in the \201 rst and second trimesters up to 24 weeks \200\231 gestation. Caesarian section is advocated with a combined tumor resection. Vaginal delivery carries a signi \201 cant maternal risk. 99-Draznin-Chap99.indd 568 3/31/2011 9:30:53 PM GLUCOCORTICOID RESISTANCE 569 Syndromes of hormone resistance De \201 nition In these syndromes there is reduced responsiveness of target organs to a pa rticular hormone, usually secondary to a disorder of the receptor or distal signaling pathw ays. This leads to alterations in feedback loops and elevated circulating hormone levels. Thyroid hormone resistance b see Resistance to thyroid hormones (p. 37). Androgen resistance b see Androgen insensitivity syndrome (p. 335). Glucocorticoid resistance Autosomal dominant and recessive forms have been described. Diminished sensitivity to glucocorticoid leads to reduced glucocorticoid feedback on CRH an d ACTH, leading to i CRH, ACTH, and cortisol concentrations. The clinical features are not due to excess glucocorticoid, as there is reduced peripheral tissue sensitivity. However, elevated ACTH leads to i secretion of mineralocorticoid (e.g., deoxycorticosterone) and andro- gen (DHEA and DHEAS). This may lead to hypertension and hy pokalemic alkalosis, hirsutism, acne, oligomenorrhea in females, and sexual precocity in ma les. Glucocorticoid resistance may be differentiated from Cushing \200\231s syn- drome because, despite evidence of i urinary cortisol, abnormal sup- pression with dexamethasone, and i re sponsiveness to CRH, the diurnal rhythm of cortisol secretion persists, there are no clinic al features of Cushing \200\231s syndrome, BMD is normal or i, and there is a normal respon se to insulin-induced hypoglycemia. Low-dose dexamethasone treatment (2 mg/day) may ef \201 ciently suppress ACTH and androgen production. 100-Draznin-Chap100.indd 569 3/31/2011 9:31:53 PM CHAPTER 100 Syndromes of hormone resistance 570 ACTH resistance This is a rare autosomal recessive disorder in which the adrenal cortex fai ls to respond to ACTH in the presence of an otherwise normal gland. (mineralocorticoid secr etion is preserved under angiotensin II control). The presenting clinical features include hypoglycemia, which is often neonatal, neonatal ja undice, i skin pigmentation, and frequent infections. Occasionally, ACTH resistance is a co mponent of the triple-A syn- drome of alacrima (absence of tears), achalasia of the cardia, and ACTH resistance. Biochemical features include undetectable or low 9 A.M. cortisol, with grossly elevated ACT H (often >1000 ng/mL), and normal renin, aldoster- one, and electrolytes, and impaired resp onse to the cortrosyn stimulation test. Treatment is with steroid replacement. Mineralocorticoid resistance Also known as type 1 pseudohypoaldosteronism, this is a rare i nherited disorder that usually presents in children with failure to thrive, salt loss, and dehydration. Both autosomal dominant and recessive forms have been described. Biochemical features are as follows: d Serum sodium \200 i Serum potassium (hyperkalemic acidosis) \200 i Urinary sodium (de spite hyponatremia) \200 i Plasma and urinary aldosterone \200 i Plasma renin activity Diagnosis requires proof of unresponsiveness to mineralocorticoids (no effect of \202 udr ocortisone on urinary sodium). Treatment with sodium supplementation has been used successfully. With time, treatment can often be weaned, and salt wasting is unusual following childhood. Further reading Charmandari, E, Kino T, Ichijo T, et al. (2008). Generalized glucocorticoid resistance: clinical aspects, molecular mechanisms, and Implications of a rare gentic diso rder. J Clin Endocrinol Med 93:1563 \200\2231572. 100-Draznin-Chap100.indd 570 3/31/2011 9:31:54 PM DIFFERENTIAL DIAGNOSIS OF POSSIBLE MANIFESTATIONS 571 Differential diagnosis of possible manifestations of endocrine disorders Sweating \200 Me nopause/gonadal failure \200 Thyrotoxicosis \200 Pheochromocytoma \200 Acromegaly \200 Hypoglycemia \200 Diabetes mellitus \200 Autonomic neuropathy (gustatory sweating ) \200 Renal cell carcinoma \200 Chronic infection (e.g., TB) \200 Hematological mali gnancy (e.g., lymphoma) \200 Anxiety \200 Idiopathic \200 Drugs, e.g., \202 uoxetin e Investigation of sweating \200 History \200 Clinical examination \200 Thyroid funct ion tests \200 Serum gonadotropin levels \200 Blood glucose level \200 Speci \201 c investigations according to clinical suspicion Management of sweating \200 Treat the unde rlying cause, where possible \200 Antiperspirants \200 Topical aluminum chloride eth anol \200 Anticholinergics \200\224glycopyrronium bromide (oral or topical) \200 Clonid ine \200\224taken at night to avoid sedation \200 Iontophoresis \200 Botulinum toxin A injections into affected areas (inhibits the release of acetylcholine at the synaptic junction of local