The timing of surgery in asymptomatic patients with borderline hyper- calcemia is still controversial. Pituitary adenomas These are managed with surgery, medical therapies, or radiotherapy as pe r sporadic pituitary tumors ( b see p. 87). Pancreatic tumors An experienced surgeon is essential to resection of these tumors. For patients with aggressive disease, the pancreas and duodenum together with surrounding l ymph nodes may be removed, whereas simple enucleation may be suf \201 cient for some lesio ns. Gastrinomas are the major cause of morbidity and mortality in MEN1 patients and these may r espond to medical therapy with proton pump inhibitors. Mutational analysis The criteria for performing mutational analysis are controversial. One approach is to recommend assessing the following categories of patient: \200 Patients wit h 2 MEN1 tumors \200 First- and second-degree relatives of patients with MEN1 \200 Cons ider screening in patients with primary hyperparathyroidism <40 years of age, particularly in the presence of multigland disease. Consider screening in patients with isolated pancreatic neuroendocrine tumors, especially gastrinomas or insulinomas. 91-Draznin-Chap91.indd 501 3/31/2011 8:55:29 PM CHAPTER 91 MEN type 1 502 Screening Screening is relevant for affected patients, asymptomatic mutation car- riers, an d \201 rst- and second-degree relatives in families with a clinical diagnosis of MEN1 but where a mutation has not been identi \201 ed. Manifestations of MEN1 are very rare before the teenage years but have been described in pa tients as young as 5 years. Careful parental counseling can encourage some childhood monito ring, which should include a careful history for symptoms (e.g., hypoglycaemia) and height and weight assess- ment in addition to calcium and prolactin measurements. Screening involves a careful clinical history and examination as well as biochemical assessment and imaging modalities ( b see Table 91.4). Age-related penetrance is as follows: age 10 \200\2237%, age 20 \200\22352%, age 30 \200 \22387%, age 40 \200\22398%, age 60 \200\223100%. Table 91.4 Screening adults in MEN1 Tumor Frequency Calcium, phosphate, and PTH Annual Basal anterior pituitary function (particularly prolactin and IGF-1) Annual Fasting gut hormones Annual Fasting glucose Annual 24-hour urinary 5HIAA and chromogranin A Annual MRI abdomen Annual \200\223every 3 years MRI pituitary Baseline Box 91.1 Prognosis Malignant pancreatic tumors, especially gastrinomas, are the major cause of mortality in ME N1, but outcomes have been improving with the introduc- tion of appropriate screening progr ams for affected and at-risk individuals. Further reading Asgharian B, Turner ML, Gibril F, et al. (2004). Cutaneous tumors in patien ts with multiple endo- crine neoplasm type 1 (MEN1) and gastrinomas: prospective study of f requency and development of criteria with high sensitivity and speci \201 city for MEN1. J Clin Endocrinol Metab 89:5328 \200\2235336. Brandi ML Gagel AF, Angeli A, et al. (2001). Guidelines for diagnosis and therapy of MEN ty pe 1 and 2. J Clin Endocrinol Metab , 86(12):5658 \200\2235671. 91-Draznin-Chap91.indd 502 3/31/2011 8:55:29 PM GENETICS 503 MEN type 2 De \201 nition MEN2 may be divided into three forms (see Table 92.1): \200 MEN2a compris es familial medullary thyroid carcinoma (FMTC) in combination with pheochromocytoma and par athyroid tumors. \200 MEN2b is de \201 ned as the occurrence of familial MTC in associat ion with pheochromocytoma, mucosal neuromas, and a marfanoid habitus. FMTC may also occur in isolation. MEN2a accounts for >75% of all MEN2 cases. Table 92.1 Classi \201 cation and presentation of MEN2 Pathology MEN2a MEN2b 7100% 50% FMTC 7100% Not present MTC 95% Pheochromocytoma 50% Parathyroid neoplasia 20 \200\22330% Not present Not present Marfanoid habitus Not present 75% Not present Mucosal neuromas Not present 10 \200\22320% 740% Not present Intestinal ganglioneuromatosis Not present Not present Genetics MEN2 is an autosomal dominant condition. The C-RET protooncogene, mutations in whi ch cause MEN2, is located on the long arm of chromo- some 10 (10q11.2). This gene encodes RET, which is a transmembrane receptor with an extracellular cysteine-ric h domain and an intracellular tyrosine kinase domain. The mutations causing MEN2 are activating mutations. Different germline mutations cause dif ferent clinical syndromes, so in contrast to MEN1, MEN2 shows a strong genotype \200\223phe notype correlation. The C-RET proto-oncogene is also involved, via inactivating mutations, in the etiology of Hirschsprung \200\231s disease. 