Talal I Dahhan, MD

• Assistant Professor of Medicine

https://medicine.duke.edu/faculty/talal-i-dahhan-md

Even some peptide hormones such as angiotensin must undergo enzymatic conversion from secreted precursor form to generate the active hormone kidney transplant and erectile dysfunction treatment generic cialis extra dosage 200 mg with amex. The central question in hormone action is how a hormone circulating in the blood stream in minute concentrations recognizes its specific target cells and regulates physiologic processes within them erectile dysfunction due to diabetic neuropathy buy cialis extra dosage visa. Research addressing this question over the past four decades defined receptors erectile dysfunction kidney transplant order 100mg cialis extra dosage with visa, previously a purely theoretical concept erectile dysfunction drugs in nigeria best 50mg cialis extra dosage, in molecular terms erectile dysfunction shake recipe generic 200 mg cialis extra dosage. Receptors are highly selective molecules that bind their cognate hormones with high affinity and specificity erectile dysfunction protocol quality cialis extra dosage 200 mg. Hormones regulate cellular physiologic processes such as secretion of hormones, enzymes, and other compounds, muscle contraction, growth, and proliferation. Signal transduction is the general term for the biochemical steps between hormone binding to receptor and alterations in cell physiology. Cell surface receptors may generate "second messengers," which in turn regulate a kinase cascade. Receptor activation may have rapid effects such as exocytosis of secretory granules, but longer-term actions involving gene regulation may also be a consequence of second messenger and kinase cascade activation. Steroid and thyroid hormones and vitamin D bind to members of the nuclear receptor family. Left, glucocorticoid receptor family members bind as homodimers to palindromic dnA sites. Thyroid hormone receptor family members bind primarily as heterodimers with retinoid X receptor to direct repeat dnA sites separated by varying numbers of base pairs. Right, As a result of hormone binding, repressor complexes dissociate and activator complexes bind to nuclear receptors. Genetic endocrine diseases include those caused by mutations in one component of a signal transduction pathway leading either to hormone "resistance" or hormone-independent activation (Tables 209-1 and 209-2). In the former, subjects present with apparent hormone deficiency, but direct hormone measurement reveals high concentrations of bioactive hormone that fails to act owing to target organ resistance. In the latter, patients present with apparent endocrine hyperfunction, but direct measurement reveals suppressed hormone concentration due to intact negative feedback. Loss-of-function mutations in receptors and in signaling intermediates such as G proteins have been identified in patients with hormone resistance. The converse, mutations that constitutively activate receptors or downstream signaling components,7 have been identified in endocrine hyperactivity diseases such as familial male precocious puberty and familial nonautoimmune hyperthyroidism. Receptor inactivating mutations that lead to hormone-resistance diseases, such as the androgen receptor mutations responsible for varying degrees of testosterone insensitivity,8 have been identified for both the cell surface and nuclear classes of receptors. Mutations in genes encoding proteins such as corepressors that form part of the nuclear receptor complex may also cause hormone resistance. Peptidyl hormones of endocrine cells origin in the gut-their discovery and physiological relevance. Levels of glucose-regulatory hormones in patients with non-islet cell tumor hypoglycemia: including a review of the literature. D is incorrect because outputs other than hormones can exert negative feedback suppression. When activated, may exert their effects by directly regulating gene transcription D. Irrespective of starting location, always translocate to the nucleus to exert their actions E. Both B and C Answer: E Because there are cell surface receptors that do not translocate to exert their action and nuclear receptors for steroid hormones, A and D are incorrect. May be caused by loss-of-function mutations in genes encoding cell surface or nuclear receptors or other components of the signal transduction pathway E. Are generally associated with autoimmune disease Answer: D All the cited examples may be causes of inherited hormone resistance diseases, not just B. Cells dispersed throughout the lining of the small intestine and within the pancreas C. All of the above Answer: E Research has shown that not only classical endocrine glands such as the thyroid and adrenal, but also dispersed enteroendocrine cells in the gut lining and islets in the pancreas, neuroendocrine cells in the posterior pituitary, and nonclassical hormone-secreting sites such as kidney, heart, and adipose are all sources of hormone secretion. All of the above Answer: A A mutation in the hormone gene altering the signal sequence of a peptide hormone and thereby impairing its ability to be secreted may cause genetic forms of hormone deficiency such as hypoparathyroidism. The mechanism whereby an "output" regulated by a hormone feeds back to regulate the secretion of that hormone C. The most important environmental factors are temperature and light, which fluctuate in a predictable way each day. Humans have a circadian clock that makes sure that the physiology and behavior are attuned to the time of day. The nervous system senses temperature and light, and it uses them as clues to guide eating, activity, sleep, and other essential life functions. The neurohypophysial neurons originate from the paraventricular and supraoptic nuclei and traverse the hypothalamic-pituitary stalk to the posterior pituitary, where nerve endings release vasopressin and oxytocin. The blood supply of the median eminence comes from the superior hypophysial artery and its richly arborized capillary beds that extend into the median eminence and then coalesce to form the portal veins that traverse the pituitary stalk and terminate in the pituitary gland. The neuroendocrine system relies on a series of feedback loops, which regulate pituitary hormones as well as the levels of target organ hormones. The target organ hormones regulate both the hypothalamus and the pituitary gland to complete the feedback loop. Perturbations in feedback loops can be altered by factors like circadian rhythms (circadian periodicity), stress, nutritional status, and response to systemic illness. Note that the multiple inputs to such neurons, using neuron 2 as an example, can be stimulatory, inhibitory, or neuromodulatory, in which another neuron may affect neurotransmitter release. Neuron 1 represents a peptidergic neuron originating in the magnocellular division of the paraventricular nucleus or supraoptic nucleus and projecting directly to the posterior pituitary by way of the hypothalamic-neurohypophyseal tract. This article reviews the principles of neuroendocrine regulation as well as neuroendocrine diseases, including congenital disorders, tumors, inflammatory and infiltrative diseases, trauma, and irradiation. Some feedback loops are redundant, and some hypophysiotropic hormones exert effects on more than one pituitary