PATOLOGI ANATOMISISTEM ENDOKRIN

HipofisisKelenjar hipofisis merupakan kelenjar berbentuk seperti kacang

(bean shape) berukuran kecil, terletak didasar otak tepatnya di sella turcica. Hipofisis berhubungan erat dengan hipotalamus dihubungkan dengan “stalk” yang terdiri dari akson yangmemanjang dari hipotalamus dan pleksus venosus. Hipotalamus berperan penting dalam pengaturan sebagian besar kelenjar endokrin. Hipofisis terdiridari dua komponen yang berbeda dalam morfologi dan fungsinya. Lobus anterior (adenohypophysis) dan lobus posterior (neurohypophysis). Penyakit pada hipofisis mengacu pada kelainan yang ada dilobus anterior atau posterior.

Adenohypophysis secara embriologi terdiri dari epitel yang berasal dari perkembangan kavum oral . Secara histologi dengan pengecatan Hematoksilin dan Eosin sel-sel yang terwarnai menunjukkan gambaran sitoplasma yang berbeda, ada sel dengan sitoplasma basophil, eosinophil dan sedikit menyerap warna (chromophobic). Dengan mikroskop elektron dan imunohistokimia menunjukkan adanya hormon tropik yang bervariasi di dalam sitoplasmanya. Lepasnya hormon tropik dibawah kendali faktor-faktor yang dilepaskan hipotalamus. Faktor-faktor hipotalamus menstimulasi dan mendorong lepasnya hormon dan lainnya( spt somatostatin dan dopamin) dan akan dihambat oleh efek hormon tersebut.

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Gejala-gejala penyakit hipofisis dapat dibagi menjadi:1. Hyperpituitarism: peningkatan sekresi hormon tropik, sebagian

besar disebabkan adenoma fungsional pada lobus anterior. Penyebab lain yang jarang ditemukan disebabkan hiperplasia dan karsinoma hipofisis anterior, sekresi hormon oleh tumor nonhipofisis dan adanya kelainan pada hipotalamus.

2. Hypopituitarism: disebabkan defisiensi hormon tropik dan hasil dari berbagai proses destruksi termasuk didalamnya jejas iskemik, pembedahan atau radiasi dan reaksi radang. Selain itu disebabkan oleh adenoma hipofisis nonfungsional memasuki jaringan parenkim hipofisis anterior normal.

3. Efek masa lokal: disebabkan oleh berbagai tumor yang mendesak, menimbulkan desrtuksi disekitar sella turcica.

Hyperpituitarism dan Adenoma hipofisisSebagian besar kasus, peningkatan produksi hormon hipofisis

yang disebabkan oleh adanya adenoma yang berasal dari lobus anterior. Adenoma hipofisis fungsional terdiri dari tipe sel tunggal dan memproduksi hormon tunggal. Ada beberapa kasus adenoma hipofisis terdiri dari tipe sel tunggal yang mensekresi beberapa hormon ( spt hormon pertumbuhan dan prolaktin) dan adenoma yang terdiri dari populasi beberapa tipe sel . Klasifikasi tumor hipofisis berdasarkan siri morfologi yang dominan ( spt asidophil, basophi atau cromophob)

Pada umumnya adenoma hipofisis berukuran < 10mm disebut sebagai microadenoam dan yang lebih dari 10mm disebut sebagai makroadenoma. Mikroadenoma tidak menunjukkan adanya gejala kecuali jika mensekresikan hormon. Makroadenoma menimbulkan eefek lokal dengan manifestasi sistemik. Gambaran klinis makroadenoma menimbulkan efek penekanan pada kiasma optika yang berakibat nyeri kepala hebat, hemianopsia bitemporal, hilangnya penglihatan. Jika menginvasi sinus kavernosus akan menimbulkan gangguan okulomotorius. Adenoma yang besar dapat menimbulkan:

1. Invasi ke hipotalamus

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2. Mengganggu input hipotalamus ke hipofisis3. Hilangnya pengaturan suhu, hiperpagia dan sindrom hormonal.