92-Draznin-Chap92.indd 503 3/31/2011 4:23:32 PM CHAPTER 92 MEN type 2 504 Clinical features \200\224MEN2a Medulllary thyroid cancer (MTC) MTC is often the initial manifestation and is generally mul tifocal. Pheochromocytoma and parathyroid disease typically develop later. Diagnosis of MTC requires histological analysis that reveals C-cell hyperplasia and stromal amyloid. Circulating calcitonin levels are generally elevated (see Box 92.1 ), but hypocal cemia is not seen. With metastatic disease, diarrhea is common (30%). Rarely, these tumors secrete ACTH, resulting in Cushing \200\231s syndrome due to ectopic ACTH secretion. Box 92.1 Pentagastrin test \200 Indication borderline basal calcitonin and screening of f amilies with medullary carcinoma (calcitonin slightly raised with thyroiditis) Patient fasting \200 0.5 mcg/kg pentagastrin IV over 5 seconds and \202 ush cannula \200 Calcitonin measured at 0, 2, and 10 minutes \200 Elevated basal levels of calcitoni n, which do not rise with pentagastrin stimulation, are seen in children, pregnancy, with some tumors (e.g., carcinoi ds), pernicious anemia, thyroiditis, and chronic renal failure. Side effects of the test include nausea, \202 ushing, and substernal tightness, which typically resolves in <5 minutes. Stimulated calcitonin Stimulated calcitonin Stimulated calcitonin 30 \200\223100 ng/L 100 \200\223200 ng/L 200 ng/L Follow-up screening recommended Probable C-cell hyperplasia or early medullary thyroid carcinoma Medullary thyroid carcinoma very likely Pheochromocytoma \200 Tend to present later than MTC \200 50% will be bilateral but mal ignancy is rare (<10%). \200 These lesions must be excluded prior to surgery for any othe r indication. Primary hyperparathyroidism \200 Generally results from hyperplasia of the glands \200 Hypercalcemia is typically mild. 92-Draznin-Chap92.indd 504 3/31/2011 4:23:32 PM MANAGEMENT 505 Clinical features \200\224MEN2b Mucosal neuromas can be found on the distal tongue, conjunc tiva, and throughout the gastrointestinal tract. A marfanoid habitus is typically evident. MTC tends to present earlier than in MEN2a and fr equently follows a more aggressive course. Management MTC The de \201 nitive treatment is adequate surgery by total thyroidectomy and careful ly mph node dissection. Postoperative levothyroxine is adminis- tered to all patients. Tumor spread is usually local but distant metastases do occur. Regular postoperative calcit onin assessment ( \201 rst 3 months, then every 6 \200\22312 months) is used to monitor for disease recurrence. MRI, octreotide scanning, and venous catheterization may all be helpful in staging disease recurrence. Treatment of recurrent disease responds poorly to radiotherapy or chemotherapy and consequently is generally surgical if appropriate. Somatostatin analogs may help symptom control, e.g., diarrhea, but do not appear to have an antitumor effect. Few data are available to date, but therapy with radiolabeled MIBG or somatostatin analogs appears to offer signi \201 cant symptomatic improve- ment, although tumor stabilization a nd/or regression was observed only rarely. Children with MEN2 should be considered for early prophylactic sur- gery. This should gener ally be performed before the age of 5 years, and before the age of 1 year in patients with the highest risk mutations. Pheochromocytoma These tumors are best treated medically with A- and B-blockade followed by surgical removal. The risk of multifocal and/or recurrent disease must be considered. Screening has resulted in earlier detection of these lesions. Primary hyperparathyroidism The criteria for diagnosis and the indications for surgery are broadly simi- lar to those for sporadic primary hyperparathyroidism. 92-Draznin-Chap92.indd 505 3/31/2011 4:23:32 PM CHAPTER 92 MEN type 2 506 Mutational analysis Mutational analysis is indicated for \201 rst- and second-degree rela tives of patients with MEN2 and genetic analysis should be performed as early as possible i n at-risk children. Consider screening in patients with sporadic MTC or sporadic pheo- chromocytoma or in patie nts with mucosal neuromas or other phenotypic features compatible with MEN2b. Somatic RET oncogene mutations confer a worse prognosis in sporadic medullary carcinoma. Screening Biochemical and radiological screening is relevant for affected patients, asympto matic mutation carriers, and \201 rst- and second-degree relatives in families with a cli nical diagnosis of MEN2 but where a mutation has not been identi \201 ed ( b see Table 92. 