hormone. Furthermore, the hypophysiotrophic hormones themselves are regulated by signals higher in the brain, such as the thalamus and the molecular clocks. The processes that cause the infantile and prepubertal quiescent periods are not understood. In women, positive and negative regulation of steroid hormone feedback in the hypothalamic-pituitary-gonadal axis occurs at both the hypothalamic and pituitary levels. Mutations in the kisspeptin gene have been associated with hypothalamic hypogonadism and impaired pubertal development, thereby demonstrating its role in the reproductive axis. These ovarian peptides are also found in the pituitary; therefore they may have additional local effects on gonadotropin secretion. Somatostatin Somatostatin (also known as somatotropin release inhibiting factor) inhibits the secretion of growth hormone. Other tissues with somatostatin include the gut mucosa, D cells of the pancreatic islets, and the myenteric neural plexus. C shows the effect of stereotaxic placement of a thyroid hormone implant adjacent to one side of the paraventricular nucleus in a hypothyroid animal. For the opioid -receptor, which mediates behavioral, analgesic, and endocrine effects, the principal peptide ligands are met- and leu-enkephalins that are derived from proenkephalin A. The -receptor, which mediates sedation and ataxia, binds principally to dynorphin and the neoendorphins. The pentapeptide enkephalins are derived from the 28-kD precursor proenkephalin A. Neuronal perikarya containing the enkephalins are widely distributed in the brain. This peptide as well as shorter peptides called -neoendorphin (with 10 amino acids) and -neoendorphin (with 9 amino acids) react almost exclusively with the -receptor. Opioid peptides that influence hormone secretion in the anterior pituitary are produced through modulation of hypothalamic bioamines and hypophysiotropic factors. The specific functions of the various opioid peptides and their receptors are incompletely understood, although evidence links them to a number of bodily functions, including stress, mental illness, narcotic tolerance and dependence, pregnancy, eating, drinking, gastrointestinal function, learning, memory, reward, cardiovascular responses, respiration, thermoregulation, locomotor activity, seizures, brain electrical activity, and neuroimmune activity. The exogenous administration of analogues of -endorphin or enkephalin increase serum levels of growth hormone and prolactin, but blocking endogenous opioid pathways with naloxone does not alter basal or stimulated levels of growth hormone or prolactin. Overall, the effects of the endogenous opioids on the normal physiologic regulation of the various pituitary hormones in humans is minimal. Pituitary hormones are secreted in a pulsatile fashion but in the context of underlying rhythms. Pulse frequency is driven by the frequency at which the hypophysiotropic factor is released, which in turn is regulated by the hypothalamic pulse generator system. The pituitary has an intrinsic rhythm of small amplitudes at a frequency of every 2 to 10 minutes. The pulsatile release of hypophysiotropic releasing factors is superimposed on this intrinsic rhythm with or without the withdrawal of a corresponding inhibitory factor. Ultradian rhythms are less than 1 day, circadian rhythms have a periodicity of about 24 hours (synchronized by an environmental cue such as the light-dark cycle), and infradian rhythms have a periodicity of more than 24 hours. The suprachiasmatic nucleus functions as a circadian pacemaker and receives light-induced electrical impulses from the retina and then transmits these impulses to the pineal gland, where they are converted to hormonal signals. Infradian rhythms include the gravitational influence of the moon, which guides the menstrual cycle. The resulting increase in cortisol then reduces the intensity of the inflammatory response and the related release of monokines, thereby completing the feedback loop. Prolactin Inhibitory Factor the inhibitory component of hypothalamic regulation of prolactin secretion predominates over the stimulatory component. Dopamine is the major factor that inhibits prolactin in most physiologic circumstances. When endogenous dopamine receptors are blocked by drugs, such as the antipsychotic agents, prolactin levels rise. Lesions that interrupt the basal hypothalamic neuronal pathways that carry dopamine to the median eminence or interrupt portal blood flow. In addition to a direct stimulatory effect on the pituitary, ghrelin amplifies secretion of growth hormone by indirect hypothalamic actions. However, ghrelin appears to be more important for the regulation of appetite and food intake. The mechanisms underlying circadian regulation are cell-autonomous, transcription-translation feedback loops. Most cells in the body have a molecular clock, and the orchestra leader of these rhythms resides in the suprachiasmatic nucleus of the hypothalamus. Signals from feeding, glucocorticoids, temperature, and metabolic markers (such as leptin) modulate this orchestra and the periodicity of various physiologic/metabolic reactions. Interesting changes occur in gonadotropin secretion as a child passes through puberty into adulthood. In patients who have anorexia nervosa (Chapter 206), the pattern of gonadotropin secretion often reverts to this pubertal pattern. This phenomenon suggests that body composition may influence the pulsatile secretion of gonadotropins. Recent studies implicate leptin levels as the signal that indicates changes in body composition. Whether the cause of abnormal sleep patterns in the elderly is a result of the changes in the circadian rhythm is not known. Furthermore, changes in the hormonal milieu associated with sleep deprivation and disruption of the axes result in significant metabolic sequelae, such as hypertension and impaired glucose tolerance. Systemic illnesses also can alter hypothalamic regulation and cause systemic illnesses. Axons that project to the median eminence contain the various hypophysiotropic factors that are concentrated in the basal portion of the hypothalamus. Thus, lesions located within this final common pathway can decrease secretion of some or all of the pituitary hormones except prolactin, which may increase because its tonic inhibition by dopamine is eliminated. Symptoms of hypothalamic dysfunction also correlate with the size of the lesion, the area of the hypothalamus involved, and the rapidity at which the lesion grows. Slowly growing lesions typically cause gradual hormone dysregulation rather than sudden symptoms. Visual field testing may detect an impingement on the optic chiasm and nerves by hypothalamic lesions. Detailed hypothalamic-pituitary function testing may reveal functional hypothalamic disruption that is not otherwise clinically evident. The most common embryopathic disorders that affect the hypothalamus are the midline cleft syndromes, which cause varying defects of midline structures, especially the optic and olfactory tracts, the septum pellucidum, the corpus callosum, the anterior commissure, the hypothalamus, and the pituitary. The clinical features of midline cleft defects vary from cyclopia to cleft lip and from isolated hypothalamic hormone defects to panhypopituitarism. Optic nerve hypoplasia is a common but complex congenital disorder of unknown cause.