Prolaktinoma (lactotroph adenoma)Umumnya adenoma hipofisis dengan hiperfungsional. Didalam sitoplasma sel tumor ditemukan prolaktin danmenimbulkan prolaktinemia yang berakibat amenorrhea, galactorrhea, hilangnya libido dan infertilitas. Pada laki-laki menimbulkan hilanynya libido dan impotensi. Pada wanita usia reproduktif dapat diketahui lebih awal namun pada wanita premenopaus dan pria manifestasi hormonal tidak tempak jelas, biasanya akan tampak setelah tumor berukuran besar. Hiperprolaktinemia dapat disebabkan keadaan lain: adenoma hipofisis yang mensekresi prolaktin termasuk kondisi kehamilan, terapi estrogen dosis tinggi, gagalginjal, hipotiroidisme, lesi hipotalmus dan obat-obat penghambat dopamin ( spt reserpin). Lactotroph adenoma mikroadenoma di terapi dengan dopamin agonis (bromocriptine) untuk menghambat sekresi prolaktin, makroadenoma dilakukan pembedahan.

Somatotroph Adenomas Secrete Growth Hormone (GH)Neoplasia yang memproduksi Growth Hormon (GH) termasuk

didalamnya yang mensekresi hormone campuran GH dan lainnya ( spt prolaktin) . Manifestasi klinis peningkatan GH tidak terlalu ketara namun dengan berjalannya waktu tumor yang bertambah besar baru akan menimbulkan manifestasi klinis. Tumor yang diderita anak-anak atau sebelum menutupnya epifisis tulang akan menimbulkan gigantime ( tumbuh besar seperti raksasa), jika terjadi pada orang yang sudah menutup epifisisnya akan timbul akromegaly. Selain itu peningkatan GH dapat menimbulkan beberapa gangguan lainnya yaitu toleransi glukosa yang abnormal, dan diabetes mellitus, kelemahan otot general, hipertensi, osteoporosis, arthritis dan gagal jantung kongestif. Beberapa kasus tumor campuran dengan hiperprolaktinemia manifestasi sama dengan hiperprolaktinemai.

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Manifestasi akromegali

Corticotroph Adenomas Produce ACTH (Adrenocorticotropic Hormone)

Corticotroph adenomas berukuran kecil saat didiagnosis microadenomas .Tumorsebagai besar tercat basophilic (densely granulated)dan kadang-kadang chromophobic (sparsely granulated). Keduanya menunjukkan positif pada pengecatan periodic acid-Schiff (PAS) karena mengandung carbohydrate didalam pre-opiomelanocorticotropin (POMC),yang merupakan molekul prekursor ACTH ;tumor ini menunjukkan immunoreactivity terhadap POMC dan turunannya termasuk ACTH and β-endorphin.

Peningkatan prodiksi ACTH oleh corticotroph adenoma mengakibatkan hipersekresi cortisol kelenjar adrenal dan menimbulkan hypercortisolism (also known as Cushing syndrome). Akan dibahas

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detilpada kelenjar adrenal.Proses terjadinya peningkatan produksi ACTH oleh tumor hipofisis disebut sebagai Cushing disease. Pengangkatan adrenal dilakukan pada penderita Cushing syndrome dan dapat menimbulkan keadaan Nelson syndrome, terjadi akibat hilangnya efek inhibisi (penghambatan) kortikosteroid kelenjar adrenal pada penderita corticotroph microadenoma. Tidak adanya adrenal mengakibatkan tidak timbulnya hiperkortikolisme pada penderita adenoma hipofisis, namun sebaliknya terjadi hiperpigmentasi karena efek stimulasi produk lainya OK ACTH merupakan precursor dalam melanosit.

GROWTH HORMONE (SOMATOTROPH CELL) ADENOMAS

Tumor yang mensekresikan GH merupakan tumor yang terbesar kedua pada adenoma hipofisis yang fungsional.Seperti telah diketahui , 40% somatotroph cell adenomas mengekspresikan mutant GTPase-deficient merupakan subunit G-protein, Gs. Secara histology adenoma yangmengandung GH diklasifikasikan menjadi 2 tipe: Bergranula kasar/padat dan bergranula halus. Adenoma bergranula padat terdiridari sel –sel monomorfik dan asidofilik pada pemeriksaan rutin. Pada pemeriksaan imunohistokimia bereaksi kuat thd GH pada sitoplasma, sitokeratin pada perinuklear. Sebaliknya pada adenoma bergranula halus terdiri dariselyang bervariasi, terdiri darisel kromofob dengan inti dan sitoplasma pleomorfisme (polimorfi),mengandung Ghlemahdan fokal (setempat). Adenoma mammosomatotroph reakstif terhadap HG dan prolaktin secara morfologi mirip dengan adenoma bergranula halus pada adenoma somatotropik yang asli.

