Approach to Amenorrhea
Diabetic Ketoacidosis and Hyperosmolar Hyperglycemic Nonketotic Coma
Approach to the Patient with Hypercalcemia and Hypocalcemia
Approach to Hyperlipidemia
Hyperthyroidism and Thyrotoxicosis
Approach to the Patient with a Thyroid Nodule
DEFINITION, EPIDEMIOLOGY, AND ETIOLOGY
Adrenal insufficiency occurs when there is inadequate production of one or both of the two major adrenocortical hormones, cortisol and aldosterone. It can develop as a consequence of destruction or suppression of the adrenal cortex (primary adrenal insufficiency) or as a result of a failure of pituitary corticotropin production or renal renin secretion (secondary adrenal insufficiency).
Primary adrenal insufficiency usually occurs sporadically; the reported prevalence is 4 to 6 cases per 100,000 population. In the United States, the most common cause is autoimmune adrenalitis, which can be associated with other autoimmune disorders such as Hashimoto’s thyroiditis, Graves’ disease, type I diabetes mellitus, and pernicious anemia. Other causes include infection (tuberculous, fungal, cytomegalovirus), bilateral adrenal hemorrhage (sepsis, pneumonia, recent abdominal surgery, anticoagulation), infiltrative disease (lymphoma, amyloidosis, metastatic neoplasia), and congenital enzyme deficiencies. The most common cause of secondary adrenal insufficiency is suppression of corticotropin secretion with chronic glucocorticoid therapy. Other causes of decreased corticotropin production include pituitary tumors and pituitary infarction. Renin deficiency occurs with diabetic nephropathy, chronic renal failure, or the administration of indomethacin or angiotensin-converting enzyme inhibitors.
In primary adrenal insufficiency, there is destruction of the adrenal cortex with resultant inability to synthesize all major adrenal cortical hormones, including cortisol, aldosterone, and androgens. Secondary adrenal insufficiency develops as a consequence of either corticotropin or renin deficiency, leading to an isolated deficiency of either cortisol or aldosterone.
History: Symptoms of cortisol deficiency include fatigue, anorexia, weight loss, generalized muscle and joint aches, and abdominal pain. Patients with primary adrenal insufficiency, owing to the elevated production of corticotropin precursors, may have hyperpigmentation. They also may have postural light-headedness because of the loss of aldosterone production. Patients with secondary adrenal insufficiency from corticotropin deficiency may have symptoms related to the deficiency of other pituitary hormones, such as amenorrhea, erectile dysfunction, dry skin, cold intolerance, and lethargy.
Physical examination: Patients with primary adrenal insufficiency have hyperpigmentation of the skin and mucous membranes, particularly the dorsum of the hands, the palmar creases, the elbows and knees, and the nipples. Orthostatic hypotension can occur. Women have a decrease in body hair. Patients with pituitary corticotropin deficiency appear pale because of a decrease in the pigmentation of the skin. The presence of hypogonadism (decreased sexual hair, mammary gland atrophy among women, decreased testicular size) indicates concomitant deficiency of other pituitary tropic hormones.
LABORATORY STUDIES AND DIAGNOSTIC TESTS
Aldosterone deficiency is associated with hyponatremia, hyperkalemia, metabolic acidosis, and urinary sodium excretion more than 20 mEq per liter. Because of intravascular volume contraction, serum urea and creatinine are increased. Cortisol deficiency is associated with normocytic anemia and leukopenia with relative lymphocytosis and eosinophilia. Fasting hypoglycemia may occur among patients who have been eating poorly.
Patients whose clinical features suggest adrenal insufficiency should undergo biochemical confirmation of the diagnosis. Because these tests can take a long time to process, therapy should be initiated and continued until the results are available. The corticotropin stimulation test serves as a good screening tool. Patients receive 250 µg of synthetic corticotropin, and serum cortisol levels are checked at baseline, 30 minutes, and 60 minutes. Increments of more than 10 µg per deciliter or peak values more than 20 µg per deciliter usually exclude adrenal insufficiency. A diagnosis of primary adrenal insufficiency is based on the finding of low random serum cortisol and aldosterone levels together with high levels of corticotropin and renin. Patients with secondary adrenal insufficiency related to inadequate corticotropin production have low corticotropin and cortisol levels but normal levels of aldosterone and renin. Those with secondary adrenal insufficiency related to diminished renin production have low renin and aldosterone levels but normal levels of corticotropin and cortisol. Additional studies may be useful in the evaluation of adrenal insufficiency, including adrenal computed tomography and tests of pituitary function.