nerves) Local excision of axillary sweat glands \200 Sympathetic denervation Video-assisted endoscopic thoracic sympathectomy \200\223 Excision \200\223 Radioablation Sympathotomy (chain disconnection between T2 ganglion and stellate ganglion) Palpitations (often associated with sweating) \200 Thyrotoxicosis \200 Hypoglycemia (in sulinoma) \200 Pheochromocytoma \200 Anxiety states \200 Cardiac arrhythmia 100-Draznin-Chap100.indd 571 3/31/2011 9:31:54 PM CHAPTER 100 Syndromes of hormone resistance 572 Caffeine excess \200 Alcohol or drug withdrawal General malaise, tiredness \200 Addison \200\231s disease \200 Hypo- or hyperthyroidism \200 Hypogonadism \200 Hypopituitarism or GH de \201 ciency \200 Osteomalacia \200 Diabetes mellitus \200 Cushing \200\231s syndrome \200 Anemia \200 Drugs (prescript ion and recreational drugs) Antihistamines \200 Antidepressants \200 Antihypertensives ( B-blockers, methyl-dopa, c lonidine) \200 Neuroleptics \200 Corticosteroids Malignancy \200 Chronic fatigue syndrome (may be associated with reduced cortisol output both basally and in response to a variety of challenges) Chronic illness (cardiac, respiratory, hepatic) \200 Fibromyalgia \200 Depression \200 Sleep disorders (obstructive sleep apnea) \200 Infection \200 Musculoskeletal or neur ological disease (mysthenia gravis) \200 Toxins \200 Idiopathic Investigation of fatigu e \200 Careful history-taking Duration, onset, recovery, and type of fatigue \200 Person \200\231s usual activity level Clinical examination \200 Serum electrolytes \200 Hemoglobin serum ferritin level \200 In \202 ammatory markers (ESR, CRP) \200 Liver function tests \200 Serum calcium and phosphate levels \200 Thyroid function tests \200 Cosyntropin stimulation test Flushing \200 Gonadal failure (with \202 ushing and sweats) \200 Drugs Chlorpropamide \200 Nicotinic acid \200 Antiestrogens \200 LHRH agonists 100-Draznin-Chap100.indd 572 3/31/2011 9:31:54 PM DIFFERENTIAL DIAGNOSIS OF POSSIBLE MANIFESTATIONS 573 Carcinoid (dry \202 ushing \200\224no sweats) \200 Mastocytosis \200 Medullary thyroi d cancer \200 Anaphylaxis \200 Pancreatic cell carcinoma \200 Pheochromocytoma (more often pallor) \200 Fever \200 Alcohol \200 Autonomic dysfunction \200 Some foods \200 Fish \200 Tyramine containing food (cheese) \200 Nitrites (cured meat) \200 Mon osodium glutamate \200 Spicy food \200 Gustatory \202 ushing \200 Benign cutaneous \202 ushing \200 Idiopathic Initial evaluation of patients with \202 ushing \200 Ca reful history \200 Physical examination (ideally during a \202 ush, although this is no t often possible) \200 Examine skin carefully \200 Pulse rate \200 BP \200 Thyroid examinat ion \200 Respiratory examination (wheeze) \200 Careful abdominal examination Biochemistry Gonadotrophin levels \200 2 x 24-hour urinary 5HIAA measurements \200 Serum chromograni n A \200 2 x 24-hour urinary catecholamine measurements \200 Plasma metanephrines (if h igh level of suspicion) \200 Serum tryptase level (if suspecting mastocytosis) \200 Cal citonin level (if suspecting medullary thyroid cancer) \200 Plasma VIP (if suspecting pan creatic carcinoma) \200 Immunoglobulin levels (raised IgE may suggest allergies) Speci \201 c investigations according to suspected diagnosis Management of \202 ushing \200 Treat the underlying cause. \200 Nadolol (nonselective B-blocker) effective in some cases of benign cutaneous \202 ushing. Somatostatin analogs can be used to treat \202 ushing associated with carcinoid syndrome. Antihistamines may be effective in some histamine-secreting carcinoid tumors. 100-Draznin-Chap100.indd 573 3/31/2011 9:31:54 PM CHAPTER 100 Syndromes of hormone resistance 574 Further reading Cleare A (2003). The neuroendocrinology of chronic fatigue syndrome. Endocr Rev 24(2):236 \200\223252. Cornuz J, Guessous I, Favrat B (2006). Fatigue: a practical approach to diagnosis in primar y care CMAJ 174(6):765 \200\223767. Eisenach J, Atkinson J, Fealey R (2005). Hyperhidrosis: evolving therapies for a well-estab lished phenomenon. Mayo Clin Proc 80(5):657 \200\223666. Izikson L, English J, Zirwas M (2006). The \202 ushing patient: differential diagnosis, w orkup and treat- ment. J Am Acad Dermatol 55(2):193 \200\223208. 100-Draznin-Chap100.indd 574 3/31/2011 9:31:54 PM DEFINITION 575 Stress and the endocrine system De \201 nition Stress may be considered as a state of threatened or perceived as threat- e ned homeostasis. The principal effectors of the stress response are corticotropin-releasing hormone (CRH), glucocorticoids (GCs), catecho- lamines, arginine vasopressin (AVP), and PO MC-derived peptides (espe- cially B-endorphins). Allostasis is a state of dyshomeostasis occurring from an inadequate, excessive, or prolonged adaptive stress response. 