3 in GHQ in 32%
patients and 26% controls: P=0.014)
(Saravanan et al, 2002)
There is a subgroup of patients
on Thyroxine with low FT3
• There is insufficient evidence for change
• No benefit of T3 therapy or of adding T3.
• Gene studies of Type 2 deiodinase (T3 to T4)
polymorphism status awaited.
• The levels of T3 needed to suppress TSH into
the usual target range results in thyrotoxic
levels of FT3 with risk.
• There may be adverse cardiovascular/bone
effects also.
Jonklaas et al Thyroid . 24, 12 2014
Trials of T3 + T4
• Meta analysis of 11 studies of 1216 patients
• Meta analysis of 11 studies of 1216 patients
• No difference in symptoms or biochemistry
• No difference in symptoms or biochemistry
• T4 should be the only monotherapy
• T4 should be the only monotherapy
• Further trials needed (?? Long acting T3)
• Further trials needed (?? Long acting T3)
Grozinsky-Glasberg et al 2006, Jonklaas et al Thyroid 24, 12 2014
Grozinsky-Glasberg et al 2006, Jonklaas et al Thyroid 24, 12 2014
Studies of T3
• Meta analysis of 11 studies of 1216 patients
No difference in symptoms or biochemistry
• T4 should be the only monotherapy
• TSH is the only test for most patients.
• Further trials needed (?? Long acting T3)
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Grozinsky-Glasberg et al 2006, Jonklaas et al Thyroid 24, 12 2014
‘Normal’ TSH reference range
Subclinical hypothyroidism
• Raised TSH and normal FT4 and FT3
• Adverse Metabolic and lipids
• Consider trial of treatment if symptoms
• Pregnancy now or later? Treat as
Hypothyroid
Treatment of Subclinical and Clinical
Hypothyroid in the Pregnant and Prepregnant woman
• 1999 NEJM
TSH above normal, the mother and pregnancy
are at increased risk. The foetus is at risk of a
lower IQ measured as -7 points between ages
7-9.
• So treat all Subclinical pre-pregnant women
‘Raised’ TSH in pregnancy risks
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Lower IQ
Small for dates
Miscarriage
Premature birth
Preeclampsia
Gestational DM
Post partum thyroiditis
Target for Normal Pregnancy
Thyroid levels
• First Trimester
TSH less than 2.5
( TSH often supressed - 30% Thyrotoxic)
• Second Trimester
TSH less than 2.5
• Third Trimester
TSH less than 3.0
Jonklaas et al Thyroid 24, 12 2014
Hypothyroid Pregnancy Guidelines
Pre-pregnancy counselling +BTF Information
• Adjust Thyroxine dose to TSH < 1.5 mu/l
• If Family History? Screen TSH
When Pregnant
Increase Thyroxine by 25 or 50 microgm/day
and take TFT, adjust for target TSH< 2.5
• Form for repeat Thyroxine 6-8 weeks later
• See in Endocrine ANC 8 weeks later adjustT4
In last Trimester see again to
1.Adjust Thyroxine to TSH of < 3.0 and
2. Advise post delivery T4 dose
3.Advise to see GP for TFT 6 wks post -partum
• Advise on pre-pregnancy for next pregnancy.
Positive Thyroid antibodies risks
• Increased miscarriages x 2 (17.0 v 8.4%)
• Increased preterm delivery x 2
• Increased stillbirth and other comorbidities
• 12-15 % Positive in reproductive age women
Thangararinam et al BMJ 342. 2011
Positive Thyroid antibodies risks
• Increased miscarriages x 2 (17.0 v 8.4%)
(reduced by 52% with T4)
• Increased preterm delivery x 2
(reduced by 69% with T4)
• Increased stillbirth and other comorbitities
Thangararinam et al BMJ 342. 2011
Lifestyle Endocrinology: thyroid
hormone in euthyroid individuals
• Increasingly vocal patient
groups in UK are
demanding ‘natural’ thyroid
extract
• 65mg of thyroid extract (1
grain) contains
approximately 38 mcg T4
and 9 mcg T3 (~3.5:1 molar
ratio)
Lifestyle Endocrinology: thyroid
hormone in euthyroid individuals
• Others are prompted to
seek treatment when TSH
levels are within the
reference range abetted by
doctors who will indulge
them
• T4 treatment has no
proven benefit on
symptoms and does not
affect body composition
(Pollock et al 2001; Dubois et al 2008)
Consensus Statement on The
Diagnosis and Treatment of Primary
Hypothyroidism 2008
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British Thyroid Association
Royal College of Physicians
Endocrine Society (GB)
British Association of Endocrine Surgeons
Endorsed by RCGP
Conclusions
• Thyroid hormone replacement is best given with
levothyroxine
• No trials of Armour vs levothyroxine but unlikely
ever to be done
• Any future trials of T3 need physiological
replacement including mimicking circadian rhythm
• Clinicians should resist giving euthyroid patients
thyroid hormone treatment
Thyrotoxicosis ? Cause
• History, Pain, Short history, viral
illness,raised ESR and CRP
• Few months wt loss, no pain, FH, signs +
• Long history, older, nodular thyroid
• Pregnant?