The insulin tolerance test is performed following an overnight fast by administering 0 erectile dysfunction caused by supplements order cialis extra dosage online now. The blood glucose level is measured every 15 minutes impotence in men over 50 purchase cheap cialis extra dosage line, monitoring for a glucose level less than 40 mg/ dL or when symptoms of hypoglycemia appear (whichever is first) erectile dysfunction drugs egypt buy cialis extra dosage 100 mg with amex. The insulin tolerance test should be conducted cautiously in patients with seizure disorders because hypoglycemia may lower the seizure threshold impotence treatment vacuum devices order cialis extra dosage 40mg overnight delivery. This test erectile dysfunction before 30 purchase cheap cialis extra dosage on-line, which is not as well standardized as the insulin tolerance test erectile dysfunction for young adults order cialis extra dosage 200mg with visa, bypasses the hypothalamus. The metapyrone test, which often is poorly tolerated and can be difficult to obtain, is now rarely used. Emergency hydrocortisone injection kits are worthwhile in case vomiting prevents oral dosing. However, if the underlying disease for which the steroids were given is still active, other immunosuppressive drugs must be substituted, or the underlying disease will flare. Cushing Disease Cushing syndrome is a clinical syndrome that reflects excessive tissue exposure to glucocorticoids. Approximately 60 to 70% of all cases of Cushing syndrome represent Cushing disease caused by a solitary corticotroph adenoma, although rare cases are caused by corticotroph hyperplasia or even more rarely a corticotroph carcinoma. The molecular pathology of most corticotroph adenomas is unknown because the usual oncogenes and tumor suppressor genes do not appear to be commonly involved. In patients with familial endocrine tumor syndromes, corticotroph producing adenomas are more rare than nonsecreting adenomas or adenomas that secrete growth hormone or prolactin. The symptoms that lead most patients to seek medical care are weight gain, sleep disturbances, emotional lability, and the typical physical changes associated with glucocorticoid excess. Most patients experience depression, and some even have suicidal ideation if left untreated. In menstruating females, the first perturbations can be oligomenorrhea and amenorrhea. Patients may also note proximal muscle weakness when entering or exiting an automobile or even brushing their hair. Occasional patients complain of headaches and vision loss depending on the size of the pituitary adenoma. Because of their immunocompromised state, the initial presentation also can be with life-threatening infections and sepsis. The associated hypercoagulable state can result in deep venous thrombosis or pulmonary embolism (Chapter 74). Common findings on physical examination include central obesity, owing to muscle wasting. Large, wide, violaceous striae ("stretch marks") are also seen on the abdomen, under the breasts, in the axillae, and in the upper inner thighs. Compared with the stretch marks in pregnancy, Cushing striae are usually wider than a fingerbreadth, purple in color, and can have subcutaneous bleeding that contributes to their pigmentation. Abnormal adipose tissue is usually seen between the scapulae ("buffalo hump") or in the supraclavicular space. In the face, fat deposition causes "moon facies," and the increased hematocrit contributes to facial plethora (ruddy cheeks) (Table 211-9). Multiple ecchymoses on the trunk and extremities can be seen due to bruising from capillary fragility. Patients can have mild glucose intolerance or flagrant diabetes depending on the absolute elevation of the cortisol level as well as its chronicity. Relatively constant high levels of cortisol do not follow the physiologic diurnal variation. Most patients with obesity, hypertension, and glucose intolerance or diabetes do not have Cushing syndrome, but the presence of the classic physical findings may suggest the need for further investigation. No single diagnostic test can confirm Cushing disease, but a constellation of test results is usually determinative. However, subjecting a patient to surgical pituitary exploration in the absence of a demonstrable mass is likely to result in an unsuccessful surgery. Measurement of the Serum Cortisol Level Inferior Petrosal Sinus Sampling Hypercortisolism is challenging to confirm by measuring a random serum cortisol level because 80% of serum cortisol is bound to cortisol-binding globulin, 10% is bound to albumin, and only 10% is free. However, biologic variation as well as problems with the over- or under-collection of urine make this test less than ideal for the initial screening of Cushing syndrome. In patients with Cushing disease and macroadenomas, only about one third of patients have long-term remission. When initial surgery fails, a second pituitary surgery has a success rate of only about 50%. Pituitary irradiation or bilateral adrenalectomy may be recommended in patients who have a recurrence, in whom surgery is contraindicated (large tumor with invasion of carotid or cavernous sinus), or when a skilled neurosurgeon is not available. Pituitary radiation can take up to 2 to 5 years to be effective, and panhypopituitarism usually results. If a pituitary tumor cannot be demonstrated with certainty, bilateral laparoscopic adrenalectomies will cure the hypercortisolism, and lifetime postoperative steroid replacement is then required. The somatostatin analogue pasireotide can normalize cortisol levels in about 20% of patients, but it worsens hyperglycemia in about 75%. Chemical adrenalectomy using ketoconazole, mitotane, metapyrone, or etomidate is poorly tolerated and difficult to titrate to normal adrenal function. Late-Night Salivary Cortisol Measurement Late-night (23:00 to 24:00 hour) salivary cortisol testing is increasingly used as an initial test to evaluate patients with a clinical suspicion of Cushing syndrome. The diagnostic sensitivity of this test is high (80 to 90%), but its specificity is lower (70 to 90%). At least five variations of dexamethasone suppression testing have been described. All versions require patients to self-administer the dexamethasone at inconvenient hours of the day (11 pm) or up to four times a day. A popular option is a single dose of 1 mg dexamethasone administered at 11 pm, with blood obtained by 8 am the following morning. Other risk factors for Nelson syndrome include longer duration of Cushing disease before diagnosis and treatment, younger patients, inadequate glucocorticoid replacement, and tumors with higher mitotic indices. Such patients should have their hormones measured prior to administration of the am dose of steroid or 1 hour thereafter. In most cases of pituitary-dependent Cushing syndrome, the increase is greater than 5. Lateralization would mean that the ratio of the left to right side is greater than 2. In females who have not yet started puberty, estrogen should be initiated at low doses to promote breast development. When breakthrough bleeding