2). Table 92.2 Screening in MEN2 Test Frequency Calcitonin pentagastrin stimulation test Annual 24h urinary catecholamines Annual Calcium Annual CT/MRI adrenals Annual \200\223every 3 years Box 92.2 Prognosis \200 Variable \200 Overall 10-year survival rate for MEN2b is 65% an d for MEN2a is 80%. \200 The prognosis for these patients is improving with earlier scree ning and intervention. Further reading Brandi ML, Gagel AF, Angeli A, et al. (2001). Guidelines for diagnosis and therapy of MEN type 1 and 2. J Clin Endocrinol Metab 86(12):5658 \200\2235671. Carling T. (2005). Multiple endocrine neoplasia syndrome: genetic basis for clinical manage ment. J Curr Opin Oncol 17:7 \200\22312. Constante G, Meringolo D, Durante C, et al. (2007). Predictive value of serum calcitonin le vels for preoperative diagnosis of medullary thyroid carcinoma in a cohort of 5817 consecut ive patients with thyroid nodules. J Clin Endocrinol Metab 92(2):450 \200\223455. Karges W, Dralle H, Raue F, et al. (2004). Calcitonin measurement to detect medullary thyro id car- cinoma in nodular goiter: German evidence-based consensus recommendations. Exp Clin Endocrinol Diabetes 112(1):52 \200\22358. Marx SJ (2005). Molecular genetics of multiple endocrine neoplasia types 1 and 2. J Nat Rev Cancer 5:67 \200\22375. 92-Draznin-Chap92.indd 506 3/31/2011 4:23:33 PM HPT-JT 507 Inherited primary hyperparathyroidism Epidemiology Parathyroid tumors affect 1 per 1000 population. Primary hyperparathy- roidism is inherited in up to 10% of patients. Causes \200 MEN1 \200 MEN2a \200 Hyperparathyroidism \200\223jaw tumor syndrome (HPT- JT) \200 Familial isolated hyperparathyroidism (FIHP) HPT-JT This is an autosomal dominant condition. It is characterized by pathology in three m ain tissues: \200 Parathyroid tumors, which show a high penetrance in these patients and in up to 15% of cases will be parathyroid carcinomas Ossifying \201 bromas, which affect the maxilla and/or mandible in around 30% of HPT-JT patients Renal manifestations may also occur, the most common being bilateral renal cysts (19% of pa tients) but also including hamartomas and Wilms \200\231 tumors. Benign and malignant uterine pathology is seen in up to 75% of women with HPT-JT and reduces reproductive \201 tness. Other tumors have also been reported in these patients, including pancreatic adenocarcinoma s, testicular mixed germ-cell tumors, H rthle cell thyroid adenomas, and benign and malign ant uterine tumors. The gene ( HRPT2 ) in activating mutations that are responsible for HPT-JT has been identi \201 ed on the long arm of chromosome 1. Mutational analysis is available in the US. The function of the protein product (para \201 bromin) encoded by this tumor suppressor gene is unknown. 93-Draznin-Chap93.indd 507 3/31/2011 4:23:57 PM CHAPTER 93 Inherited primary hyperparathyroidism 508 FIHP Affected individuals within a kindred suffer only from primary hyperpar- athyroidism a s an isolated endocrinopathy. In some kindreds, mutations in the MEN1 or HRPT2 genes have been identi \201 ed, but in the majority the cause is still unknown. Further reading Carpten JD, Robbins CM, Villablanca A, et al. (2002). HRPT2, encoding para \201 bromin, is mutated in hyperparathyroidism-jaw tumor syndrome. Nat Genet 32(4):676 \200\223680. Marx SJ (2002). Hyperparathyroidism in hereditary syndromes: special expressions and specia l managements. J Bone Miner Res 17(2):N37 \200\223N43. 93-Draznin-Chap93.indd 508 3/31/2011 4:23:57 PM DEFINITIONS 509 Inherited renal calculi De \201 nitions Renal calculi affect 12% of men and 5% of women by the seventh decade of l ife. Renal calculi arise due to a reduced urine volume or i excretion of stone-forming comp onents such as calcium, oxalate, urate, cystine, xanthine, and phosphate. A variety of causes for renal stones are established ( b see Box 94.1 for general causes of nephrolithiasis), but the most common etiology is hypercalciuria. Calcium stones account for >80% of all renal calculi. Uric acid stones comprise 5 \200\22310% of all renal calculi. The most common cause of hypercalciuria is hypercalcemia. This in turn is most frequently secondary to primary hyperparathyroidism. Nephrolithiasis is frequently a recurrent condition with a relapse rate of 75% in 20 years. Features associated with recurrence include early age of onset, positive fam- ily history, and lithiasis related to infection or underlying medical conditions. Box 94.1 Causes of renal calculi \200 Hypercalciuria \200 Hyperoxaluria \200 Hyperuri cosuria \200 Hypocitraturia \200 Urinary tract infection, e.g., Proteus , Pseudomonas , Klebsiella . \200 Primary renal disease, e.g., polycystic kidney disease \200 Drugs, e .g., indinavir, diuretics, salicylates, allopurinol, some chemotherapeutic agents 94-Draznin-Chap94.indd 509 3/31/2011 4:24:19 PM CHAPTER 94 Inherited renal calculi 510 Genetics Renal calculi generally arise from complex multifactorial disease result- ing from an interaction between genetic and environmental factors. The disorder may be familial in up to 45% of patients. The majority of causative genes are probably as yet unidenti \201 ed and account for much of \200\234idiopathic \200\235 calcium nephrolithiasis. Many cases of hypercalciuria are likely to be polygenic, but two exam- ples of monogenic ca uses are Dent \200\231s disease and autosomal dominant hypocalcemic hypercalciuria (ADHH). Box 94.2 Mutational analysis \200 Currently largely a research