Kabir J. Singh, MD

• Echocardiography Fellow, Division of Cardiology
• Department of Medicine, University of
• California San Francisco
• San Francisco, California

Variations on the theme have been developed that measure urinary cortisol excretion over short (and different) periods of time to obtain a circadian pattern skin care di bandung discount 100mg dapsone visa. Unsurprisingly skin care games buy dapsone 100mg mastercard, urinary cortisol excretion shows the same variations as plasma cortisol acne 6 year old daughter discount 100 mg dapsone fast delivery. Thus acne jensen boots sale cheap dapsone 100 mg fast delivery, synthetic steroid analogues were selected because of high glucocorticoid potency acne is a disorder associated with 100 mg dapsone with mastercard. In adults or in pediatric patients weighing more than 40 kg acne jensen effective 100mg dapsone, dexamethasone is given in doses of 0. For pediatric patients weighing less than 40 kg, the dose is adjusted to 30 g/kg per day (in divided doses) [5]. Although original assessment was by measurement of the urinary 17-hydroxycorticosteroids, the suppressive effect of the low-dose dexamethasone test has been subsequently evaluated by measuring morning serum (normal response: less than 50 nmol/L; or 1. Some authors have proposed improvement of the test by tailoring the dose of dexamethasone according to body weight and administering 20 g/kg each day rather than a fixed dose of 2 mg/day [327]. In children, the dexamethasone dose may be adjusted [339], usually to body surface area at 2 mg/day per 1. Based on the same theoretical grounds, numerous alternate suppression tests have been proposed which attempted to offer some practical advantage over the classic approach. In normal subjects, plasma cortisol values will be suppressed below a definite limit (established by each laboratory, and depending on the assay method). Drugs that modify dexamethasone metabolism are the same as those seen for the classic low-dose dexamethasone suppression test. A number of series have established the high sensitivity of the test, but, even so, around 5% of patients with proven Cushing disease will suppress normally [327]. Although it is a highly sensitive test, false-positives (lack of normal suppression) are encountered in as many as 13% of obese subjects and in 23% of hospitalized or chronically ill patients [327]. As an alternative to blood collection, salivary cortisol has been used to assess suppressive effect of the overnight 1 mg dexamethasone with essentially similar results [307]. Further studies are needed to establish whether this approach will have the same accuracy. As with other tests, it is essential to interpret the outcome of the test in the context of the pretest likelihood for the diagnosis, with repeated measurements if needed. Some have proposed suppression of cortisol by intravenous dexamethasone infusion in order to avoid (hypothetical) variations due to interindividual differences in the rate of dexamethasone absorption. Nevertheless, samples should be kept in ice-cold tubes and immediately separated ahead of storage at 240 C to prevent inadvertent degradation. These approaches have their limitations, as they are only available to highly specialized laboratories, and sensitivity is low and specificity not perfect. The explanation is that patients with the ectopic syndrome usually have higher rates of cortisol secretion. Therefore, cortisol levels do not suppress with low-dose dexamethasone but do so after high doses. Plasma Adrenocortical Androgens the pattern of adrenocortical steroid secretion provides some clues in the etiologic work-up. These may be divided into noninvasive baseline and dynamic tests and invasive dynamic tests. In the modern test, serum cortisol is measured at 0 and 148 hours, and a greater than 50% suppression of plasma cortisol from the basal value has been used to define a positive response. The specificity can be improved using a cutoff of cortisol suppression greater than 90%, although a specificity of 100% is never attained [11,359]. In this test, 8 mg of dexamethasone is given orally as a single dose at 23:00 or 24:00 hours and the 08:00 hours or 09:00 hours serum cortisol the next morning is compared with that of the previous (control) day. The proposed cutoff point for a positive response (suppressibility) is a serum cortisol decrease to 50% or less of its control value [360]. This test appeared at least as efficient if not better, with 89% sensitivity and 100% specificity for diagnosis of Cushing disease [361]. That this overnight suppression test reaches higher diagnostic accuracy than the classic test may be explained by the fact that the 8 mg dose is given as a single administration. In the same manner as for the classic test, there is no theoretical reason to fix a rigid cutoff at a 50% decrease. Patients have to restrict fluid intake for the remainder of the day to avoid water overload. Adverse effects are limited to shortlived flushing sensation, transient tachycardia, mild and transient decrease in blood pressure, headache, abdominal pain, or weight increase. It might prove more useful in the postoperative assessment to predict recurrence after pituitary surgery as normal subjects rarely respond to the test [11,367,368]. This discovery opened up new avenues to investigators of corticotroph function in humans [369,370]. A positive response is highly suggestive of Cushing disease, and the stronger the response the higher the probability. This investigation should only be considered and performed in centers where there is a great deal of experience. Unfortunately, the test has a lateralization accuracy of 70% at best, and although successful blind hemihypophysectomies directed by sampling lateralization have been claimed [401,402], this approach is not generally recommended. Although very rare, corticotrophic adenoma should be sought outside the intrasellar region (in the cavernous sinuses, sphenoidal sinuses, nasopharyngeal area) if the pituitary has no focal signal abnormality that is suggestive of adenoma. Falsepositives occur where there is pituitary incidentaloma (10% of the population) and artifact [406]. Skull X-rays Because most pituitary corticotroph adenomas are small, gross deformation of the pituitary sella is rarely encountered in untreated Cushing disease [409]. They may be demonstrated in patients who develop Nelson syndrome, and in the rare patients with an initial macroadenoma. In these circumstances, other tests are advised: salivary cortisol and 24-hour urinary cortisol. This is especially important when using dexamethasone suppression tests as false-positive results may occur as a result of accelerated dexamethasone metabolism [327]. It is essential to undertake adrenal imaging before bilateral adrenalectomy [1,11,328]. Antiglucocorticoids (Mifepristone) Although this drug is primarily an antiprogesterone, it also exerts antiglucocorticoid actions readily observed within a few hours after a single oral administration [416]. As expected, plasma and urinary cortisol are elevated and suppressibility by dexamethasone is altered. Because of the long duration of action of the drug, this state of general glucocorticoid resistance is still noticeable up to 3 days after single-dose administration [417]. The diagnosis may be easily made in the case of an autonomously secreting adrenocortical tumor. Because this enzyme activity is present in the kidney, inhibition induces local cortisol excess, which binds to the kidney mineralocorticoid (or glucocorticoid type I) receptor and exerts a mineralocorticoidlike effect [419]. As a consequence of the blockade of cortisol metabolism in the kidney urinary cortisol is increased; plasma cortisol is unchanged. Thus, urinary cortisol is falsely elevated in subjects taking excess quantities of licorice [420]. This functional hypercortisolemic state (sometimes termed "pseudo-Cushing") is usually mild and transient and regresses with its cause. Plasma cortisol and urinary steroids excretion are increased, and are not suppressed normally on low-dose dexamethasone testing. The hypercortisolemic state that accompanies depression often creates a serious diagnostic challenge. A depressed patient may present with obesity, mild hirsutism, slight hypertension, and moderate glucose intolerance. Classically in depression, the hypercortisolemic state is clinically and biologically mild. Urinary cortisol excretion almost never exceeds three times the upper limit of normal. The circadian pattern of plasma cortisol levels is less disrupted and sometimes a phase-shift phenomenon is merely observed [425]. Anorexia Nervosa Anorexia nervosa is associated with an array of neuroendocrine disorders among which sustained hypercortisolism is frequent. Increased urinary cortisol and lack of normal suppression by the classic low-dose dexamethasone test may be found. An exceptional case has been reported where authentic Cushing disease with a pituitary adenoma found at surgery occurred 2 years after the onset of anorexia nervosa [429]. In contrast with depressed patients, there is generally no