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Endocrine disease
Diabetes mellitus
Normal glucose physiology requires a balance between glucose utilization and endogenous production or dietary delivery ( Fig. 22.1 ). The liver is the primary source of endogenous glucose production via glycogenolysis and gluconeogenesis. Approximately 70% to 80% of glucose released by the liver is metabolized by insulin-insensitive tissues such as the brain, gastrointestinal tract, and red blood cells. Following a meal, plasma glucose level increases, which stimulates an increase in plasma insulin secretion that promotes glucose utilization. Late in the postprandial period, approximately 2 to 4 hours after eating, when glucose utilization exceeds glucose production, a transition from exogenous glucose delivery to endogenous production becomes necessary to maintain a normal plasma glucose level. During this time, diminished insulin secretion is fundamental to the maintenance of a normal plasma glucose concentration. Hyperglycemia-producing hormones such as glucagon, epinephrine, growth hormone, and cortisol comprise the glucose counterregulatory system and support glucose production. Glucagon plays a primary role by stimulating glycogenolysis and gluconeogenesis, and inhibiting glycolysis.
Diabetes mellitus is the most common endocrine disease and affects 1 in 10 adults. Diabetes mellitus results from an inadequate supply of insulin and/or an inadequate tissue response to insulin. This leads to increased circulating glucose levels with eventual microvascular and macrovascular complications. Type 1a diabetes is caused by a T-cell–mediated autoimmune destruction of β cells within pancreatic islets resulting in complete absence or minimal circulating levels of insulin. Type 1b diabetes is a rare disease of absolute insulin deficiency that is not immune mediated. Type 2 diabetes is also not immune mediated and results from defects in insulin receptors and postreceptor intracellular signaling pathways.
Signs and symptoms
Type 1 diabetes
Between 5% and 10% of all cases of diabetes are type 1. There are 1.4 million individuals with type 1 diabetes and using insulin in the United States. The disorder is usually diagnosed before the age of 40 and is one of the most common chronic childhood illnesses.
The exact cause of the autoimmune process in type 1a diabetes is unknown, although environmental triggers such as viruses (especially enteroviruses), dietary proteins, or drugs or chemicals may initiate the autoimmune process in genetically susceptible hosts. A long preclinical period (9–13 years) characterized by production of antibodies to β-cell antigens with loss of β-cell function precedes the onset of clinical diabetes in the majority of patients. At least 80% to 90% of β-cell function must be lost before hyperglycemia occurs. The autoimmune attack initially presents as islet inflammation (insulitis), with immune cells infiltrating the pancreatic islets. Circulating antibodies signify islet cell injury.
The presentation of clinical disease is often sudden and severe secondary to loss of a critical mass of β cells. Patients demonstrate hyperglycemia over several days to weeks associated with fatigue, weight loss, polyuria, polydipsia, blurring of vision, and signs of intravascular volume depletion. The presence of ketoacidosis indicates severe insulin deficiency and unrestrained lipolysis.
Type 2 diabetes
Type 2 diabetes is responsible for over 90% of all cases of diabetes mellitus in the world. In 2000, there were approximately 151 million individuals with type 2 diabetes globally, with about 463 million people living with diabetes in 2019. By 2030, there will be an estimated 578 million adults with diabetes. Patients with type 2 diabetes are typically in the middle to older age group and are overweight, although there has been a significant increase in younger patients and even children with type 2 diabetes over the past decade. Type 2 diabetes continues to be underrecognized and underdiagnosed because of its subtle presentation. It is estimated that most individuals with type 2 diabetes had the disease for approximately 4 to 7 years before the disorder was diagnosed.
Type 2 diabetes is characterized by relative β-cell insufficiency and insulin resistance. In the initial stages of the disease, an insensitivity to insulin on the part of peripheral tissues leads to an increase in pancreatic insulin secretion to maintain normal plasma glucose levels. As the disease progresses and pancreatic cell function decreases, insulin levels are unable to compensate, and hyperglycemia occurs. Three important defects are seen in type 2 diabetes: (1) an increased rate of hepatic glucose release, (2) impaired basal and stimulated insulin secretion, and (3) inefficient use of glucose by peripheral tissues (i.e., insulin resistance). The increase in hepatic glucose release is caused by the reduction of insulin’s normal inhibitory effect on the liver, as well as abnormalities in regulation of glucagon secretion. Although relative β-cell insufficiency is significant, type 2 diabetes is characterized by insulin resistance in skeletal muscle, adipose tissue, and the liver. Causes of insulin resistance include (1) an abnormal insulin molecule; (2) circulating insulin antagonists, including counterregulatory hormones, free fatty acids, antiinsulin and insulin receptor antibodies, and cytokines; and (3) target tissue defects at insulin receptors and/or postreceptor sites. It appears that insulin resistance is an inherited component of type 2 diabetes, with obesity and a sedentary lifestyle being acquired and contributing factors. Impaired glucose tolerance is associated with an increase in body weight, a decrease in insulin secretion, and a reduction in peripheral insulin action. The transition to clinical diabetes is characterized by these same factors plus an increase in hepatic glucose production.
