By N. Gamal. Bluefield College. 2019.
Clinical and genomic characterization of distal duplications and deletions of chromosome 4q: study of two cases and review of the literature buy generic imipramine 25 mg on line. Cri du chat syndrome and congenital heart disease: a review of previously reported cases and presentation of an additional 21 cases from the Pediatric Cardiac Care Consortium imipramine 75 mg otc. Delineation of the critical deletion region for congenital heart defects buy imipramine 75 mg low price, on chromosome 8p23 buy imipramine 50mg cheap. Noncompaction of the left ventricular myocardium in a boy with a novel chromosome 8p23. Detailed characterization of, and clinical correlations in, 10 patients with distal deletions of chromosome 9p. The phenotypic spectrum of the 10p deletion syndrome versus the classical DiGeorge syndrome. Molecular and clinical characterization of patients with overlapping 10p deletions. Genotype-phenotype correlation in Smith-Magenis syndrome: evidence that multiple genes in 17p11. Gender, genotype, and phenotype differences in Smith-Magenis syndrome: a meta-analysis of 105 cases. Congenital anomalies and anthropometry of 42 individuals with deletions of chromosome 18q. Narrowing critical regions and determining penetrance for selected 18q-phenotypes. Cardiac anomalies in individuals with the 18q deletion syndrome; report of a child with Ebstein anomaly and review of the literature. Phenotypic delineation of Emanuel syndrome (supernumerary derivative 22 syndrome): Clinical features of 63 individuals. Spectrum of clinical features associated with interstitial chromosome 22q11 deletions: a European collaborative study. Char syndrome: a new family and review of the literature emphasising the presence of symphalangism and the variable phenotype. Cardiovascular malformations and other cardiovascular abnormalities in neurofibromatosis 1. Congenital heart diseases in children with Noonan syndrome: An expanded cardiac spectrum with high prevalence of atrioventricular canal. Cardiac malformations in patients with oral-facial-skeletal syndromes: clinical similarities with heterotaxia. Contemporary management of congenital malformations of the heart in infants with Ellis-van Creveld syndrome: a report of nine cases. Variable phenotype in Kaufman-McKusick syndrome: report of an inbred Muslim family and review of the literature. Phenotypic overlap of McKusick-Kaufman syndrome with bardet-biedl syndrome: A literature review. Association of Adams-Oliver syndrome with pulmonary arterio-venous malformation in the same family: a further support to the vascular hypothesis. Cardiovascular malformations in Fryns syndrome: is there a pathogenic role for neural crest cells? Assignment of the locus for hydrolethalus syndrome to a highly restricted region on 11q23–25. Ritscher-Schinzel cranio-cerebello-cardiac (3C) syndrome: report of four new cases and review. Congenital heart defects in patients with oculo-auriculo-vertebral spectrum (Goldenhar syndrome). Extracardiac anomalies in the heterotaxy syndromes with focus on anomalies of midline- associated structures. Genomic microarrays in mental retardation: from copy number variation to gene, from research to diagnosis. Consensus statement: chromosomal microarray is a first-tier clinical diagnostic test for individuals with developmental disabilities or congenital anomalies. Alagille syndrome is caused by mutations in human Jagged1, which encodes a ligand for Notch1. Rare copy number variations in congenital heart disease patients identify unique genes in left-right patterning. Contribution of global rare copy-number variants to the risk of sporadic congenital heart disease. Rare copy number variations in adults with tetralogy of Fallot implicate novel risk gene pathways. Increased frequency of de novo copy number variants in congenital heart disease by integrative analysis of single nucleotide polymorphism array and exome sequence data. Analysis of chromosomal structural variation in patients with congenital left-sided cardiac lesions. Recurrence risks in offspring of adults with major heart defects: results from first cohort of British collaborative study. Patterns of recurrence of congenital heart disease: an analysis of 6,640 consecutive pregnancies evaluated by detailed fetal echocardiography. Maternal transmission of congenital heart diseases: new recurrence risk figures and the questions of cytoplasmic inheritance and vulnerability to teratogens. A second-generation study of 427 probands with congenital heart defects and their 837 children. Linkage analysis of left ventricular outflow tract malformations (aortic valve