tool \200 Mutations in a variety of genes have been reported to result in renal calculi due to hypercalciuria, hype roxaluria, cystinuria, or hyperuricosuria. As these research tests move into the clinical domain, family screening will become increasingly relevant. Dent \200\231s disease \200 X-linked condition \200 Due to inactivating mutations in a chloride channel ( CLC5 ) gene \200 Characterized by hypercalciuria, nephrocalcinosis, B2 microglobinuria, progressive glomerular disease, and mild rickets due to renal phosphate loss in affected ma les ADHH \200 Autosomal dominant condition \200 Due to activating mutations in the calcium- sensing receptor gene \200 May be asymptomatic or present early with neonatal or childhoo d seizures Investigation of renal calculi \200 24-hour urine volume and urine osmolarity (low urine volume raises production of solutes) 24-hour urinary calcium excretion \200 Urine pH \200 Stone composition, if possible \200 Exclude causes of hypercalcemia (hyperparathyroidism, immobilization, or renal tubular acidosis) Exclude hypercalciuria (excess chloride, excess sodium, malignancy, sarcoidosis, renal calc ium leak, and drugs, e.g., levothyroxine or loop diuretics) Exclude causes of hyperoxaluria (primary hyperoxaluria, vitamin B 6 de \201 ciency, short bowel syndrome, and excess dietary oxalates) Exclude urinary tract infection \200 Exclude causes of hyperuricosuria (gout, dietary, ur icosuric drugs, binge drinking, or myeloproliferative disorders) 94-Draznin-Chap94.indd 510 3/31/2011 4:24:19 PM MANAGEMENT 511 Exclude causes of hypocitraturia \200\224citrate is the primary agent for removal of excess calcium (renal tubular acidosis, potassium or magnesium de \201 ciency, urinary tract infection, renal failure, and chronic diarrhea) Exclude cysteine (usually genetic in origin) or xanthine (usually secondary to allopurinol treatment) stones Management \200 Increase \202 uid intake. \200 Appropriate dietary modi \201 cations \200 Treat underlying cause. Further reading Langman CB (2004). The molecular basis of kidney stones. Curr Opin Paediatr 16(2):188 \200\223193 Thakker RV (2004). Diseases associated with the extracellular calcium-sensing receptor. Cel l Calcium 35(3):275 \200\223282. 94-Draznin-Chap94.indd 511 3/31/2011 4:24:19 PM This page intentionally left blank Part 10 Miscellaneous endocrinology Marc-Andre Cornier 95 Hypoglycemia 96 Obesity 97 Endocrinology and aging 98 Endocrinology of critical illness 99 Perioperative management of endocrine patients 100 Syndromes of hormone resistance 101 S tress and the endocrine system 102 Alternative or complimentary therapy and 514 522 534 544 561 569 575 577 endocrinology 95-Draznin-Chap95.indd 513 3/31/2011 8:59:29 PM CHAPTER 95 Hypoglycemia 514 Hypoglycemia De \201 nition (Whipple \200\231s triad) \200 Plasma glucose of <50 mg/dL associated wit h \200 Symptoms of neuro-glycopenia and \200 Reversal of symptoms with correction of gl ucose levels. For causes, see Box 95.1. Box 95.1 Causes of hypoglycemia \200 Spontaneous hypoglycemia \200 Drug induced (the mo st common cause; both accidental and non- accidental) \200 Antidiabetic agents used either alone (e.g., insulin, sulfonylureas, pra ndial glucose regulators) or in combination (e.g., insulin and thiazolidinediones) Alcohol (impairs hepatic gluconeogenesis and is often associated with poor glycogen stores) Quinine can promote hyperinsulinemia. \200 Salicylates can act by inhibiting hepatic gluc ose release and increase insulin secretion. \200 Organ failure and critical illness Acute liver failure \200 Chronic renal failure Hormone de \201 ciency \200 Addison \200\231s disease \200 Isolated ACTH de \201 cien cy \200 GH de \201 ciency \200 Hypopituitarism Insulinoma Benign 85%, malignant 15% \200 Occasionally part of MEN1 ( 10%) Other tumors Excessive IGF-2 secretion from large mesenchymal tumors (non \200\223islet cell tumor hypoglycemia [NICH]), e.g., \201 brosarcoma, mesothelioma ( 1/3 are retroperitoneal, 1/3 intra-abdominal, and 1/3 intra-thoracic) Hepatocellular carcinoma \200 Adrenal carcinoma, pheochromocytoma \200 Lymphoma, myelom a, leukemia \200 Advanced metastatic malignancy 95-Draznin-Chap95.indd 514 3/31/2011 8:59:29 PM EPIDEMIOLOGY 515 Box 95.1 (Contd. ) \200 Infection Septicemia, e.g., gram-negative or meningococcal; related to high metabolic requirements, r educed energy intake, and possibly cytokines from the in \202 ammatory process Malaria Starvation or malnutrition Anorexia nervosa \200 Kwashiorkor or marasmus B-cell hyperplasia: very rare in adults \200 Autoimmune Antibodies to insulin (antibody-bound insulin dissociates leading to elevated free insulin; typically associated with postprandial hypoglycemia) Insulin receptor activating antibodies (rare, most common in middle-aged women; may require treatment with plasmapheresis or immunosuppression) Inborn errors of metabolism \200 Glycogen storage disease \200 Hereditary fructose into lerance \200 Maple syrup disease Hypoglycemias of infancy and childhood \200 Reactive (postprandial) hypoglycemia: b see p . 