Chronic adrenal insufficiency: Physiologic doses of hydrocortisone usually are administered in a way that mimics the normal circadian rhythm of cortisol secretion (e.g., 10 to 15 mg on arising, 5 to 10 mg in the early afternoon, and 5 mg before bed). The maintenance therapy should be altered under conditions of physical stress (e.g., infection, trauma, or surgical procedures). Systemic infections associated with fever necessitate a doubling of the usual oral dose. Patients undergoing general anesthesia should receive about 300 mg parenteral cortisol in divided doses throughout the day of the procedure. Patients with primary adrenal insufficiency also need therapy with fludrocortisone, which has mineralocorticoid activity similar to that of aldosterone. The usual dose is 0.05 to 0.2 mg daily, adjusted according to serum electrolyte and blood pressure response. During hot, humid weather, a higher dose may be needed.
Acute adrenal insufficiency: Acute adrenal insufficiency is a medical emergency. It may develop as a result of progression of undiagnosed or untreated chronic insufficiency or in patients with chronic insufficiency who undergo acute physical stress without a concomitant increase in hydrocortisone doses. Patients have nausea, vomiting, rapid weight loss, and hypotension. Therapy should begin with an infusion of 5% dextrose in 0.9% saline solution (1 L in the first hour). If adrenal insufficiency has not previously been diagnosed, blood samples for hormone levels should be obtained as outlined earlier. A dose of 100 mg intravenous hydrocortisone should be given immediately and followed by a continuous infusion of 10 mg per hour for the next 5 hours.
Chapter 407 and Chapter 408
APPROACH TO AMENORRHEA
PATHOGENESIS AND ETIOLOGY
The menstrual cycle is controlled by the interaction of the hypothalamus (pulsatile secretion of gonadotropin-releasing hormone), pituitary (secretion of luteinizing hormone [LH] and follicle-stimulating hormone [FSH]), ovaries (follicular growth, ovulation, and corpus luteum formation), and uterus (cyclic growth and shedding of the endometrium). Abnormalities in any of these systems can cause menstrual abnormalities.
Primary amenorrhea is present when the first menses has not occurred by 16 years of age. It is usually caused by a genetic or congenital defect, particularly gonadal dysgenesis, and often is associated with disorders of puberty. Secondary amenorrhea is present when a woman who has undergone menarche experiences the absence of periods for a time greater than three of her previous cycle intervals. One common cause, of course, is pregnancy. Once that is excluded the causes can be listed as follows: hypothalamic dysfunction (35%, usually related to stress, poor nutrition, or strenuous exercise), pituitary disease (17%, usually hyperprolactinemia), which is the single most common cause of secondary amenorrhea, ovarian disease (10% with ovarian failure and another 30% with the polycystic ovary syndrome), and uterine disease (7%, often Asherman’s syndrome of intrauterine syechiae). Adrenal hyperplasia, hypothyroidism, and ovarian and adrenal tumors also can cause secondary amenorrhea.
Primary amenorrhea: Evaluation should focus on breast development, the presence or absence of the uterus and cervix, and FSH level. If there is no breast development and the FSH level is elevated, the probable diagnosis is gonadal dysgenesis. If the uterus is absent, the probable diagnosis is müllerian agenesis. Karyotyping is indicated for patients with gonadal dysgenesis.
Secondary amenorrhea: Pregnancy must be excluded. Height and weight should be measured. Women who are more than 10% below their “ideal” body weight should be evaluated for anorexia nervosa. The evaluation includes a measurement of prolactin and FSH levels for all patients and thyroid testing and serum testosterone levels when the there is still diagnostic uncertainty. High levels of prolactin suggest prolactinoma, though hypothyroidism, medications, and renal failure can be responsible. FSH levels are elevated in ovarian failure, which may be caused by premature menopause (women older than 30 years) or chromosomal abnormalities (women younger than 30 years). Patients also should undergo a progestin withdrawal test, which is performed by means of administration of medroxyprogesterone acetate (10 mg a day for 5 days) and monitoring any uterine bleeding. The absence of uterine bleeding suggests that endogenous estrogen levels are particularly low or that Asherman’s syndrome is present. Uterine bleeding indicates that Asherman’s syndrome is not present.