Hyperthyroid Pregnancy
Guidelines ? Graves
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Propylthyiouracil 1st trimester only
Carbimazole after 12/40
Measure TSH Receptor Ab (TBII) at 20/40
Review every 2 – 4 weeks,
Tail off therapy?
Can breastfeed ?
PP relapse
NB No need for routine FBC measurement
Why Treat Subclinical
Hyperthyroidism ?
• Low TSH
• Normal FT3 and FT4
Key Questions
Subclinical hyperthyroidism
• How is it defined & physiology
• How common is it?
• Is it bad for you?
• What is the evidence for treatment?
• Trial of Radioiodine Intervention for Subclinical
Hyperthyroidism
TRISH-UK
Subclinical Hyperthyroidism
65% MNG
35% GD
Persistent undetectable TSH (<0.1 mU/l); normal FT4 & FT3
Risk of progression to full
thyrotoxicosis
• Parle et al. 1991 TSH <0.1
2 % / year
• Weirsinga et al. 1995
5 % / year
• Pirich et al. 2000 TSH <0.1
7 % / year
Prevalence of AF in SH
No.
examined
No. with % AF
AF
P value
Euthyroid
22,300
513
2.3
Subclinical
hyperthyroid
613
78
12.7
<0.01
Overt
hyperthyroid
725
100
13.8
<0.01
• Consecutive clinic patients over 9 yrs
Auer et al. Am Heart J 2001
Functional cardiac effects of subclinical
hyperthyroidism
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Resting tachycardia
LV hypertrophy
Increase LV mass index
Increase cardiac workload
Diastolic dysfunction (impaired relaxation)
Increased systolic function at rest
Impaired systolic response to excercise
Biondi, Klein and others
Overall survival
“Circulatory” survival
• Community-living >60 year olds; overt thyroid disease excluded
Parle et al. Lancet 2001
Bone Health: Fracture
• 9700 women, >65 years
• Adjusted odds ratio for Fracture compared to normal TSH
group
Hip
Vertebral
– TSH 0.1- 0.5
1.9 (0.7-4.8)
2.8 (1.0-8.5)
– TSH <0.1
3.6 (1.0-12.9)
4.5 (1.3-16)
• Irrespective of thyroid hormone use, previous thyrotoxicosis or
oestrogen use
Bauer et al. Ann Intern Med 2001
Muscle strength
EC- euthyroid control
OH- overt hyperthyroidism
SCH-subclinical hyperthyroidism
Baseline
Post Thyroid ablation
Strength of Knee extension, before and after Rx
Brennan et al. Thyroid 2006
Dementia
• Rotterdam study
• 1843 subjects >55 years old, MMTS
• Risk of dementia = 3.5 (1.2-10.0) if
TSH <0.4 vs normal TSH
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Increases to = 3.7 (4.0-14.0) if
TSH < 0.4 and +ve TPO Abs
Kalmijn et al. 2000
Summary
Subclinical hyperthyroidism; TSH <0.1
• Common in elderly
• Is associated with:
- AF
- Adverse cardiac outcome
- Fracture, BMD
- Dementia
• No evidence that treatment is beneficial
• Trials urgently needed
Recommendations
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TSH<0.1
Treatment should be considered
No modality recommended
Particularly for:
– >60 yrs
– Heart disease
– Osteopenia
– Symptoms
• Younger subjects: diagnose & follow up
Low TSH ≠ Subclinical hyperthyroidism
• TSH undetectable (<0.05)
– T3 thyrotoxicosis
– Pituitary disease ignore TSH
• TSH 0.1-0.4 mU/l
– Non-thyroidal illness (sick-euthyroid syndrome)
– Iodide load (CT scan with contrast)
– Chronic opiate use, glucocorticoids, dopamine agonists, T4
– Extreme old age (>95 yrs)
• Repeat TFTs in 3 months time: ? consistent finding
Thyroid Nodules ? Cancer
1. History of thyroid Cancer Risk
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History of irradiation to neck and in childhood
Goitre or any thyroid swelling/nodule
Hashimoto's thyroiditis (risk of lymphoma)
Family or personal history of thyroid adenoma
Marine-Lenhart disease
Familial adenomatous polyposis
Familial thyroid cancer
Cowden's syndrome (macrocephaly, mild learning
difficulties, carpet-pile tongue, with benign or
malignant breast disease)
Chernobyl < age 10 1986 up to 30x in Belarus
Cancer risk in a Multinodular Goitre
Multinodular goitre has cancer risk
Thyroid nodules are common
• 5% by palpation
• 10-41% by ultrasound
• 50% at post-mortem
Prevalence of nodules increases with age
Cancer more common <20 and >60