occurs about 6 months later, cyclical therapy can be started by adding a progestogen and then increasing estrogen doses gradually over a 2- to 3-year period. Chapter 223 provides guidance for inducing ovulation for women who hope to become pregnant. In men, testosterone can be replaced using intramuscular injections at 2- to 4-week intervals. Doses and the intervals between injections should be adjusted based on peak and trough testosterone levels (one week after and just before the next dose) and self-reported libido. Oral androgens can cause hepatotoxicity and should be avoided, but transdermal testosterone is effective for maintaining stable levels. The protein is glycosylated in the Golgi apparatus, and this glycosylation is responsible for the proper synthesis and transport of the molecule from the pituitary into the blood. These peptides interact with their cognate receptors located in the cell membrane of their target cells. These transmembrane receptors classically have an extracellular domain that binds the hormone, an intramembranous domain, and an intracellular domain that transduces the hormone signal to the cell. Mutations in the extracellular or intracellular domain can cause constitutive activation of the receptor even in the absence of the ligand. The result is the appearance of a hormone-rich state in the absence of the hormone. Similarly, mutations in the receptor can make it insensitive to the ligand, so that even high hormone levels are not recognized by the receptor. Lastly, due to the similarity of the -subunit among these glycoprotein hormones, there can be some promiscuity of ligand stimulation when ligand levels are high. Gonadotropins regulate sexual differentiation, the production of sex steroids, and gametogenesis. Most gonadotrophinomas are clinically silent except when their size results in neurologic findings such as visual field problems or headaches. Patients usually present with hypogonadism because secreted gonadotropins are ineffective for stimulating the gonads. Some patients may have nonspecific moderate elevations of prolactin, but almost all cases are diagnosed postoperatively when the surgical specimen is analyzed. Functional gonadotropin deficiency can be transient as seen in chronic illness, starvation, Cushing syndrome, anorexia nervosa (Chapter 206), or alcoholism (Chapter 30). The clinical presentation of hypogonadotrophic hypogonadism depends on the onset (acquired or congenital), the severity of the defect, and any associated conditions. Classically, patients present in the second or third decade of life with poorly or absent sexual characteristics, failure to enter puberty, and primary amenorrhea or infertility. The endocrine diagnosis of hypogonadotrophic hypogonadism is rather straightforward when there are low levels of testosterone in men or estradiol in women in the presence of low or normal levels of gonadotropins. Occasionally a provocative test is necessary to confirm hypogonadotrophic hypogonadism and to distinguish hypothalamic from pituitary disease. Transsphenoidal surgery usually can completely or partially reverse any hypopituitarism and visual field impairment but is rarely curative because the tumors are large. Postoperative radiation therapy may benefit patients who have minimal residual tumor. Feedback by thyroid hormone is dependent on intranuclear thyroid hormone receptors, which bind T3. Occasionally, patients do not have hyperthyroid symptoms, most likely due to habituation to the mildly elevated hormone concentrations. Another cause of the constellation of thyroid tests consistent with central hypothyroidism would be in euthyroid sick syndrome (Chapter 213) or nonthyroidal illness. In patients with concurrent critical illness, cytokines inhibit the release of hypothalamic and pituitary hormones. Furthermore, euthyroid sick syndrome is characterized by an increase in serum reverse T3, which is formed by 5 deiodination of T4 and is not biologically active. The conversion to the inactive reverse T3 occurs in the tissues and is thought to preserve metabolic demand during critical illness. Treatment of secondary hypothyroidism is straightforward once the diagnosis is made. Treatments and outcomes are similar to those for gonadotropin-producing adenomas (see above). A -blocker such as propranolol (80 to 160 mg daily) or atenolol (25 to 50 mg daily) can be given to ameliorate some of the symptoms and signs of hyperthyroidism (Chapter 213). However, if euthyroidism cannot be achieved with somatostatin analogs or dopamine agonists, short-term administration of a thionamide is necessary to restore euthyroidism prior to neurosurgery. Nonfunctioning pituitary adenomas do not cause hormonal excess,17 although hyperprolactinemia can occur if the pituitary stalk is sufficiently compressed. As a result, these tumors are usually detected when their size causes neurologic symptoms, especially visual field abnormalities, headaches, and ophthalmoplegias. Elevated prolactin levels from stalk compression are much lower than the levels seen with a macroprolactinoma. Oftentimes a nonfunctioning pituitary adenoma is found incidentally when a pituitary mass is discovered in a patient who has a brain imaging study for an unrelated reason. With few exceptions, pituitary tumors are adenomas that can grow around the sella and invade the carotids and sphenoid sinuses but that do not metastasize. The Ki-67 proliferation index of greater than 3% can be useful as a guide to suggest a more aggressive pituitary tumor. Surgical debulking is the standard therapy, but radiotherapy and temozolomide chemotherapy also have been used because pituitary tumors can have multiple recurrences and be resistant to standard treatments. Efficacy and safety of long-acting pasireotide in Japanese patients with acromegaly or pituitary gigantism: results from a multicenter, open-label, randomized, phase 2 study. Hormonal replacement in hypopituitarism in adults: an Endocrine Society clinical practice guideline. Analysis of volumetric response of pituitary adenomas receiving adjuvant CyberKnife stereotactic radiosurgery with the application of an exponential fitting model. During transport, the processing enzymes cleave provasopressin into vasopressin (9 amino acids), vasopressin-neurophysin (95 amino acids), and vasopressin glycopeptide, or copeptin (39 amino acids). Pro-oxytocin is similarly cleaved to oxytocin (which differs from vasopressin by only two of nine amino acids) and oxytocinneurophysin. Physiologic release of vasopressin or oxytocin into the general circulation occurs at the level of the posterior pituitary, where, in response to an action potential, intracellular calcium is increased and causes the neurosecretory granules to fuse with the axon membrane, thereby releasing each hormone into the general circulation. Although each of the other prohormone fragments are released into the circulation, vasopressin and oxytocin are the only known biologically active components of the prohormones. The primary physiologic action of vasopressin is its function as a water-retaining hormone.

