Graves disease (Basedow's disease, exothalmic goiter)
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Introduction
Graves disease is characterized by hyperthyroidism accompanied by infiltrative ophthalmopathy & sometimes infiltrative dermopathy.
Etiology
- autoimmune with IgG Ab reactive with plasma membrane domains that include the TSH receptor. (2 distinct classes of Ab identified, a 3rd is controversial)
- thyroid-stimulating immunoglobulin (antibody) (TsAb or TSI). These Ab stimulate formation of cAMP in vitro
- thyrotropin-binding inhibitory immunoglobulin (TBII) binds to the TSH receptor & inhibits TSH binding; in most cases TBII stimulates thyroid function, but in some cases, it may be inhibitory
- thyroid growth immunoglobulin (TGI) a controversial entity suggested by some to be responsible for proliferation of follicular cells
- hypothesized organ-specific defect in suppressor T-cells which allows emergence of CD4+ helper cells targeted to TSH receptor epitopes. Cooperation with B-cells then leads to autoantibody formation
- PROSITE suggests (at least in some cases) target may be Graves' disease carrier protein
- long-term variations in iodine intake do not affect risk, but rapid repletion can transiently increase incidence[7]
- increased frequency of co-existing autoimmune diseases:
Epidemiology
- most common cause of hyperthyroidism[7]
- prevalence: in the US is 0.4% (0.2-0.5%)[7]
- peak incidence in 4th & 5th decades of life, but may occur at any age[7]
- female to male ratio of 5-10:1
- lifetime risk is 3% for women & 0.5% for men[7]
Pathology
- thyroid
- diffuse hyperplasia
- thyroid gland enlargement > 80-90 grams is uncommon
- capsule is intact & non-adherent
- dominant histologic feature is too many cells
- tall columnar epithelium
- colloid diminished
- subcellular changes
- Golgi hypertrophied
- mitochondria increased
- microvilli more abundant
- increased lymphoid tissue with lymphoid follicles
- increased vascularization (thyroid bruit)[8]
- morphology dependent upon medication
- iodine induces:
- colloid storage
- devascularization
- involution of gland
- thiourea derivatives induce hyperplasia
- iodine induces:
- ophthalmology
- lymphocytic infiltrate of:
- extraocular muscles
- retro-orbital fibro-fatty tissue
- increase in glycosaminoglycans in
- extraocular muscles
- orbital fibrous & fatty tissue
- edema
- fibrosis late in the course of the disease
- lymphocytic infiltrate of:
- generalized lymphoid hypertrophy throughout body
Genetics
- familial predispositions frequently noted
- well defined association with HLA-B8 & HLA-DR3 among Caucasians, but different haplotypes among Asians
- little evidence to suggest increased risk of thyroid cancer
- susceptibility linked to CTLA4, FCRL3
- SLC25A16 recognized by IgG in patients with active Graves disease
Clinical manifestations
- thyroid
- diffuse goiter (less common in older patients <50%)
- thyrotoxicosis
- thyroid bruit*[8]
- firm, smooth texture[4]
- ophthalmopathy signs/symptoms (Graves ophthalmopathy)
- lid lag
- upper lid retraction
- stare
- weakness of eye muscles (extaocular eye muscle palsy)[4]
- diplopia
- periorbital edema
- proptosis to the point to which the lids cannot close
- ophthalmologic signs/symptoms may or may not be present
- hyperthyroidism & ophthalmopathy typically occur within 1 year of each other but can be separated by decades[7]
- severe cases may result in optic neuropathy & blindness
- dermatologic signs/symptoms (thyroid dermopathy)*
- localized edema over dorsal area of legs & feet (pretibial myxedema)[4]
- present in 10-15% of patients
- acropachy resembles clubbing of the fingers or toes
- occurs only in patients with thyroid dermopathy[7]
- neuromuscular signs/symptoms
- weakness due to myopathy
- hyperkalemic periodic paralysis predominantly in Asians
- myasthenia gravis may coexist in 5% of patients
- heat intolerance[7]
- fine tremor
- hyperreflexia
- hyperkinesis
- other[7]
- chronic disorder
- weight loss
- anorexia
- palpitations
- tachycardia
- dyspnea
- atrial fibrillation in patients > 60 years of age[7]
- diarrhea
- polydipsia, polyuria
- anxiety, mood disorder, nervousness, hyperactivity
- insomnia
- amenorrhea
- loss of libido
- systolic hypertension, increased pulse pressure
- heart failure
- diaphoresis
- cervical lymphadenopathy[4]
- palmar erythema
- onycholysis
- alopecia
- case report[5]
- intermittent dizziness
- near syncope
- chest pain, abdominal pain
- headaches
* distinguishing features of Graves disease from subacute thyroiditis[4]
Laboratory
- decreased serum TSH levels*
- increased total & free T3 & free T4
- occasionally T4 may be normal with elevated free T3 (T3-toxicosis)
- thyroid-stimulating immunoglobulin (TSI)
- persistence of TSI predicts relapse after antithyroid agent discontinuation[11]
- autoantibodies to LMOD1
