Clinical Focus Series Disorders of Thyroid Romesh Khardori, KM Prasanna Kumar
INDEX
Page numbers followed by f refer to figure and t refer to table
A
Addison disease 151153
Adenocarcinoma 28
Adenoma 27
follicular 107
toxic 12, 72, 74, 94
Adenovirus 53
Agranulocytosis 14
Alanine transaminase 54
Allan-Herndon-Dudley syndrome 125, 176
Alopecia 1, 83, 151, 152
Alzheimer's disease 66
Amenorrhea 1
American Thyroid Association's risk scoring system 34t
Aminoglutethimide 148
Amiodarone 148, 155, 174
Anemia 157
aplastic 14
hemolytic 148
pernicious 83, 151, 152
Ankle jerks 1
Antibodies
anti-insulin 14
anti-thyroglobulin 106
maternal 174
Antithyroid
agents 23
antibodies 67, 79, 80, 82, 104, 108, 149, 152
peroxidase 106
drugs 6, 13, 16, 23, 126, 148
APGAR score 172
Aplasia 174
Arthralgias 54
Aspartate transaminase 54
Atrial fibrillation 73
Autoimmune encephalitis 151
Autoimmune polyglandular syndromes 148, 151, 152
Azathioprine 142
B
Bacterial infection 51
Ballet sign 137
Benzodiazepines 155
Bethesda scoring system 35, 35t
Biopsy 162
Body mass index 5, 15
Bone 116
metastasis 46
mineral density 71
Borrelia burgdorferi 150
Boston's sign 137
Bradycardia 158
Breast imaging reporting and data system 33, 90
C
Calcitonin 106
Carbimazole 13, 14
Carcinoma
follicular 39, 102, 107
medullary 28
mucoepithelial 28
papillary 37
Cardiac dysrhythmia 83b
Carotid 87
artery, internal 88f
Carpenter syndrome 152
Celiac disease 151, 152
Cell membrane thyroid hormone transport defects 120
Central nervous system 4, 65, 73, 116
Cerebrospinal fluid 151
Cervical lymph node 91f
Chemosis 140
Chromosomal syndromes 148
Cold nodule 96f
Collier's sign 137
Congestive heart failure 83
Cowden's syndrome 29
Coxsackievirus 150
Craniopharyngioma 148
C-reactive protein 55
Cyclophosphamide 142
Cyclosporine 142
Cystinosis 148
Cysts
ovarian 3
thyroglossal 109
Cytokines, role of 186
Cytomegalovirus 53
Cytotoxic T-cell activation 143
D
Dalrymple's sign 137
De Quervain's thyroiditis 51, 52, 57
Dementia 83
Depression 65
Diabetes 4, 83, 131
mellitus 148, 151, 152
Diiodotyrosine 153, 175
Dopamine 155
Down syndrome 148, 151, 152, 164
Drug-induced hypersensitivity syndrome 53
Dysgenesis 148, 174
Dyshormonogenesis 148, 156, 174, 175
Dyslipidemia 81
Dysphagia 165
Dyspnea 165
Dysthyroid optic neuropathy 134, 137
E
Ectodermal dysplasia 152
Ectopia 174
Ectopic thyroid 148, 162f, 167f
tissue 95
Edematous facial appearance 167f
Epiphyseal dysgenesis 161
Epstein-Barr virus 53
Erythrocyte sedimentation rate 52, 55
Euthyroid ophthalmopathy 134, 136
Euthyroid sick syndrome 148
External beam radiation therapy 43
F
Familial adenomatous polyposis 29
Farnsworth-Munsll panel detects 137
Fatigue 54, 66
Fetal growth retardation 24
Fibrosarcoma 28
Fine needle aspiration cytology 27, 34, 56, 87, 91, 92f, 93, 104, 106, 107
Fluorodeoxyglucose positron emission tomography 32, 98f, 99f, 101
Follicle stimulating hormone 46
Foramen cecum 173
Free thyroxine 6, 126, 129, 163, 185
Free triiodothyronine 6, 126
Furosemide 155
G
Galactorrhea 3, 157
Giant cell 53
multinuclear 56
thyroiditis 51
Gifford's sign 137
Glasgow Coma Scale 2
Glucocorticoids 130, 155
Glycosaminoglycan 135
Glycosylated hemoglobin 4, 182
Goiter 51, 118, 150, 154, 158, 165f