Pheochromocytoma in pregnancy can cause the death of both the fetus and the mother erectile dysfunction treatment bay area purchase cialis extra dosage 100mg mastercard. The approach to the biochemical diagnosis is the same as for nonpregnant patients erectile dysfunction medication shots order cialis extra dosage without prescription. The treatment of hypertensive crises is the same as for nonpregnant patients erectile dysfunction doctor in philadelphia proven cialis extra dosage 40 mg, except that nitroprusside should be avoided safe erectile dysfunction pills buy cialis extra dosage master card. Although the most appropriate management is debated erectile dysfunction after radiation treatment for prostate cancer effective cialis extra dosage 200mg, adrenal pheochromocytomas should be removed promptly after - and -adrenergic blockade if the diagnosis is made during the first two trimesters of pregnancy erectile dysfunction treatment options generic cialis extra dosage 200mg online. If the pregnancy is in the third trimester, one operation is recommended for cesarean delivery and removal of the adrenal pheochromocytoma at the same time. The management of catecholaminesecreting paragangliomas in pregnancy may require modification of these guidelines, depending on tumor location. Careful preoperative pharmacologic preparation is crucial for successful treatment. The laparoscopic approach to the adrenal gland is the procedure of choice for a solitary intra-adrenal pheochromocytoma smaller than 8 cm in diameter. Laparoscopic adrenalectomy for pheochromocytoma should be converted to open adrenalectomy in cases of difficult dissection, invasion, adhesions, or an inexperienced surgeon. An anterior midline abdominal surgical approach is indicated for abdominal paragangliomas. Paragangliomas of the neck, chest, and urinary bladder require specialized approaches. Consensus statement on next-generation-sequencing-based diagnostic testing of hereditary phaeochromocytomas and paragangliomas. Von Hippel-Lindau and hereditary pheochromocytoma/paraganglioma syndromes: clinical features, genetics, and surveillance recommendations in childhood. New perspectives on Pheochromocytoma and Paraganglioma: towards a molecular classification. Testing for germline mutations in sporadic pheochromocytoma/ paraganglioma: a systematic review. Positive impact of genetic test on the management and outcome of patients with paraganglioma and/or pheochromocytoma. Pheochromocytoma and paraganglioma-an update on diagnosis, evaluation, and management. Update of pheochromocytoma syndromes: genetics, biochemical evaluation, and imaging. Current status of functional imaging in neuroblastoma, pheochromocytoma, and paraganglioma disease. Preoperative levels of catecholamines and metanephrines and intraoperative hemodynamics of patients undergoing pheochromocytoma and paraganglioma resection. Selective versus non-selective -blockade prior to laparoscopic adrenalectomy for pheochromocytoma. Management of an acute catecholamine-induced cardiomyopathy and circulatory collapse: a multidisciplinary approach. Per-operative hemodynamic instability in normotensive patients with incidentally discovered pheochromocytomas. Medications and agents that frequently increase measured levels of catecholamines and metanephrines include: A. In addition, -adrenergic inhibitors do not affect circulating levels of catecholamines or metanephrines in a clinically important way. Tyrosine hydroxylase is the rate-limiting step in catecholamine synthesis, and inhibition of this step decreases total body catecholamine production. Use of tricyclic antidepressants is the most common cause of falsepositive results of biochemical testing for pheochromocytoma. In preparing the patient with pheochromocytoma for surgery, which of the following statements is correct with regard to -adrenergic blockade The -adrenergic antagonist should be administered before the -adrenergic blocker is started. It is indicated to control the tachycardia associated with both the high concentrations of circulating catecholamines and the -adrenergic blockade. The dosing of the -adrenergic antagonist is not affected by asthma or congestive heart failure in this unique setting of catecholamine excess. The dose of the -adrenergic antagonist should be titrated for a heart rate of 50 beats per minute. The dose of the -adrenergic antagonist should be titrated for a systolic blood pressure of 100 mm Hg. The -adrenergic antagonist should be administered only after -adrenergic blockade is effective; with -adrenergic blockade alone, hypertension may be more severe from the unopposed -adrenergic stimulation. The clinician should exercise caution if the patient is asthmatic or has heart failure. Therefore the -adrenergic blocker should be administered cautiously and at a low dose. An effective class of antihypertensive drugs could be based on which of the following Agonism at the presynaptic 2-receptor is the only option listed that would decrease catecholamine synthesis or release. Hence, the disease does not manifest when the mutation is inherited from the mother but is highly penetrant when it is inherited from the father. In a patient with an incidentally discovered adrenal mass, which of the following imaging characteristics is consistent with pheochromocytoma Rapid contrast washout with more than 50% washout at 10 minutes Answer: D See section on diagnosis. Diabetes comprises a cluster of heterogeneous disorders with elevated blood glucose levels as a common diagnostic feature; however, as genetic and molecular studies have suggested, it is likely that the cluster includes many subcategories, each of which requires tailored prevention, diagnosis, and treatment approaches. Depending on the context in which the patient presents, diabetes can be an acute life-threatening condition, a pregnancy-associated disorder, or a gradually evolving chronic disorder that carries with it secondary complications that may be ultimately more debilitating than hyperglycemia. Other factors make diabetes an unusual clinical challenge, including the need for active participation by patients in their treatment, the varying presentations across the age spectrum, and the unstable and evolving clinical presentation. Because the severity of the underlying metabolic defects does not remain static, diabetes management always requires changes in treatment according to the stage of the disease. These patterns of evolution are superimposed on the phenotypes at presentation and depend on a host of factors, including age, sex, race, societal setting, and others. It is now established that diabetes-related vascular and neuropathic complications stem from imperfect treatment of the metabolic disturbances, defined principally by hyperglycemia. There is also evidence that genetic factors may predispose or protect individual patients from the deleterious effects of hyperglycemia. Regardless of the specific subtype of diabetes, all have in common some degree of insulin deficiency; insulin deficiency may be absolute, as in type 1 diabetes, or a relative deficit with coexisting insulin resistance, as in type 2 diabetes. Deficient insulin is the primary driver of impaired fuel homeostasis, whereas hyperglycemia plays the dominant role in disease-related complications. Major strides in our understanding of diabetes have been made during the last 40 years, with accompanying additions to the diagnostic and treatment armamentarium. The major clinical features of type 1 and type 2 are shown in Table 