101-Draznin-Chap101.indd 575 3/31/2011 9:32:40 PM CHAPTER 101 Stress and the endocrine system 576 Endocrine effects of stress Hypothalamic \200\223pituitary axis \200 i Amplitude of synch ronized pulsatile release of CRH and AVP (potent synergistic factor of CRH) into the hypophyseal portal system i Stimulated ACTH production \200 i Adrenal glucocorticoid and androgen secretion GCs als o play a role in termination of the normal stress response by negative feedback at the pitu itary, hypothalamus, and extrahypothalamic regions. Growth hormone axis GCs suppress GH production and inhibit the effects of IGF-1 (thus, chil - dren with anxiety disorders may have short stature). CRH increases somatostatin production, inhibiting GH production. GH response to IV glucagon is blunted. Thyroid axis GCs reduce the production of TSH and limit the conversion of T 4 to the more a ctive T 3 by reducing deiodinase activity. Somatostatin suppresses both TRH and TSH release. b See Sick euthyroid syndrome (p. 15). Reproductive axis CRH reduces GnRH secretion. GCs suppress GnRH neurons and pituitary gonadotropes and render the gonads resistant to gon adotropins. GCs also render peripheral tissues resistant to estradiol. Chronic stress leads to amenorrhea in females and low LH and testo- sterone in males. Estrogens increase CRH expression via an estrogen response element in the promoter region o f the CRH gene. This may account for the sex- related differences in the stress response an d HPA axis activity. CRH is produced by the ovary, endometrium, and placenta during the latter half of pregnancy leading to physiological hypercortisolism. Metabolism GCs via their direct effect, and via reduced GH and sex hormone activity, result in muscle and bone catabolism and fat anabolism. Chronic activation of the stress system is associated with i visceral adiposity, d lean bod y mass, and suppressed osteoblastic activity (which may ultimately lead to osteoporosis). GCs induce insulin resistance and other features of the metabolic syndrome. Further reading Charmandari E, Tsigos C, Chrousos G (2005). Endocrinology of the stress res ponse. Annu Rev Physiol 67:259 \200\223284. 101-Draznin-Chap101.indd 576 3/31/2011 9:32:41 PM INTRODUCTION 577 Alternative or complementary therapy and endocrinology Introduction Many patients use natural products alongside or instead of conventional therap y. Products and information are available from many sources, par- ticularly the Internet. Patients need to be asked speci \201 cally about usage. Hospital pharmacists can be extrem ely helpful in sourcing informa- tion about natural products, including interactions with c onventional medicines. Quality control of natural products is usually poor, with content ranging anywhere from 0% of stated level to several-fold higher. Safety data are often absent or inadequate. Discussion of any natural products listed here is not intended in any way to imply ef \201 cacy or safety of these products or to recomme nd their usage but rather to illustrate the compounds being promoted for these conditions b y alternative information sources. 102-Draznin-Chap102.indd 577 4/1/2011 6:05:28 PM CHAPTER 102 Alternative therapy and endocrinology 578 Alternative therapy used in patients with diabetes mellitus A major concern with natural pr oducts used by patients with diabetes mellitus is of interaction with conventional medicine s placing the patient at risk of hypoglycemia. Hypoglycemic agents These work by i insulin secretion from the pancreas or through direct i nsulin-like action at the insulin receptor. Banaba (Lagerstroemia speciosa) \200\224crepe myrtle Banaba extracts contain corosolic acid and ellagitannins, which may have direct insulin-like effects at insulin receptors. Bitter melon (Momordica charantia) This contains a polypeptide with insulin-like effects. I t is used as juice, powder and extracts and in fried food. It is often part of Asian and In dian foods. Fenugreek (Trigonella foenum-gracum) This is used as powder, seeds, or part of a dietary su pplement. It may enhance insulin release and may also decrease carbohydrate absorption due to a laxative effect. It may also inhibit platelets and thus increase bleeding diathesis. Gymnema (Gymnema sylvestre) Gurmar in Hindi means \200\234sugar destroying \200\235. The e xtract GS4 is also used. Gymnema may increase endogenous insulin secretion ( i C-peptide le vels noted in users). In some preliminary studies, gymnema improved HbA1c and d insulin or OHA requirements. Insulin sensitizers Cassia cinnamon (Cinnamomum aromaticum) This is also known as Chinese c innamon. It may increase insulin sensitiv- ity and lower fasting blood glucose levels. It a ppears to be safe and well tolerated. Chromium Chromium de \201 ciency is associated with impaired glucose tolerance, hyperglyce mia, and d insulin sensitivity. Chromium forms part of a glu- cose tolerance factor complex , thus supplements are sometimes labeled \200\234chromium GTF. \200\235 In patients with diabetes and chromium de \201 ciency, addition of chro- mium improves gly cemic control. However the role of chromium in patients without de \201 ciency is not clea r. The American Diabetes Association (ADA) only recommends chro- mium usage in patients with d ocumented chromium de \201 ciency. Excessive chromium may cause renal impairment. 