* stop methimazole after 12-18 months if serum TSH & TSH receptor Ab are normal[11]
Radiology
- increased radioactive iodine uptake
Complications
- thyroid storm may be triggered by iodinated contrast agents, surgery, infections, myocardial infarction, trauma or parturition[4]
- antibodies to TSH receptors of IgG class may cross the placenta & cause neonatal thyrotoxicosis in the newborn
- inability to work
- increased mortality[7]
Differential diagnosis
- subacute thyroiditis (subacute vs chronic, no thyroid bruit)
- subacute granulomatous thyroiditis
- subacute lymphocytic thyroiditis
- subacute thyroiditis generally resolves in 2-3 months[11]
- Reidel's thyroiditis
- rare fibrosing disorder generally not associated with hyperthyroidism[11]
- toxic multinodular goiter
- thyroid nodules, thyroid asymmetry
- no ophthalmopathy. no dermopathy
- factitious thyrotoxicosis
- iodine-induced hyperthyroidism
Management
- beta-blockers:
- decrease beta-adrenergic mediated effects of thyrotoxicosis
- decrease peripheral conversion of T4 to T3
- indicated for all forms of thyrotoxicosis
- titrate according to heart rate
- propranolol 20-40 mg PO QID
- antithyroid drug therapy 1st line
- methimazole is 1st line
- propylthiouracil (for use in 1st trimester of pregnancy)
- drug-free remission at 1 year is 30-50%[4]
- remission more common in patients with small goiter
- continuing antithyroid agent > 18 months may of no benefit[11]
- stop methimazole after 12-18 months if serum TSH & TSH receptor Ab are normal[11]
- iodide inhibits release of hormone from thyroid gland
- saturated solution of KI (SSKI)
- Lugol's solution
- not recommended in pregnant women[3]
- safe for fetus, but less effective than propylthiouracil
- radioactive I-131 ablation of the thyroid
- subtotal thyroidectomy
- topical glucocorticoids for thyroid dermopathy generally ineffective
More general terms
More specific terms
Additional terms
- factitious hyperthyroidism; factitious thyrotoxicosis; thyrotoxicosis facticia
- Graves disease carrier protein; GDC; Graves disease autoantigen; GDA; mitochondrial solute carrier protein homolog; solute carrier family 25 member 16 (SLC25A1, GDA)
- radioactive iodine uptake (RAIU) test
- subacute granulomatous thyroiditis; De Quervain's thyroiditis; giant-cell thyroiditis
- subacute lymphocytic thyroiditis
References
- ↑ Saunders Manual of Medical Practice, Rakel (ed), WB Saunders, Philadelphia, 1996, pg 638-41
- ↑ Cotran et al Robbins Pathologic Basis of Disease, 5th ed. W.B. Saunders Co, Philadelphia, PA 1994 pg 1129
- ↑ 3.0 3.1 Mayo Internal Medicine Board Review, 1998-99, Prakash UBS (ed) Lippincott-Raven, Philadelphia, 1998, pg 203-206
- ↑ 4.0 4.1 4.2 4.3 4.4 4.5 4.6 4.7 4.8 4.9 Medical Knowledge Self Assessment Program (MKSAP) 11, 15, 16, 17, 18, 19. American College of Physicians, Philadelphia 1998, 2009, 2012, 2015. 2018, 2022.
Medical Knowledge Self Assessment Program (MKSAP) 19 Board Basics. An Enhancement to MKSAP19. American College of Physicians, Philadelphia 2022 - ↑ 5.0 5.1 Hazen EP, Sherry NA, Parangi S, Rabito CA, Sadow PM. Case records of the Massachusetts General Hospital. Case 10-2015. A 15-year-old girl with Graves' disease and psychotic symptoms. N Engl J Med. 2015 Mar 26;372(13):1250-8 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/25806918 <Internet> http://www.nejm.org/doi/full/10.1056/NEJMcpc1314239
- ↑ Bartalena L Diagnosis and management of Graves disease: a global overview. Nat Rev Endocrinol. 2013 Dec;9(12):724-34 PMID: https://www.ncbi.nlm.nih.gov/pubmed/24126481
- ↑ 7.00 7.01 7.02 7.03 7.04 7.05 7.06 7.07 7.08 7.09 7.10 7.11 Smith TJ, Hegedus L. Graves' Disease. N Engl J Med 2016; 375:1552-1565. October 20, 2016 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/27797318 <Internet> http://www.nejm.org/doi/full/10.1056/NEJMra1510030
- ↑ 8.0 8.1 8.2 NEJM Knowledge+ Question of the Week. May 16, 2017. https://knowledgeplus.nejm.org/question-of-week/806/
Brent GA. Graves' Disease N Engl J Med 2008; 358:2594-2605. June 12, 2008 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/18550875 <Internet> http://www.nejm.org/doi/full/10.1056/NEJMcp0801880 - ↑ NEJM Knowledge+ Question of the Week. Oct 9, 2017. https://knowledgeplus.nejm.org/question-of-week/899/
Ross DS, Burch HB, Cooper DS et al 2016 American Thyroid Association Guidelines for Diagnosis and Management of Hyperthyroidism and Other Causes of Thyrotoxicosis. Thyroid. 2016 Oct;26(10):1343-1421. PMID: https://www.ncbi.nlm.nih.gov/pubmed/27521067 - ↑ Hesarghatta Shyamasunder A, Abraham P. Measuring TSH receptor antibody to influence treatment choices in Graves' disease. Clin Endocrinol (Oxf) 2017 May; 86:652 PMID: https://www.ncbi.nlm.nih.gov/pubmed/28295509
- ↑ 11.0 11.1 11.2 11.3 11.4 11.5 11.6 NEJM Knowledge+ Endocrinology
Patient information
Graves disease patient information