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

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

Hypothyroidism Standard Guideline

Optimising Therapy• 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

• No difference in symptoms or biochemistry

• T4 should be the only monotherapy

• Further trials needed (?? Long acting T3)

Grozinsky-Glasberg et al 2006, Jonklaas et al Thyroid 24, 12 2014

• Meta analysis of 11 studies of 1216 patients

• No difference in symptoms or biochemistry

• T4 should be the only monotherapy

• Further trials needed (?? Long acting T3)

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)

• 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 Pre-

pregnant 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

• 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 womenThangararinam 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

• 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

• 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

Auer et al. Am Heart J 2001

Prevalence of AF in SHNo. 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

Functional cardiac effects of subclinical hyperthyroidism

• 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

Parle et al. Lancet 2001

• Community-living >60 year olds; overt thyroid disease excluded

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 strengthEC- euthyroid controlOH- overt hyperthyroidismSCH-subclinical hyperthyroidism

Strength of Knee extension, before and after Rx

Brennan et al. Thyroid 2006

Baseline Post Thyroid ablation

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

• 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

• 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

• 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-mortemPrevalence of nodules increases with age Cancer more common <20 and >60Cancer 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

• 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

• 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

British Thyroid Association Guidelines Latest 3rd Ed 2014

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, whetherclinical (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 -- + +

Hi LH -- + +

The PCO Spectrum

Normal Ov PCO Anov PCO

Ov + + --

Hi T -- + +

Hi LH -- + +

Insulin Res -- -- +

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 = 1.0

• usually regular = 1.25

• Very irregular = 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

• 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•

Questions