216-1 and are described in detail in the corresponding sections later. Diabetes may occur as part of several inherited syndromes, including the Turner, Klinefelter, Prader-Willi, Down, and Wolfram syndromes, among others. The genetic and metabolic defects involved are heterogeneous but usually result in impaired -cell function. The obesity (and resulting insulin resistance) associated with many of these syndromes also contributes. Diseases of the exocrine pancreas, such as pancreatitis, pancreatic cancer, hemochromatosis, and cystic fibrosis, can be accompanied by impaired pancreatic endocrine function, leading to insulin-deficient diabetes. Several endocrinopathies that are associated with insulin resistance, including acromegaly, Cushing syndrome, and pheochromocytoma, may result in impaired glucose tolerance or frank diabetes in predisposed individuals. Viral infections, such as congenital rubella and cytomegalovirus, may cause diabetes by -cell destruction. Finally, hyperglycemia may be associated with the use of certain drugs, including those that worsen insulin resistance. Diabetes is diagnosed on the basis of one of several criteria, including fasting plasma glucose concentration, plasma glucose concentration after a standard 75-g oral glucose challenge (oral glucose tolerance test), and percentage of glycosylated hemoglobin (HbA1c) (Table 216-2). In most cases, abnormal results require a confirmatory test, but diabetes can be diagnosed in the presence of unequivocal hyperglycemia (casual plasma glucose concentration >200 mg/dL) and typical symptoms of polyuria, polydipsia, and weight loss. Because plasma glucose levels range on a continuum, the selection of a specific diagnostic threshold is in some respects arbitrary. Current criteria are based on the plasma glucose or HbA1c level above which the risk of diabetesspecific microvascular complications. In situations of altered red blood cell turnover or certain hemoglobinopathies, HbA1c may not accurately reflect mean plasma glucose levels (see later section on glycosylated hemoglobin), and direct glucose measurement should be used. Separate glucose criteria exist for the diagnosis of gestational diabetes (see section on gestational diabetes under clinical manifestations of type 2 diabetes). States of impaired glucose regulation, not meeting the criteria for diabetes, have also been defined (fasting glucose concentration of 100 to 125 mg/dL, 2-hour glucose concentration of 140 to 199 mg/dL, or HbA1c level of 5. Individuals in these categories are at increased risk for diabetes, although not all will progress and some may revert to normal glucose regulation. Hemoglobin A1c (HbA1c) is formed by the nonenzymatic glycosylation of hemoglobin, and its percentage reflects the exposure of the hemoglobin A molecule to glucose during the lifespan of circulating red blood cells (about 120 days). Modified from American Diabetes Association Standards of Medical Care in Diabetes-2018. Type 1 diabetes results from autoimmune destruction of pancreatic beta cells and results in total (or near total) insulin deficiency. Type 2 diabetes is strongly associated with obesity and is characterized by relative insulin deficiency and variable defects in insulin sensitivity. Chronic hyperglycemia from all forms of diabetes can result in microvascular complications (retinopathy, nephropathy, neuropathy), as well as increased risk for atherosclerotic cardiovascular disease. Aggressive control of hyperglycemia and related risk factors, which includes medical nutrition therapy, exercise, weight management, and medications, can substantially reduce the risk of complications. Treatment of type 1 diabetes requires physiologic insulin replacement using multiple daily injections or a continuous subcutaneous insulin infusion pump. Pharmacologic options for treating type 2 diabetes include several classes of oral and injectable medications, which are often used in combination in order to achieve and maintain adequate glucose control. Acute, life-threatening complications of diabetes can occur and include diabetic ketoacidosis, hyperglycemic hyperosmolar state, and iatrogenic hypoglycemia. Recent advances in technology, including continuous glucose monitors, and availability of newer pharmacologic agents have improved quality of life for many patients with diabetes and have the potential to reduce the burden of the disease. HbA1c results may be influenced by a number of factors, including conditions that alter red cell survival. In these situations, measurement of fructosamine (a glycosylated serum protein) or glycated albumin, both of which reflect mean glucose levels during the preceding 2 to 3 weeks, may provide more accurate assessment of recent glucose levels. However, these assays have not been as well standardized, and the relationship with mean plasma glucose levels is less well established. However, because many other diabetogenic factors can be operative and there is interdependence among many of these homeostatic mechanisms, teasing out their individual contributions is virtually impossible in any given patient. Normal insulin physiology is orchestrated in a complex dynamic involving metabolic fuels, neurotransmitters, and other hormones. Insulin is synthesized as preproinsulin in the ribosomes of the rough endoplasmic reticulum of pancreatic islet cells and is then converted to proinsulin, which in turn is transported to the Golgi apparatus, where it is packaged into secretory granules. Proinsulin is cleaved into equimolar amounts of insulin and a connecting segment (C-peptide) in the secretory granules. The stimulation of insulin secretion results in release of equimolar quantities of insulin and C-peptide (as well as a small amount of proinsulin) into the hepatic portal vein. Whereas a large proportion of insulin is bound to its hepatic receptor and metabolized in its "first pass" through the liver, C-peptide is much less prone to hepatic metabolism and is a better reflection of insulin secretion, although it is quantitatively of limited usefulness in the clinical diagnosis or treatment of diabetes. The magnitude of the insulin secretory response is determined by the level of blood glucose as well as by the rate and mode of glucose entry. Glucose is taken up by the cell through the Glut2 glucose transporter and is metabolized (initially through phosphorylation by the glucokinase to glucose 6-phosphate). With more persistent elevations of plasma glucose concentration, insulin secretion is sustained (so-called second-phase insulin secretion). The earliest pathophysiologic indicator of defective -cell function may be the loss of first-phase secretion of insulin, which precedes by years the decline in insulin secretory reserve sufficient to lead to overt glucose intolerance or diabetes. National Diabetes Statistics Report: Estimates of Diabetes and Its Burden in the United States, 2014. This pathway is also responsible for the vasodilator effects of insulin (through increased expression of endothelial nitric oxide synthase), which may contribute to glucose utilization by increasing nutrient delivery to tissues. Defects in these intracellular signaling pathways are an important cause of impaired insulin action, or "insulin resistance" (see section on impaired insulin action [insulin resistance] under pathobiology of type 2 diabetes). The overall actions of insulin tend to promote uptake and storage of nutrients in the fed state and release of nutrients from body stores in the fasting state, as summarized in Table 216-4.