Primary amenorrhea: In many cases, long-term therapy with estrogen and progesterone is needed to stimulate development of secondary sex characteristics and to protect bone mass. Women with gonadal dysgenesis due to 45X are at high risk of thyroid disease and diabetes mellitus.
Secondary amenorrhea: The underlying cause should be managed when possible (e.g., prolactinomas can be controlled with surgical resection or bromocriptine therapy). Because women with secondary amenorrhea are at risk of osteoporosis, some authorities recommend that all be treated with estrogen–progestin hormone replacement.
DEFINITION AND ETIOLOGY
Cushing’s syndrome is the clinical expression of the metabolic effects of persistent, inappropriate hypercortisolism. Exogenous administration of glucocorticoids is the most common cause. Pituitary corticotropin hypersecretion (Cushing’s disease), usually from microadenoma, accounts for about 60% of noniatrogenic cases; ectopic production of corticotropin by tumors (most often lung cancer) accounts for an additional 10%. The diseases that cause corticotropin-independent elevations in cortisol secretion (adrenal adenoma, adrenal carcinoma, and adrenal hyperplasia) each account for approximately 10% of noniatrogenic cases.
History: Patients with Cushing’s disease usually have had symptoms for 2 to 3 years before diagnosis. The earliest symptoms include weight gain, hypertension, and glucose intolerance. A redistribution of adipose tissue causes facial rounding, increased central adiposity, and thinning of the upper and lower extremities. Patients may have striae, easy bruising, and increased growth of body hair. Women may have irregularities of menses; men may have gynecomastia. Proximal muscle weakness and peripheral edema are common. Back pain and loss of height may occur if osteoporosis and vertebral compression fractures have developed. Cognition and affect may be impaired.
Patients with adrenal adenoma and adrenal hyperplasia have signs and symptoms similar to those of patients with Cushing’s disease. Patients with ectopic corticotropin syndrome usually have a shorter duration of symptoms. Some have minimal symptoms of Cushing’s syndrome because of the short duration of hypercortisolemia. Among these patients, very high levels of cortisol often are associated with manifestations of mineralocorticoid excess, including weakness from hypokalemia. Symptoms related to the underlying tumor also may be evident. Patients with adrenocortical carcinoma also a shorter duration of symptoms before they seek medical attention. They typically have severe manifestations of androgen excess; for this reason, muscle atrophy may be less prominent.
Physical examination: The examination reveals plethora, a round face with preauricular fullness, a prominent upper lip, supraclavicular fossa fullness, and a cervicodorsal fat pad (buffalo hump) disproportionate to the degree of obesity. Patients have torso obesity but thin extremities with decreased muscle mass. Peripheral edema may be present. The skin is thin, and there are wide, purple straie over the abdomen and chest. Other skin lesions include tinea versicolor, verruca vulgaris, acne vulgaris, and hirsutism. Patients with ectopic corticotropin production or adrenocortical carcinoma may have abnormalities related to the underlying tumor, such as a palpable mass.
LABORATORY STUDIES AND DIAGNOSTIC TESTS
Laboratory evaluation first requires confirmation of hypercortisolism by means of detection of either an elevated level of free cortisol in a 24-hour urine collection or an abnormal result of an overnight dexamethasone suppression test (the failure of 1 mg of dexamethasone given at 11 P.M. to suppress the serum cortisol level to less than 5 µg per deciliter at 8 A.M. the following day). If the screening test result is abnormal, further testing is needed to determine the cause of hypercortisolism (Fig. 407.3).