chronic lymphocytic 148
endemic 148, 153
euthyroid 148
fetal 24
multinodular 94, 94f, 104, 105, 120
staging of 159
toxic 108
Goitrogens 154
Gonadotropins 5
Graves’ disease 1017, 23, 24, 29, 32, 54, 56, 74, 96f, 102, 120, 128, 130, 134, 136, 150
Graves’ hyperthyroidism 24
Graves’ ophthalmopathy 15, 16, 134
Graves’ orbitopathy 143
Graves’ thyrotoxicosis 10, 17, 102
H
Hashimoto's encephalopathy 151
Hashimoto's thyroiditis 2, 27, 51, 147, 150, 156, 157, 162
Hashitoxicosis 150
Head trauma 148
Helicobacter pylori 150
Helper T-cell proliferation 143
Hemithyroidectomy 109
Hepatic injury 14
Hepatitis
cholestatic 14
toxic 14
Hirschberg principle 140
Histiocytosis 148
Human chorionic gonadotropin 12, 20, 53, 72
Human herpes viruses 53
Human immunodeficiency virus 53, 150
Human leukocyte antigen 51, 135, 149
Hurthle cell 37
neoplasm 37
Hydrops fetalis 24
Hyperemesis gravidarum 22
Hyperglycemia 143
Hyperplasia, glandular 27
Hyperprolactinemia 5, 157
Hyperreflexia 11
Hypertension 11, 131, 143
Hyperthyroidism 11, 12, 17, 22, 24, 59, 150
endogenous subclincal 75
euthyroid 24
exogenous subclinical 75
fetal 24
gestational 24
primary 12
secondary 12
subclinical 71, 72t, 73, 76t
treatment of 83
Hyperthyrotropinemia 164
Hyperthyroxinemia, familial dysalbuminemic 126
Hypertrophy, pseudomuscular 3
Hypoglycemia 14, 158
Hypoosmolar euvolemic hyponatremia 3
Hypoplasia 148, 174
Hypoprothrombinemia 14
Hypothalamic disorders 148
Hypothalamic pituitary
gonadal axis 5
hypothyroidism 174
region, inflammatory disorders of 3
thyroid axis 151, 116, 184
Hypothyroidism 1, 36, 8, 59, 65, 66, 68, 72, 147150, 154, 161, 174
acquired 148, 157, 158t
autoimmune 118, 150
central 74, 148, 156, 158, 164, 174, 176
congenital 148, 153, 157, 158t, 162, 167f, 172, 174, 178, 178f, 179
diagnosis 5
drug-induced 148
etiology 3
juvenile 147, 148, 156, 163
management of 21
neonatal 65, 172
overt 3, 20, 80
pituitary 176
presentation 3
prevalence of 19
primary 1f, 3, 6, 158, 166, 158t, 174
secondary 2f, 3, 6t, 149, 156
subclinical 3, 6, 21, 66, 67, 7780, 80t, 83, 84t, 85, 150, 151, 164
symptoms of 158
tertiary 149
treatment 6
Hypothyroxinemia 164
I
Infections 148
Infertility 3
Inflammatory disorders 148
Influenza virus A, B 53
Iodide transport, defect of 174, 175
Iodine
deficiency 3, 148, 153, 154, 174
diseases, spectrum of 154t
disorder 158, 159
excess 154
Iodotyrosine deiodinase, deficiency of 175
J
Jendrassik's sign 137
Joffroy's sign 137
Juvenile hypothyroidism 148, 156
causes of 148b
K
Kinase inhibitor therapy 47
Klinefelter syndrome 148, 151
Knies’ sign 137
Kocher's sign 137
Kocher-Debre-Semelaigne syndrome 3, 157
L
Leukemia 148
Levator muscle 136
Levothyroxine 5, 21, 119
Levotriiodothyronine suppression test 120
Lithium 148
Lobectomy plus isthmectomy 109
Longus coli muscles 87
Lugol's iodine 109
Lugol's solution 109
Lymphoma 28
M
Madarosis 1
Malaise 54
Marcus Gunn pupil 137
McCune-Albright syndrome 12
Memory loss 66
Meningioma 148
Meningoencephalitis 148
Mental retardation 1, 158
Metastatic disease, management of 45
Methimazole 13, 148, 174
Methotrexate 142
Minimally invasive, video-assisted thyroidectomy 110
Mobius sign 137
Modified American Thyroid Association 2009 risk stratification 41t