stenosis, coarctation of the aorta, and hypoplastic left heart syndrome). Hypoplastic left heart syndrome links to chromosomes 10q and 6q and is genetically related to bicuspid aortic valve. Associations between chromosomal anomalies and congenital heart defects: a database search. Collaboratively charting the gene-to-phenotype network of human congenital heart defects. Congenital heart disease among spontaneous abortuses and stillborn fetuses: prevalence and associations. Array comparative genomic hybridization as a diagnostic tool for syndromic heart defects. Prevalence of Down syndrome among children and adolescents in 10 regions of the United States. Poor outcome in Down syndrome fetuses with cardiac anomalies or growth retardation. Is Down syndrome a risk factor for poor outcome after repair of congenital heart defects? The phenotype of persons having mosaicism for trisomy 21/Down syndrome reflects the percentage of trisomic cells present in different tissues. Lack of maternal folic acid supplementation is associated with heart defects in Down syndrome: a report from the National Down Syndrome Project. Contribution of copy-number variation to Down syndrome-associated atrioventricular septal defects. Adults with genetic syndromes and cardiovascular abnormalities: clinical history and management. Molecular mapping of the Edwards syndrome phenotype to two noncontiguous regions on chromosome 18. Sex chromosome abnormalities found among 34,910 newborn children: results from a 13-year incidence study in Arhus, Denmark. A comparison of echocardiography and magnetic resonance imaging in cardiovascular screening of adults with Turner syndrome. Coarctation of the aorta in Turner syndrome: a pathologic study of fetuses with nuchal cystic hygromas, hydrops fetalis, and female genitalia. Vasculopathy in Turner syndrome: arterial dilatation and intimal thickening without endothelial dysfunction. Risk of death in pregnancy achieved through oocyte donation in patients with Turner syndrome: a national survey. Materno-fetal cardiovascular complications in Turner syndrome after oocyte donation: insufficient prepregnancy screening and pregnancy follow-up are associated with poor outcome. Conotruncal anomaly face syndrome is associated with a deletion within chromosome 22q11.
What is the importance of measurement of calcium proﬁle in patients with McCune–Albright syndrome? McCune–Albright syndrome is due to post-zygotic somatic mutation associ- ated with constitutive action of Gsα subunit manifesting as ﬁbrous dysplasia (monostotic/polyostotic) generic 75mg imipramine, cafe-au-lait macules best order imipramine, and endocrinopathies buy discount imipramine 50mg on line. The common endocrine disorders include gonadotropin-independent precocious puberty order generic imipramine online, toxic nodular goiter, acrogigantism, and hypophosphatemic rickets/ osteomalacia. Hyperphosphatemia in a patient with McCune–Albright syn- drome should prompt evaluation for hypersomatotropism, while hypophospha- temia suggests the possibility of ﬁbrous dysplasia-associated hypophosphatemic rickets/osteomalacia, renal tubular defects (due to Gsα mutation), or rarely pri- mary hyperparathyroidism. Is universal screening for vitamin D deﬁciency recommended prior to vita- min D replacement? Ideally, screening for vitamin D deﬁciency should be done prior to vitamin D replacement. However, vitamin D deﬁciency is rampant and is an independent risk factor for fracture; therefore, in routine clinical practice, it should be sup- plemented without screening. Supplementation with oral vitamin D should be preferred over parenteral preparations, as the risk of vitamin D toxicity is neg- ligible with oral preparations. These include chronic kidney disease, hypoparathyroidism, pseudohypoparathyroid- ism, hypophosphatemic osteomalacia, and renal tubular acidosis. Further, patients with primary hyperparathyroidism who develop hungry bone syn- drome or hypoparathyroidism postoperatively also require treatment with cal- citriol. In addition, vitamin D-dependent rickets, type 1 (inactivating mutations of 1α-hydroxylase) and type 2 (vitamin D receptor defects), are indications for calcitriol therapy. However, the beneﬁt in prevention of osteoporotic fracture in this population is not proven. On evaluation, she was found to have a lytic lesion in the upper part of left tibia and underwent bone curettage with implantation of ﬁbular graft. Histopathology revealed giant cell tumor, for which localized radiation therapy was advised, and she received external beam radiotherapy (30 Gy in 10 fractions over 2 weeks). Subsequently, a bone scan was performed which showed