Cushing’s disease: Transsphenoidal selective resection of the pituitary microadenoma is the most effective therapy for pituitary corticotropin-dependent Cushing’s disease. If the operation fails or cannot be performed, pituitary irradiation can be useful. When these treatments have failed, bilateral total adrenalectomy is the preferred treatment. The main disadvantage of this approach is that the pituitary tumor may continue to grow and become locally invasive and difficult to control (Nelson’s syndrome). Various inhibitors of adrenal function have been used to suppress cortisol secretion, including aminoglutethimide, ketoconazole, and mitotane.
Other etiologic factors: Management of ectopic corticotropin syndrome entails surgical resection of the primary tumor followed by radiation therapy or chemotherapy if necessary. If the neoplasm cannot be resected, the use of adrenal inhibitors can be considered. Adrenocortical adenoma should be surgically removed. Adrenal hyperplasia can be managed with adrenalectomy or adrenal inhibitors. Adrenocortical carcinoma typically responds poorly to attempts at resection or chemotherapy.
DEFINITION AND EPIDEMIOLOGY
Diabetes mellitus is a chronic metabolic syndrome caused by a relative or absolute deficiency of insulin. Although the condition is recognized because of hyperglycemia, the metabolism of fats and proteins also is affected. One in every 20 persons in the United States has diabetes. The condition with its complications is the seventh leading cause of death of disease in the United States.
CLASSIFICATION, PATHOPHYSIOLOGY, AND ETIOLOGY
Type I diabetes accounts for 5% to 10% of cases of diabetes in the United States and usually has its onset in the first two decades of life. There is a familial predisposition. The disease is characterized by immune-mediated destruction of pancreatic islet b cells, absolute insulin deficiency, and a dependence on insulin therapy for the preservation of life. These patients are prone to ketosis.
Type II diabetes accounts for 90% to 95% of cases of diabetes in the Untied States and usually begins after 40 years of age. As with type I disease, there is a genetic predisposition. The disease is characterized by altered insulin secretory dynamics but retention of endogenous pancreatic insulin secretion, the absence of ketosis, and insulin resistance in target cells. Most patients are obese. Other associations include a family history of diabetes mellitus, hypertension, dyslipidemia, or a particular ethnic background (African American, Hispanic, Native American).
Secondary diabetes can occur with pancreatic disease or surgery, chronic liver disease, Cushing’s syndrome, acromegaly, pregnancy, and the use of glucocorticoids. Women with gestational diabetes usually return to normal glucose tolerance after parturition.
Diabetes mellitus can be diagnosed when at least one of the following criteria is met: (a) unequivocal symptoms (polyuria, polydipsia, polyphagia, unexplained weight loss) and a random plasma glucose level of 200 mg per deciliter or more; (b) fasting plasma glucose (FBG) level 126 mg per deciliter or more; or (c) 2-hour plasma glucose level 200 mg per deciliter or more after the ingestion of 75 g glucose during an oral glucose tolerance test. In the absence of unequivocal hyperglycemia with acute metabolic decompensation, such as ketoacidosis, these criteria should be confirmed by means of another test on a different day.
Acute complications include diabetic ketoacidosis and hyperosmolar hyperglycemic nonketotic coma (described in the next entry). Two infections occur almost exclusively among patients with diabetes. Malignant otitis externa is potentially fatal, erosive Pseudomonas aeruginosa infection of the soft tissue and cartilage around the external auditory canal. It can cause progressive destruction of the temporal and petrous bones and requires vigorous debridement and prolonged therapy with intravenous (IV) antibiotics. Rhinocerebral mucormycosis is a very rapidly progressive invasive infection caused by the mycelia of Mucor and Rhizopus fungi. Aggressive surgical debridement and IV amphotericin B are the mainstays of therapy.
Chronic complications include neurologic deficits and accelerated vascular disease. The vascular disease is of two types: microangiopathy, characterized by thickening of capillary basement membranes and manifested principally in the retina and kidney, and macroangiopathy, increased frequency and severity of arterial atherosclerotic disease. The development of diabetic complications is likely multifactorial and caused by a combination of protein glycation, sorbitol accumulation within cells, glycosylation of basement membranes, platelet and endothelial dysfunction, and hemodynamic abnormalities. The Diabetes Control and Complications Trial (DCCT) firmly established the beneficial effects of improved glucose control on the risk of retinopathy, neuropathy, and nephropathy among patients with type I diabetes. Subsequent studies extended these findings to patients with type II disease.