520 Epidemiology Hypoglycemia is uncommon in adults, apart from patients with diabetes being tr eated with certain agents either alone or in combination (e.g., insu- lin, sulfonylureas, p randial glucose regulators, thiazolidinediones). 95-Draznin-Chap95.indd 515 3/31/2011 8:59:29 PM CHAPTER 95 Hypoglycemia 516 Pathophysiology Physiology of glucose control The liver is the major regulator (80 \200\223 85%) of circulating blood glucose lev- els in healthy individuals and responds to changes i n circulating insulin, growth hormone (GH), cortisol, glucagon, and adrenaline. \200 Post prandial state: Hepatic glucose production is inhibited by both raised glucose and insulin concentrations. Fasting state: Serum glucose falls with a consequent decrease in insulin secretion, stimula ting hepatic ef \202 ux of glucose (in the presence of cortisol, GH, and glucagon). The brain is dependent on circulating glucose for its energy demands, which are high and co mprise up to 50% hepatic glucose output. Mechanisms of hypoglycemia \200 Excessive or inappropriate action of insulin or IGF-1: in hibiting hepatic glucose production despite adequate glycogen stores, while peripheral glucose uptake is enh anced Impaired neuroendocrine response, with inadequate counterregulatory response (e.g., cortisol or GH) to insulin Impairment of hepatic glucose production, due to either structural damage or abnormal liver enzymes Types of spontaneous hypoglycemia \200 Fasting hypoglycemia occurs several hours (typical ly >5 hours) after food intake (e.g., early morning, following prolonged fasting or exercis e) and almost always indicates underlying disease. Postprandial (reactive) hypoglycemia occurs 2 \200\2235 hours after food intake ( b see Post-prandial reactive hypoglycemia, p. 520). Symptoms of hypoglycemia \200 Autonomic (adrenergic) symptoms: sweats, pallor, tachycardi a, tremor, hunger, anxiety Neuroglycopenic symptoms: poor concentration, drowsiness, double vision, irritability, peri oral tingling, poor judgment, confusion, violent behavior, personality change, unexplained collapse, focal neurological signs, seizures, loss of consciousness, and death 95-Draznin-Chap95.indd 516 3/31/2011 8:59:29 PM CLINICAL FEATURES 517 Clinical features Responses to hypoglycemia are sequential with the following: \200 Deter ioration in neuropsychological performance at plasma glucose 50 \200\22360 mg/dL Subjective perception of hypoglycemia at 50 mg/dL \200 EEG changes at 35 mg/dL Patients with recurrent hypoglycemia may not get symptoms until glu- cose concentrations ar e very low (so-called hypo-unawareness), whereas patients with poorly controlled diabetes m ellitus may experience hypogly- cemic symptoms at \200\234normal \200\235 blood glucose le vels. Most symptoms of acute hypoglycemia are adrenergic, but neuroglyco- penic symptoms occur with subacute and chronic hypoglycemia. Investigation of fasting hypoglycemia \200 Glucose strip: unreliable for low-glucose conc entrations. If the level is <70 mg/dL, a laboratory glucose should be measured. Liver and renal function tests \200 Fasting insulin, C-peptide, proinsulin, and glucose d uring hypoglycemia (Table 95.1) Inappropriately elevated insulin in the presence of hypoglycemia suggests insulinoma or self-administration of insulin or sulfonylurea. \200 Presence of C -peptide indicates endogenous insulin release \200\224either insulinoma or sulfonylurea. Insulinomas are often associated with elevated pro-insulin/insulin ratio. \200 Consider a n assay for presence of sulfonylureas. \200 Ethanol concentration \200 Cortisol ( cos yntropyn stimulation test) \200 Fasting B-hydroxybutyrate (elevated in most causes of hyp oglycemia, but suppressed if insulin is present, e.g., insulinoma, self-administration of i nsulin or sulfonylureas) Consider IGF-1 and 2: IGF-2 may be normal in NICH, but this is in association with suppressed IGF-1 and GH; the usual IGF-2/IGF-1 ratio is 3:1, ratio >10 is seen in NICH ( b see Box 95.2 ). \200 Chest and abdominal radiographs/CT \200\224?NICH so urce \200 Consider insulin and insulin receptor antibodies. Table 95.1 Biochemical features of insulinoma and factitious hypoglycemia Plasma marker Insulinoma d Sulfonylurea d Insulin injection d Glucose i i i Insulin d i i C-peptide 95-Draznin-Chap95.indd 517 3/31/2011 8:59:29 PM CHAPTER 95 Hypoglycemia 518 Box 95.2 Non-islet cell tumor hypoglycemia (NICH) Excess secretion of abnormal IGF-2 ( i IG F-2) from tumors such as \201 b- rosarcomas and mesotheliomas leads to hypoglycemia assoc iated with the following: \200 Suppressed insulin, C-peptide, and IGF-1 \200 Low GH \200 Low B-hydroxybutyrate levels \200 Autonomous