Hipersekresi persisten GH menstimulasi heparuntukmensekresikan faktorpertumpuhan seperti insulin (insulin-like growth factor I (IGF-I or somatomedin C), yang menimbulkan berbagai manifestasi klinik .Apabila adenoma terjadi pada masa anak-anak dimana epifisis belum menutup akan terjadi gigantism. Jika peningkatan GH terjadi setelah menutupnya epifisis ( pada dewasa)akan timbul acromegaly, pada konsidi ini pertumbuhan terbatas pada kulit dan jaringan lunak,alat visera, dan tulang pada wajah, tangan dan kaki, densitas tulang meningkat (hyperostosis) pada tulang belakang dan pinggul.Penungkatan GH jug berkaitan dengan timbulnya kelainan termasuk disfungsi gonad, DM, kelemahan otot secara umum, hipertensi, artritis, gagal jantung kongestif dan peningkatan resiko kanker gastrintestinal.

Diagnosis peningkatan GH dengan melihat kadar GH dan IGGF-1 dalamserum.

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HypopituitarismHypopituitarism merupakan defisiensi sekresi satu atau lebih hormon hipofisis. Panhypopituitarism drfisiensi pada semua hormon hipofisis.PITUITARY TUMORS: Sebagain hypopituitarism pada dewasa disebabkan pituitary tumors, biasanya adenomas. Tumor tersebut dapat fungsional namun gejal hypopituitarism sering menyertai akibat penekanan oleh masa tumor ke jaringan sekitarnya.SHEEHAN SYNDROME: keadaan yang jarang ditemukan, panhypopituitarism disebabkan ischemic necrosis pada kelenjar hipofisis sering disebabkan hipotensi berat pada perdarahan pospartum. Akibatnya terjadi Agalactia, amenorrhea, hypothyroidism, and adrenocortical insufficiency.PITUITARY APOPLEXY: Perdarahan dan infark dapat terjadi pada hipofisis normal,menimbulkan hipopituitarisme.IATROGENIC HYPOPITUITARISM: Therapeutic radiation or neurosurgical procedures frequently cause neuroendocrine abnormalities, including hypopituitarism.TRAUMA: Traumatic brain injury is associated with significant risk to the pituitary gland, with the potential development of diabetes, hypopituitarism, and other endocrinopathies.GENETIC ABNORMALITIES OF PITUITARY DEVELOPMENT: Congenital growth hormone deficiency constitutes a unique group of disorders. It may occur in isolation, as so-called isolated growth hormone deficiency, which is related to mutations in the growth hormone (GH) gene or the growth hormone-releasing hormone receptor. The latter is the cause of Laron dwarfism, the condition that is responsible for the dwarfism of African pygmies. Because GH exerts its effects by promoting IGF-I secretion, IGF-I is effective replacement therapy for Laron syndrome, mimicking most of the effects ascribed to GH itself. In addition, a number of mutations affecting transcription factors important in pituitary development have been identified. These mutations generally cause combined deficiencies of pituitary hormones.EMPTY SELLA SYNDROME: This is primarily a radiologic term that describes an enlarged sella containing a thin, flattened pituitary at the base. It is secondary to a congenitally defective or absent diaphragma sella, which permits transmission of cerebrospinal fluid pressure into the sella. Endocrine disturbances are generally minor but may include hyperprolactinemia, oligomenorrhea or amenorrhea, frank hypopituitarism, acromegaly, diabetes insipidus, and Cushing syndrome.

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The clinical manifestations of anterior pituitary hypofunction depend on the specific hormone(s) that are lacking. Children can develop growth failure (pituitary dwarfism) due to growth hormone deficiency. Gonadotropin (GnRH) deficiency leads to amenorrhea and infertility in women and decreased libido, impotence, and loss of pubic and axillary hair in men. TSH and ACTH deficiencies result in symptoms of hypothyroidism and hypoadrenalism, respectively, and are discussed later in the chapter. Prolactin deficiency results in failure of postpartum lactation. The anterior pituitary is also a rich source of melanocyte-stimulating hormone (MSH), synthesized from the same precursor molecule that produces ACTH; therefore, one of the manifestations of hypopituitarism includes pallor due to a loss of stimulatory effects of MSH on melanocytes.

Posterior Pituitary Syndromes

The clinically relevant posterior pituitary syndromes involve ADH and include diabetes insipidus and secretion of inappropriately high levels of ADH.