Diabetic retinopathy: Diabetic retinopathy is the leading cause of blindness among working-age adults in the United States. The earliest stage is background retinopathy, which consists of microaneurysms, dot and blot hemorrhages, and exudates. It affects 80% of patients within 5 years of the onset of diabetes. With advancing disease, proliferative retinopathy develops and is characterized by neovascularization. Because laser photocoagulation has a dramatic effect in preventing visual loss among patients with high-risk retinal characteristics, a yearly comprehensive ophthalmologic examination is recommended for all patients who have had diabetes for more than 5 years.
Diabetic nephropathy: Diabetic nephropathy is the leading cause of end-stage renal disease in the United States. The risk increases with the duration of diabetes, although it is rare for nephropathy to develop after 25 to 30 years. The earliest clinical manifestation is a slightly elevated level of urinary albumin excretion (microalbuminuria) of 30 to 300 mg per day. There is associated glomerular hyperfiltration at this stage. With advancing disease, the amount of proteinuria increases to more than 300 mg per day, and the patient eventually has hypertension and a progressive decline in creatinine clearance. The development of nephropathy can be slowed with meticulous blood pressure control and the use of angiotensin-converting enzyme inhibitors by patients whose daily albumin excretion exceeds 30 mg, even if they have normal blood pressure.
Diabetic neuropathy: Diabetic neuropathy manifests as a peripheral neurologic deficit or autonomic dysfunction (Table 411.6). Among patients with distal symmetric neuropathy, neuropathic foot ulceration can necessitate limb amputation. There is no effective means of reducing the risk of neuropathy other than improved glycemic control. The risk of amputation, however, can be reduced by patient education about appropriate foot care, regular inspection of the feet by health care providers and patients, use of appropriate shoes and footwear, appropriate podiatric and pedorthic referral, aggressive early control of foot ulcers, and appropriate use of vascular surgical intervention. Painful neuropathy can be managed with tricyclic antidepressants, gabapentin, carbamazepine, or topical capsaicin cream. Narcotics should be avoided because of the high risk of addiction in this setting and a predictable loss of effectiveness due to tachyphylaxis.
Type I diabetes: There are three major components of therapy—a nutritional plan, exercise, and insulin dosage. Patient education is essential to successful therapy, and the treatment program must be sufficiently flexible to allow highly varied and changing lifestyles without sacrificing careful metabolic control. Dietary protein should contribute about 10% to 20% of the total daily calories, leaving 80% to 90% of the total to be distributed between dietary fat and carbohydrate. Foods that cause rapid increases in blood glucose level should be avoided.
Monitoring consists of measurement of glycosylated hemoglobin every 3 months and patient monitoring of blood glucose level, typically before meals and at bedtime and whenever hypoglycemia is suspected. Therapeutic objectives are listed in Table 399.1. The insulin dosage needed for meticulous glucose control is typically 0.5 to 1.0 U per kilogram per day. During the honeymoon period of relative remission early in the disease, insulin requirements are less. During intercurrent illness, the necessary dosage may increase markedly.
Because patients with type I diabetes lack both basal and prandial insulin secretion, contemporary flexible insulin programs have multiple components. The most precise way to mimic normal insulin secretion is to use an insulin pump in a program of continuous subcutaneous insulin infusion. More commonly, basal therapy, usually about 40% to 50% of the daily insulin dose, is given as either intermediate-acting human insulin (NPH or lente) at bedtime with or without a small morning dose or as two daily injections of long-acting ultralente human insulin. Prandial insulin secretion is best duplicated by giving preprandial injections of rapid-onset regular insulin before each meal. Regular human insulin takes at least 20 minutes to become effective, but lispro insulin acts rapidly enough to be given immediately before a meal. Typically, 50% to 60% of the daily insulin is divided among the meals in proportion to carbohydrate content, although any given dose can be adjusted if the amount of food to be ingested differs from the patient’s usual pattern or if the simultaneous blood glucose reading deviates from the target range.