Monoiodotyrosine 153, 175
Muller's muscle 136
Muscles
sternocleidomastoid 87
weakness 11
Muscular hypertrophy 157
Myalgias 54
Myxedematous syndrome 159
N
Neck pain 55
Necrotizing enterocolitis 176
Neoplasm, follicular 35, 37
Newborn screening 172, 178
Nocardia asteroides 58
Nodular thyroid disease 54
Nodules 93
autonomous 97f
functional status of 94
multiple 94f
rapid growth of 31
Nonsteroidal anti-inflammatory drugs 56
Nonthyroidal illness syndrome 148, 156, 182
Noonan syndrome 151
O
Obesity 5
Ophthalmopathy, thyroid associated 139t, 140t
Opiates 155
Orbital radiotherapy 144
Orbitopathy, thyroid associated 134, 135, 137t, 140142, 144
Ovarian masses 165f, 166
P
Pancreatitis 14
Panhypopituitarism 174
Papillary thyroid
cancer 28, 40, 41
microcarcinoma 40, 41
Papilledema 137
Paranoid schizophrenia 65
Pendred syndrome 175
prevalence of 175
Peroxidase system defects 175
Phenobarbitone 148, 155
Phenytoin 148
Pituitary hormone deficiencies 158
Polyendocrinopathy, autoimmune 152
Polyserositis 3
Polyuria 158
Povidone iodine 155t
Pregnancy 22, 25, 128
Propranolol 130, 155
Propylthiouracil 13, 130, 148, 174
Pseudogiant cell 51
Psychiatric disorders 83
Psychosis, steroid-induced 143
R
Radiation 28
safety precautions 99
thyroiditis 59
Radioactive iodine 28, 41, 104
refractory 46
therapy 42
Radioiodine 17, 148
ablation 14
Recurrent laryngeal nerve 105, 158
Regional lymph nodes 158, 164
Retroviruses 150
Riedel's thyroiditis 51, 60
S
Sarcoidosis 148
Schizophrenia 66
Schmidt syndrome 152
Sheehan's syndrome 2, 2f
Sistrunk's operation 109
Snellen-Rieseman's sign 137
Sodium iodide symporter 30, 149
Solitary nodule 96f, 97f, 107
Spongiform nodules 35
Squamous cell epidermoid carcinoma 28
Stellwag's sign 137
Stereotactic body radiotherapy 45
Steroid therapy 56
Strabismus 140
Strain tissue elastography image 92f
Stromal cells 116
Struma granulomatosa 51
Struma ovarii 12
Suker's sign 137
Sulfonamides 155
Superior laryngeal nerve 105
Surgery 16, 38, 104
T
Tachycardia 11, 24
Tanner stage 1
Thalassemia 148
Thalidomide 148
Thelarche 165f
Thionamides 19, 23
Thrombocytopenia 14
Thyroglobulin 55, 163
serum 106
synthesis
abnormalities 174
defect of 175
Thyroid 87, 155
abscess 54
antibodies 19
autoantibodies 5, 160
biopsy of 162
cancer 28, 32, 38, 40, 44, 46, 47, 89, 108
follicular 29, 33, 40, 41
staging of 96
carcinoma 28, 29, 40t, 158t
destruction, causes of 12
disease 10, 88, 106
autoimmune 3, 20, 24, 61, 83, 148, 149, 151, 152, 164, 168
disorder 19, 25, 104, 124, 152
dysfunction 82, 126, 155, 168, 176
subclinical 83
dysgenesis 161
dyshormonogenesis 175
enlargement 158
function test 3, 6t, 20, 106, 108, 124, 126f
gland 12, 27, 33, 51, 72, 90, 95f, 100, 100f, 101f, 155, 158, 159, 164, 165
agenesis of 162f
fetal 82
normal 88f
palpation of 157
radioiodine ablation of 3
hormone 3, 4, 12, 22, 65, 67, 115, 116, 118, 119, 121, 124, 127, 147, 159, 186
cell membrane transport defects 121
levels 164
maternal 19
metabolism defect 120, 121
receptor 116, 116t, 117, 117f, 125, 186
replacement 112
resistance 115, 120, 174
response element 116, 117
transport 174, 176
illness 80, 124
infection, chronic 59
lesions, benign 90f
neoplasms 29
