Download - Wed. Clinical Presentation
-
8/12/2019 Wed. Clinical Presentation
1/57
GRAVES DISEASE
PRESENTING TEAM: ENDOCRINOLOGYUNIT.
PRESENTER: DR. NWAGBARA CT.
DATE: 6THFEBRUARY, 2013.
-
8/12/2019 Wed. Clinical Presentation
2/57
OUTLINE
Introduction Epidemiology
Pathophysiology
Clinical features Differential diagnosis
Investigations
Treatment Conclusion
References
-
8/12/2019 Wed. Clinical Presentation
3/57
INTRODUCTION
Graves disease, named after Robert J.Graves, MD, 1830, is an autoimmunedisease characterized by hyperthyroidism,
ophthalmopathy and dermopathy. Thyroid stimulating immunoglobulins (TSIs)
bind to and activate thyrotropin receptors,
causing the thyroid gland to grow and thethyroid follicle to increase sythesis of thyroidhormones.
-
8/12/2019 Wed. Clinical Presentation
4/57
Sometimes Graves disease is associatedwith other autoimmune conditions like;
- Pernicious anemia
- Vitiligo
- Diabetic mellitus type 1
- Autoimmune adrenal insfficiency
- Systemic sclerosis
- Myasthenia gravis
-
8/12/2019 Wed. Clinical Presentation
5/57
- Sjogren syndrome
- Rheumatoid arthritis
- Systemic lupus erythematosis
-
8/12/2019 Wed. Clinical Presentation
6/57
Epidemiology
Prevalence of hyperthyroidism in the generalpopulation is 1.2%
0.7% subclinical hyperthyroidism
0.4% Graves Diseasemost common etiology;note there is overlap with the subclinical group
Graves Disease is more common in females
(7:1 ratio)
-
8/12/2019 Wed. Clinical Presentation
7/57
The Classic Triad of Graves Disease
Hyperthyroidism (90%)
Ophthalmopathy (20-40%)
proptosis, ophthalmoplegia, conjunctival irritation
3-5% of cases require directed treatment
Dermopathy (0.5-4.3%)
localized myxedema, usually pretibial
especially common with severe ophthalmopathy
There is also a close association with autoimmune findings(e.g. vitiligo) and other autoimmune diseases (e.g. ITP)
-
8/12/2019 Wed. Clinical Presentation
8/57
PATHOGENESIS
In Graves disease,B and T lymphocyte-mediated autoimmunity are known to bedirected at 4 well-known thyroid antigens:
thyroglobulin, thyroid peroxidase, sodium-iodide sympoter, and thyrotropin receptor.
However, the thyrotropin receptor is the
primary autoantigen of Graves disease and isresponsible for the manifestation ofhyperthyroidism.
-
8/12/2019 Wed. Clinical Presentation
9/57
Pathogenesis contd
Direct proof of an autoimmune disorder thatis mediated by autoantibodies is thedevelopment of hyperthyroidism in healthy
individual by transferring thyrotropin receptorantibodies in serum from patients with gravesdisease and the passive transfer of the
thyrotropin receptor antibodies to the fetus inpregnant women.
-
8/12/2019 Wed. Clinical Presentation
10/57
Pathogenesis contd
The thyroid gland is under continuousstimulation by the circulating autoantibodiesagainst the thyrotropin receptor, and pituitary
thyrotropin secretion is suppressed becauseof the increased production of thyroidhormones.
The stimulating activity of thyrotropin receptorantibodies is found mostly in theimmunoglobin G1 subclass.
-
8/12/2019 Wed. Clinical Presentation
11/57
Pathogenesis contd
These will lead to stimulation of iodineuptake, protein synthesis and thyroid glandgrowth.
Several autoimmune thyroid diseasesusceptibility gene have been identified:CD40, CTLA-4, thyroglobulin,TSH receptor
and PTPN22.
-
8/12/2019 Wed. Clinical Presentation
12/57
Pathogenesis
An autoimmune phenomenonpresentationdetermined by ratio of antibodies
TSH
Receptor
Thyroid StimulatingAb (TSAb)
Thyroid Stimulation
Blocking Ab (TSBAb)
Thyroid
+
-
Graves Disease
AutoimmuneHypothyroidism(Hashimotos)Thyroglobulin Ab
Thyroid peroxidaseAb (anti TPO)
-
8/12/2019 Wed. Clinical Presentation
13/57
-
8/12/2019 Wed. Clinical Presentation
14/57
-
8/12/2019 Wed. Clinical Presentation
15/57
Symptoms contd
Cardiovascular: palpitations, dyspnoea onexertion, chest pains, edema.