multiple lytic lesions, and she was referred to endocrinology for opinion. Preoperatively, hypercalcemia was managed with saline diuresis and intravenous zoledronic acid (5 mg), after which serum calcium decreased to 9. She was managed with intravenous calcium infusion, calcitriol, and cholecalciferol with frequent monitoring of serum calcium and phosphate. The differential diagnosis for a lytic lesion at this site includes osteoclas- toma, osteitis ﬁbrosa cystica, ﬁbrous dysplasia, simple/aneurysmal bone cyst, and osteosarcoma. Imaging and histopathology may help in the diagnosis of these disorders, but not conclusively in all cases. In the index case, histopathol- ogy revealed a giant cell tumor, and she was managed accordingly. Bone scan was performed to exclude the possibility of malignant giant cell tumor, which revealed multiple lytic lesions. The closest differential diagnosis of osteoclas- toma (giant cell tumor) is osteitis ﬁbrosa cystica; however, the two disorders cannot be differentiated either by imaging or histopathology. Hypercalcemia and multiple lytic lesions favor the diagnosis of osteitis ﬁbrosa cystica due to primary 14 Hyperparathyroidism 311 hyperparathyroidism, while single lytic lesion with eucalcemia supports the diagnosis of osteoclastoma. Preoperative imag- ing consistently localized right inferior parathyroid adenoma in the index patient. Preoperatively severe hypercalcemia, if present (serum calcium >14 mg/ dl), should be managed in view of high risk of arrhythmia. Prior use of zole- dronic acid not only reduces serum calcium but also decreases the risk of post- operative hungry bone syndrome. Initially, she was managed with calcium infusion, calcitriol, and cholecalciferol, and after resolution of symptoms of hypocalce- mia, she was continued on oral calcium, calcitriol, and cholecalciferol. Therefore, periodic monitoring of calcium proﬁle is required, and therapy should be opti- mized accordingly. After parathyroidectomy, intervention should also be planned for nephrolithiasis to prevent deterioration in renal function. In view of her severe bone disease, she requires long-term regular follow-up for optimal bone health. In addition, poor oral intake because of hypercalcemia-induced anorexia and increased demand of calcium during puberty further worsens mineralization. Parathyroid gland predominantly comprises of chief cells in addition to oxyphil cells and clear cells. Calcitriol has antiproliferative effects on parathyroid cells, and estrogen deﬁciency results in decreased 1α-hydroxylase activity, thereby promoting parathyroid cell growth and proliferation. The exact pathogenesis of parathyroid tumorigenesis is still elusive, but it seems to be multifactorial in origin, except in familial syndromes where exact mutation can be detected. Parathyroid glands are endodermal in origin and develop from the pharyn- geal pouch. Superior parathyroid glands originate from the fourth pharyn- geal pouch, while inferior parathyroid glands from third pharyngeal pouch. Superior parathyroid glands descend along with thyroid gland to their eutopic location in the neck, whereas inferior parathyroid glands descend along with thymus and have to migrate a longer distance to reach their ﬁnal destination in the neck. Because inferior parathyroid glands have to travel a longer distance as compared to superior parathyroid glands, they are more likely to be ectopic in location. The most common site of ectopic parathyroid gland is intrathyroidal, followed by thymus, mediastinum, retro-esophageal groove, and pericardium. Why is there a differential effect of parathyroid hormone on cortical and cancellous bone? The skeletal tissue is composed of cortical and cancellous bone in varying proportions. Distal forearm predominantly have cortical bone, and spine 314 14 Hyperparathyroidism has cancellous bone, while the hip comprises of cortical and cancellous bone in equal proportions. What is the distribution of cortical and cancellous bone at different sites in an adult? The adult human skeleton is composed of 80% cortical bone and 20% cancel- lous bone. The ratio of cortical to cancellous bone is different in different bones, and even within the same bone, it is different at different sites. It com- monly occurs in the trabecular portion of long bones, pelvis, ribs, and mandible 14 Hyperparathyroidism 315 c Fig. The name brown tumor is actually a misnomer, as it is not a tumor but represents hemorrhage into a cystic lesion, and the brown color is a result of hemosiderin deposition. However, osteoclastoma (giant cell tumor) is a neoplasm of bone and manifest as a soli- tary lytic lesion in long