All adenomas contain some dysplasia erectile dysfunction kidney disease purchase 60 mg cialis extra dosage mastercard, and higher-grade dysplasia carries about a 30% risk of undergoing malignant transformation erectile dysfunction protocol review scam buy cialis extra dosage 50 mg without a prescription. However erectile dysfunction treatment clinics order cialis extra dosage overnight delivery, the adenomatous polyps in Gardner syndrome and in familial adenomatous polyposis have similar malignant potential erectile dysfunction and proton pump inhibitors purchase 40mg cialis extra dosage mastercard, so screening and treatment recommendations also are similar erectile dysfunction oral treatment cheap 50 mg cialis extra dosage visa. Turcot syndrome is the combination of colorectal polyposis erectile dysfunction medication samples generic cialis extra dosage 40mg line, colorectal cancer, and central nervous system malignancy. The central nervous system malignancies include medulloblastomas, glioblastomas, and ependymomas. Patients have up to hundreds of adenomas throughout the colon and may also have multiple hyperplastic polyps as well as serrated adenomas. Extra-colonic features include gastroduodenal polyps, duodenal carcinoma, breast cancer, ovarian cancer, bladder cancer, skin cancer, osteomas, and congenital hypertrophy of the retinal pigment epithelium. Nearly all patients have characteristic melanin spots on their lips, buccal mucosa, and skin. The syndrome is characterized by benign hamartomatous polyps predominantly in the small intestine, stomach, and colon, occasionally accompanied by adenomatous and hyperplastic polyps. Nearly 50% of patients develop a malignancy by age 65, most commonly in the small intestine, stomach, colon, pancreas, testes, breast, ovary, cervix, or uterus. Because genetic testing is not widely available, first-degree relatives should be screened annually from birth, looking especially for melanotic spots, precocious puberty, and testicular tumors. Symptoms and signs include abdominal pain, rectal bleeding, intestinal obstruction, and anemia by early adolescence. They usually are asymptomatic but can occasionally cause bleeding, prolapse, or obstruction. Non-neoplastic polyps are not premalignant, but neoplastic polyps can become a true cancer. Nevertheless, colonoscopy may miss 6 to 12% of large (1 cm) polyps and 5% of cancers. Flexible sigmoidoscopy, which can be used to screen average risk asymptomatic individuals, detects only 50 to 60% of all polyps and cancers. When patients with polyps discovered by flexible sigmoidoscopy also undergo subsequent colonoscopy, the incidence of colorectal cancer can be reduced by about 80%. This need for subsequent colonoscopy explains the attractiveness of using it as the initial screening modality. Sessile serrated adenomas, which are a recently recognized neoplastic lesion with right colon predominance and malignant potential at least as high as with conventional carcinomas,8 have a disorganized and distorted crypt growth pattern. Traditional serrated adenomas are rare and histologically distinct from sessile serrated adenomas. After removal of a large (2 cm) adenoma or the piecemeal resection of any adenoma, colonoscopy should be repeated within 6 months to determine whether the original resection was complete. For sessile serrated polyps smaller than 10 mm without dysplasia, surveillance colonoscopy is recommended at 5 years, but the recommended interval is 3 years if the serrated polyp showed high-grade dysplasia or was a traditional serrated adenoma (Video 184-3). Many of the mutational events have downstream effects on the Wnt signaling pathway. Microsatellites, which are short repeating nucleotide sequences, are prone to errors because of their repetitive nature. Patients with early-stage colon cancer are typically asymptomatic, and the cancer is usually discovered upon routine screening. If symptoms arise, they do so when the tumor grows into the bowel lumen or when the tumor invades adjacent anatomic structures. Anorexia, weight loss, and fatigue may develop, and liver metastases can be manifested by hepatomegaly, jaundice, abdominal fullness, or ascites. A pedunculated adenoma usually can be removed intact by snare polypectomy (Video 184-2), whereas sessile polyps may require piecemeal snare resection. Pathologic evaluation should assess the presence or absence of cancer; if malignant tissue is identified, it should be evaluated for its histologic grade, vascular and lymphatic spread, and adenoma-free margin. Unfavorable histopathologic factors that require prompt surgical resection after endoscopic polypectomy include poorly differentiated histology, vascular invasion, lymphatic invasion, and incomplete resection. When a malignant sessile polyp is removed endoscopically, the potential risk of recurrence or lymph node involvement must be weighed against the risks of definitive surgery in each individual patient. Patients who have undergone endoscopic removal of a previously diagnosed adenomatous or sessile serrated polyp are at increased risk for the subsequent development of adenomas and colorectal cancer. The recommended surveillance post-resection depends on the primary lesions, size, and histology, as well as the number of adenomas (Table 184-2). If a low-risk patient has just 1 or 2 small tubular adenomas, surveillance colonoscopy can be delayed for 5 to 10 years. Colorectal cancer in the distal colon typically presents with a change in bowel habits, such as constipation or diarrhea, and hematochezia. Tumors arising in the rectum usually present with changes in stool caliber, rectal bleeding, and rectal pain. In some cases when the rectal tumor involves sacral nerve plexi, significant neuropathic pain may be present. A careful history, physical examination, and radiologic evaluation are important in making the diagnosis. The patient should be questioned about a prior history of adenomatous polyps or colorectal cancer, history of inflammatory bowel disease, and any family history of colorectal cancer or other solid tumors. On physical examination, extra-intestinal lesions characteristic of Peutz-Jeghers syndrome or Gardner syndrome may be noticed. Metastatic disease to the liver or lymph nodes may be suggested by the presence of hepatosplenomegaly or lymphadenopathy, and abdominal fullness or ascites may reflect peritoneal involvement. Digital rectal examination may reveal a mass in the distal rectal region or spread of the tumor to the rectal shelf or pelvis. Examination of the stool may show frank or occult blood in up to 80% of advanced cases. The approaches for making the definitive diagnosis of colorectal cancer are similar to those used to detect adenomatous polyps. This procedure also is highly sensitive for detecting recurrent rectal cancer after a low anterior resection. Plain chest radiographs are not sufficiently sensitive to detect the presence of metastatic lesions in the lungs, and plain abdominal films are useful only to aid in the diagnosis of bowel obstruction. Histopathologic analysis is critical for making the diagnosis of colorectal cancer. Additional studies to evaluate immunohistochemical expression of certain key cellular proteins may be helpful in identifying adenocarcinomas of colorectal cancer origin. The role of screening is to reduce colorectal cancer-related mortality by removing any precursor adenomas and by detecting true cancers at an earlier, more curable stage. For average-risk individuals, the relatively long latency between adenoma development and the development of cancer is of the order of 8 to 12 years, thereby making colorectal cancer a highly preventable disease using colonoscopy with polypectomy. For sporadic colorectal cancer, age is the major risk