nodule 25, 27, 28, 31, 32t, 34, 57, 161
classification of 28t
peroxidase 51, 77, 83
antibodies 53, 55
receptor 183
antibodies 23
blocking antibody 177
removal of 148
scintigraphy 91
solitary nodule of 27
status, fetal 24
stimulating hormone 6, 10, 12, 1921, 24, 30, 32, 55, 74, 77, 78, 80, 82, 82f, 83, 97, 106, 115, 126, 147, 159, 160, 163, 174, 176, 182, 183
deficiency 174
measurement 129
receptor 19, 28, 174
secreting pituitary tumor 119
suppression 36
surgery 83, 111, 148
surgical problems of 109
swellings, management of 113
tissue 94, 98f
ultrasonography of 161
Thyroidectomy 16, 38
complications of 111
subtotal 109
total 105, 109
Thyroiditis 6, 12, 51, 52, 59, 72, 92, 95f, 151
acute infectious 58
atrophic 150
autoimmune 153, 156f, 158t
causes of 59
chronic
autoimmune 59
lymphocytic 53
infectious 51, 58
lymphocytic 51
nonsuppurative 51
painful 52
subacute 51, 52
painless 51, 59
postpartum 24, 54, 55, 60, 61
recurrence of 57
secondary 51
subacute 12, 51, 53, 57, 72
suppurative 51
trauma induced 59
Thyroperoxidase 149, 163
Thyrotoxicosis 11, 12, 17, 72
causes of 12
gestational 12
signs of 11
symptoms of 55
Thyrotropin releasing hormone 3, 19, 119, 163, 183
deficiency 148, 174
stimulation test 120, 160
Thyroxine 6, 19, 55, 69, 83, 159, 163, 182, 183, 185
binding globulin 20, 185
therapy 44, 84
TNM staging system 39
Topolanski's sign 137
Toxic multinodular goiter 12, 71, 72, 74
Toxoplasmosis 148
Trachea 87, 88
Tracheostomy 105
Triiodothyronine 19, 55, 83, 117, 124, 159, 163, 182, 183, 185
measurement 129
toxicosis 14
Tubercles of Zuckerkandl 105
Tuberculosis 148
Tumors 148
metastatic 28
suppressor genes 31
Turner syndrome 148, 151, 152
Tyrosine kinase inhibitors 126
V
Valproate 148
Van Wyk Grumbach syndrome 3, 157, 165f, 166
Vasculitis 14
Video-assisted thyroidectomy 110
Vigouroux sign 137
Vitamin
A deficiency 154
D supplement 112
Vitiligo 151
von Graefe's sign 137
W
Wilder's sign 137
Williams syndrome 148
Wolff-Chaikoff effect 154
Y
Yersinia enterocolitica 150
Z
Zinc deficiency 154
×
Chapter Notes

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HypothyroidismCHAPTER 1

Subhankar Chowdhury,
Partha P Chakraborty
3  
INTRODUCTION
Hypothyroidism, one of the common endocrine diseases across the globe, has multiple etiologies and varied clinical manifestations. It is broadly classified into overt hypothyroidism (OH) and subclinical hypothyroidism (SCH) based on the thyroid function tests (TFTs). Subclinical hypothyroidism, essentially a biochemical diagnosis, is strictly defined as elevated serum TSH with a normal serum free thyroxine (FT4) level in absence of ongoing or recent severe illness and abnormal functioning of the hypothalamic-pituitary-thyroid axis. It, probably, represents a compensated early state of primary thyroid disease where an elevated level of TSH is required to maintain serum thyroid hormones (TH) within the normal range. Though, it is called subclinical, many patients are symptomatic and significant clinical improvement is noticed after LT4 supplementation. Low FT4 combined with elevated TSH constitutes OH. Appropriate and successful treatment requires an accurate diagnosis which is also influenced by coexisting medical ailments.