clinical confusion for the diagnosis. Abnormal corticotroph dynamics are corrected with calorie replenishment and weight restoration [430]. Alcohol Patients with chronic alcohol dependence may present with clinical and biochemical features of glucocorticoid excess [431,432], with hypothalamicpituitary-adrenal axis activation. Whatever the mechanism involved, alcoholic hypercortisolemia syndrome is a diagnostic challenge. The simplest and most effective way to avoid a false diagnosis is to assess patients with a known history of excess alcohol intake after a period of abstinence. Stress Transient states of glucocorticoid excess without clinical stigmata commonly accompany an array of stressful conditions. Many such situations are encountered, including surgery, test-taking, various acute and chronic illnesses, terminal illnesses, extended burns, and diabetes mellitus [327]. The simple stress of hospitalization has been claimed to increase glucocorticoid secretion. These observations emphasize the absolute need to await the resolution of stressful intercurrent conditions before initiating a proper diagnostic evaluation. Pregnancy Normal pregnancy is associated with significantly altered glucocorticoid homeostasis (see also chapter: the Pituitary Gland in Pregnancy). This generates a parallel rise in plasma cortisol but does not induce a true hypercortisolemic state since plasma free cortisol, and salivary and urinary cortisol remain within the normal range. With time, more significant alterations develop that culminate in the third trimester when unequivocal features of biochemical hypercortisolemia are observed. Mean unbound and salivary cortisol and urinary cortisol excretion show a two- to threefold increase [316,317,436]. Thirty percent of women have 24-hour urinary cortisol excretion above the upper limit of normal, nonpregnant women, and most have an abnormal response to the classic low-dose dexamethasone suppression test [437]. The mechanism and consequences of this mild state of authentic hypercortisolism are not totally understood. Progesterone exerts an antiglucocorticoid action on rat pituitary corticotroph cells [441]; it has been hypothesized that prolonged and highly elevated progesterone levels induce a state of relative and general glucocorticoid resistance [317]. This would explain the slight shift in plasma free cortisol with conserved normal circadian rhythm, the abnormal dexamethasone suppressibility, and also the absence of peripheral clinical features of hypercortisolism. This hypothesis is reinforced by the recent finding that the change in salivary cortisol concentrations after delivery correlated with increased serum progesterone concentration in late pregnancy [317]. Familial Resistance to Glucocorticoids this rare syndrome was first identified in a patient with hypertension and hypokalemia [442], and has been shown to be due to a single base substitution (A-T) at position 2054 changed Asp641 to Val within a highly conserved region of the ligand-binding domain of the glucocorticoid receptor, explaining the loss of affinity [443]. This results in elevation of plasma cortisol and urinary cortisol but normal aldosterone levels. Two features are different: there is a normal circadian rhythm of plasma cortisol and an absence of clinical features of hypercortisolism. These observations suggest that the state of glucocorticoid resistance was not restricted to the pituitary, but was general. The clinical and biochemical features severely affect patients with homozygous defects. A more favorable diagnostic accuracy was obtained with a cortisol threshold of 70 nmol/L (25 ng/mL or 2. When unilateral adrenalectomy is performed, although transiently ameliorated, hypercortisolism inevitably recurs, allowing a correct and a posteriori diagnosis of Cushing disease in its macronodular hyperplastic form. Although it may be highly asymmetrical to the point of mimicking a unilateral adrenocortical tumor, macronodular hyperplasia of Cushing disease is not accompanied by contralateral atrophy, as is the case in a true autonomous adrenocortical adenoma [410].

Therefore acne jawline order dapsone no prescription, sophisticated endocrinological testing is necessary to diagnose the condition and to identify the cause acne diagram proven dapsone 100mg. A gradient between right and left petrosal sinus helps to identify the site of the lesion intraoperatively and offers the option of a hemihypophysectomy if no adenoma is identified skin care 50th and france buy dapsone 100 mg on line. A summary of the results of our series of 382 surgically treated patients is demonstrated in Table 24 acne fighting foods order dapsone mastercard. Because of the severity of the disease skin care essentials buy dapsone 100 mg visa, patients are almost always in reduced general condition and need specific expert peri- and postoperative care acne during pregnancy boy or girl purchase discount dapsone line. After endocrinological remission, the high recurrence rate of up to 25% in 5 years makes longterm postoperative endocrinological follow-up necessary [58]. In the case of persistence or recurrence of the disease the treatment options include second-look surgery, bilateral adrenalectomy, medical treatment, and radiotherapy [59]. Gonadotrophin-Producing Adenomas these are uncommon and mostly remain undetected because of the lack of specific symptoms. Approximately 40% of the patients are children aged less than 16 years at the time of surgery. The vast majority of patients harboring such a lesion present with impairment of anterior pituitary function, hypogonadism being the most frequent deficiency, followed by failure of the corticotroph and thyrotroph axis. Surgical treatment still remains a technical challenge and a subject of controversy. In many early reports, radical surgery led to an unacceptably high mortality and morbidity because of the involvement of both the hypothalamus and the pituitary gland. For this reason, other authors favored the therapeutic concept of conservative incomplete surgery followed by radiotherapy [68,69]. Concerning the many improvements which have been made in recent years, the goal of therapy should be selective removal of the tumor with preservation of the hypothalamus, midbrain, perforating vessels of the circle of Willis, optic pathways, pituitary stalk, and pituitary gland. Depending on the tumor location, all available surgical approaches to the sellar region may be used. The cases (up to 40%) in which the transsphenoidal approach is suitable have the advantage of a favorably low morbidity and mortality. The rate of recurrence-free survival after total removal of the tumors may attain 80% after a follow-up interval of 10 years. The adamantinomatous type is more frequent and usually presents as a cystic, partially calcified lesion containing cholesterol crystals. As much as one-half of the newly diagnosed Meningiomas originate from arachnoidal cap cells and are surgically classified by their site of origin. The tuberculum sellae meningioma is the classic suprasellar meningioma, causing slowly progressive loss of vision and headache. These tumors may invade the bony skull base, causing hyperostosis of the sphenoidal plane, may extend into the optic canal and displace the carotid and the anterior cerebral arteries and the pituitary stalk. They thus cause hyperprolactinemia, which is the only endocrine disturbance that usually can be detected. Meningiomas of the cavernous sinus usually cause the so-called cavernous sinus syndrome: diplopia and proptosis due to palsy of the sixth and third nerves, and periorbital pain and numbness due to compression of the fifth cranial nerves [71]. Meningiomas of the clinoid process, however, expand into the suprasellar cistern and the optic canal and invade the cavernous sinus. Various histology types, including the rare hemangiopericytoma and malignant meningioma, can be found. Depending on several factors, like the site of origin, extension, consistency, vascularization, but also dura, bone, and soft tissue infiltration, several meningiomas can be totally removed; others cannot, at least not without unacceptable morbidity. The best results are obtained in suprasellar meningiomas, in which the tumor can be completely resected under preservation of the optic and oculomotor nerves. Treatment of meningiomas of the cavernous sinus is handled controversially among neurosurgeons, complete removal may lead to significant new neurological deficits and ischemia. The authors thus frequently prefer to perform a "slice technique," transsphenoidal decompression of the cavernous sinus and the pituitary gland in tumors with intra- and parasellar extensions [72,73]. In cases with progressive neurological deficit, transcranial decompression by resection of the lateral portions of the cavernous sinus meningioma is performed, followed by radiotherapy. Medical treatment with hydroxyurea for tumor shrinkage may be useful, especially in combination with radiotherapy [74]. Postoperatively, a normalization of pituitary function is observed in more than 80% of patients. In such a case, metrizamide