Respiratory: dyspoea
Gastrointestinal: increased bowel motility withincreased frequency of bowel movement.
Ophthalmologic: tearing, gritty,sensation in
the eye, photophobia, protruding eye,diplopia, visual.
-
8/12/2019 Wed. Clinical Presentation
16/57
Symptoms contd
Renal: polyuria, polydipsia
Hematologic: easy bruising.
Metabolic: heat intolerance, weight lossdespite increase or similar appetite,worsening DM control.
Endocrine/reproductive: irregular menstrual
periods, amenorrhea, gynecomastia,impotence.
Psychiatric: restlessness, anxiety, insomnia
-
8/12/2019 Wed. Clinical Presentation
17/57
Physical findings
Eyes:
- Lid lag,
- lid retraction
- proptosis
- periorbital edema
- chemosis
-
8/12/2019 Wed. Clinical Presentation
18/57
Graves Ophthalmopathy
Antibodies to the TSH receptor also targetretroorbital tissues
T-cell inflammatory infiltrate -> fibroblast growth
Severe: exposure keratopathy, diplopia, com-pressive optic neuropathy
Strong link with tobacco
-
8/12/2019 Wed. Clinical Presentation
19/57
Classification of eye changes
(NOSPECS)0. No s igns no symptoms
Only signs (l id-retract ion and lag), no
symptoms
Soft t issue invo lvement (sym ptom s & signs )
Prop tos is (>20mm by Hertels
exopthalometer)
Extra ocu larmusc le involvement
Corneal involvement
Sight loss (op t ic nerve invo lvement)
-
8/12/2019 Wed. Clinical Presentation
20/57
Ophthalmopathy in Graves
Periorbital edema and chemosis
-
8/12/2019 Wed. Clinical Presentation
21/57
Exopthalamos inGraves Disease
Lid Lag in GravesDisease
-
8/12/2019 Wed. Clinical Presentation
22/57
Dermopathy
Usually occurs over the dorsum of the legs orfeet and is termed localized or pretibialmyxedema.
It is usually a late phenomenon The affected area is usually demarcated from the
normal skin by being raised and thickened andhaving a peau d orangeappearance ;it may bepruritic and hyperpigmented.
The most common presentation is non pittingoedema, but lesions maybe plaque like, nodular
or polypoid. Clubbing of the fingers and toes accompanies
and is termed thyro id acropachy
-
8/12/2019 Wed. Clinical Presentation
23/57
Myxedema of Graves
Activation of fibroblasts leads to increasedhyaluronic acid and chondroitin sulfate
Asymmetric, raised,firm, pink-to-purple,brown plaques ofnonpitting edema
-
8/12/2019 Wed. Clinical Presentation
24/57
-
8/12/2019 Wed. Clinical Presentation
25/57
-
8/12/2019 Wed. Clinical Presentation
26/57
-
8/12/2019 Wed. Clinical Presentation
27/57
Physical findings contd
Neck:
- thyroid gland enlargement
- thyroid bruits
- thyroid nodules may be palpable
-
8/12/2019 Wed. Clinical Presentation
28/57
-
8/12/2019 Wed. Clinical Presentation
29/57
Physical findings contd
CVS:
- murmur
- hyperdynamic precordium
- S3, S4 heart sounds
- ectopic beats
- irregular heart rates and rhythm
-
8/12/2019 Wed. Clinical Presentation
30/57
Differential Diagnosis
Toxic Multinodular Goiter
Toxic Adenoma
Thyroiditis
silent (Hashimotos) painless, often post partum
subacute (de Quervains) painful, post viral
drug-inducedamiodarone, lithium, interferon
Thyrotoxicosis factitia
-
8/12/2019 Wed. Clinical Presentation
31/57
Differential diagnosis
Anxiety
Pheochromocytoma
Hydatidiform mole
Ectopic thyroid tissue(struma ovarii)
Pituitary macroadenomas
Pituitary microadenomas
Hyperemesis gravidarum
-
8/12/2019 Wed. Clinical Presentation
32/57
Laboratory Evaluation
Suppressed TSH ( 20- Graves Disease- Toxic MN Goiter
T3:T4 < 20- Non-thyroid illness- Thyroiditis- Exogenous thyroxine
-
8/12/2019 Wed. Clinical Presentation
33/57
Its Good to be Free
Thyroxin is 99% bound to thyroid bindingglobulin (TBG), albumin, and transthyretin
Elevated TBG in viral hepatitis, pregnancy, and in
patients taking estrogens and opiates Decreased TBG binding with heparin, dilantin,
valium, NSAIDs, lasix, carbamazepine, ASA