 
ETIOLOGY
Hypothyroidism can be primary, when the disease involves the thyroid gland itself with abnormal TH synthesis and/or release; or secondary when the defect lies in the hypothalamus and/or pituitary with inappropriate thyrotropin-releasing hormone (TRH) or TSH signaling; or peripheral/consumptive which results from accelerated conversion of thyroxine (T4) to reverse T3 and T3 to diiodothyronine (T2) by excessive production of type 3 deiodinase usually from a tumor.
The commonest type of hypothyroidism is primary hypothyroidism; its usual causes are:
  • Autoimmune thyroiditis
  • Iodine deficiency
  • Surgical removal or radioiodine ablation of the thyroid gland
  • Medications.
Usual causes of secondary hypothyroidism are:
  • Sellar or suprasellar space-occupying lesions
  • Vascular insult to the pituitary
  • Inflammatory disorders of the hypothalamic-pituitary region.
 
PRESENTATION
The signs and symptoms of hypothyroidism have poor sensitivity and specificity and vary according to the degree of thyroid dysfunction. They are subjective and commonly include fatigue, somnolence, aches and pains, menstrual irregularities, cold intolerance, dry skin, constipation, vocal changes, and non-pitting edema.
Hypothyroidism, at times, may have monosymptomatic presentation like short stature in children, infertility, galactorrhea, polyserositis, and hypoosmolar euvolemic hyponatremia (secondary hypothyroidism).
Atypical presentations, like Van Wyk-Grumbach syndrome (combination of primary hypothyroidism, peripheral isosexual precocity, delayed bone age, feedback pituitary adenoma, and ovarian cysts), Kocher-Debre-Semelaigne syndrome (primary hypothyroidism with pseudomuscular hypertrophy in children), Hoffman's syndrome (primary hypothyroidism with pseudomuscular hypertrophy in adults), and delayed ejaculation, are not uncommonly encountered in clinical practice.1,24
 
HYPOTHYROIDISM AND COMORBIDITIES
A number of comorbidities are commonly associated with hypothyroidism of which dyslipidemia, cardiovascular morbidities, menstrual irregularities, infertility, depression, and diabetes are of significant clinical importance.
Thyroid hormones play an important role in different steps of cholesterol metabolism. It stimulates hepatic cholesterol synthesis by inducing 3-hydroxy-3-methylglutaryl-coenzyme A reductase. On the other hand, TH increases hepatic low-density lipoprotein receptor expression and decreases intestinal cholesterol absorption, and thereby, decreases serum TC and LDL-C concentration. Thyroid hormones can potentially decrease high-density lipoprotein cholesterol (HDL-C) concentration by stimulating cholesteryl ester transfer protein and hepatic lipase activity. However, effects on cholesterol clearance predominates over cholesterol synthesis; so, hypothyroidism, both overt and subclinical, are associated with increased TC, TG, very-low-density lipoprotein cholesterol, LDL-C, HDL-C, and lipoprotein(a) [Lp(a)] levels. There are suggestions of qualitative abnormalities of LDL-C particles in hypothyroidism as well. What is of interest is that even in patients with TSH level within the so-called reference range, lipid levels are more deranged as the TSH rises.
Patients of hypothyroidism have more cardiovascular risks due to underlying atherogenic lipid profile, abnormal hemodynamics, endothelial dysfunction, hypercoagulability, and abnormal nontraditional risk factors [elevated Lp(a), homocysteine, and C-reactive protein]. The trend is same for both OH and SCH; SCH with TSH more than 10 µIU/mL is considered as definite cardiovascular risk factor.
Hypothyroidism has long been associated with depression. Thyroid hormones has an established role in central nervous system (CNS) function and the prevalence of depression has been shown to be significantly high even in patients with SCH. Interestingly, patients with autoimmune hypothyroidism are more prone to mental disturbances compared to patients with hypothyroidism secondary to other etiologies as evidenced by a positive correlation of depression scores with elevated anti-thyroid peroxidase (anti TPO) antibody even in patients with normal TFT. Levothyroxine, though alone is ineffective in inducing complete remission, can enhance the effect of concurrent antidepressant medications. Conversely, patients with endogenous depression may manifest abnormal TFTs characterized by higher T4 and reverse T3 (rT3) with lower T3 and TSH. Absent nocturnal surge of TSH and blunted TSH response to TRH explain the suppressed value in those patients. Elevated circulatory glucocorticoids and resultant reduced activity of peripheral deiodinases alter the TH metabolism and the TFT resembles a state seen in sick euthyroid syndrome.