cisternography provides a reliable preoperative diagnosis. Transsphenoidal or transcranial approaches are used in symptomatic arachnoid cysts for drainage, partial removal of the cyst wall, and fenestration to the suprasellar cisterns [78]. The patients present with visual disturbances (loss of vision, papilledema, optic atrophy, visual field defects). However, various endocrine disturbances including hypopituitarism, diabetes insipidus, or even Russell syndrome (hypothalamic cachexia) and precocious puberty may occur. In some cases, hydrocephalus is present due to obstruction of the foramen of Monro. Treatment options include total surgical removal (intraorbital gliomas), removal of exophytic tumor parts (chiasmatic gliomas), chemotherapy (usually vincristine and carboplastine), or radiation therapy, which is reserved for older patients. In cases without progressive neurologic deficit, observation is recommended since many tumors do not enlarge during long-term follow-up interval. Metastatic Tumors Symptomatic metastatic tumors to the sella area are rare lesions, but in autopsy series of patients with various types of cancer the incidence is reported to be as high as 27% [81]. The most common cancers that metastasize to the pituitary region are lung, prostate, and stomach cancer in men; and breast, lung, and stomach cancer in women [82]. Depending on their location some 90% of these lesions can be removed by the transsphenoidal approach. Intra- and Suprasellar Colloid Cysts Also termed pars intermedia cysts, they consist of a circumscribed collection of colloid material within the pituitary gland that lacks a cyst wall [77]. Involvement of the sellar region in metastasis of hematopoietic neoplasms is rarely observed [83]. However, lymphomas, which involve the hypothalamic area, and plasmocytomas both occur and are associated with poor prognosis whatever treatment is chosen [84]. Chordomas Chordomas are histologically benign tumors that are derived from notochondral remnants and almost always involve the clival area. Their biologic character is extremely aggressive, which is expressed by bone destruction, infiltration of the cavernous sinus and basal dura, and extension into all cranial fossae [85]. Depending on the location of the chordomas, patients may present with visual compromise, pituitary deficiencies and ophthalmoplegia. Because of the invasive growth pattern total removal is not possible without high mortality and morbidity. Even after radiotherapy, the recurrence rate in our series was found to be 80% in 5 years. The survival rate after a follow-up period of 10 years is lower than 30%, but in individual patients no tumor progression is observed even after 15 years. The granulomatous hypophysitis is characterized by granulomas with histiocytes and multinucleated giant cells but also shows a collection of lymphocytes. The most frequent presenting syndrome is headache occurring in a fluctuating course due to recurrent aseptic meningitis, followed by diabetes insipidus, menstrual irregularities, and visual compromise. Repeat surgery, medical treatment with corticosteroids, and radiation therapy are additional treatment options. Pituitary Abscess Pituitary abscesses may be a rare manifestation of an acute bacterial infection that develops per continuitatem in cases with perisellar infections like sinusitis and mastoiditis. However, this entity is not clearly defined and thus significant confusion exists. The diagnosis is made intraoperatively and histologically because the pituitary abscess mimics nonfunctional pituitary tumors in radiological and endocrinological evaluations [90]. Staphylococcus aureus is the most relevant microorganism and can be isolated from bacterial cultures, but in many cases these cultures remain sterile. In the few known cases the lesions led to precocious puberty in young males as a result of hypothalamic compression [91]. Germ Cell Tumors Germ cell tumors develop in the midline and affect the pineal, the suprasellar, or both, regions simultaneously [95]. The 30% nongerminomatous lesions include teratomas, embryonal carcinomas, endodermal sinus tumors, and choriocarcinomas. Germinomas show an invasive growth pattern and infiltrate the surrounding tissue causing typical clinical symptoms like visual disturbances, diabetes insipidus, hypopituitarism, and hydrocephalus [96]. Recurrence in cases of incomplete removal is probable, thus necessitating repeat surgery. Endoscope-assisted microsurgery means that an endoscope is used within the classical microsurgical operation, when the surgeon feels that the additional assets of the endoscope could be helpful. The visual field is no more restricted by the straight beam of light within the nasal tunnel kept open by the speculum. Introduction of an endoscope into the sphenoid sinus allows a more panoramic visualization of the anatomy, an excellent orientation, and additional control of the radicality of tumor resection. In one study significantly more tumor was extracted when the surgeon additionally used an endoscope after he had finished microsurgical resection [99]. Alternatively, fully endoscopic procedures, in which septal dissections were no longer required with the use of a speculum, were devised [99]. To date, still few data are available on the hormonal and imaging outcomes which allow a comparison of remission and complication rates, respectively, of open microsurgical procedures and entirely endoscopic operations. To date, endoscopic transsphenoidal surgery is an established widespread procedure [102]. One disadvantage of the endoscopic technique is the learning curve with a technically somewhat different procedure during which the surgeon controls his instruments from a screen rather than from the lenses of the operating microscope. The three-dimensional view, which the operating microscope allows, is only preserved if an expensive 3D endoscope is used. With "extended" nasal approaches, even lesions become accessible transsphenoidally which had previously been considered as contraindications for nasal approaches [102]. However, to date, most of the data available on safety and efficacy of pituitary operations still come from microsurgical operations [112]. Neuronavigation is to date widely used in the entire field of microneurosurgery and may be used during pituitary operations. The three-dimensional data set provided by preoperative imaging is related to the patients head in the operation room. Critical structures such as the tumor shape or the brain-supplying major arteries can be localized with a "pointer" or segmented and superimposed onto the surgical field [26,103]. Image-guided surgery can be used in each and every case, but is associated with increased costs and might not be always needed. Neuronavigation to date is highly reliable and substitutes for the traditional fluoroscopic control [104]. The microdoppler system, which is widely used in neurovascular microsurgery, can also be considered a useful technical tool for pituitary operations. It allows localization of the carotid artery within the cavernous sinus or within parasellar tumor. While in an ideal case of an intra- and suprasellar adenoma, the elevated arachnoid descends into the sella in only one smooth arachnoidal plane, a complex situation may occur in which residual tumor cannot be directly visualized. There might be tumor hidden below any one of the arachnoidal pouches or in the lateral, anterior, or posterior portions of the sella. Only high-field systems can also depict the parasellar structures with sufficient image quality and thus allow a decision about total removal of intra- and parasellar lesions. In a modern high-field system intraoperative images can be obtained that correspond perfectly to the delayed postoperative scans which constitute the standard of postoperative imaging [108,109]. In several reports, it has been convincingly demonstrated that, even in experienced hands, the rate of total tumor resection could be increased by about one-third [109]. However, even with all the technical refinements in the surgery of pituitary adenomas, the factors defined by the tumor growth characteristics and location and the individual experience and technical skills of the surgeon are still the main determinants of the surgical outcome for an individual patient. Centers with a high case load and experienced neurosurgeons have less complications and achieve a more efficient outcome in terms of both the extent of tumor resection as visualized by imaging and normalization of hormonal oversecretion [110,111]. Some remarks on tumors of the chiasm, with a proposal on how to reach the same by operation. Uber den Endausgang und Obduktion meines ersten operativen Falles von Hypophysentumor. Partial hypophysectomy for acromegaly: with remarks on the functions of the hypophysis. Notes upon a series of two thousand verified cases with surgical-mortality percentages pertaining thereto. Microsurgery anatomy and dissection of the sphenoid bone, cavernous sinus and sellar region. Stereotactic radiosurgery for pituitary adenomas: Imaging, visual and endocrine results.