Measuring Free T4 instead of total T4 avoids this
problem all together
-
8/12/2019 Wed. Clinical Presentation
34/57
Laboratory Evaluation
Direct measurement of TSH receptorantibodies (TSAb and TBAb)
Can help with Graves diagnosis in confusing
cases (as high as 98% sensitivity) Can predict new-onset Graves in the post-partum
period
Anti TPO Antibody and anti Tg Antibody
Can be mildly elevated in Graves
Usually most active in Hashimotos
-
8/12/2019 Wed. Clinical Presentation
35/57
Diagnostic Imaging
Radioactive Iodine Uptake
Provides quantitative uptake (nl 5-25% after 24h)
Shows distribution of uptake
Technetium-99 Pertechnetate Uptake Distinguishes high-uptake from low-uptake
Faster scanonly 30 minutes
Thyroid ultrasonography Identifies nodules
Doppler can distinguish high from low-uptake
-
8/12/2019 Wed. Clinical Presentation
36/57
-
8/12/2019 Wed. Clinical Presentation
37/57
Immediate Medical Therapy
Thionamidesinhibit central production of T3and T4; immunosuppressive effect
Methimazoleonce daily dosing
PTUadded peripheral block of T4 to T3conversion; preferred in pregnancy
Side effects: hives, itching; agranulocytosis,hepatotoxicity, vasculitis
Beta-blockadedecrease CV effects, also itinhibits the peripheral conversion of T4 to T3.
High-dose iodineWolff-Chaikoff effect
-
8/12/2019 Wed. Clinical Presentation
38/57
Long-term Therapeutic Options
Continued Medical Management
Low dose (5-10mg/day of methimazole) for 12 to18 months then withdraw therapy
Lasting remission in 50-60% Radioiodine Ablation
Discontinue any thionamides 3-5 days prior
Overall 1% chance of thyrotoxicosis exacerbation Hypothyroidism in 10-20% at 1 yr, then 5% per yr
Lasting remission in 85%
-
8/12/2019 Wed. Clinical Presentation
39/57
Titration Regimen
titrate the dose of antithyroid drug, givingcarbimazole (or methimazole) 20 mg two orthree times daily, and then lowering the doseevery 3 to 4 weeks or so, based on free T4
measurements, until a maintenance dose of 5 to10 mg once daily is achieved.
Equivalent starting and maintenance doses ofpropylthiouracil are 100 to 200 mg three times
daily and 50 mg once or twice daily. Maximumremission rates occur after 18 to 24 months oftreatment.
-
8/12/2019 Wed. Clinical Presentation
40/57
Block and Replace Regimen
start with the same dose of antithyroid drug butthen to add thyroxine 100 g daily after 3 to 4weeks when free T4 levels are usually becoming
normal, rather than lowering the dose of drug. Thereafter the patient is maintained on 40 mg
carbimazole or methimazole once daily(alternatively, 100 to 150 mg propylthiouracil
three times daily) and thyroxine, the latter beingadjusted if necessary 4 weeks after starting toachieve normal free T4 levels.
-
8/12/2019 Wed. Clinical Presentation
41/57
-
8/12/2019 Wed. Clinical Presentation
42/57
Treatment of Ophthalmopathy
Mild Symptoms
Eye shades, artificial tears
Progressive symptoms (injection, pain)
Oral steroidstypical dosage from 30-40mg/dayfor 4 weeks
Impending corneal ulceration, loss of vision
Oral versus IV steroids Orbital Decompression surgery
-
8/12/2019 Wed. Clinical Presentation
43/57
Treatment of Dermopathy
Milder cases do not require therapy otherthan Rx of thyrotoxicosis
For severe cases, therapy with topical
steroids applied under an occlusive plasticdressing for 3 -10 weeks
Also pulse glucocorticoid therapy may be
tried
-
8/12/2019 Wed. Clinical Presentation
44/57
-
8/12/2019 Wed. Clinical Presentation
45/57
Thyroid Storm aka Thyrotoxic crisis
A life threatening hypermetabolic state due tohyperthyroidism
Mortality rate is 10%
Usually occurs as a result of previouslyunrecognized or poorly treated hyperthyroidism
Thyroid hormone levels do not help todifferentiate between uncomplicatedhyperthyroidism and thyroid storm
-
8/12/2019 Wed. Clinical Presentation
46/57
Thyroid Storm Precipitants of Thyroid Storm