102-Draznin-Chap102.indd 578 4/1/2011 6:05:29 PM ALTERNATIVE THERAPY USED IN PATIENTS 579 Vanadium Vanadium is thought to stimulate hepatic glycogenolysis; inhibit gluconeo- genesis , lipolysis, and intestinal glucose transportation; and increase skeletal muscle glucose up take, utilization, and glycogenolysis. High-dose vanadium (taken as vanadyl sulfate) may im prove insulin sensitivity and glycemic con- trol in patients with type 2 diabetes, with lar ge doses of elemental vana- dium required for these effects. However, doses >1.8 mg/day van adium may cause renal impairment. Ginseng This includes both Panax ginseng and American ginseng ( Panax quinquefo- lius ). Th ey both contain ginsenoisides, which may improve insulin sensitiv- ity. Ef \201 cacy and s afety are not established. Prickly pear cactus (Opuntia \201 cus-indica) Also called opuntia or nopals (referring to the cooked leaves of the cac- tus, this agent is prominent in Mexican folk medicine as a t reatment for diabetes. Opuntia streptacantha stems may improve glycemic control by either a cting as an insulin sensitizer or slowing carbohydrate absorption; however this is not obse rved with other prickly pear cactus species. Carbohydrate absorption inhibitors Soluble \201 ber increases viscosity of intestinal con tents, thus slowing gastric emptying time and carbohydrate absorption, resulting in lower p ospran- dial blood glucose levels. The following products have some evidence of reducing postprandial blood glucose levels and may also improve total and LDL cholesterol lev- els in patients. They may also interfere w ith absorption of drugs and thus should not be taken at the same time as conventional medic ines: \200 Blond psyllium seed ( Plantago ovata ) \200 Guar gum ( Cyamopsis tetragonolo ba ) \200 Oat bran ( Avena sativa ) \200 Soy ( Glycine max ) \200\224contains both solu ble and insoluble \201 ber and may improve insulin resistance, fasting basal metabolism, lipid pro \201 le, and HbA1c in type 2 diabetes Insoluble \201 ber . Glucomannan ( Amorphophallus konjac ) \200\224can delay glucose abso rption. Other products used by patients with diabetes mellitus \200 A-Lipoic acid. Antioxidant. M ay improve insulin resistance. It may help symptoms of diabetic neuropathy (?mechanism). Stevia ( Stevia rebaudiana ) may enhance insulin secretion. It may be toxic. 102-Draznin-Chap102.indd 579 4/1/2011 6:05:29 PM CHAPTER 102 Alternative therapy and endocrinology 580 Alternative therapy used in menopause Phytoestrogens The main types are iso \202 avones (w hich are the most potent and most widespread), lignans, and coumestans. Sources include the following: Iso \202 avones: legumes (soy, chickpea, garbanzo beans, red clover, lentils, beans). The main active iso \202 avones are genistein and daidzein. \200 Lignans: \202 axseed, lentils, whole grains, beans, many fruits and vegetables Coumestans: red clover, sun \202 ower seeds, sprouts Other phytoestrogens include chastebe rry (vitex agnus-castus) These agents are not structurally similar to estrogen or to selective estrogen receptor mod ulators (SERMs) but contain a phenolic ring that allows binding to estrogen receptors- A an d - B. Effects of binding depend on ambient estrogen levels, relative ratio and concentrati on of ER- A and ER- B , and tissue type and location. Phytoestrogens are relatively much le ss potent than endogenous estrogen (by 100- to 10000-fold). Phytoestrogens in vitro stimulate proliferation of normal human breast tissue and of estrog en-sensitive breast tumor cells. Theoretically, phytoes- trogens may stimulate ER+ breast c ancer and other estrogen-sensitive tumors. Phytoestrogens may also antagonize the effects o f tamoxifen or other SERMs. Phytoestrogens have not been shown to stimulate endometrial growth; however, they are not u sually taken with progestogenic compounds. It is not known whether the other serious side e ffects of conventional estro- gens (e.g., DVT, pulmonary emboli, IHD, stroke) occur with ph ytoestro- gen use. Many sources of phytoestrogens (e.g., coumestans) interfere with warfari n. Soy protein (20 \200\22360 mg/day; containing 34 \200\22376 mg iso \202 avones) modestly d ecreases frequency and severity of vasomotor symptoms in a proportion of menopausal women. Synthetic iso \202 avones (ipri \202 avone) do not have antivasomotor activity. Phytoestr ogens from red clover have not shown consistent improve- ment in vasomotor