IGFBP-2 secretion by tumors leads to s uppression of GH secretion and reduced IGF-1 and IGFBPs and a high IGF-2/IGF-1 ratio. IGF-2 is usually IGFBP bound, which maintains it within the circulation. IGF-2 may therefore remain \200\234free \200\235 in the circulation, with i tissue bioavai lability, leading both to suppression of IGF-1 and GH and to hypoglycemia due to binding an d stimulation of insulin receptors. De \201 nitive treatment is removal of the tumor. High-dose glucocorticoids are the most effective medical therapy. Therapy with GH replaceme nt stimulates an increase in binding pro- teins (IGFBP-3) and IGF-1 and a reversal of hypoglycemia. Further investigation of fasting hypoglycemia Glucose and insulin After a 15-hour fast, glu cose <40 mg/dL and insulin >5 mU/L is inappropri- ate. This a good screening test if repeat ed 3 times. 72-hour fast This is the most reliable test for hypoglycemia (detects 98% patients with ins ulinoma, compared with 71% at 24 hours). The patient should remain active. Plasma glucose, insulin, C-peptide, and pro-insulin are m easured q6h (unless the patient is symptomatic or the glucose level is <60 mg/dL when measu rements are made every 1 \200\2232 hours). The test is terminated if the laboratory glucose is <40 mg/dL or after 72 hours. B-hydroxybutyrate should be measured at the end of the fas t (its presence makes insulinoma unlikely). Exercise test This is used to precipitate hypoglycemia in patients with endogenous hyperins ulinism who might tolerate prolonged periods of fasting. Blood is collected before and at 10-minute intervals during 30 minutes of intense exercise and for 30 minutes afterward. Patients with spontaneous hypoglycemia become exhausted and their glucose concentration falls below 40 mg/dL. Localization of tumor b See Tumor localization (p. 473). This is only performed once an ins uli- noma is con \201 rmed biochemically. MRI or spiral CT are usually \201 rst-line inv estigations (equal sensitivity 50 \200\22370%); endoscopic and intraoperative US have an im proved resolution and sensitivity but are more invasive. 95-Draznin-Chap95.indd 518 3/31/2011 8:59:29 PM MANAGEMENT 519 111 I Octreotide scan This has 50% sensitivity and may detect metastases. It is less good f or insulinomas than for other pancreatic tumors. Selective angiography Angiography with selective arterial calcium gluconate or secretin sti mula- tion (rarely required) is done in centers with experienced radiologists, when biochem ically proven insulinomas cannot be visualized on imaging. Management Acute hypoglycemia If the patient is conscious, oral carbohydrate (ideally food and a sugary drink) should be administered as soon possible. A glucose-containing gel, whic h is absorbed by the buccal mucosa, may be used in drowsy, but conscious, individuals. If the patient is unconscious, administer 25 \200\22350 mL 25% glucose IV into a large vein , followed by a saline \202 ush, as the high concentration of glucose is an irritant and may even lead to venous thrombosis. A maintenance infusion of 5% or 10% dextrose is often r equired thereafter, especially if there is an ongoing risk of recurrent hypoglycemia (e.g., overdose of a long-acting insulin/analog). A dose of 1 mg glucagon IM may be administered if there is no IV access. This increases hep atic glucose ef \202 ux, but the effect only lasts for 30 min- utes, allowing other means of blood glucose elevation (e.g., oral), before the blood glucose falls again. It is \200 Ineffective with hepatic dysfunction and if there is glycogen depletion, e.g., ethanol-related hypoglycemia. Relatively contraindicated in patients with known insulinoma, as it may induce further insulin secretion. Ineffective within 3 days following a previous dose of glucagon. Secondary cerebral edema may complicate hypoglycemia and should be considered in cases of p rolonged coma despite normalization of plasma glucose. Mannitol and/or dexamethasone may be helpful. Recurrent chronic hypoglycemia If de \201 nitive treatment of the underlying condition is unsuccessful or impossible, symptoms may be alleviated by frequent (e.g., q4h) small meals, including overnight. Diazoxide, administered by mouth, is useful in the management of patients with chronic hypo glycemia from excess endogenous insulin secre- tion due to an insulinoma or islet cell hype rplasia. Further reading Gama R, Teale, JD, Marks V (2003). Clinical and laboratory investigation of adult spontaneous hypoglycemia. J Clin Pathol 56 : 641 \200\223646. Service FJ (1997). Hypoglycemia. Endocrinol Metab Clin North Am 126(4):937 \200\223952. 