Infection Trauma
DKA MI
CVA PE
Surgery, Anasthesiainduction
Withdrawal of thyroidmed
Iodine administration,RAI therapy
Vigorous Palpation ofthyroid gland
Ingestion of thyroid
hormone
Unknown etiology (20-
25%)
-
8/12/2019 Wed. Clinical Presentation
47/57
-
8/12/2019 Wed. Clinical Presentation
48/57
-
8/12/2019 Wed. Clinical Presentation
49/57
Thyroid Storm
Diagnosis
Thyroid storm is a clinical diagnosis based uponsuspicion and treated empirically
Lab work is non specific and may includeLeukocytosis, hyperglycemia, elevatedtransaminase and elevated bilirubin
-
8/12/2019 Wed. Clinical Presentation
50/57
Thyroid Storm
Treatment Initial stabilization includes airway protection,
oxygenation, fluids and cardiac monitoring,hyperthermia control
Treatment can then be divided into 5 areas: General supportive care
Inhibition of thyroid hormone synthesis
Retardation of thyroid hormone release
Blockade of peripheral thyroid hormone effects
Identification and treatment of precipitating events
-
8/12/2019 Wed. Clinical Presentation
51/57
Thyroid Storm
Drug Treatment of Thyroid Storm(table 216-6)
Decrease de novo synthesis:
Porpythiouracil 600-1000mg PO initially, followedby 200-250 mg q 4 hrs
Methimazole 40 mg PO initial dose, then 25 mg PO q6h
Prevent relases of hormone(after synthesis blockadeintiated)
Iodine Iaponoric acid (Telepaque) 1 gm IV q8hfor the first 24 h, then 500 mg bid or Potassiumiodide (SSKI) 5 drops PO q6h or Lugol solution 8-10
drops PO q6h Lithuim 800-1200 mg PO every day
-
8/12/2019 Wed. Clinical Presentation
52/57
Prevent peripheral effects: B-Blocker Propanolol (IV) titrate 1-2 mg q 5min prn
(may need 240-480mg PO q day) or Esmolol (IV)500 mcg/kg IV bolus, then 50-200 mcg/kg per minmaintenance
Guanethidine 30-40 mg PO q 6 h Reserpine 2.5-5 mg IM q4-6h
Other consideration:
Corticosteroids Hydrocortisone 100 mg IV q 8 h or
dexamethosone 2 mg IV q 6 hr Antipyretics Cooling blanket
acteaminophen 650 mg PO q 4-6h
-
8/12/2019 Wed. Clinical Presentation
53/57
Thyroid Storm
Treatment cont
Propranolol has the additional effects or blockingperipheral conversion of T4-T3
Avoid Salicylates because it may displace T4 fromTBG
If the patient continues to deteriorate despiteappropriate therapy circulating thyroid hormone maybe removed by dialysis, plasmapheresis
Remember you must not administer iodine until
the synthetic pathway has been blocked
-
8/12/2019 Wed. Clinical Presentation
54/57
Conclusion
Graves disease is an autoimmune disease.
It has three major manifestations:hyperthyroidism, ophthalmopathy and
dermopathy. Graves disease is the commonest cause of
hyperthyroidism; about 80% of cases.
Graves disease is commoner in female tomale; ratio of 7: 1.
-
8/12/2019 Wed. Clinical Presentation
55/57
Conclusion contd
Pathogenesis is by immune mediated whichtargets mainly TSH receptor.
Some genes are implicated in the
pathogenesis: CD40, PTPN22, thyroglobulin. Evaluation can be by TFT assay, radiological
and radioactive iodine uptake.
Treatment can be medical or surgical.
-
8/12/2019 Wed. Clinical Presentation
56/57
References
Alguire et al. MKSAP14 Endocrinology and Metabolism. 2006. 27-34. Andreoli et al. Cecil Essentials of Medicine. 6th Edition, 2004. 593-7.
Nayak, B et al. Hyperthyroidism. Endocrinol Metab Clin N Am. 36(2007) 617-656.
In H et al. Treatment options for Graves disease: a cost-effectiveness
analysis. J Am Coll Surg. 2009 Aug;209(2):170-179.e1-2. Stiebel-Kalish H et al. Treatment modalities for Graves'
ophthalmopathy: systematic review and metaanalysis. J Clin EndocrinolMetab, August 2009, 94(8):27082716
Uptodate OnlineDisorders that Cause Hyperthyroidism, Diagnosis ofHyperthyroidism, Cardiovascular Effects of Hyperthyroidism, Treatment
of Graves Ophthalmopathy
-
8/12/2019 Wed. Clinical Presentation
57/57
THANK YOU FOR
LISTENING