A small number of proliferating centroblasts can give rise to a larger number of centrocytes present in the basal light zone acne guidelines effective dapsone 100mg. Centrocytes in the apical light zone are nondividing cells that undergo differentiation into memory B cells or plasma cells acne xia discount dapsone online. It has been suggested that centrocytes may return to the dark zone acne x soap dapsone 100mg on-line, where additional somatic mutations may be acquired acne popping safe 100mg dapsone. Resting B cells that are not activated by antigen are pushed aside to form the follicular mantle zone acne research buy discount dapsone 100mg on-line. Should they receive survival signals skin care korean brand generic dapsone 100mg free shipping, they continue to differentiate into memory B cells or plasma cells. In contrast to the germinal centers of the secondary lymphoid organs, these structures are not encapsulated. The B cells in these structures, therefore, are continuously exposed both to the local antigens that might be absent from the lymphoid organs85 and to the inflammatory microenvironment that may facilitate bypass of the regulatory points in B cell differentiation, hence contributing to a potential autoimmune bias in these sites. Although no evidence exists that these structures are the underlying cause of any disease, in some diseases they may contribute to tissue pathology and augment the pool of autoreactive plasma and memory cells. B cell clones that express surface Ig with an increased affinity for antigen are selectively expanded during the affinity maturation process, whereas B cells that express somatically mutated Igs with low affinity for antigen or novel binding to self-antigens are targeted for apoptosis or inactivation. Isotype switching requires preactivation of the particular H-chain locus to be involved in the recombination event, which is controlled by the cytokine milieu in which the cell is activated. This innate-like humoral response generates mostly short-lived plasma cells that produce antibodies with low affinity, but it provides an early and fast protection against blood-borne microbes. It has been postulated that these B cells either persist throughout the lifetime of the host81 or are renewed constantly through either nonspecific stimulation86 or antigen-specific stimulation. I, After antigen presentation of a foreign peptide that is recognized by crossreactive T cells, co-stimulatory signals are delivered to B cells with surface immunoglobulin receptors that recognize a self-antigen as part of a complex of self-molecules. I, A foreign antigen that mimics a self-molecule can mediate the endocytosis of a self-molecule that is included in a selfantigen complex. After antigen presentation of peptide to Th cells, memory B cells undergo expansion and may differentiate to plasma cells. Plasma Cells the B cell differentiation cascade ends with the generation of a plasma cell. They initiate increased protein synthesis and secretion and consequently exhibit a large cytoplasm with a well-developed endoplasmic reticulum devoted to antibody production. Any molecule derived from the intracellular or extra-cellular components of the host can be considered self-antigen; the censoring of the responses against these antigens occurs throughout B cell maturation and includes multiple mechanisms in the B cells themselves and in cells that cooperate in their activation and differentiation. The same mechanisms that induce tolerance to self-antigen can induce tolerance to pathogens, and because some autoantigens are sequestered in sites of immune privilege, cells specific to them are not subject to tolerance mechanisms. When mechanisms that regulate autoreactive B cells fail, the breakdown of self-tolerance can lead to the development of autoimmune disease. During B cell development, autoreactive B cells are generated in the bone marrow after V(D)J rearrangement and expression of surface Ig on immature B cells. Because of the vast number of different antibody molecules that can be Nonconventional B Cell Activation Although it is a central paradigm that B cells require cognate antigen for activation, it has also been known for years that infections induce an antibody response in which only a fraction of the responding B cells are specific for microbial antigen. This phenomenon, known as polyclonal activation, is induced by several mediators such as superantigen, cytokines, or noncognate T cell co-stimulation and leads to the production of self-reactive antibodies. The simpler one is bystander activation of noncognate B cells by inflammatory cytokines. This process involves a secondary gene rearrangement of the H-chain or L-chain genes. This was the first mechanism of tolerance described for B cells97 and was long believed to be the main mechanism of central tolerance. Tolerance through deletion is mediated primarily through the activation of a series of endogenous proteases. In B cells the Fas pathway and the Bcl-2 pathway play important roles in regulating apoptosis. Clustering of Fas on the cell surface, which occurs when Fas molecules bind Fas ligand, activates apoptosis. For example, excess Bcl-2 or Bcl-xL promotes cell survival, whereas excess Bax or Bim induces cell death. The fact that certain mouse strains that overexpress Bcl-2 in B cells produce autoantibodies highlights the importance of apoptosis in tolerance. Exposure of anergic B cells in vivo to multivalent antigen in the presence of activated Th cells may also lead to their activation. B Cells as Immune Regulators B cells produce cytokines in response to their environment. Thus, activated B cells and plasma cells play an important role in regulating immune responses. These Bregs not only harness autoimmunity but also restrain immune responses against microbial infection. Regulation by Small Molecules Beyond the classic activators and regulators, the molecules described in the following sections play a particularly important role in the biology of B cells and are highlighted given their potential as biomarkers and therapeutic agents. Vitamin D Vitamin D is acquired from the diet or synthesized in the skin, followed by a conversion into a biologic product in the liver and kidney. Circulating levels of vitamin D tend to be decreased in patients with autoimmune disease; whether this phenomenon contributes to the disease process is not known. However, estrogens have been shown to modify the B cell repertoire, allowing survival of autoreactive B cells, and to alter the peripheral compartments in mice. The understanding of the tolerance mechanisms that prevent the generation of autoreactive memory B cells and plasma cells is still incomplete. Molecular Triggers of Autoimmunity Several prevailing theories attempt to explain the activation and expansion of autoreactive B cells that should normally be silenced. Autoimmunity is thought to arise by a combination of environmental factors such as infectious agents that initiate an autoimmune response and genetic defects that alter B cell regulation. Much of our understanding of the breakdown of selftolerance and the progression of autoimmunity comes from the examination of mouse models. Autoimmune mouse models can be divided into two broad categories: induced autoimmunity and spontaneously occurring autoimmunity. Even though the progression of autoimmunity in humans is thought to be a highly complex process that involves multiple genetic and environmental factors, these animal models have provided much information about the molecular events that lead to a loss of self-tolerance. Molecular Mimicry One proposed model for the initiation of autoreactivity is that cross-reactive anti-self, anti-foreign B cells escape central tolerance because self-antigen is present at too low a concentration to trigger tolerance induction or because the affinity of the antibody for autoantigen is below the signaling threshold. These B cells become activated in the periphery by foreign pathogens resembling self-antigen and produce antibodies that bind both foreign and self-antigen. This cross-reactivity is known as molecular mimicry, and it is a popular model to explain the induction of many autoimmune disorders. We have detailed multiple mechanisms operating throughout B cell maturation and differentiation that are designed to avoid autoreactivity. The failure of only one tolerance checkpoint rarely leads to autoimmune disease114; it may, however, increase the level of circulating autoantibodies, without clinical disease. Origin of Autoreactive B Cells Theoretically, autoreactive cells can arise from any B cell subpopulation. The B cell may, therefore, present cryptic epitopes of many self-antigens and activate autoreactive T cells representing multiple autospecificities. In the periphery, T cells are