symptoms. Other sources of phytoestrogens have not shown improvement in menopausal symptoms. b For use in osteoporosis, see Alternative therapy used by patients with osteoporosis (p. 582). Other compounds with estrogenic activity \200 Kudzu ( Pueraria lobata ) \200 Alfalfa ( Medicago sativa ) \200 Hops ( Humulus lupulus ) \200 Licorice ( Glycyrrhiza glabra ) \200 Panax ginseng (ginseng) \200\224in vitro evidence of stimulation of breast cancer cells 102-Draznin-Chap102.indd 580 4/1/2011 6:05:29 PM ALTERNATIVE THERAPY USED IN MENOPAUSE 581 Other substances used Black cohosh ( Actaea racemosa , formerly Cimicifuga racemosa ) is no t to be confused with blue cohash and white cohash, which are entirely separate plants. Bla ck cohash is widely used in menopause. Although often adver- tised as such, black cohash do es not bind to estrogen receptors or have estrogen effects and there is little evidence for ef \201 cacy for hot \202 ashes. Dong quai ( Angelica sinensis ) \200\224it is not clear if it is estrogenic. There is in vitro evidence of promotion of breast cancer cells. 102-Draznin-Chap102.indd 581 4/1/2011 6:05:29 PM CHAPTER 102 Alternative therapy and endocrinology 582 Alternative therapy used by patients with osteoporosis Calcium There are hundreds of prepar ations available. Several types of calcium salts are available (including citrate, carbonate, lactate, glucon ate, and phosphate) with little evidence of superiority of absorption between the different compounds, other than calcium citrate, which is useful in patients with low gastric acidit y (e.g., on concomitant proton pump inhibitors or H2 antagonists). Magnesium Magnesium is necessary for release of PTH. It is not effective alone in treating osteoporosis unless patients are de \201 - cient in magnesium. Fluoride Fluoride increases bone density but not strength \200\224bones are less elastic, a nd more brittle, with resultant i fracture rate. Trace elements Examples are manganese, zinc, boron, and copper. While many trace elements are important for multiple enzyme systems including those in bone , most patients are not de \201 cient, thus supplements have negligible positive effect on osteoporosis. Moreover, many minerals in high doses cause serious side effects (e.g., mang anese doses >11 mg/day can cause extrapyramidal side effects). Vitamin D Multiple preparations are available, mainly as ergocalciferol or colecalcif- erol (vitamin D metabolites require prescription). Iso \202 avones b See Alternative therapy used in menopause (p. 580), for more detail abou t phytoestrogens \200\231 mechanism of action. Soy protein in doses >80 mg/day may improve bone mineral density but no studies of soy have shown improvement in fracture rate. There are possible adverse effects on estrogen-sensiti ve tissues such as ER-positive breast cancer. from daidzein. There are no estrogenic effects. There is no evidence of improved frac- ture outcome. Some studies of ipri \202 avone with calcium have reported improved BMD, althoug h other studies have not shown an improvement. Ipri \202 avone can cause serious lymphopen ia (<1 x 10 9 mL), which may take up to a year to recover. Ipri \202 avone \200\224semisynthetic iso \202 avone \200\224is produced 102-Draznin-Chap102.indd 582 4/1/2011 6:05:29 PM ALTERNATIVE THERAPY USED BY PATIENTS 583 Tea Tea consists of green tea (unfermented), oolong tea (partially fermented), and black te a (completely fermented). All teas contain \202 uoride and have high iso \202 avonoid co ntent in addition to caffeine. Coffee (with a high caffeine content) has been associated with i hip fracture risk. However , tea drinking of all types of has been associated with higher BMD, although no fracture ou tcome has been reported. DHEA b See Miscellaneous (p. 203). Wild yam Wild yam contains diosgenin, which is used commercially as a source for DHEA synth esis; however this does not occur in humans. Other compounds used by patients for osteoporosis \200 Flaxseed (alphalinolenic acid and lignans) \200 Gelatin \200 Dong quai \200 Panax ginseng \200 Alfalfa \200 Licoric e There is no evidence of a positive effect on bone of these compounds. 