  

•    Diabetes insipidus. ADH deficiency causes diabetes insipidus, a condition characterized by excessive urination (polyuria) owing to an inability of the kidney to resorb water properly from the urine. It can result from a variety of processes, including head trauma, tumors, and inflammatory disorders of the hypothalamus and pituitary as well as surgical procedures involving these organs. The condition can also arise spontaneously, in the absence of an underlying disorder. Diabetes insipidus from ADH deficiency is designated as central to differentiate it from nephrogenic diabetes insipidus, which is a result of renal tubular unresponsiveness to circulating ADH. The clinical manifestations of the two diseases are similar and include the excretion of large volumes of dilute urine with an inappropriately low specific gravity. Serum sodium and osmolality are increased owing to excessive renal loss of free water, resulting in thirst and polydipsia. Patients who can drink water can generally compensate for urinary losses; patients who are obtunded, bedridden, or otherwise limited in their ability to obtain water may develop life-threatening dehydration.

   •    Syndrome of inappropriate ADH (SIADH) secretion. ADH excess causes resorption of excessive amounts of free water, resulting in hyponatremia. The most frequent causes of SIADH include the secretion of ectopic ADH by malignant neoplasms (particularly small cell carcinomas of the lung), non-neoplastic diseases of the lung, and local injury to the hypothalamus or

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posterior pituitary (or both). The clinical manifestations of SIADH are dominated by hyponatremia, cerebral edema, and resultant neurologic dysfunction. Although total body water is increased, blood volume remains normal, and peripheral edema does not develop.

Hypothalamic Suprasellar Tumors

Neoplasms in this location may induce hypofunction or hyperfunction of the anterior pituitary, diabetes insipidus, or combinations of these manifestations. The most commonly implicated lesions are gliomas (sometimes arising in the chiasm; and craniopharyngiomas. The craniopharyngioma is thought to be derived from vestigial remnants of Rathke pouch. These slow-growing tumors account for 1% to 5% of intracranial tumors; a small minority of these lesions arise within the sella, but most are suprasellar, with or without an intrasellar extension. A bimodal age distribution is observed, with one peak in childhood (5 to 15 years) and a second peak in adults in the sixth decade or older. Children usually come to clinical attention because of endocrine deficiencies such as growth retardation, whereas adults usually present with visual disturbances. Pituitary hormonal deficiencies, including diabetes insipidus, are common.

KELENJAR TIROIDNORMALThyroid follicular epithelial cells convert thyroglobulin into thyroxine (T4) and lesser amounts of triiodothyronine (T3). T4 and T3 are released into the systemic circulation, where most of these peptides are reversibly bound to circulating plasma proteins, such as thyroxine-binding globulin (TBG) and transthyretin, for transport to peripheral tissues. The binding proteins serve to maintain the serum unbound ("free") T3 and T4 concentrations within narrow limits yet ensure that the hormones are readily available to the tissues. In the periphery, the majority of free T4 is deiodinated to T3; the latter binds to thyroid hormone nuclear receptors in target cells with tenfold greater affinity than does T4 and has proportionately greater activity. The interaction of thyroid hormone with its nuclear thyroid hormone receptor (TR) results in the formation of a multi-protein hormone-receptor complex that binds to thyroid hormone response elements (TREs) in target genes, regulating their transcription. Thyroid hormone has diverse cellular effects, including up-regulation of carbohydrate and lipid catabolism and stimulation of protein synthesis in a wide range of cells. The net result of these processes is an increase in the basal metabolic rate. One of the most important functions of thyroid hormone is its critical role in brain development, since absence of thyroid hormone

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during the fetal and neonatal periods may profoundly interfere with intellectual growth

Homeostasis in the hypothalamus-pituitary-thyroid axis and mechanism of action of thyroid hormones. Secretion of thyroid hormones (T3 and T4) is controlled by trophic factors secreted by both the hypothalamus and the anterior pituitary. Decreased levels of T3 and T4 stimulate the release of thyrotropin-releasing hormone (TRH) from the hypothalamus and thyroid-stimulating hormone (TSH) from the anterior pituitary, causing T3 and T4 levels to rise. Elevated T3 and T4 levels, in turn, suppress the secretion of both TRH and TSH. This relationship is termed a negative-feedback loop. TSH binds to the TSH receptor on the thyroid follicular epithelium, which causes activation of G proteins, and cyclic AMP (cAMP)-mediated synthesis and release of thyroid hormones (T3 and T4). In the periphery, T3 and T4 interact with the thyroid hormone receptor (TR) to form a hormone-receptor complex

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that translocates to the nucleus and binds to so-called thyroid response elements (TREs) on target genes initiating transcription.