present that have not been tolerized to these (cryptic) epitopes and thus are activated by self-peptide. These activated T cells in turn help provide co-stimulation and activate other autoreactive B cells. These B cells internalize self-antigen and present cryptic peptides to T cells that have not been tolerized, leading to activation of autoreactive T cells and initiation of the cascade. Thus molecular mimicry and epitope spreading could lead to the activation of T cells and B cells specific for multiple autoantigens as long as the autoantigens form a complex in vivo. Supraoptimal B Cell Co-Stimulation It is evident that co-stimulatory signals provided by T cells play a critical role in B cell activation. Therefore inappropriate co-stimulation may lead to the propagation of an immune response directed against a self-antigen. Intriguing examples include the cross-reactivity observed between the M protein of group A Streptococcus and cardiac myosin in rheumatic heart disease and the cross-reactivity between Campylobacter and aquaporin. Because both nonautoimmune and autoimmune-prone persons have the capacity to generate autoantibodies, it is unlikely that cross-reactivity between foreign and selfantigens is solely responsible for breakdown of tolerance. A plausible explanation is that foreign antigen acts as a molecular trigger to initiate an immune response to self-molecules, and a defect in the mechanism that regulates B cell activation leads to the propagation of an autoimmune response. In general, an initial immune response is generated against a dominant set of epitopes, followed by a later response to secondary or "cryptic" epitopes, a process known as epitope spreading. When an autoimmune response has been triggered, epitope spreading can lead to the production of additional autoantibodies with specificity for multiple self-antigens. There are several proposed mechanisms by which epitope spreading triggers a cascade of T and B cell activation. Such cross-reactive T cells become activated and provide co-stimulation to autoreactive B cells that recognize selfantigen, which results in the production of autoantibodies specific for the antigen recognized by the T cell. After internalization of the self-antigen by the autoreactive B cells, the autoantigen is processed and new cryptic epitopes of the self-antigen are presented to T cells. Thus, lowering thresholds for antigen-induced B cell activation can lead to the activation of autoreactive B cells. Only a small percentage of B cell precursors generated completes the maturation pathway. During the pro-B and pre-B cell stages of development, B cells with aberrantly rearranged H- or L-chain genes are eliminated. Autoreactive B cells can be censored at multiple developmental checkpoints: (1) After surface expression of surface immunoglobulin, immature B cells that encounter autoantigen in the bone marrow are subject to negative selection. Long-lived plasma cells that emerge from the selection process home primarily to the bone marrow, and memory B cells circulate throughout the periphery. Akira S, Okazaki K, Sakano H: Two pairs of recombination signals are sufficient to cause immunoglobulin V-(D)-J joining. Herzog S, Reth M, Jumaa H: Regulation of B-cell proliferation and differentiation by pre-B-cell receptor signalling. B cells that are stimulated by foreign antigen are selectively expanded and undergo further Ig gene diversification in peripheral lymphoid tissue. B cells that pass through these critical developmental checkpoints differentiate into long-lived memory B cells or plasma cells. In Paul W, editor: Fundamental Immunology, Philadelphia, 1999, LippincottRaven, p 831. Muller G, Lipp M: Concerted action of the chemokine and lymphotoxin system in secondary lymphoid-organ development. Treanor B, et al: the membrane skeleton controls diffusion dynamics and signaling through the B cell receptor. Paus D, et al: Antigen recognition strength regulates the choice between extrafollicular plasma cell and germinal center B cell differentiation. Busso N, et al: Leptin signaling deficiency impairs humoral and cellular immune responses and attenuates experimental arthritis. McCluskey J, et al: Determinant spreading: lessons from animal models and human disease. Brack C, Hirama M, Lenhard-Schuller R, et al: A complete immunoglobulin gene is created by somatic recombination. Ramirez J, Lukin K, Hagman J: From hematopoietic progenitors to B cells: mechanisms of lineage restriction and commitment. Igarashi H, Kouro T, Yokota T, et al: Age and stage dependency of estrogen receptor expression by lymphocyte precursors. Ohnishi K, Melchers F: the nonimmunoglobulin portion of lambda5 mediates cell-autonomous pre-B cell receptor signaling. Weller S, et al: Human blood IgM "memory" B cells are circulating splenic marginal zone B cells harboring a prediversified immunoglobulin repertoire. Kruetzmann S, et al: Human immunoglobulin M memory B cells controlling Streptococcus pneumoniae infections are generated in the spleen. Hunziker L, et al: Hypergammaglobulinemia and autoantibody induction mechanisms in viral infections. Wardemann H, et al: Predominant autoantibody production by early human B cell precursors. Yurasov S, et al: Defective B cell tolerance checkpoints in systemic lupus erythematosus. Berland R, et al: Toll-like receptor 7-dependent loss of B cell tolerance in pathogenic autoantibody knockin mice. Tissue fibroblasts may be recruited from a number of sources and cell types including the bone marrow, blood, and local stromal cells and act as organ-specific innate immune sentinel cells.

Thousands of the expanded T cells that survive after the pathogen is destroyed become memory cells acne 7 year old buy dapsone 100mg overnight delivery. Memory cells respond rapidly to recurrence of the same infection acne jeans mens discount 100mg dapsone with amex, and together with antibodies acne adapalene cream 01 purchase discount dapsone online, they rapidly eradicate that same agent if it is encountered a second time acne laser treatment generic dapsone 100mg on-line. These memory cells may also cross-react with other pathogens acne between eyebrows dapsone 100mg lowest price, and depending on the degree of cross-reaction acne wallet buy discount dapsone 100mg on line, this type of response can result in rapid clearance of a new pathogen or, sometimes, an impaired response. Antigens from Blood Are Detected Most Efficiently in the Spleen and Liver (Portal System) the spleen is a large visceral organ that filters approximately 5% of the cardiac output. The red pulp is an important location for removal of aged red blood cells from the circulation. The blood is then re-collected into a venous system that drains to the liver, joining with the portal tract. Left, Tissue section from a mouse injected with low-molecular-weight (blue) and high-molecular-weight (red) fluorescent dextrans. The low-molecular-weight dextran labels the red pulp (blue) and the high-molecular-weight dextran labels macrophages in the marginal zone (red) such that the white pulp nodule, which contains approximately 109 lymphocytes per cm3, is dark. The white pulp nodule forms around a central arteriole (O) from which smaller arterioles branch to the red pulp sinuses. B and T cells are segregated into follicles (B) and the periarteriolar lymphoid sheath (T). The blood carrying the dextran passes through the white pulp in small blood vessels (arrows) emanating from the central arteriole (not shown) and connected to red pulp sinuses that rapidly fill with blood, which fills the marginal sinus but not the white pulp itself. White pulp lymphocytes are not in direct contact with blood and need antigen presentation by cells that migrate from the marginal zone or antigens that are delivered to dendritic cells via reticular fibers. Thus the spleen provides multiple opportunities to mount primary and recall responses to particulate or soluble antigens in the blood. Immune responses in the liver are poorly understood, but this site is important because many pathogens colonize the liver. Two blood circulations supply the liver: the portal vein with deoxygenated blood from the gut and spleen, and the hepatic artery with oxygenated blood. These circulations mix in the liver sinusoids, a lowpressure network of blood spaces between sheets of hepatocytes connecting the portal tract and the central collecting vein. The major antigen-presenting cells in the liver are not Kupffer cells but the perivascular Ito cells. The gut presents a barrier between the host and billions of commensal bacteria and food antigens. There are also many pathogens, such as bacteria, viruses, protozoans, and worms, that exploit this niche. Recently it has been found that new-onset rheumatoid arthritis is associated with expansion of particular