Diabetes and hypothyroidism are the two most frequently encountered endocrinological disorders and thyroid dysfunction is more common in diabetes, in particular type 1 diabetes. About 20% of children with type 1 diabetes may have antithyroid antibodies and 3–8% suffer from hypothyroidism. Thyroid hormones has its role in glucose homeostasis. It increases hepatic glucose output and stimulates intestinal glucose absorption, and thereby tends to increase blood glucose levels. It also stimulates peripheral utilization of glucose minimally. A particular polymorphism of type 2 deiodinase is associated with insulin resistance. The effect of hypothyroidism on blood glucose level, thus, varies but hypothyroidism is known to adversely affect the cardiovascular and nephropathy risks in patients with diabetes. Glycolsylated hemoglobin is a commonly used biochemical marker of long-term glycemic control; it could be spuriously high in patients with OH, making it unreliable as a glycemic marker.5
Menstrual irregularities and infertility are common in hypothyroidism and the prevalence of infertility is estimated to be around 10–15% due to abnormal function of the hypothalamic-pituitary-gonadal axis. Abnormal pulsatility of the gonadotropins, hyperprolactinemia, and structural abnormalities of the ovaries are the important underlying mechanisms. Levothyroxine administration normalizes these abnormalities, reverses menstrual abnormalities, and improves chances of spontaneous fertility.
 
Obesity and Hypothyroidism
About a quarter of overweight or obese patients have abnormal TFTs which mimic SCH. In individuals with normal body mass index (BMI), T4 produces equal amount of T3 and rT3. There is increased T3 production and decreased rT3 production in obesity. The high leptin level in obesity is perhaps the main underlying mechanism for elevated TSH. Leptin stimulates TRH, proopiomelanocortin/cocaine- and amphetamine-regulated transcript (POMC/CART) neurons and inhibits neuropeptide Y/agouti-related protein (NPY/AGRP) neurons and pituitary conversion of T4 to T3, and thus, elevates serum TSH. The other postulations for elevated TSH in obesity are injury of thyroid cells and sodium-iodide symporter due to chronic systemic inflammation, low levels of TH receptors in hypothalamus/pituitary with resultant TH resistance, derangement of hypothalamic-pituitary axis with secretion of immunoreactive but bioinactive TSH, TSH receptor mutation, and impaired mitochondrial function and coexisting thyroid disease.
These patients usually have a TSH value of less than 10 µIU/mL and usually do not require LT4 therapy. Thyroid-stimulating hormone and BMI have a positive correlation, and with reduction of weight, the TSH value falls within the reference range.
 
DIAGNOSIS
Diagnosis of hypothyroidism is confirmed by simple laboratory test. It is suggested that when the clinical suspicion of hypothyroidism is high, a combination of FT4 and TSH should be ordered; however, as a routine screen for thyroid dysfunction, serum TSH alone is sufficient. A combination of elevated TSH and low FT4 fulfils the diagnostic criteria of overt primary hypothyroidism. Subclinical hypothyroidism is said to be present when TSH is elevated but the FT4 is within the laboratory reference range. Low FT4 with low or inappropriately normal or mildly elevated TSH constitutes secondary (pituitary) or tertiary (hypothalamic) hypothyroidism and should ask for imaging of the hypothalamus and pituitary gland, and ensuring normal serum cortisol level before starting on levothyroxine therapy. Though at present, TSH is commonly measured using a third-generation chemiluminescence assay, older generation assays are sufficient enough to diagnose primary hypothyroidism. There is much controversy worldwide as far as normal reference range of TSH is concerned and a value between 0.3 and 5.0 mIU/L is commonly used as the normal reference range. A monograph by the National Academy of Clinical Biochemistry suggested that 95% of euthyroid volunteers had a serum TSH between 0.4 and 2.5 mIU/L on routine screening.3 Alterations in TFTs in different clinical situations mimicking primary or secondary hypothyroidism have been summarized in table 1.