Hyperthyroidism

Thyrotoxicosis is a hypermetabolic state caused by elevated circulating levels of free T3 and T4. Because it is caused most commonly by hyperfunction of the thyroid gland, it is often referred to as hyperthyroidism.

Prolonged hypersecretion of thyroid hormone can result from (1) abnormal thyroid stimulator (Graves disease), (2) intrinsic disease of the thyroid gland (toxic multinodular goiter or functional adenoma), and (3) excess TSH production by a pituitary adenoma (rare).

Disorders Associated with Thyrotoxicosis

Associated with Hyperthyroidism

Primary

  Diffuse toxic hyperplasia (Graves disease)

  Hyperfunctioning ("toxic") multinodular goiter

  Hyperfunctioning ("toxic") adenoma

  Hyperfunctioning thyroid carcinoma

  Iodine-induced hyperthyroidism

  Neonatal thyrotoxicosis associated with maternal Graves disease

Secondary

  TSH-secreting pituitary adenoma (rare) *

Not Associated with Hyperthyroidism

Subacute granulomatous thyroiditis (painful)

Subacute lymphocytic thyroiditis (painless)

Struma ovarii (ovarian teratoma with ectopic thyroid)

Factitious thyrotoxicosis (exogenous thyroxine intake)* Associated with increased TSH; all other causes of thyrotoxicosis associated

with decreased TSH.

IMMUNE MECHANISMS: Patients have IgG antibodies that bind to the TSH receptor on the plasma membrane of thyrocytes. These antibodies act as agonists; that is, they stimulate the TSH receptor, thereby activating adenylyl cyclase and increasing thyroid hormone secretion.

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Under this continued stimulation, the thyroid becomes diffusely hyperplastic and excessively vascular.GENETIC FACTORS: The strongest risk factor for Graves disease is a positive family history. No single gene is responsible, and the concordance rate in monozygotic twins is only 30% to 50%, whereas in dizygotic twins, it is merely 5%. Thus, both genetic and environmental factors are probably involved. Histocompatibility class II molecules (e.g., HLA-DR3, HLA-DQA1) increase the relative risk of Graves disease up to fourfold. Graves disease is also associated with polymorphism of cytotoxic T-lymphocyte antigen-4 (CTLA-4), which indicates the importance of autoreactive T cells. Patients with Graves disease and their relatives have a considerably higher incidence of other autoimmune diseases, including pernicious anemia and Hashimoto thyroiditis.GENDER: Like other autoimmune diseases, Graves disease is far more common (7 to 10 times) in women than in men.EMOTIONAL INFLUENCES: Endocrinologists have long observed that the onset of Graves disease often follows a period of emotional stress; however quantitative data are lacking.SMOKING: Smoking is associated with an increased risk of Graves disease, and it increases the severity of the eye disease in patients who develop ophthalmopathy.OPHTHALMOPATHY: Although exophthalmos (protrusion of eyeballs) is a common complication of Graves disease , its occurrence and severity correlate poorly with levels of thyroid hormone. Both T and B lymphocytes are sensitized to antigens shared by thyroid follicular cells and orbital fibroblasts. These cells stimulate orbital fibroblasts to proliferate and produce collagen and glycosaminoglycans, either by cytokine synthesis or by antibody-mediated receptor activation.

The clinical manifestations of hyperthyroidism are protean and include changes referable to the hypermetabolic state induced by excess thyroid hormone as well as those related to overactivity of the sympathetic nervous system (i.e., an increase in the β-adrenergic "tone").

Excessive levels of thyroid hormone result in an increase in the basal metabolic rate. The skin of thyrotoxic patients tends to be soft, warm, and flushed because of increased blood flow and peripheral vasodilation to increase heat loss. Heat intolerance is common. Sweating is increased because of higher levels of calorigenesis. Increased basal metabolic rate also results in characteristic weight loss despite increased appetite.