bone. Brown tumor and osteoclastoma are indistin- guishable on imaging and histology; however, calcium proﬁle can differentiate between the two disorders. Treatment for brown tumor is parathyroidectomy, while osteoclastoma requires local excision. In addition, dental caries, enamel hypoplasia, loss of lamina dura, and early loss of teeth may occur in these patients. Brown tumor and bone cyst are skeletal manifestations of primary hyperpara- thyroidism. Brown tumors are located in the trabecular portion of the jaw, ribs, and long bones and may be single or multiple. These are composed of multi- nucleated giant cells, ﬁbroblasts, and red blood cells, whereas bone cysts tend to occur in the shaft of the metacarpals, ribs, and pelvis and contain a brownish serous ﬂuid. Brown tumors usually heal after curative parathyroidectomy, while bone cysts may additionally require bone grafting. A 22-year-old lady presented with a painful swelling over the left shin for the past 2 years. X - ray revealed an expansile lytic lesion and ﬁne-needle aspiration cytology showed giant cell tumor. Therefore, a calcium proﬁle must be done in all patients to establish the etiological diagnosis. The differences between common lytic bony lesions are sum- marized in the table given below. Renal tubular dysfunction manifests as polyuria because of the decreased concen- trating ability of tubules. However, a higher prevalence (60–80%) has been reported from developing countries, which possibly may be related to delayed presentation and severe disease.
D: Intraoperative photo demonstrating the mobilized anterior and inferior (posterior) leaflets buy imipramine mastercard. Natural fenestrations are shown at the junction of the anterior and inferior leaflets (arrows) buy 75 mg imipramine with mastercard. E: After the anterior order imipramine master card, inferior order imipramine canada, and septal leaflets have been completely mobilized, the cut edge of the inferior leaflet is rotated clockwise to meet the proximal edge that has been prepared of the septal leaflet. The two are approximated with interrupted 6-0 monofilament sutures completing the cone reconstruction. The inferior annulus is usually plicated with two to four simple or figure-of-eight 5- 0 monofilament sutures. A: Preoperative examination, demonstrating no remnants of tricuspid septal leaflet tissue within the anatomic right ventricular inlet. The anterior leaflet is severely tethered by multiple attachments to the right ventricular free wall. Even though this is a frame from peak systole, the leaflet tissue remains parallel to and very near the right ventricular free wall. The patient underwent a cone reconstruction of her tricuspid valve a short time later. By attaching the “annulus” of the reconstructed “cone” to a plane near the anatomic atrioventricular junction (arrows), the surgeon has completely eliminated the large atrialized portion of the right ventricle, as well as the regurgitation. Despite the severe deformity of the native valve, the color flow image in the postreconstruction echocardiogram (D) showed only mild tricuspid regurgitation. But if valve repair is not feasible, then porcine bioprosthetic valve replacement is a good alternative, particularly in older adults. Bioprostheses are preferred to mechanical valves due to the relatively good durability and the lack of need for anticoagulation (118). However, bioprosthetic valves are less durable and are more prone to structural valve deterioration in infants and young children. The decreased durability observed in young children is related to increased calcification and also to rapid somatic growth that results in patient prosthesis mismatch. In children and adults with Ebstein anomaly, a bioprosthesis placed in the tricuspid position has greater durability than valves placed in non-Ebstein patients. Mechanical valve disc immobility may be a nidus for thrombosis despite adequate anticoagulation. Right reduction atrioplasty routinely is performed at the time of atriotomy closure and suture lines near the crista terminalis are avoided to decrease atrial tachyarrhythmias. Surgical Treatment of Arrhythmias Atrial fibrillation, atrial flutter, and reentrant supraventricular tachycardia are common arrhythmias in adults with Ebstein anomaly. Locations for surgical lesions in both atria have been previously described (124,125). It extends from the posterolateral tricuspid valve annulus to the coronary sinus and to the inferior vena cava. In cases of accessory pathway conduction, preoperative mapping and ablation are performed in the electrophysiology laboratory. In the current era, intraoperative mapping and