Cancer incidence after FNA is 9-13%
Assessment with ultrasound
Confirm structure
Detect malignancy risk
Biopsy of Dominant Thyroid Nodule
Classification of Thyroid Cytology
Ultrasound to identify higher risk
nodules
• Number
• Size
• Characteristics
Number of nodules
• more nodules = less risk per
nodule
• Overall neck risk remains
unchanged
Ultrasound characteristics of nodules
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Solid – cystic
Density
Capsule
Blood supply
Microcalcification
Shape
Solid nodule
Mainly cystic nodule
Mixed cystic solid nodule
High density nodule
Low density nodule
Poorly encapsulated nodule
Low doppler blood flow
High doppler blood flow
High flow in cyst inclusion
Microcalcifications in carcinoma
British Thyroid Association
Guidelines Latest 3rd Ed 2014
• Abnormal lymph nodes – always biopsy nodes or
ipsilateral nodule(s)
• FNA probably unnecessary if
- cystic or almost entirely cystic
- no substantial growth (if prior US)
• Multiple nodules
– Consider US guided FNA of 1 or more nodules with
selection based on criteria for solitary nodule
VOMIT
• Chance finding on CT scan of neck –do U/S
to assess risk, refer if high.
• Chance finding on U/S assess risk refer if
high.
Polycystic Ovarian Syndromes
Diagnosis 1990 NIH
• Menstrual irregularity due to oligo- or anovulation
• Evidence of hyperandrogenism, whether
clinical (hirsutism, acne, or male pattern balding) or
biochemical (high serum androgen concentrations)
• Exclusion of other causes of hyperandrogenism and
menstrual irregularity, such as congenital adrenal
hyperplasia, androgen-secreting tumors, and
hyperprolactinemia
Rotterdam 2003
• Oligo- and/or anovulation
• Clinical and/or biochemical signs of
hyperandrogenism
• Polycystic ovaries (by ultrasound)
The PCO Spectrum
Normal
Ov PCO
Anov PCO
Ov
+
+
--
Hi T
--
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+
Hi LH
--
+
+
The PCO Spectrum
Normal
Ov
Hi T
Hi LH
Insulin Res
+
----
Ov PCO
+
+
+
--
Anov PCO
-+
+
+
Mechanism of PCO Syndromes
• 1st Hit - Ovarian increase in Androgens
• 2nd Hit – Genes regulating insulin action
(similar to T2DM)
But heterogeneous, many genes, several
genetic studies near T2DM gene
e.g FTS gene (fat accessibility) Chrom 16
Metabolic Consequences of PCO
• 1 Diabetic Risk
– Gestational diabetes – 52% have PCO
– Metabolic syndrome
• 40-50% have IGT, 45-55% have T2DM
• T2 DM risk after adjusting for obesity = 2 fold
• T2 DM risk if obese = 3 fold
• 2 Cardiovascular risk
– Overall risk + 1.5
– Endothelial dysfunction
– Risk of fatal and non-fatal CVS events
• regular cycles
• usually regular
• Very irregular
= 1.0
= 1.25
= 1.53
Diagnosis of PCO
1. No need to measure insulin
If obese, anovulatory and hirsute = ↑insulin
2. Obese BMI > 30 DM screen HbA1c and lipids
3. Use/value of tests if non-obese uncertain
Treatment Plan for PCO
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Lean women should not get fat
Fat women should get lean – lifestyle/diet
Increase ovulation with lifestyle and diet
Metformin – no good evidence for ovulation
– Not good for hirsuitism
– Maybe for pre-diabetic women, 50% effect of lifestyle
– Lifestyle still best results
• (Glitazones -as for metformin but increased risk)
General Medical presentations of
rare Endocrine conditions
• 28 Year old woman with sudden onset of fits
• 78 Year old woman with COPD presented
with several episodes of dizziness and
collapse diagnosed as cough syncope.
• 36 Year old man presenting with right
hemiplegia. Previous parathyroidectomy.
Hypocalcaemia
• Venesection
• Vitamin D
• Hypoparathyroid
• Others
Who needs treating?
Deficient serum Vitamin D (<25 nmol/L)
• Initial high dose (60,000 IU/ week for 8 weeks)?
followed by maintenance (800-1000 IU/day)
Insufficient serum Vitamin D (25-50 nmol/L)
• Either prescribe long term maintenance (800-1600
IU/day) +/- calcium
• Advise long term supplementation
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Questions