microbial taxa in the gut. Confocal imaging of hepatocytes (green autofluorescence) and blood space (red fluorescent dextran) is shown. Right, intravital imaging of natural killer T (nK T) cells (blue-green) and sign R1+ Kupffer cells in liver sinusoids (dark spaces) between hepatocytes (green autofluorescence). The ito cells would also be lining the sinusoids, but on the other side of the endothelial cells in the space of disse. The dCs extend processes through the epithelial layer to assist uptake of luminal antigens (arrows in bottom right point to the dC projections in the gut lumen). The floor of the subcapsular sinus covers the lymph node parenchyma and is the point of origin of the reticular fiber network that connects to the high endothelial venules and medullary cords, where cells move from the parenchyma into the efferent lymph. Lymph does not come into direct contact with cells in the parenchyma, but cells lining the reticular fibers and a space between the high endothelial venules and the reticular fibroblast sheath are exposed to lymph fluid. Peripheral Tolerance Induction under Steady-State Conditions Lymph nodes are associated with peripheral tolerance induction. T cells enter the lymph node via the high endothelial venules and exit via medulla to the efferent lymphatic. Changes in the Lymph Node during Infection/Vaccination Infection or vaccination in tissues induces a strong reaction in draining lymph nodes. T cells that are activated in the lymph nodes regain expression of S1P1 after 3 to 4 days, along with a new repertoire of homing molecules, and migrate to effector sites. Germinal Center Reactions: Sites of Antibody Affinity Maturation and Class Switch Recombination Low-molecular-weight antigens that enter the subcapsular sinus are directly accessible to B cells. The Tfh cells provide help to B cells that maintain or increase their affinity for antigens and can also provide cytokine signals to promote class switching. The induction of tertiary lymphoid tissues can be compared with the formation of lymph nodes during normal development. Thus steady-state presentation of inflammatory cytokines plays a key role in this process. A gC was induced by vaccination after introduction of fluorescent antigenspecific B cells and antigen. Reticular fibers, which serve as antigen conduits into the follicle, are labeled blue. The gC is outlined and divided into a dark zone (dz) containing aggregated centroblasts (green) and a light zone (Lz) containing loosely aggregated centrocytes, follicular dendritic cells (fdC-m1+), and follicular T cells (not shown). The surrounding follicle is densely packed with bystander B cells (not shown), which often enter and traverse the Lz. Green cells in the medullary region are plasma cells produced in the germinal center reaction. The generation of gut-associated Th17 cells in mice has been linked to a single species of segmented filamentous bacteria. This flexibility has a dangerous side that is constrained by anatomy and strong coupling to innate immunity. Autoimmune disease may result when weak points in tolerance mechanisms intersect with infection or tissue damage, leading the adaptive system to attack its own organs in a self-amplifying process of tissue destruction, inflammation, and inappropriate anatomic adaptation such as tertiary lymphoid tissue genesis. Thomas C, Le Deist F, Cavazzana-Calvo M, et al: Results of allogeneic bone marrow transplantation in patients with leukocyte adhesion deficiency. Sixt M, Kanazawa N, Selg M, et al: the conduit system transports soluble antigens from the afferent lymph to resident dendritic cells in the T cell area of the lymph node. Woolf E, Grigorova I, Sagiv A, et al: Lymph node chemokines promote sustained T lymphocyte motility without triggering stable integrin adhesiveness in the absence of shear forces. Wardemann H, Yurasov S, Schaefer A, et al: Predominant autoantibody production by early human B cell precursors. Pulendran B, Ahmed R: Translating innate immunity into immunological memory: implications for vaccine development. Sallusto F, Lenig D, Forster R, et al: Two subsets of memory T lymphocytes with distinct homing potentials and effector functions. Winau F, Hegasy G, Weiskirchen R, et al: Ito cells are liver-resident antigen-presenting cells for activating T cell responses. Ito Y, Hashimoto M, Hirota K, et al: Detection of T cell responses to a ubiquitous cellular protein in autoimmune disease. Gong Q, Ou Q, Ye S, et al: Importance of cellular microenvironment and circulatory dynamics in B cell immunotherapy. Jacob J, Kassir R, Kelsoe G: In situ studies of the primary immune response to (4-hydroxy-3-nitrophenyl)acetyl. Autoimmune diseases can be classified by the extent of organ involvement (organ-specific to systemic), innate immune system requirements, and effector mechanisms. However, each type of autoimmune disease has unique pathophysiologic characteristics. Advances in defining the mechanisms underlying autoimmune diseases have been greatly facilitated by delineation of the innate and adaptive immune systems. Autoimmune disease susceptibility is multifactorial, involving genetic, environmental, sex, and other factors, with genetic predisposition usually playing a central role. The contributions of these factors are typically heterogeneous, partial, and additive. Animal models have been critical for understanding the pathophysiology of autoimmune diseases and provide fundamental insights into genetic, mechanistic, and pathologic processes. Progress in delineating pathways has revealed many key genes and molecules in autoimmune diseases that are of potential therapeutic relevance. From the clinical perspective, it is the transformation to pathogenic autoimmunity that demarcates significant from insignificant self-reactivity. For many common autoimmune diseases, more definitive evidence for an autoimmune cause has come from studies showing transfer of disease by autoantibodies or self-reactive T cells and from animal models exhibiting congruent characteristics. However, no universally accepted criteria exist, and some less well-characterized diseases that are currently considered to be autoimmune may turn out to have other causes. An example of disorders that exhibit some characteristics of autoimmunity but are distinct in their pathogenesis are the autoinflammatory diseases. Included in this category are familial Mediterranean fever, the cryopyrinopathies, hyperimmunoglobulinemia D with recurrent fever, familial cold urticaria, Blau syndrome, and others. These syndromes could be considered part of a broader definition of autoreactivity in which autoinflammatory diseases mediated entirely through the innate arm of the immune system comprise one end of the spectrum, while at the other end are autoimmune diseases that require both the innate and adaptive responses. The immune system must effectively defend against a diverse universe of pathogens while simultaneously maintaining tolerance to self-antigens. Recent advances have begun to clarify how this equilibrium is established and sustained and, importantly, have identified many critical factors and processes involved in the pathogenesis of autoimmune diseases. This chapter provides a general overview of autoimmunity, covering the definition of the term, general tolerance mechanisms for T and B lymphocytes, theories of how tolerance can be breached, and ways in which genetic and environmental factors have been implicated in breaking tolerance and producing disease. Autoimmune diseases can be classified as systemic or organ-specific depending on the extent of their clinicopathology (Table 19-2). In systemic disease, autoimmunity targets ubiquitously expressed self-antigens, and end-organ injury is typically mediated by autoantibodies and, less commonly, T cells. In contrast, in organ-specific diseases, the self-antigens are typically cell- or tissue-specific in location or accessibility, and end-organ damage can be mediated by antibodies and/or T cells. It should be emphasized, however, that although the distinction of systemic and organ-specific disorders provides a conceptual framework, the individual pathophysiologies are more diverse than is implied by this simple classification. Many well-characterized autoimmune models exist in which investigators can manipulate genomes and immune systems, test interventions, and modify environments. Animal models of autoimmune disease can be divided into three main types based on their derivation: (1) spontaneous, (2) genetically modified, and (3) induced. Similarly, autoreactive B cell receptor transgenics or knockin models have been developed that have been crucial for defining B cell tolerance mechanisms. This approach makes it possible to induce autoimmunity in virtually all organ systems and to produce diseases