ablation for accessory pathways rarely are performed. Cardiac Transplantation Cardiac transplantation rarely is required for Ebstein anomaly. Outcomes Short Term Despite advances in medical and surgical techniques, management of small infants with Ebstein anomaly and cyanosis remains challenging. The severity of the valve malformation and dysfunction of both ventricles will affect outcome. In the current era, early results in children are more favorable and operative mortality is ∼3% in experienced centers. Patients with Ebstein anomaly experience a high incidence of atrial tachyarrhythmias. Atrial fibrillation and atrial flutter are the most common arrhythmias in older patients. Except for very ill newborns, adult survival with a good quality of life is expected for patients with Ebstein anomaly (105). The Mayo Clinic surgical experience with Ebstein anomaly now exceeds 1,000 patients. In a small subset of these patients, formal exercise testing was conducted (127,128). There was improvement in exercise tolerance after operation, but this may be a result of the elimination of the atrial right-to-left shunt rather than improvement in ventricular function. Freedom from rehospitalization for cardiac causes was 68% and 35% at 10 and 20 years, respectively (105,126). Novel techniques have emerged for long-term management of patients with previous tricuspid valve repair or replacement. Patients with previous tricuspid valve replacement with bioprosthesis dysfunction can be approached with percutaneous valve-in-valve techniques that may obviate or delay some reoperations (130,131) (Video 38. Pregnancy Results Pregnancy in women with Ebstein anomaly is usually well tolerated. In a large series from Mayo Clinic, 89% of women with Ebstein anomaly had vaginal deliveries (132). Most importantly, women with Ebstein anomaly should undergo thorough medical evaluation when considering pregnancy (133). Pregnancy with Ebstein anomaly has been associated with increased risk for prematurity, fetal loss, and congenital heart disease in the offspring (132,133). A multidisciplinary team of obstetricians, congenital cardiac specialists, and cardiac anesthesiologists is required to manage these patients. In the Mayo Clinic experience (105), there were a total of 275 pregnancies among 82 women. The incidence of congenital heart disease in offspring of a parent with Ebstein anomaly was 3. Tricuspid Valve Regurgitation: Congential and Acquired Tricuspid valve regurgitation, not related to Ebstein anomaly, is relatively uncommon and includes a heterogeneous group of lesions with unique management strategies. There are wide anatomical variations that lead to tricuspid regurgitation in patients without Ebstein anomaly. Congenital etiologies include absence of chordae (134) tricuspid valve dysplasia (leaflet thickening with chordal shortening), or unguarded tricuspid valve orifice (135). Patients with pulmonary valve atresia and intact ventricular septum (136) can have tricuspid valve morphology similar to Ebstein anomaly or tricuspid valve dysplasia. Age at presentation depends on the etiology and severity of tricuspid regurgitation (139). In general, there are two categories of tricuspid valve dysplasia: with and without leaflet displacement. Patients with leaflet displacement fulfill a diagnostic criterion for Ebstein anomaly. In “tricuspid valve dysplasia” the leaflets are abnormal but not displaced (140) (Fig. Echocardiography confirms the diagnosis, determines the degree of tricuspid regurgitation, allows accurate evaluation of the tricuspid leaflets and subvalvar apparatus (displacement, tethering, dysplasia, etc. Tricuspid valve repair, rather than replacement, is the preferred treatment strategy when feasible, particularly in children. The tricuspid leaflets are thickened and chordae are shorter than normal (red arrow), restricting the motion of all three leaflets. Despite the restricted mobility, these leaflets are not adherent to the underlying myocardium and the apical displacement index, representing the offset of the mitral and tricuspid 2 valve septal insertions (white arrow), with only 6 mm/m. In 1905, William Osler, described the term “parchment heart,” but Henry Uhl reported the first case in 1952 (141). The septomarginal trabeculations and the papillary muscles of the tricuspid valve are normally muscularized (143). The absence of myocardium may be the result of primary nondevelopment of myocytes or a form of selective apoptosis. Congestive heart failure with associated peripheral edema, pleural effusions, and/or cyanosis are frequent signs and symptoms of Uhl anomaly.