Type II diabetes: The recommended treatment goals are fasting and preprandial glucose levels less than 120 mg per deciliter with glycosylated hemoglobin levels normal or near normal. Differing patient circumstances, however, such as advanced age and comorbid conditions, may dictate that higher degrees of hyperglycemia be tolerated. Normalizing weight among obese patients also is important. Because atherosclerotic risk is substantial among these patients, attention should be given to smoking cessation and meticulous control of hypertension and hyperlipidemia. Glycosylated hemoglobin levels should be obtained quarterly. Patient monitoring of FBG should be performed every day, and preprandial and bedtime levels should be checked periodically.
The treatment program consists of diet and exercise for all patients, and pharmacologic therapy for most. Moderate calorie restriction (250 to 500 calories less than average daily intake) usually is recommended for obese patients. Additional dietary principles include (a) balanced nutrient intake, (b) emphasis on appropriate alterations as necessary to achieve lipid and blood pressure goals, (c) adequate spacing of meals (4 to 5 hours), (d) consideration of consuming additional dietary fiber, and (e) avoidance of intake of rapidly absorbed simple sugars (sucrose, glucose, maltose) unless they are substitutes for other carbohydrates.
Many oral antidiabetic drugs are available. Sulfonylurea drugs such as glipizide and glyburide augment insulin secretion but may cause weight gain and hypoglycemia. Meglitinides such as repaglinide and nateglinide also augment endogenous insulin secretion. Because of their short duration of action, these agents can be given at meals for extra flexibility. They also may cause hypoglycemia and weight gain. Metformin decreases hepatic glucose output and increases peripheral glucose utilization. It does not cause weight gain or hypoglycemia but may cause nausea, abdominal discomfort, and diarrhea. It is contraindicated in the care of patients with elevated serum creatinine levels, hepatic disease, or congestive heart failure, who are at increased risk of lactic acidosis. Metformin should be withheld in the period surrounding the use of intravenous contrast agents.
Thiazolidinediones such as rosiglitazone and pioglitazone enhance insulin sensitivity and augment uptake of glucose in muscle and adipose tissue. They work best in combination with insulin or other oral agents. Because use of troglitazone has been associated with hepatotoxicity, monthly monitoring of liver enzymes is recommended. a-Glucosidase inhibitors such as acarbose compete with carbohydrates for binding to the enzymes in the intestinal brush border that digest complex carbohydrates. They therefore retard gastrointestinal glucose absorption. The primary role of these drugs is in combination with other agents when glycemic targets have not been met. Unabsorbed carbohydrates can cause flatulence, nausea, abdominal pain, and diarrhea.
If diet and exercise do not yield satisfactory glucose control, an oral agent (generally a sulfonylurea, meglitinide, or metformin) usually is chosen as first-line therapy. Glycemic control is then assessed at intervals. The dose of the oral agent can be increased or additional oral agents with different mechanisms of action can be added to achieve optimal control. Because of the number of oral agents that can be used alone or in combination, insulin therapy may be unnecessary for patients with mild disease. For those with moderate disease, a single dose of NPH or lente insulin can be added at bedtime (usually 0.3 to 0.6 U per kilogram per day) to provide basal insulin therapy. For patients with severe disease (those with FBS greater than 250 mg per deciliter), more intensive insulin programs usually are necessary (0.5 to 1.2 U per kilogram per day) to attain glucose control. Options include continuous insulin infusion and the use of twice-daily injections of 70/30 insulin, which contains 70% NPH and 30% regular insulin. Although oral agents have traditionally been discontinued when insulin therapy is initiated, current strategies often combine insulin with one or more oral agents, particularly the agents that enhance the peripheral effects of insulin, such as metformin or the thiazolidinediones.
Because 35% to 40% of cases of type II diabetes mellitus are undiagnosed, screening is considered an important public health measure. Asymptomatic patients older than 45 years should have a FBG determination every 3 years. Screening at a younger age should be considered for persons who are at higher risk.