95-Draznin-Chap95.indd 519 3/31/2011 8:59:29 PM CHAPTER 95 Hypoglycemia 520 Postprandial reactive hypoglycemia (PRH) De \201 nition PRH is hypoglycemia following a me al due to an imbalance between glu- cose in \202 ux into (exogenous from food, and endogen ous glucose produc- tion) and glucose ef \202 ux out of the circulation. Pathophysiology and causes \200 Exaggerated insulin response related to rapid glucose abs orption, e.g., post-gastrectomy dumping syndrome. This results in a delayed insulin peak wi th respect to the peak blood glucose, probably related to an exaggerated GLP-1 (glucagons-l ike peptide 1) response. Incipient diabetes mellitus occasionally presents with postprandial hypoglycemia, possibly related to disordered insulin secretion. Insulin resistance related hyperinsulinemia, e.g., obese subjects with or without impaired glucose tolerance Increased insulin sensitivity with de \201 ciency of counterregulatory hormones, glucagon, and adrenaline (rapid action), as well as cortisol and GH (delayed acti on, up to 12 hours) Impaired glucagon sensitivity and secretion in response to hypoglycemia are involved in the pathogenesis of PRH. Renal glycosuria accounts for up to 15% of patients with PRH. Body composition \200 20% o f very lean people are prone to PRH. \200 Massive weight reduction increases the risk of PRH. \200 Lower-body obesity (especially in women) is associated with high- normal insulin sensitivity and PRH. Diet \200 High-carbohydrate, low-fat diet, by i insulin sensitivity \200 Prolonged very low \200\223calorie diets (>2 weeks), by reducing counterregulatory hormones, especially GH. Alcohol \200 Inhibits hepatic glucose output \200 Increases insulin secretion in respon se to glucose and sucrose There are also idiopathic causes of PRH. Investigation Prolonged oral glucose tolerance test is not physiological; 10% of the normal (asymptomatic) population has a positive response with blood glucose levels <47 mg/dL. The mixed-meal test is more physiological; 47% of patients with sus- pected PRH have a positive test vs.1% of asymptomatic subjects. Ambulatory glucose sampling is gaining favor, as it may correlate symp- toms with low sugar readings, and improvement of symptoms with recov- ery from hypoglycemia. 95-Draznin-Chap95.indd 520 3/31/2011 8:59:29 PM POSTPRANDIAL REACTIVE HYPOGLYCEMIA (PRH) 521 Management Diet \200 Frequent, small, low-carbohydrate, high-protein meals \200 Avoid r apidly absorbed carbohydrates \200 Avoid sugary drinks, especially in combination with al cohol \200 Addition of soluble dietary \201 bers, e.g., 5 \200\22310 g guar gum, or pec tin, or hemicellulose per meal, delays absorption and lowers the glycemic and insulinemic indices ( especially effective in rapid gut transit time). Drugs \200 Acarbose, an intestinal A-glucosidase inhibitor, delays sugar and starch absorption, thus reducing the insulin response to a meal. Metformin 500 mg can be useful with meals. \200 Supplemental chromium is reported to down -regulate B-cell activity and increase glucagon secretion. In exceptional cases, with debilitating PRH, diazoxide (side effects are water retention, h ypertrichosis, digestive disorders), or somatostatin analogs may be required. Propranolol and calcium antagonists have been used; however, controlled studies are lacking. Further reading Brun JF, Fedou C, Mercier J (2000). Postprandial reactive hypoglycemia. Dia bet Metab 26:337 \200\223351. Gama R, Teale JD, Marks V (2003). Clinical and laboratory inv estigation of adult spontaneous hypoglycemia. J Clin Pathol 56:641 \200\223646. Teale JD, Wark G (2004). The effectiveness of different treatment options for non-islet cel l tumor hypoglycemia. Clin Endocrinol 60:457 \200\223460. 95-Draznin-Chap95.indd 521 3/31/2011 8:59:29 PM CHAPTER 96 Obesity 522 Obesity De \201 nition Obesity is de \201 ned as an excess of body fat (adiposity) suf \201 cien t to adversely affect health. In the almanac of direct measurements of body fat mass, body mass index (BMI) is a commonly used surrogate marker (see Box 96.1 ). \200 Obesity is oft en de \201 ned in terms of BMI. \200 BMI does not take body build or fat distribution in to consideration, and thus can be misleading in the presence of large muscle mass. Lower cutoff values may be applicable to non-Caucasian ethnic groups. \200 Fat distributi on: central (abdominal) obesity ( \200\234apple shape \200\235) vs. gluteofemoral obesity ( \200\234pear shape \200\235). Apple-shaped people have an i cardiovascular risk compared to that of pear-shaped people. Adverse consequences of central obesity may re \202 ect i visceral (intra- abdominal fat) stores, (blood draining into the portal vein may expose the liver directly to the ef \202 uent from visceral fat). Assess fat distribution using waist circumference (see Boxes 96.2 and 96.3). Box 96.1 BMI BMI (kg/m 2 ) = weight (kg) / [height (m)] 2 Classi \201 cation BMI (kg/m 2 ) WHO class <18.5 18.5 \200\22324.9 25.0 \200\22329.9 30.0 \200\22334.9 35.0 \200\22339.9 >40.0 Underweight Healthy Pre-obese (overweight) Obese class I (obese) Obese class II (obese) Obe se class III (severely obese) 96-Draznin-Chap96.indd 522 3/31/2011 4:25:06 PM EPIDEMIOLOGY 523 Box 96.2 Waist circumference Suggested indicators of central obesity (and i cardiovascular risk): Waist circumference \200 Men >40 in (102 cm) \200 Women >35 in (88 cm) Another s tudy suggested a waist circumference of <100 cm makes insu- lin resistance unlikely (irresp ective of sex). tain racial and ethnic backgrounds. Waist circumference cutoffs should be adjusted for individuals of cer- Box 96.3 Measurement of waist circumference Measurements should be recorded over underwear or light clothing. The subject should stand with their arms by their sides. The position of the waist is midway between the lower rib margin and the iliac crest. 