Cardiac manifestations are among the earliest and most consistent features of hyperthyroidism. Patients with hyperthyroidism can have

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an increase in cardiac output, owing to both increased cardiac contractility and increased peripheral oxygen requirements. Tachycardia, palpitations, and cardiomegaly are common. Arrhythmias, particularly atrial fibrillation, occur frequently and are more common in older patients. Congestive heart failure may develop, particularly in elderly patients with pre-existing cardiac disease. Myocardial changes, such as foci of lymphocytic and eosinophilic infiltration, mild fibrosis in the interstitium, fatty changes in myofibers, and an increase in size and number of mitochondria, have been described. Some patients with thyrotoxicosis develop a reversible diastolic dysfunction and a "low-output" failure, so-called thyrotoxic dilated cardiomyopathy.

In the neuromuscular system, overactivity of the sympathetic nervous system produces tremor, hyperactivity, emotional lability, anxiety, inability to concentrate, and insomnia. Proximal muscle weakness is common with decreased muscle mass (thyroid myopathy).

Ocular changes often call attention to hyperthyroidism. A wide, staring gaze and lid lag are present because of sympathetic overstimulation of the levator palpebrae superioris . However, true thyroid ophthalmopathy associated with proptosis is a feature seen only in Graves disease (see below).

In the gastrointestinal system, sympathetic hyperstimulation of the gut results in hypermotility, malabsorption, and diarrhea.

The skeletal system is also affected in hyperthyroidism. Thyroid hormone stimulates bone resorption, resulting in increased porosity of cortical bone and reduced volume of trabecular bone. The net effect is osteoporosis and an increased risk of fractures in patients with chronic hyperthyroidism.

Other findings throughout the body include atrophy of skeletal muscle, with fatty infiltration and focal interstitial lymphocytic infiltrates; minimal liver enlargement due to fatty changes in the hepatocytes; and generalized lymphoid hyperplasia with lymphadenopathy in patients with Graves disease.

Thyroid storm is used to designate the abrupt onset of severe hyperthyroidism. This condition occurs most commonly in patients with underlying Graves disease and probably results from an acute elevation in catecholamine levels, as might be encountered during infection, surgery, cessation of antithyroid medication, or any form of stress. Patients are often febrile and present with tachycardia out of proportion to the fever. Thyroid storm is a medical emergency: A significant number of untreated patients die of cardiac arrhythmias.

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Apathetic hyperthyroidism refers to thyrotoxicosis occurring in the elderly, in whom old age and various comorbidities may blunt the typical features of thyroid hormone excess seen in younger patients. The diagnosis of thyrotoxicosis in these patients is often made during laboratory work-up for unexplained weight loss or worsening cardiovascular disease.

hipotiroidisme

Hypothyroidism refers to the clinical manifestations of thyroid hormone deficiency. It can be the consequence of three general processes:

Defective thyroid hormone synthesis, with compensatory goitrogenesis (goitrous hypothyroidism)

Inadequate thyroid parenchyma function, usually due to thyroiditis, surgical resection of the gland, or therapeutic administration of radioiodine

Inadequate secretion of TSH by the pituitary or of thyroid-releasing hormone (TRH) by the hypothalamus

Symptoms of hypothyroidism that develop insidiously reflect decreased circulating thyroid hormone (Fig. 21-6). Often, the first manifestations are tiredness, lethargy, sensitivity to cold, and inability to concentrate. Many organ systems are affected, and all are hypofunctional. Hypothy-roidism is treated effectively with thyroid hormone.SKIN: Alterations in the skin are almost universal in patients with clinically apparent hypothyroidism. Proteogly-cans accumulate in the extracellular matrix and bind water, resulting in a peculiar form of edema termed myxedema. Myxedematous patients have boggy facies, puffy eyelids, edema of the hands and feet, and enlarged tongues. A pale, cool skin reflects cutaneous vasoconstriction. The skin is also dry and coarse, because sebaceous and sweat gland secretions are inadequate.NERVOUS SYSTEM: Hypothyroidism in pregnancy has grave neurologic consequences for the fetus, expressed after birth as cretinism (see below). Hypothyroid adults are lethargic and somnolent and show memory loss and slowed mental processes. Psychiatric symptoms are prominent; paranoid ideation and depression are common. Severe agitation (myxedema madness) may develop.HEART: In untreated hypothyroidism, so-called myxedema heart develops, which is characterized by a dilated heart and a pericardial effusion (see Chapter 11).GASTROINTESTINAL TRACT: Constipation, due to decreased peristalsis, is common, and may be severe enough to lead to fecal impaction (myxedema megacolon).