factor; for this reason, most patients should begin screening at age 50. Current professional society guidelines recognize multiple screening options but recommend structural tests that can both detect and prevent colorectal cancer. For example, the American College of Physicians recommends screening average-risk adults for colorectal cancer starting at age 50 years and high-risk individuals starting at age 40 years (or 10 years before the age when the youngest relative was diagnosed with colorectal cancer). Colonoscopy, flexible sigmoidoscopy, or a stool-based test are recommended in averagerisk patients, but flexible sigmoidoscopy or colonoscopy is recommended in high-risk patients. The general recommendation is to discontinue colorectal cancer screening in individuals who are older than 75 years of age or have a life expectancy of less than 10 years. Patients with ulcerative colitis (Chapter 132) are 10 to 20 times more likely to develop colorectal cancer than is the general population, with a 25-year cumulative incidence of about 12%. The risk is even higher in patients who have both primary sclerosing cholangitis (Chapter 146) and ulcerative colitis. If Crohn disease (Chapter 132) involves more than one third of the colon, the risk of colorectal cancer risk is increased 6- to 8-fold. Multifocal low-grade dysplasia or any dysplasia that cannot be excised endoscopically is an indication for colectomy. Fecal occult blood tests, either guaiac- or immunochemical-based, detect hemoglobin from bleeding tumors. The sensitivities of guaiac-based tests for detecting colorectal cancer range from 35 to 80%. In randomized trials guaiac-based testing decreases colorectal cancer mortality by 15 to 33%, with the mortality benefit persisting for 30 years. Immunochemical-based tests, which have higher sensitivities and specificities than guaiac tests, are performed similarly to the traditional guaiac test but do not require any dietary restrictions and require only one stool specimen. Fecal occult blood tests should be repeated on an annual basis, and any positive test should prompt colonoscopy. Flexible sigmoidoscopy (Chapter 125) is an endoscopic procedure that examines the rectum and distal colon up to the splenic flexure. This procedure detects distal cancers or polyps with the same accuracy as colonoscopy. If an adenoma is found on sigmoidoscopy, colonoscopy is required because of the high risk of synchronous polyps or cancer in the more proximal colon. In one randomized trial, screening with flexible sigmoidoscopy (with subsequent colonoscopy as indicated) reduced the incidence of both the distal and proximal colorectal cancer by about 30%, with a significant 50% decrease in the mortality from distal colorectal only. In a recent randomized trial, single flexible sigmoidoscopy performed once between ages 55 to 64 years reduced the incidence of colorectal cancer by 28% and mortality by 27%. A4 In a pooled analysis of randomized trials, sigmoidoscopy was proven effective for colorectal cancer screening in men and younger women, and it reduces colorectal cancer mortality in both younger and older men and in women younger than age 60 years. A5 In contrast, the benefit of one-time sigmoidoscopy was smaller and not statistically significant for women older than age 60 years. Colonoscopy allows complete visualization of the colon and removal of any visualized polyps. In the United States, this procedure is performed in a sedated patient after an oral bowel preparation by specifically trained physicians. Screening colonoscopy finds cancer in about 1% of patients, advanced adenoma (size >10 mm, villous histology, or high-grade dysplasia) in 5 to 10%, and 1 or more adenomas in at least 20% of patients. The major complication rate is less than 5%, with more than half of such complications related to a polypectomy. The National Polyp Study, which followed patients after colonoscopic polypectomy, reported a 76 to 90% lower incidence of colorectal cancer compared to three reference populations. The benefit of colonoscopy is higher if it is performed by an experienced gastroenterologist, when the cecum is intubated (indicating a complete examination), and when it is performed by a physician who removes more polyps per examination. If the initial screening colonoscopy is completely normal, future screening can be deferred for 10 years. Double-contrast barium enema (Chapter 124) can evaluate the mucosal surface of the entire colon. Calcium supplementation decreases the rate of metachronous adenomas by 20%,14 and total calcium intake (>1400 vs. It is rarely recommended for routine screening because of this low sensitivity and the small but real risk of ionizing radiation. The sensitivity is 85 to 92% for large polyps (10 mm), with a specificity of 83 to 89%, and about 65% for polyps 5 mm or larger. Dietary Prevention Staging Accurate staging is critical for determining both prognosis and treatment. Up to 40 to 50% of patients who initially present with early-stage disease will recur with metastatic involvement. In general, primary tumors that arise in the colon follow an orderly spread to the regional lymph nodes, then to the liver, and then to the lungs and other distant sites. In contrast, because of the dual venous drainage of the rectum to the portal vein and inferior vena cava, primary rectal tumors may spread via hematogenous dissemination to the lungs before any liver involvement. Epidemiologic studies have identified a correlation of colorectal cancer with diets high in fat and low in fiber, green leafy vegetables, and fruits; physical inactivity; smoking; and excessive alcohol use. However, three randomized trials of modest dietary changes (10% less fat, 25 to 75% more fiber, 50% more fruits and vegetables) have not reduced the incidence of adenomas or colorectal cancer over 3 to 8 years of follow-up. It is possible that prolonged dietary modification may be required to effect significant changes in the molecular events that mediate the development of adenomas and/or colorectal cancer. In patients with familial adenomatous polyposis, sulindac and celecoxib can cause existing adenomas to regress and inhibit the formation of new adenomas. In randomized trials, aspirin reduced the recurrence of adenomas by up to 20 to 40% with pooled data suggesting up to a 70% reduction in the incidence of colorectal cancer when at least 75 mg of aspirin daily is taken for 5 or more years. Highly selected patients with site-limited metastatic disease also may undergo surgery with curative intent. Curative surgery aims to remove the primary tumor with tumor-free margins, as well as to remove the primary feeding arterial vessel and corresponding lymphatics en bloc. A minimum of 12 lymph nodes should be removed and examined microscopically for accurate staging. Prophylactic oophorectomy is not recommended, but if one ovary is grossly involved, the other should be removed as well because of the risk of contralateral involvement. Laparoscopic resection is as safe and effective as open resection and requires a modestly shorter recovery time. A8 For rectal cancer, an important consideration is to try to preserve the function of the anal sphincter. For distal cancers, the recommendation is total mesorectal excision with en bloc removal of the lymphovascular and fatty envelope surrounding the rectum. For upper rectal tumors, by comparison, tumor-specific mesorectal excision (en bloc removal of the mesorectum 5 cm distal to the tumor) is sufficient. For minimal-risk (T1 disease, size <3 cm, well differentiated, within 8 cm of the anal verge, no lymphovascular invasion, and less than one third circumferential) low rectal cancers, local transanal excision is acceptable.

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