102-Draznin-Chap102.indd 583 4/1/2011 6:05:29 PM CHAPTER 102 Alternative therapy and endocrinology 584 Miscellaneous Iodine and the thyroid Sources include kelp and shell \201 sh-derived produc ts. Effects include iodine-induced goiter or hypothyroidism, particularly in patients with unde rlying thyroid disease (may have a Wolff \200\223Chaikoff effect in patients with Graves \200\231 disease, causing inhibition of iodide organi \201 cation and thus thyroid hormone production). Iodine-induced hyperthyroidism occurs in areas of endemic goiter and iodine de \201 ciency. DHEA \200\224 \200\234elixir of youth \200\235 DHEA is reported to slow or improve changes associated with aging, including general well-being, cognitive function, sexual function, e nergy levels, body composition, and muscle strength, and to aid weight loss and treat the m etabolic syndrome. The mechanism of action is that DHEA is secreted by the adrenal glands and interconverted t o DHEAS. Both DHEAS and DHEA are converted to androgens and estrogens that then act directl y at their receptors. DHEA and DHEAS may play a role in replacement of adrenal androgens in patients with adrenal insuf \201 ciency, resulting in improved well-being, par- ticularly with respect to sexua l function. It is not proven in controlled trials to improve health in other patients without adrenal insuf \201 ciency. There are risks of androgenic effects in women when taken at high doses (100 \200\223200 mg /DHEA daily). DHEA has a theoretical risk of promot- ing hormone-sensitive cancers such as prostate and breast cancers. DHEA may also interfere with antiestrogen effects of anastrazo le and other aro- matase inhibitors. Further information Natural Medicines Comprehensive Database. Available at www.naturaldatab ase.com (requires subscription). 102-Draznin-Chap102.indd 584 4/1/2011 6:05:29 PM Part 11 Diabetes Boris Draznin 103 Classi \201 cation and diagnosis 104 General management and treatment 105 Diabetic eye disease 106 Diabetic renal disease 107 Diabetic neuropathy 108 Macrovascular disease 109 D iabetic foot 110 Diabetes and pregnancy 111 Intercurrent events or disease 112 Emergencies in diabetes 586 593 604 612 619 627 636 641 648 651 103-Draznin-Chap103.indd 585 3/31/2011 4:46:07 PM CHAPTER 103 Classi \201 cation and diagnosis 586 Classi \201 cation and diagnosis Background Diabetes mellitus (DM) is characterized by an elevated blood glucose. The classi \201 cation of diabetes gives an idea of the underlying cause or defect. Currently, 4 \200\2237% of the U.S. population has diabetes, with about half that many stil l undiagnosed. In 2003, worldwide, 189 million people were known to have diabetes; this \201 gure may reach 324 million by 2025. Diagnosis DM is a biochemical diagnosis based on fasting and postprandial glucose levels. T he venous plasma glucose levels for this are shown in Table 103.1. In 1997, the American Di abetes Association (ADA) suggested lowering the normal fasting plasma glucose level to <110 mg/dL and the diabetic level to >126 mg/dL. A fasting glucose is therefore the diagnostic test of choice. Only pregnant woman are expected to have a 2-hour postprandial level checke d routinely. A diagnosis of diabetes is made in any symptomatic person with a ran- dom blood glucose >20 0 mg/dL. Asymptomatic patients or those with intercurrent illness still require a further a bnormal result before a diagno- sis of diabetes can be made. Table 103.1 WHO classi \201 cation Venous plasma glucose (mg/dL) Status Measurement condition Normal Fasting and 2-hour postprandial <110 <140 Diabetes Fasting or 2-hour postprandial >126 >200 Impaired glucose tolerance (IGT) Fasting and 2-hour post-prandial <126 140 \200\223200 Impaired fasting glucose (IFG) Fasting 110 \200\223126 103-Draznin-Chap103.indd 586 3/31/2011 4:46:07 PM CLASSIFICATION 587 Classi \201 cation The \201 rst accepted classi \201 cation of diabetes was drawn up by the WHO and modi \201 ed in 1985 ( b see Table 103.1). The original classi \201 cation i nto insulin-dependent DM (IDDM), or type 1, and non \200\223insulin-dependent DM (NIDDM), o r type 2 (Table 103.2), is now no longer used but is still seen in non-diabetes literature. The current classi \201 cation includes both clinical stage and etiology and has been used since 1997. The clinical staging is from normal glucose tol- erance through impaired gluco se tolerance (IGT) and/or impaired fasting hyperglycemia (IFG) and on to frank DM, which is split into non-insulin requiring, insulin requiring for control, and insulin requiring for survival. The etiological groups are listed in Box 103.1. Table 103.2 Differences between type 1 and type 2 diabetes Factor Type 1 diabetes Type 2 diabetes Peak age of onset 12 years 60 years U.S. prevalence 0.25 \200\2230.7% 5 \200\2237% (10% of those >65 years) Etiology Autoimmune Combination of insulin resistance, B-cell destruction, and B-cell dysfunction Initial presentation Polyuria, polydypsia, and weight loss with ketoacidosis Hyperglycemic symptoms but often with complication of diabetes Treatment Diet and insulin from outset Diet with or without oral hypoglycemic agents or insulin 103-Draznin-Chap103.indd 587 3/31/2011 4:46:08 PM CHAPTER 103 Classi \201 cation and diagnosis 588 Box 103.1 Classi \201 cation of diabetes Type 1 (5 \200\22310% of cases): pancreatic islet B-cell de \201 ciency \200 Autoimmune \200\224associated with autoantibodies to islet autoantigens (glutamate decarboxylase (GAD), IA-2 and insulin) Idiopathic Type 2 (80 \200\22395% of cases): defective