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REPRODUCTIVE SYSTEM: Women with hypothyroidism suffer ovulatory failure, progesterone deficiency, and irregular and excessive menstrual bleeding. In men, erectile dysfunction and oligospermia are common.

Endemic GoiterEndemic goiter is goitrous hypothyroidism due to dietary iodine deficiency in locales with a high prevalence of the disease. The widespread availability of iodized salt has eliminated endemic goiter in many areas. Nevertheless, more than 200 million persons worldwide still have the disease. The pathologic evolution of endemic goiter is like that of nontoxic goiter (see above). However, unlike the latter, endemic goiter rarely causes hyperthyroidism. Administration of iodine may reverse the early, diffuse stage of endemic goiter but has little effect on a fully developed multinodular goiter. Replacement therapy with thyroid hormone is indicated, and local symptoms may necessitate surgical resection.Goiter Induced by Antithyroid Agents and IodideA number of drugs and naturally occurring chemicals in foods suppress thyroid hormone synthesis and so are goitrogenic. Such goiters may or may not be associated with hypothyroidism. Common goitrogenic drugs include lithium (which is used to manage bipolar disorders), phenylbutazone, and p-aminosalicylic acid. Certain cruciferous vegetables (turnips, rutabaga, cassava) contain goitrogens, and their ingestion can potentiate an iodine-deficient diet to produce goitrous hypothyroidism. Goiter and hypothyroidism may also occur in persons who consume large amounts of iodide, either as a medicinal component (potassium iodide-containing expectorants) or in foods particularly rich in this halide (e.g., seaweed in Japan).

ThyroiditisThyroiditis describes a heterogeneous group of inflammatory disorders of the thyroid gland, including those that are caused by autoimmune mechanisms and infectious agents.

HASHIMOTO THYROIDITIS

Hashimoto thyroiditis (or chronic lymphocytic thyroiditis) is the most common cause of hypothyroidism in areas of the world where iodine levels are sufficient. It is characterized by gradual thyroid failure because of autoimmune destruction of the thyroid gland. The name Hashimoto thyroiditis is derived from the 1912 report by Hashimoto describing patients with goiter and intense lymphocytic infiltration of the thyroid (struma lymphomatosa). This disorder is most prevalent between 45 and 65 years of age and is more common in women than in men, with a female predominance of 10:1 to 20:1. Although it is

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primarily a disease of older women, it can occur in children and is a major cause of nonendemic goiter in children.

Pathogenesis.

Hashimoto thyroiditis is an autoimmune disease in which the immune system reacts against a variety of thyroid antigens. The overriding feature of Hashimoto thyroiditis is progressive depletion of thyroid epithelial cells (thyrocytes), which are gradually replaced by mononuclear cell infiltration and fibrosis. Multiple immunologic mechanisms may contribute to the death of thyrocytes. Sensitization of autoreactive CD4+ T-helper cells to thyroid antigens appears to be the initiating event. The effector mechanisms for thyrocyte death include the following:

  

•    CD8+ cytotoxic T cell-mediated cell death: CD8+ cytotoxic T cells may cause thyrocyte destruction by one of two pathways: exocytosis of perforin/granzyme granules or engagement of death receptors, specifically CD95 (also known as Fas) on the target cell

  

•    Cytokine-mediated cell death: CD4+ T cells produce inflammatory cytokines such as IFN-γ in the immediate thyrocyte milieu, with resultant recruitment and activation of macrophages and damage to follicles.

  •    Binding of antithyroid antibodies (anti-TSH receptor antibodies,

antithyroglobulin, and antithyroid peroxidase antibodies) followed by antibody-dependent cell-mediated cytotoxicity (ADCC)

SUBACUTE (GRANULOMATOUS) THYROIDITIS

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Subacute thyroiditis, which is also referred to as granulomatous thyroiditis or De Quervain thyroiditis, occurs much less frequently than does Hashimoto disease. The disorder is most common between the ages of 30 and 50 and, like other forms of thyroiditis, affects women considerably more often than men (3:1 to 5:1).

Pathogenesis.

Subacute thyroiditis is believed to be caused by a viral infection or a postviral inflammatory process. The majority of patients have a history of an upper respiratory infection just before the onset of thyroiditis. The disease has a seasonal incidence, with occurrences peaking in the summer, and clusters of cases have been reported in association with coxsackievirus, mumps, measles, adenovirus, and other viral illnesses. Although the pathogenesis of the disease is unclear, one model suggests that it results from a viral infection that provides an antigen, either viral or a thyroid antigen that is released secondary to virus-induced host tissue damage. This antigen stimulates cytotoxic T lymphocytes, which then damage thyroid follicular cells. In contrast to autoimmune thyroid disease, the immune response is virus-initiated and not self-perpetuating, so the process is limited.