DIABETIC KETOACIDOSIS AND HYPEROSMOLAR HYPERGLYCEMIC NONKETOTIC COMA
DEFINITIONS, EPIDEMIOLOGY, AND ETIOLOGY
Diabetic ketoacidosis (DKA) is acute, life-threatening, metabolic acidosis that represents the most extreme result of uncontrolled diabetes mellitus. It occurs most commonly among patients with type I diabetes mellitus but can occur with type II diabetes, particularly when there is a severe intercurrent illness. Hyperosmolar hyperglycemic nonketotic coma (HHNC) is an acute syndrome that occurs with uncontrolled type II diabetes mellitus. It usually affects elderly patients, particularly those with other underlying medical problems and concurrent infections.
PATHOPHYSIOLOGY AND DIAGNOSIS
Diabetic ketoacidosis: DKA develops as a consequence of severe insulin deficiency and an excess of the glucose counterregulatory hormones such as glucagon, cortisol, and the catecholamines. Hyperglycemia is caused by both decreased glucose uptake and utilization and increased hepatic gluconeogenesis. The hyperglycemia causes osmotic diuresis, hypovolemia, and large urinary losses of potassium and phosphate. Uninhibited lipolysis stimulates production of ketones (acetoacetate and b-hydroxybutyrate) from free fatty acids and produces metabolic acidosis and compensatory hyperpnea. The cardinal diagnostic features are hyperglycemia (250 mg per deciliter or more), ketosis (ketonemia or ketonuria), and acidosis (arterial pH less than 7.3 and serum bicarbonate less than 15 mEq per liter). Other features include an elevated anion gap, volume depletion, and Kussmaul’s respirations. The degree of hyperglycemia need not be great; a large proportion of patients have a glucose concentration less than 350 mg per deciliter.
Hyperosmolar hyperglycemic nonketotic coma: Because insulin levels are sufficient to suppress lipolysis, ketosis and acidosis do not occur. For this reason, the syndrome tends to last longer than DKA before it is recognized clinically. The severity of hyperglycemia, hyperosmolarity, and dehydration tends to be worse than with DKA because of the more prolonged period of osmotic diuresis. The extreme hyperosmolarity causes dehydration of the brain and altered mental status. The diagnosis is confirmed when a patient with abnormal mental status has severe hyperglycemia (usually 600 to 1,200 mg per deciliter), elevated serum osmolarity (more than 350 mOsm per kilogram), and minimal or absent ketonemia or ketonuria.
Diabetic ketoacidosis: Patients with mild acidemia can be treated at home as long as they can tolerate large amounts of oral fluid. For patients with more severe illness, hospitalization is necessary. Because average fluid losses are 10% of body weight, vigorous fluid supplementation is necessary to restore intravascular volume (1 to 2 L of isotonic saline solution over the first hour, 1 L per hour for the next 3 to 4 hours, then a decrease in rate based on clinical assessment). Insulin administration is initiated rapidly, unless there is evidence of severe hypovolemia or hypokalemia. An initial priming dose of 0.1 units of regular insulin IV per kilogram body weight is followed by a continuous infusion of regular insulin at a rate of 0.1 U per kilogram per hour. Because too rapid a decline in serum glucose levels can lead to cerebral edema, the insulin infusion rate should be adjusted about every 2 hours so that glucose levels decrease at a rate of approximately 100 mg per deciliter per hour.
Hyperglycemia usually resolves more quickly than metabolic acidosis. For this reason, when the glucose level reaches 200 to 300 mg per deciliter, glucose or dextrose is added to the intravenous fluids to allow continuation of the insulin infusion without the risk of hypoglycemia. At the same time, the insulin infusion rate is decreased to 0.05 U per kilogram per hour and maintained for at least 6 hours after the acidosis has resolved.
Serum potassium levels in DKA do not reflect total body levels, which are almost invariably reduced, because the acidosis and insulin deficiency cause a redistribution of potassium from the intracellular to the extracellular compartment. The potassium deficiency therefore becomes more evident as treatment progresses. If the patient is not treated, the deficiency places the patient at risk of cardiac arrhythmia. Potassium supplementation is given immediately unless the patient has anuria, has an initial serum potassium level more than 6.0 mEq per liter, or has hyperkalemic T-wave changes on an electrocardiogram. The recommended rate of potassium infusion ranges from 10 mEq per hour for those with initial levels of 5 to 6 mEq per liter to 40 mEq per hour for patients with initial serum potassium levels less than 3 mEq per liter.