In young women buy 75 mg imipramine mastercard, hypothyroidism is asso- ciated with menstrual irregularities in about 23–30% of patients and these include menorrhagia buy imipramine visa, oligomenorrhea buy online imipramine, and secondary amenorrhea effective imipramine 75 mg. Premature ovarian failure may also occur in patients with primary hypothyroidism as a manifestation of polyglandular endocrine syndrome. Reproductive system abnormalities in a woman with hypothyroidism include oligo- or amenorrhea, menorrhagia, and infertility. Hyperprolactinemia is observed in 20–30% of patients with primary hypothy- roidism. If hyperprolactinemia does not resolve despite optimal dose and duration of levothyroxine therapy, a possibility of concurrent prolactinoma should be considered. Hyperprolactinemia can also be associated with second- ary hypothyroidism in patients with macroprolactinoma with thyrotrope com- pression, lymphocytic infundibulitis, and stalk compression by nonfunctioning pituitary adenoma with thyrotrope dysfunction. When to suspect thyro-lactotrope hyperplasia in a patient with primary hypothyroidism? Patients with long-standing, severe untreated primary hypothyroidism are pre- disposed for the development of thyro-lactotrope hyperplasia. The presence of headache, visual ﬁeld defects, amenorrhea–galactorrhea, and multiple pituitary hormone deﬁciencies in a patient with primary hypothyroidism should raise a suspicion of thyro-lactotrope hyperplasia. Emergencies in a patient with primary hypothyroidism are usually an outcome of undiagnosed or untreated long-standing disease. They may present with altered sensorium due to hyponatremia, hypoglycemia, myxedema coma, or Hashimoto’s encephalopathy. The cardiac emergencies in patients with hypo- thyroidism are syncope due to sinus bradycardia, cardiac tamponade due to massive pericardial effusion, and congestive cardiac failure. They may also 198 9 Hypothyroidism present as acute abdomen due to ovarian torsion, megacolon, paralytic ileus, and acute cholecystitis. Rarely, they may present as severe myoedema masquer- ading as tetanus, or rhabdomyolysis precipitated by use of statins or vigorous activity. In addition, hypokalemic periodic paralysis may rarely be a presenting manifestation. Severity of symptoms of hypothyroidism depends upon serum free T4 levels and the rapidity of develop- ment of hypothyroidism. In addition to those who have classical symptoms and signs of hypothy- roidism, history of prior ablative therapy, or sellar-suprasellar mass evaluation for hypothyroidism should be performed in the disorders/conditions listed in the table given below. What is the rationale of screening for hypothyroidism in patients with depression? The prevalence of depressive symptoms in patients with subclinical hypothy- roidism has been reported to vary from 13 to 63%. On the contrary, 8–20% of patients with depressive disorders have subclinical hypothyroidism and treat- ment with levothyroxine in these patients may augment the response to antide- pressants. In addition, there are studies demonstrating the usefulness of liothyronine as well as levothyroxine in patients with refractory mood disorders, 200 9 Hypothyroidism even with normal thyroid function; however, the data are inconsistent. Therefore, every patient with depression should be evaluated for hypothyroidism and par- ticularly those who are resistant to anti-depressant therapy. However, the use of thyroid hormone supplementation is not recommended in euthyroid patients with depression. The measurement of antithyroid peroxidase antibod- ies helps in establishing the etiological diagnosis of autoimmune thyroid disease. Twenty percent of the circulating serum T3 is secreted directly from thyroid gland, while the rest is derived by peripheral T to T 4 3 neogenesis, which is regu- lated by type 2 and type 1 monodeiodinases. However, type 2 monodeiodinase contributes more (60%) to plasma T3 than type 1 monodeiodinase (20%). In addition, propranolol and glucocorti- coids inhibit type 2 monodeiodinase, while propylthiouracil and amiodarone inhibit type 1 monodeiodinase. Amiodarone consists of 37% iodine by weight; thus a 200 mg tablet of amioda- rone contains 75 mg iodine, which far exceeds the recommended daily allowance of iodine (150 μg). Administration of amiodarone is associated with thyroid dys- function in 20% of patients. However, patients residing in iodine-deﬁ- cient area are at increased risk for developing amiodarone-induced thyrotoxicosis (10%). Therefore, thyroid function should be performed prior to initiating amio- darone and monitored periodically. Despite normal thyroid function in majority of patients on amiodarone