1. Identify the bony landmarks in the mid-axillary line. a. The lower rib margin (bottom of the rib cage) b. The iliac crest (highest bony part of the pelvis) 2. Measure the vertical distance between them. Note the midpoint. 3. Ask the subject to sta nd with their feet 23 \200\22330 cm apart. 4. Ensure that the tape measure is at the same l evel around the body at the midpoint. Gently tighten the tape measure so that it is taut bu t not too tight. 5. Ask the subject to breathe normally and record the measurement at the end of normal expi ration. 6. Record waist circumference. Epidemiology There has been a rapid increase in obesity in both the developed and developin g worlds. In the United States, the prevalence of obesity has increased \200\224in 1980, 12% of men a nd 16% of women were obese. By 2004, the \201 gures had increased to 31% and 33%, respect ively. Now, 2/3 of the population is either overweight or obese. Prevalence in children has also increased rapidly (17% of adolescents in 2004) with an attendant risk of type 2 diabetes. In some ethnic populations, prevalence of overweight is >75%. Prevalence varies with age (p eak prevalence at 50 \200\22370 years) and socio- economic class. 96-Draznin-Chap96.indd 523 3/31/2011 4:25:06 PM CHAPTER 96 Obesity 524 Etiology Genetic factors Monogenic This is rare. \200 Leptin de \201 ciency or resistance (massive obesity and hy perphagia in early childhood) (see Box 96.4 ) Prader \200\223Willi syndrome (obesity, learning dif \201 culties, chromosome 15) \200 L awrence \200\223Moon \200\223Biedl syndrome (obesity, polydactyly, learning dif \201 culties, retinitis pigmentosa) Melanocortin 4 receptor (MC4R) de \201 ciency (obesity, hyperphagia, dominant inheritance (see Box 96.5 ) Box 96.4 Leptin \200 First hormone described to be secreted from adipose tissue \200 En coded by Lep gene (chromosome 7q31.3) \200 Synthesized in and secreted by adipose tissue \200 Affects the hypothalamus to decrease food intake and increase energy expenditure (by sympathetic activation) Primary role in humans may be to indicate nutritional depletion or fasting and for falling leptin levels to indicate insuf \201 cient energy reserves for growth and reproduction Exerts potent anti-obesity effects in animals such as the ob / ob (leptin de \201 cient) mouse Leptin therapy bene \201 ts humans with congenital leptin de \201 ciency and leptin-de \201 cient partial lipodystrophy. Most obese humans do not have abnormalities of the leptin gene. Plasma leptin i in obese hu mans, and obese humans appear to be leptin resistant. Reduced leptin transportation to the brain has been suggested as a potential mechanism of leptin resistance in humans. Trials in humans with polygenic obesity are equivocal (high doses of SC leptin lead to more weight loss than placebo, but long- term consequences of supraphysiological doses are unkn own; sympathetic activation for weight loss by other agents has unwanted side effects). Loss of function mutations in the leptin receptor gene is associated with hyperphagia and e arly-onset obesity; serum leptin levels do not predict leptin receptor mutations. \200 Le ptin is stimulated by glucocorticoids. 96-Draznin-Chap96.indd 524 3/31/2011 4:25:06 PM ETIOLOGY 525 Box 96.5 Melanocortin peptides \200 Melanocortin peptides are derived by cleavage from pr o- opiomelanocortin (POMC). Mutations result in ACTH de \201 ciency, obesity, and pale skin (and no hair in Caucasians). Mutations in the receptor (MC4R) are the most common mongenic causes of obesity found \200 \2241% of adults with BMI >30 kg/m 2 and 5 \200\2236% of overly obese children under the ag e of 10. MC4R mutations are dominantly inherited. Polygenic Estimates of heritability range from 40 to 80%, thus genetic factors play a major role in obesity. Environmental factors Excess energy intake or d energy expenditure due to physical inactivi ty are major determinants of obesity in genetically susceptible individuals. Secondary causes These include Cushing \200\231s disease or syndrome, hypothyroidism, and h ypothalamic lesions ( i appetite). 96-Draznin-Chap96.indd 525 3/31/2011 4:25:06 PM CHAPTER 96 Obesity 526