Measuring thyroid autoantibodies (anti-TPO and anti-Tg) in hypothyroid patients not only helps to determine the underlying etiology of primary hypothyroidism, it can assess the risk of progression of SCH to OH. Though anti-TPO antibodies are commonly present in patients of chronic autoimmune thyroiditis, a subset of patients who are negative for anti-TPO antibody are tested positive for anti-Tg antibody.6
Table 1   Alteration in thyroid function tests in disorders of hypothalamo-pituitary-thyroid axis and non-thyroidal illnesses mimicking primary or secondary hypothyroidism
Free thyroxine
Free triiodothyronine
Thyroid-stimulating hormone
Possibilities
Low
Low/normal
High
Primary hypothyroidism
Normal
Normal
High
SCH/recovery from sick euthyroid syndrome/recovery from thyroiditis/heterophile antibody against TSH/macro-TSH/partial TSH resistance
Low
Low
Low/normal
Secondary hypothyroidism/sick euthyroid syndrome/drug effect like dopamine, steroid/patients of hyperthyroidism treated with antithyroid drugs or radioiodine in recent past
Low
Low
Mildly elevated (Usually <20 mIU/L)
Rule out secondary hypothyroidism/sick euthyroid syndrome
TSH, thyroid-stimulating hormone; SCH, subclinical hypothyroidism.
It has to be kept in mind that a minority of patients with histologically confirmed autoimmune hypothyroidism are negative for both antibodies. Thyroid scintigraphy and ultrasound do not provide any extra information in patients of hypothyroidism; the latter has a role to characterize any associated thyroid nodule.
It would be relevant to rule out hypothyroidism before embarking on statin treatment for dyslipidemia (especially, if any clinical suspicion). It is because if frankly hypothyroid, thyroxine treatment may be enough to correct or at least to improve the dyslipidemia, and the risk of statin-induced myopathy is significantly higher in untreated hypothyroidism.
 
TREATMENT
The initiating dose of LT4 replacement varies depending on etiology of hypothyroidism, age, body weight, and associated comorbidities. Neonates and infants with hypothyroidism should be initiated with a higher dose whereas children with long-standing severe hypothyroidism and elderly individuals should be put on a significantly lower dose of LT4 at the beginning. Caution should also be exercised when initiating and titrating LT4 therapy in individuals with known or suspected coronary artery disease to avoid development of new onset angina or worsening of preexisting ischemic heart disease. A typical starting dosage of 25–50 µg per day followed by a slow up-titration every 4–6 weeks is recommended in patients with underlying heart disease. Patients with complete absence of functional thyroid tissues typically require a replacement dose of 1.6–1.8 µg/kg/day and the calculation should be made using the ideal body weight.4,5
Thyroxine has a plasma half-life of about 6.7 days and provided that there is an intact hypothalamic-pituitary-thyroid axis, the dose adjustment is usually done every 8–12 weeks to allow achievement of a new steady state which requires 5–6 half-lives. However, in special circumstances like in pregnancy or in infants and children, dose titration every 4–6 weeks is recommended.
Many a time, patients on a stable dose of LT4 present with elevated TSH with normal FT4. A detailed history to ensure compliance is of importance before increasing the dose of LT4.7
In nonpregnant, non-elderly individuals, the dose of LT4 is adjusted to maintain the TSH level within the normal reference range for the performing laboratory. Though, there are some suggestions for aiming a TSH within the lower half of the reference range (0.4–2.0 mIU/L), this level of TSH has not been consistently associated with symptomatic improvement, better quality-of-life scores or clinical outcomes.6,7 However, a minority of patients prefer LT4 dosages that result in low-normal or even sub-normal serum TSH values.8,9
A recent reanalysis of the third National Health and Nutrition Examination Survey data, using age, sex, and ethnicity specific TSH reference limits, the 97.5 percentile for TSH values in whites between 70 and 79 years old was 5.6 mIU/L, and for those over age 80, it was 6.6 mIU/L. This age-dependent increase in serum TSH and the fact that longevity has been reported to be associated with high serum TSH should make the target TSH level in elderly individuals somewhat higher than the general population.
The current American Thyroid Association (ATA) guidelines for pregnancy and postpartum management of thyroid disease recommend that if trimester-specific TSH reference ranges are not available, the following target TSH ranges may be used: first trimester 0.1–2.5 mIU/L; second trimester 0.2–3.0 mIU/L; third trimester 0.3–3.0 mIU/L.