Paratiroid

HypoparathyroidismHypoparathyroidism results from decreased secretion of PTH or end-organ insensitivity (pseudohypoparathyroidism) due to congenital or acquired conditions. The disease is clinically characterized by hypocalcemia and hyperphosphatemia.

Disebabkan:

Pembedahan, Kelainan congenital (tidak terdapat kelenjar paratirois), Paratiroidismefamilial dan idiopatik.

The major clinical manifestations of hypoparathyroidism are referable to hypocalcemia and are related to the severity and chronicity of the hypocalcemia.

   •    The hallmark of hypocalcemia is tetany, which is characterized by neuromuscular irritability, resulting from decreased serum ionized calcium concentration. These findings can range from circumoral numbness or paresthesias (tingling) of the distal extremities and carpopedal spasm, to life-threatening laryngospasm and generalized seizures. The classic findings on physical examination of patients with neuromuscular irritability are Chvostek sign and Trousseau sign. Chvostek sign is elicited in subclinical disease by tapping along the course of the facial

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nerve, which induces contractions of the muscles of the eye, mouth, or nose. Occluding the circulation to the forearm and hand by inflating a blood pressure cuff about the arm for several minutes induces carpal spasm, which disappears as soon as the cuff is deflated (Trousseau sign).

  •    Mental status changes can include emotional instability, anxiety

and depression, confusional states, hallucinations, and frank psychosis.

  •    Intracranial manifestations include calcifications of the basal

ganglia, parkinsonian-like movement disorders, and increased intracranial pressure with resultant papilledema.

  •    Ocular disease results in calcification of the lens leading to

cataract formation.

  •    Cardiovascular manifestations include a conduction defect, which

produces a characteristic prolongation of the QT interval in the electrocardiogram.

  

•    Dental abnormalities occur when hypocalcemia is present during early development. These findings are highly characteristic of hypoparathyroidism and include dental hypoplasia, failure of eruption, defective enamel and root formation, and abraded carious teeth.

Hyperparathyroidism

Hyperparathyroidism occurs in two major forms—primary and secondary—and, less commonly, tertiary. The first condition represents an autonomous, spontaneous overproduction of PTH; the latter two conditions typically occur as secondary phenomena in patients with chronic renal insufficiency.

PRIMARY HYPERPARATHYROIDISM

Primary hyperparathyroidism is one of the most common endocrine disorders, and it is an important cause of hypercalcemia. The frequency of the various parathyroid lesions underlying the hyperfunction is as follows:

   •    Adenoma: 75% to 80%   •    Primary hyperplasia (diffuse or nodular): 10% to 15%   •    Parathyroid carcinoma: less than 5%

Parathyroid carcinomas tend to be larger than adenomas and appear as lobulated, firm, tannish, unencapsulated masses, often adherent to surrounding soft tissues. Microscopically, most show a trabecular pattern, with significant mitotic activity and thick

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fibrous bands. Capsular or vascular invasion is occasionally noted. Importantly, the cell atypism often seen in parathyroid adenomas is rare in carcinomas.

Clinical Features of Hyperparathyroidism are Highly VariableHypercalcemia and hypophosphatemia are characteristic of hyperparathyroidism, although some patients have asymptomatic disease detected only on routine blood analysis. Others show florid systemic, renal, and skeletal disease (Fig. 21-15). Excessive parathyroid hormone (PTH) leads to excessive loss of calcium from bones and enhanced calcium resorption by the renal tubules. The production of the activated form of vitamin D (1,25[OH]2D) by renal tubules is

also stimulated by PTH, thereby increasing intestinal calcium absorption. The action of PTH on the kidney, together with hypercalcemia, leads to hypophosphatemia. Common symptoms include nausea, vomiting, fatigue, weight loss, anorexia, polyuria, and polydipsia. A neck mass is palpable in many patients. The classic bone lesions of hyperparathyroidism are known as osteitis fibrosa cystica, which occurs in a minority of patients who have an accelerated form of the disease. The kidney as well as nervous and gastrointestinal systems are also affected. See Chapter 26 for a detailed discussion.

Terjadinya proptosis pada Graves, disease

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