insulin action or secretion \200 Insulin resi stance \200 Insulin secretory defect Others Genetic defects of B-cell function \200 Maturity-onset diabetes of the young (MODY ) \200 Chromosome 20, HNF4B (MODY 1) \200 Chromosome 7, glucokinase (MODY 2) \200 Chr omosome 12, HNF1A (MODY 3) \200 Chromosome 13, IPF-1 (MODY 4) Mitochondrial DNA 3242 mutation \200 Mutations associated with neonatal diabetes (KIR6.2, SUR) Others Genetic defects of insulin action \200 Type A insulin resistance \200 Leprechaunism (ty pe 2 diabetes, intrauterine growth retardation + dysmorphic features) Rabson \200\223Mendenhall syndrome (DM + pineal hyperplasia + acanthosis nigricans) Lipoatrophic diabetes \200 Others Diseases of the exocrine pancreas \200 Pancreatitis \200 Trauma or surgery (pancreatect omy) \200 Neoplasia \200 Pancreatic destruction, e.g., cystic \201 brosis, hemochroma tosis \200 Others Endocrinopathies \200 Cushing \200\231s syndrome \200 Acromegaly \200 Pheochromocytom a \200 Glucagonoma \200 Hyperthyroidism \200 Somatostatinoma \200 Others 103-Draznin-Chap103.indd 588 3/31/2011 4:46:08 PM CLASSIFICATION 589 Box 103.1 (Contd.) Drug or chemical induced Infections \200 Congenital rubella or cytomegalovirus (CMV) \200 Others Uncommon forms of immune-mediated diabetes \200 Anti-insulin receptor antibodies \200 S tiff man syndrome (type 1 diabetes, rigidity of muscles, painful spasms) \200 Others Other genetic syndromes associated with diabetes \200 Down syndrome \200 Klinefelter sy ndrome \200 Lawrence \200\223Moon \200\223Biedl syndrome \200 Myotonic dystrophy \200 Prader \200\223Willi syndrome \200 Turner syndrome \200 Wolfram syndrome (or DIDMOAD \200\223 d iabetes i nsipidus, DM , o ptic a trophy + sensorineural d eafness) Others Gestational diabetes 103-Draznin-Chap103.indd 589 3/31/2011 4:46:08 PM CHAPTER 103 Classi \201 cation and diagnosis 590 Genetics Type 1diabetes The overall lifetime risk in a Caucasian population of developing type 1 dia betes is only 0.4%, but this rises to \200 1 \200\2232% if your mother has it. \200 3 \200\2236% if your father has it. \200 6% if siblings have it. \200 Monozygotic twins h ave a 40% concordance rate. Islet cell antibodies are seen in only 0.3% of the general popu lation but in 40 \200\22350% of monozygotic twins and 5% of siblings of type 1 patients. A genetic predisposition is therefore suggested, but this also highlights the importance of e nvironmental triggers, as not all those with antibodies go on to develop diabetes. Genetic predisposition accounts for 1/3 of suscep- tibility to type 1 diabetes. Although several different regions of the human genome are linked to the development of typ e 1 diabetes, the most common are the major histocompatibility complex (MHC) antigens and h uman leukocyte antigens (HLA). In the United States, more than 90% of patients with type 1 diabe- tes have HLA-DR3, DR4, or both. Certain variants of the DQB1 or DQA1 gene result in expression of susceptible alleles of DR 3/DR4. This association is not true in all races, notably the Japanese. There are currently 10 distinct genetic areas (IDDM1 \200\223IDDM10) known to be linked to type 1 diabetes; some relate to MHC genes, others to the insulin gene region. MHC antigens commonly found in those with type 1 diabetes and felt to predispose to it are B15, B8, and DQ8. The DR2, DQ6, and DQ18 genes appear to be protective. Linkage studies have suggested type 1 susceptibility genes on the fol- lowing chromosomes: \200 6q (also known as IDDM5) \200 11p (IDDM2) \200 11q (IDDM4) \200 15q (IDDM3) These genetic variations may help explain susceptibility, but their link to i levels of islet cell antibodies, antiglutamate decarboxylase (GAD) antibodies, and ant ityrosine phosphatase antibodies (anti-IA-2 antibodies) often seen soon after diagnosis is less clearly decided. If all of these three antibodies are present in a nondiabetic individual, the person has an 88% chance of developing type 1 diabetes within the next 10 years. Maturity-onset diabetes of the young (MODY) The genes known to be involved in MODY are grad ually i as our under- standing of insulin signaling and receptors expands. 