mediated by cellular as well as humoral mechanisms. Other induced models of arthritis include streptococcal cell wall and antigeninduced arthritis. Just over 50 years ago, Burnet and Medawar advanced the critical concept that tolerance was imposed by clonal deletion of self-reactive lymphocytes during early development-that is, central tolerance. To achieve this objective, T and B cells utilize several mechanisms that can be grouped into three general strategies. For example, immature lymphocytes respond to strong antigen receptor stimulation by cell death, whereas a similar signal in mature cells leads to activation. Through this mechanism, selfreactive clones are eliminated from the nascent lymphocyte repertoire before they can cause injury. Second, activation of mature lymphocytes requires, in addition to antigen receptor engagement, a second co-stimulatory signal, the absence of which results in anergy or cell death. Third, lymphocytes are fine-tuned in various ways by a fairly extensive list of modulating factors necessary for controlling self-reactive clones. The Innate System and Tolerance Given its vital role in initiating and modulating adaptive immune responses, it is not surprising that the innate immune system strongly influences both tolerance and autoimmunity. Indeed, although its contributions have yet to be fully delineated, several ways in which self-tolerance is influenced by the innate arm have been defined. Second, some cells of the innate immune system actively suppress adaptive immune system activation under certain conditions. Although the mechanism for this association is uncertain, both defective clearance of apoptotic material/immune complexes and a shift in the activation threshold of lymphocytes have been suggested. T Cell Tolerance T cells are critical players in not only achieving but also fine-tuning tolerance to a high degree of specificity. Several mechanisms have been identified that can be divided into three main areas: central tolerance wherein T cells first acquire their antigen receptor, peripheral tolerance where T cells encounter self-antigens not present in the thymus, and postactivation regulation wherein activated and expanded T cell clones are returned to their resting state. This leakiness is probably necessary to generate a broad repertoire, but it then creates vulnerability to autoimmunity and necessitates peripheral tolerance mechanisms. In the periphery, multiple mechanisms for avoiding autoreactivity have been identified. Among these, a common explanation is that most self-antigens are not accessible to trigger a response, a situation that can be caused by low abundance, specific characteristics of the self-antigen, or location. Yet, these so-called "ignorant" T cells are fully functional and respond to selfantigen when presented in a conventional context. Tregs participate in every adaptive immune response, are critical for maintaining the proper level of immune response, and are activated at the same time as conventional T cells. Second, soluble inhibitors of inflammation and immune activation are secreted by particular tissues. In addition to central and peripheral tolerance, the immune system must also avert autoimmunity by suppressing or eliminating T cells after their activation or expansion. Several checkpoints considered important for controlling autoreactive B cells and maintaining self-tolerance have been identified and include many central and peripheral mechanisms similar to those described for T cells, as well as a few additional ones.

Although the somatotroph is clearly transformed acne nyc purchase dapsone overnight delivery, the sequence of events leading to clonal expansion is multifactorial acne reviews cheap dapsone 100mg mastercard. Thus acne redness purchase dapsone overnight, a spectrum of genetic events appears to culminate in somatotroph transformation and adenoma pathogenesis acne on arms cheap dapsone 100mg overnight delivery. Excision or functional ablation of the ectopic hormone-producing tumor source should ideally result in biochemical and clinical cure of acromegaly acne zones and meaning order dapsone 100mg overnight delivery. A definitive diagnosis of the etiology of hypersomatotrophism should therefore be made prior to instituting acromegaly therapy acne meaning buy discount dapsone 100mg on line. Patients also often experience systemic effects, obvious metastatic disease, or other humoral effects of the carcinoid syndrome [73]. The pituitary often shows evidence of somatotroph hyperplasia with preserved reticulin network. Embryonal pituitary development involves dorsal migration of fetal adenohypophyseal cells. Residual tumor cells may also be dislodged after neurosurgical resection of invasive pituitary adenomas and give rise to subsequent recurrent ectopic adenomas. Acromegaloidism Patients who manifest clinical features of acromegaly but do not harbor a demonstrable pituitary or extrapituitary tumor have been termed "acromegaloid. These patients exhibit soft tissue and skin changes usually associated with acromegaly and some may even have bony features of the disorder, and occasionally hyperglycemia. The disorder is associated with decreased life expectancy, with larger, more aggressive multisite tumors; genetic screening and subsequent counseling is recommended. In four of eight patients, Gs mutations were detected in both endocrine and nonendocrine organs [98]. This is the most commonly identified mutation, but is likely to be overrepresented secondary to a Finnish founder effect. Because of the very low penetrance, the value of follow-up of carriers without overt disease is not resolved [108,109]. Prevalence of the mutation is very low (B5%) in apparently sporadic tumors and is negligible after the age of 40 years [110]. Familial tall stature, redundancy of Y chromosomes, Marfan syndrome, and homocystinuria should be excluded prior to considering the endocrine causes of tall stature. If pituitary imaging reveals the presence of an adenoma, surgical resection should be attempted, but these are usually large tumors, and as B80% are invasive, they are difficult to resect. Radiation therapy should be considered for failed responses to surgery and medical treatment. Central features of the expanding pituitary mass are common to all pituitary masses. They include headache, visual dysfunction due to chiasmal compression, and rarely hypothalamic and frontal lobe dysfunction. Inferior extension of the mass may cause cerebrospinal fluid rhinorrhea and nasopharyngeal sinus invasion. These local signs are especially important in acromegaly, as most series report a relatively higher preponderance of macroadenomas (. Effects of hypersomatotrophism on acral and soft tissue growth, as well as metabolic function, may occur insidiously over several years [120,121] (Table 15. The overall clinical and biochemical features of acromegaly, as well as the pituitary tumor characteristics of patients presenting with acromegaly, appears to be unchanged from 1981 to 2006 [126]. These findings underscore the elusiveness of the symptomatology, which often results in the disease being diagnosed only when patients seek care for dental, orthopedic, or rheumatologic disorders. In a review of several hundred patients worldwide, 98% were reported with acral enlargement, while hyperhidrosis was prominent in 70% [120]. Moreover, the time between onset of symptoms and diagnosis of acromegaly ranges from 6. Generalized visceromegaly occurs with enlargement of the tongue, bones, salivary glands, thyroid, heart, liver, and spleen [129]. Patients have characteristic facial features, large fleshy nose, spade-like hands, and frontal bossing. Some patients, if presenting early, may have subtle facial and peripheral features. Serial review of old photographs often accentuates the progress of these subtle physical changes [130]. Although skeletal muscle mass is largely unchanged in acromegaly, the nonsmooth muscle lean compartment is increased [131]. Mechanisms underlying metabolic adaptation to maintaining steady-state protein mass include enhanced protein breakdownsynthesis rates, with intact protein oxidation [132]. Note acromegaly facial features and mild left proptosis consistent with cavernous sinus tumor invasion [123]. Characteristic voice deepening with a sonorous resonance occurs because of laryngeal hypertrophy and enlarged paranasal sinuses. A meta-analysis showed that acromegaly is associated with increased bone formation and resorption, higher femoral neck bone mineral density, and increased frequency of vertebral fractures (odds ratio 8. Arthropathy occurs in about 70% of patients, most of whom exhibit objective signs of joint swelling, hypermobility, and cartilaginous thickening [137,138]. Up to half of patients experience joint symptoms severe