Many factors including food, medications, and disease processes are known to adversely affect the absorption of LT4. A number of commonly used drugs, like gastric antisecretory agents, antacids, calcium carbonate, and iron preparations, interfere with absorption of LT4. It is commonly advised that LT4 should be taken on an empty stomach, without other medications, supplements, or food for 1 hour to allow consistent absorption and to maintain serum TSH within a narrow target range.10 Levothyroxine may also be taken in a similar fashion 4 hours after the last meal or at bed time with identical clinical and biochemical outcomes. In fact, it has been seen that the nocturnal absorption of LT4 is better because of higher basal secretion of gastric acid and slower intestinal motility overnight combined with the fasting state.11
However, considering the food habits of the majority of Indian population, patients should be instructed to take LT4 tablets at empty stomach in the morning, and bed time administration of LT4 should not be entertained. Poor compliance and difficulty with adherence to a daily regimen is common in clinical practice. Study with randomized crossover design has shown that euthyroidism can be achieved with once-weekly dosing of LT4, at a dose slightly higher than 7 times the usual daily dose, without systemic side effects,12 and once-weekly LT4 administration may be tried only in exceptional cases to counteract noncompliance.
Different brands of LT4 are available in the market with different bioequivalence, and changes in LT4 brands are strongly discouraged as such a wide difference in bioequivalence may put patients at risk for incorrect dosing, if different brands are used interchangeably.
Animal studies have demonstrated that LT4 therapy in post-thyroidectomy subjects may not achieve euthyroidism in all tissues simultaneously and required the combination of LT4 and liothyronine.13,14 However, randomized clinical trials comparing LT4 monotherapy with LT4 plus liothyronine combination therapy were unable to support the superiority of the combination therapy in general.15 The positive outcome of combination therapy in some of the studies may be explained by favorable effects of combination therapy in a subset of patients harboring genetic polymorphism in relevant TH transporters or deiodinase enzymes resulting in low levels of T3 in the tissues.
In some of the studies, weight loss was somewhat higher in patients receiving combination therapy or desiccated thyroid compared to LT4 monotherapy16,17 and was thought 8to be the explanation for patients’ preference for combination therapy or desiccated thyroid which contains significant amount of T3. Though the determinants of patients’ preferences for combination therapy still remain unknown, it has been speculated that higher serum and tissue T3 levels might be associated with improvement in T3-dependent functions of the CNS, including regulation of body weight. Despite all these evidences, only the European Thyroid Association have offered specific guidance for the use of LT4 and liothyronine combination therapy, but still consider it experimental.18 On a futuristic note, based on a landmark study published in 2012 that has described the generation of functional thyroid tissue from embryonic stem cells, we can speculate that hypothyroid patients can also be treated with thyroid-generating stem cells in the coming years.19
 
CONCLUSION
Hypothyroidism may be primary, secondary, or peripheral. Biochemically, it can also be classified into overt or subclinical. Primary hypothyroidism is the most commonly encountered form of the disease while peripheral type is rare. Signs and symptoms of hypothyroidism are nonspecific and a high degree of clinical suspicion is required for diagnosis. Monosymptomatic presentations or atypical presentations are not uncommon. A number of comorbidities like dyslipidemia, cardiovascular disease, menstrual irregularities and infertility, depression, and diabetes are commonly associated with hypothyroidism, both overt and subclinical. One-fourth of overweight or obese patients have altered thyroid function, manifesting biochemically as SCH. Excess weight itself alters the hypothalamic-pituitary-thyroid axis by a number of mechanisms. There are significant controversies regarding management of SCH which requires individualization of therapy. The usual indications of treatment are pregnancy, infertility, cosmetically unaccepted goiter, TSH more than 10 µIU/mL, elevated antithyroid antibodies and dyslipidemia. Therapy with LT4 may also be tried in symptomatic patients of SCH if those are suggestive of hypothyroidism. Levothyroxine is the mainstay of therapy, which should preferably be taken at empty stomach in the morning. Changing of brands is discouraged. The target TSH in LT4-treated, nonpregnant patients depends on age, presence of comorbidities, and clinical scenarios. Trimester-specific TSH ranges provided by ATA may be used in pregnant patients.
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