103-Draznin-Chap103.indd 590 3/31/2011 4:46:08 PM GENETICS 591 MODY 1 (HNF4A) \200 Accounts for <0.0001% of all type 2 patients and about 5% of cases of MODY Usually presents in adolescence or early adulthood, <25 years of age \200 Can give severe hyperglycemia, with 20% needing insulin therapy and 40% needing oral agents Results in a high frequency of microvascular complications \200 Inherited as an autosomal dominant disorder with a defect on chromosome 20q, resulting in altered activity of the hepatic nuclear factor (HNF)4A gene, w hich is a positive regulator of HNF1A. This is a transcription factor found in the liver an d B cells of the pancreas, where it acts as a transactivator of the insulin gene in rat mod els. MODY 2 (glucokinase) \200 Accounts for <0.2% of type 2 patients and 10 \200\22314% of cas es of MODY \200 Presents in early childhood \200 Gives only mild hyperglycemia and thus infrequent microvascular complications, with 90% of patients being controlled on diet alone and insulin usually only needed when becoming pregnant Autosomally dominantly inherited with a defect in the glucokinase gene on chromosome 7. This results in altered glucose sensing in the B cells of the pancrea s and impaired hepatic production of glycogen. MODY 3 (HNF1A) \200 Affects 1 \200\2232% of type 2 patients and accounts for 70% of MODY patients Presents in adolescence or early adulthood (peaks around 21 years of age) Causes severe hyperglycemia and frequent microvascular complications; 1/3 require insulin therapy and 1/3 require oral agents Linked to a mutation on chromosome 12q24 that directly alters HNF1A activity. How this caus es type 2 diabetes is not fully understood. MODY 4 (IPF-1) \200 Accounts for <1% of cases of MODY \200 A mutation occurs in transcr iption factor gene IPF-1, which in its homozygous form leads to total pancreatic agenesis. MODY 5 (HNF1-B) \200 Accounts for 3% of cases of MODY \200 Average age of presentation is 22 years, with renal cysts (RCAD \200\224renal cysts and diabetes) and often uterine abn ormalities, gout, and insulin resistance Type 2 diabetes In patients with type 2 diabetes, the concordance between monozygotic twins for diabetes is much higher (60 \200\223100% vs. 40% for type 1), but the rate among dizyg otic twins is much less, suggesting a much stronger genetic element in its etiology than fo r type 1 diabetes. Unlike patients 103-Draznin-Chap103.indd 591 3/31/2011 4:46:08 PM CHAPTER 103 Classi \201 cation and diagnosis 592 with type 1 diabetes, however, those with type 2 do not seem to have the same HLA-linked ge nes. In most families this appears to be polygenic, although the much less common MODY is autoso mal dominant but only accounts for a few per- cent of all type 2 patients. MODY is currently split into four types, with type 4 accounting for 15% of cases and for th ose cases that do not \201 t into types 1 \200\2233, although a chromosome 13 defect in t he insulin promoter factor 1 gene may fall into this group. Other recognized genetic subtypes of type 2 diabetes include mitochon- drial diabetes, whic h affects 1 \200\2233% of type 2 patients and is maternally trans- mitted. It is associated with deafness and other neurological abnormalities. Insulin resistance is an important par t of type 2 diabetes, and rare genetic defects causing this are recognized. A 40% reduction in the biological effect of any given insulin molecule is suggested by clamp studies in ty pe 2 patients, but these rarer genetic syndromes may result in a more severe picture. Further reading Alberti KG, Zimmet PZ, for the WHO consultation (1998). De \201 nition, di agnosis and classi \201 cation of DM and its complications. Part 1: Diagnosis and classi \201 cation of DM. Provisional report of a WHO consultation. Diabet Med 15:539 \200\223553. Alcolado JC, Thomas AW (1995). Maternally inherited DM: the role of mitochondrial DNA defec ts. Diabet Med 12(2):102 \200\223108. Hattersley AT (1996). Maturity onset diabetes of the young (MODY). Bailliere Clin Paediatr 4(4):663 \200\223680. Robinson S, Kessling A (1992). Diabetes secondary to genetic disorders. Bailliere Clin Endo crinol Metab 6:867 \200\223898. World Health Organization (1985). Diabetes Mellitus: Report of a WHO Study Group (Technical Report Series no. 727). Geneva: World Health Organization. World Health Organization (1999). De \201 nition, Diagnosis and Classi \201 cation of Dia betes Mellitus and its Complications. Report of a WHO Consultation. Part 1, Diagnosis and C lassi \201 cation of Diabetes Mellitus . Geneva: World Health Organization. 103-Draznin-Chap103.indd 592 3/31/2011 4:46:08 PM BACKGROUND 593 General management and treatment Background After diagnosis, all patients with diabetes need to see a dietitian and have a f ull medical assessment. The \201 rst priority is to decide whether this is a person with type 1 or type 2 diabetes, as the former needs insulin imme- diately whereas the later need s initial dietary advice. Such advice should always take into account the patient \200\231s circumstances and culture and be individually tailored to be achievable. 104-Draznin-Chap104.indd 593 3/31/2011 4:47:45 PM CHAPTER 104 General management and treatment 594 Assessment of the newly diagnosed patient History \200 Duration of symptoms, e.g., thirst , polyuria, weight loss \200 Possible secondary causes of diabetes, e.g., acromegaly \200 Family history \200 Presence of complications of diabetes \200 Risk factors for d eveloping complications, e.g., smoking, hypertension, hyperlipidemia