enough to limit or impair daily activities [139,140]. Knees, hips, shoulders, lumbosacral joints, elbows, and ankles are affected in decreasing order of frequency. Joint involvement may be mono- or polyarticular, and although crepitus, stiffness, tenderness, and hypermobility are common, joint effusions are rarely encountered [141]. Local periarticular fibrous tissue thickening may cause subsequent joint stiffening, deformities, and nerve entrapment. Neural enlargement, local fluid retention, and swelling of wrist soft tissues may lead to carpal tunnel syndrome, a painful edematous entrapment median neuropathy, which occurs in up to half of all patients. About 70% of patients exhibit large-joint and axial arthropathy, including synovitis and periarticular calcifications [138,144,145]. Ulcerations and fissures on the weight-bearing areas of new cartilage are often accompanied by new bone formation. This process eventually results in debilitating osteoarthritis associated with bone remodeling, osteophyte formation, subchondral cysts, narrowed joint spaces, and lax periarticular ligaments. Osteophytes are seen at the tufts of the phalanges and over the anterior aspects of spinal vertebrae. Ossification of ligaments and periarticular calcium pyrophosphate deposition are also found [138]. The duration of hypersomatotrophism appears to directly correlate with the severity of the joint changes, and responses to therapy (see below) will usually depend on the degree of irreversible cartilage degeneration already in place. Skin Changes Hyperhidrosis and oily skin with an unpleasant odor are common early signs, occurring in up to 70% of patients. Patients often relate the need to increase their use of deodorant or cosmetic powders. Facial wrinkles, nasolabial folds, and heel pads are increased in thickness, and body hair may become coarsened [146]. Thickening of the skin has been attributed to glycosaminoglycan deposition [147], while connective tissue collagen production is also increased [148]. Skin tags are common and may be important markers for the concomitant presence of adenomatous colonic polyps [149]. Cardiovascular Complications Cardiovascular disease is a major cause of morbidity and mortality [150], with symptomatic cardiac disease present in up to 60% of patients. Arrhythmias, hypertension, valvular disease, and sodium and fluid retention leading to expanded extracellular fluid volume are common manifestations. Hypertension (systolic and diastolic), diabetes mellitus, elevated HbA1c, decreased low density lipoprotein, and elevated cholesterol all lead to increased Framingham risk score in acromegaly versus a control population (p, 0. Overall, the constellation of glucose intolerance, hypertension, arrhythmias, and diastolic overload may lead to intractable heart failure, especially if rigorous biochemical acromegaly control is not achieved [20]. About half of all patients are at "intermediate-to-high" risk for coronary atherosclerosis [152,153]. About half of patients with active acromegaly have hypertension, and 50% of these have evidence of left ventricular dysfunction. Interestingly, left ventricular hypertrophy is also reported in 20% of young normotensive patients, and in up to 90% of those with long-standing disease. Increased postexercise ventricular ejection fraction is observed in B70% of patients [150,155]. Subclinical left ventricular diastolic dysfunction is consistent with unique pathologic findings, including myocardial hypertrophy, interstitial fibrosis, and lymphocytic myocardial infiltrates. Electrocardiograms are abnormal in about 50% of patients, with S-T segment, T-wave abnormalities, conduction defects, and arrhythmias accounting for most changes. Cardiovascular disease is the most important cause of mortality in acromegaly, accounting for B60% of deaths. Pathologic features of median neuropathy have been ascribed to increased edema, rather than extrinsic compression [142]. About half of all patients develop proximal myopathy, which may be accompanied by myalgias and cramps, nonspecific electromyogram myopathic changes with hypertrophy and necrosis of muscle fiber, and elevated creatine phosphokinase levels [167]. Open-angle glaucoma may also result from impaired aqueous filtration through hypertrophied tissue surrounding the canal of Schlemm. Psychologic Changes Respiratory Complications Prognathism, thick lips, macroglossia, and hypertrophied nasal structures may result in significant airway obstruction [161]. Additional clinical features of acromegaly contribute to impaired upper respiratory function. Irregular hypertrophy of laryngeal mucosa and cartilage may lead to unilateral or bilateral vocal cord fixation or laryngeal stenosis with accompanying voice changes [161]. These obstructive features may necessitate tracheostomy either to maintain adequate baseline airway function, or especially at the time of surgical anesthesia. Difficulty in tracheal intubation is often encountered in patients undergoing anesthesia. Central respiratory center depression as well as upper airway obstruction may contribute to the development of paroxysmal daytime sleep (narcolepsy), sleep apnea, and habitual excessive snoring. Obstructive sleep apnea, characterized by excessive daytime sleepiness with at least five nocturnal episodes of obstructive apnea per hour, has been documented in. The sleep apnea of acromegaly may be due to obstruction of the respiratory tract, or central in origin [163,164]. Development of Neoplasms Several benign and malignant tumors have been reported in association with acromegaly and retrospective studies have suggested increased risk for gastrointestinal malignancies [168]. In the German acromegaly registry of 446 patients with 6656 person-years of follow-up since diagnosis, no increased cancer incidence was found [174]. Although coexistence of acromegaly and meningioma has been reported, meningiomas are known to develop at sites of previous head trauma, inflammation, or irradiation [175]. No association has been reported between acromegaly and other intracranial neoplasms. Reports of high prevalence of colonic polyps in acromegaly may reflect increased physician awareness in screening for these tumors, as well as the use of diagnostic colonoscopy. Prospectively, B45% of patients with acromegaly harbor colonic polyps, but a controlled study in 161 patients revealed no increased polyp incidence in acromegaly [171]. Acrochordons (skin tags) have been noted in most patients found to harbor colonic lesions [149]. Hypertrophic mucosal folds, colonic hypertrophy, dolichocolon, and slow colonic transit times are commonly encountered, and intestinal bacterial overgrowth has been attributed to autonomic dysfunction [176]. Colonoscopy is warranted in these Neuromuscular Changes Peripheral acroparesthesias occur in almost half of all patients. Synovial edema and hyperplastic wrist ligaments and tendons contribute to painful median nerve compression with the resultant carpal tunnel syndrome [166]. Timely diagnosis and resection of premalignant polyps is prudent for improved morbidity in this relatively high-risk group of patients. As patients with acromegaly are living longer due to improved biochemical control, it is apparent that long-term prospective controlled studies are required to resolve this question, as the incidence of malignancy increases with aging. Functional pituitary stalk compression by an adenoma may prevent hypothalamic dopamine from impinging upon pituitary lactotrophs, resulting in release from tonic hypothalamic inhibition [181]. Hypopituitarism, which develops as a result of the tumor mass compressing surrounding normal Cardiovascular disease: 1. Benign prostatic hypertrophy has been documented with no apparent increase in prostate cancer rates [185]. Reduced life expectancy in a series of 194 patients was due to cardiovascular disorders in 24% of deaths, followed by respiratory (18%), and cerebrovascular disease (14%) [187]. Other reports confirming these findings showed a two- to threefold increase in mortality primarily due to cardio/cerebrovascular and respiratory disease, with some series also showing differences in mortality in age- and sex-specific subgroups (Table 15. As achieving optimal biochemical control may be challenging, rigorous diagnosis and treatment of comorbidities that contribute to mortality is important. Hypertension and diabetes mellitus are amenable to early interventions, which have likely contributed to the observed trend of reduction in mortality rates more recently reported [190]. While cardiovascular and cerebrovascular diseases contributed to overall increased mortality, cerebrovascular disease was the major cause of death in patients who had undergone radiotherapy (Table 15.

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