therapy, there is a “cardiac myxedema. Amiodarone-induced subclinical/overt hypothyroidism should be treated with levothyroxine without discontinuation of amiodarone. Levothyroxine replace- ment does not increase the risk of cardiac arrhythmias in this scenario; how- ever, thyroid function should be closely monitored to avoid iatrogenic thyrotoxicosis. Lithium therapy is associated with development of goiter (4–60%), subclinical hypothyroidism (34%), and overt hypothyroidism (15%). Females and those with underlying autoimmune thyroid disease are predisposed for lithium- induced thyroid dysfunction. Lithium-induced autoimmune thyroid dysfunction and/or worsening of preex- isting autoimmune thyroid disease results in subclinical/overt hypothyroidism. Thyroid function test should be done prior to initiation of lithium therapy and 6–12 monthly thereafter, as lithium-induced thyroid dysfunction can occur any- time during therapy. Lithium-induced hypothyroidism should be managed with levothyroxine without discontinuation of lithium. Circulating T4 predominantly binds with thyroxine-binding globulin (70%) and a small fraction of it binds to albumin (20%) and prealbumin (10%), also known as transthyretin. These binding proteins act as circulating reser- voir for thyroid hormones and maintain constant free thyroid hormone level. How to differentiate between subclinical hypothyroidism and recovery phase of subacute thyroiditis? Thyroid hormone proﬁle may be similar in patients with subclinical hypothy- roidism and recovery phase of subacute thyroiditis. However, recent history of rapid weight loss, neck pain, and palpitations with or without tender goiter sup- ports the diagnosis of subacute thyroiditis, while patients with subclinical hypothyroidism may be asymptomatic or may present with nonspeciﬁc symp- toms. This entity should only be considered after excluding overzealous treatment either with antithyroid drugs or levothyroxine, non-compliance to treatment, and factitious use of levothyroxine. The presence of goiter is a prerequisite for the development of “ﬂuctuating thyroid function. The treatment of choice in patients with hypothyroidism is levothyroxine and is initiated at a dose of 1. However, because of practical constraints in estimating lean body mass, the dose of levo- thyroxine is calculated based on ideal body weight. In patients with long- standing hypothyroidism, in those with cardiovascular disease, and in elderly individuals, it seems prudent to initiate levothyroxine therapy at a lower dose with gradual increment thereafter. Levothyroxine is preferred over liothyronine as levothyroxine is a prohormone and its supplementation ensures sustained and stable T3 neogenesis. In addition, levothyroxine has a longer half-life (7 days) and is associated with lesser ﬂuctuations in serum T levels. Long-standing hypothyroidism is a hypometabolic state and results in upregu- lation of thyroid hormone receptors; hence, administration of initial high doses of levothyroxine may cause palpitation, tremor, tachycardia, and angina. Therefore, levothyroxine therapy should be built up slowly in patients with long-standing hypothyroidism, in elderly subjects and in those with cardiovascular disease. Similarly, children and adolescents with long- standing hypothyroidism should also be replaced with levothyroxine slowly, as patients in this age group is susceptible for pseudotumor cerebri (due to ﬂuid and electrolyte imbalance), hyperkinetic disorder, and poor scholastic perfor- mance with initial full-dose replacement. However, neonates, and pregnant women should be started with full doses of levothyroxine to normalize serum T level faster. Patients with secondary hypothyroidism, long-standing isolated primary hypo- thyroidism, and primary hypothyroidism with polyglandular endocrine failure are predisposed for the development of adrenal crisis on initiation of levothy- roxine therapy. Therefore, in these patients a 0800h sample for serum cortisol should be obtained and glucocorticoid replacement should precede levothyrox- ine supplementation. A 0800h serum cortisol <100 nmol/L conﬁrms the diag- nosis of adrenal insufﬁciency, while a value >550 nmol/L excludes it. In patients with severe hypothyroidism who are critically ill, a random cortisol should be obtained and empiric intravenous hydrocortisone therapy should be initiated followed by administration of levothyroxine. A random serum cortisol <400 nmol/L suggest adrenal insufﬁciency, whereas a value >900 nmol/L suggest adequate adrenal reserve. Levothyroxine is commonly administered early morning in fasting state as its absorption is interfered by food intake.