The increasing prevalence of type 2 diabetes among children and adolescents appears related to obesity, since 85% of affected children are overweight or obese at the time of diagnosis. Obese patients exhibit a compensatory hyperinsulinemia to maintain normoglycemia. These increased insulin levels may desensitize target tissues, causing a reduced response to insulin. The mechanism for hyperinsulinemia and insulin resistance from weight gain remain elusive.
Diagnosis
The American Diabetes Association has established diagnostic criteria for diabetes mellitus ( Table 22.1 ). Measurement of fasting plasma glucose level is the recommended screening test for diabetes mellitus. The same tests used to screen for and diagnose diabetes can also be used to identify individuals with prediabetes ( Table 22.2 ). Glucose levels, especially in type 2 diabetics, usually increase over years to decades, progressing from the normal range to the impaired glucose tolerance range and finally to clinical diabetes.
TABLE 22.1
American Diabetes Association Criteria for the Diagnosis of Diabetes
Classification and Diagnosis of Diabetes: Standards of Medical Care in Diabetes—2021. American Diabetes Association. Diabetes Care . 2021;44(suppl 1):S15–S33. doi:10.2337/dc21-S002 .
|
A 1c : Glycated hemoglobin; DCCT: Diabetes Control and Complications Trial; FPG: fasting plasma glucose; NGSP: National Glycohemoglobin Standardization Program; OGTT: oral glucose tolerance test.
a In the absence of unequivocal hyperglycemia, diagnosis requires two abnormal test results from the same sample or in two separate test samples.
TABLE 22.2
Categories of Increased Risk for Diabetes (Prediabetes) a
Reprinted with permission from the American Diabetes Association. Classification and Diagnosis of Diabetes: Standards of Medical Care in Diabetes—2021. American Diabetes Association. Diabetes Care . 2021;44(suppl 1):S15–S33. doi:10.2337/dc21-S002 .
|
A1C: Glycated hemoglobin; FPG: fasting plasma glucose; IFG: impaired fasting glucose; IGT: impaired glucose tolerance; OGTT: oral glucose tolerance test.
a For all three tests, risk is continuous, extending below the lower limit of the range and becoming disproportionately greater at higher ends of the range.
The HbA 1c test provides a valuable measure of long-term glycemic control. Hemoglobin is nonenzymatically glycosylated by glucose, which freely crosses red blood cell membranes. The percentage of hemoglobin molecules participating in this reaction is proportional to the average plasma glucose concentration during the preceding 60 to 90 days. Evidence suggests that the risk of microvascular and macrovascular disease is increased even in the nondiabetic range, compared with normoglycemia ( Table 22.3 ).
TABLE 22.3
Diagnosing Prediabetes or Diabetes
| Normal | <5.7% |
| Prediabetes | 5.7–6.4% |
| Diabetes | ≥6.5% |
A normal A 1c level is <5.7%, a level of 5.7–6.4% indicates prediabetes, and a level of ≥6.5% indicates diabetes. Within the 5.7–6.4% prediabetes range, the higher your A 1c , the greater your risk is for developing type 2 diabetes.
Treatment
The cornerstones of treatment for type 2 diabetes are dietary adjustments along with weight loss, exercise therapy, and oral antidiabetic drugs. Reduction of body weight through diet and exercise is the first therapeutic measure to control type 2 diabetes. The decrease in adiposity improves hepatic and peripheral tissue insulin sensitivity, enhances postreceptor insulin action, and may possibly increase insulin secretion. Nutritional guidelines of the American Diabetes Association emphasize maintenance of optimal plasma glucose and lipid levels.
Oral antidiabetic drugs
In the absence of contraindications, metformin, a biguanide, is the preferred initial treatment for patients with newly diagnosed type 2 diabetes who are asymptomatic. This class of drugs decreases hepatic gluconeogenesis and enhances utilization of glucose by skeletal muscle and adipose tissue by increasing glucose transport across cell membranes. In addition, they decrease plasma levels of triglycerides and low-density lipoprotein cholesterol and reduce postprandial hyperlipidemia and plasma-free fatty acids. Lactic acidosis is a rare but serious side effect of the biguanides; the risk is particularly high in patients with renal insufficiency.
The sulfonylureas act by stimulating insulin secretion from pancreatic β cells; they can also enhance insulin-stimulated peripheral tissue utilization of glucose. The second-generation agents (glyburide, glipizide, glimepiride) are more potent and have fewer side effects than their predecessors. Unfortunately, because of the natural history of type 2 diabetes characterized by decreasing β-cell function, these drugs are not effective indefinitely. Hypoglycemia and weight gain are side effects. Sulfonylureas may increase risk of cardiovascular events and may prevent protective ischemic cardiac preconditioning after myocardial infarction.
Other glucose-lowering drugs are available, including gliptins, SGLT-2 inhibitors, and thiazolidinediones ( Table 22.4 ). Primary management of diabetes is outside the scope of this chapter. Tight control of type 2 diabetes provides significant benefits in preventing and slowing the progression of micro- and macrovascular disease.
TABLE 22.4
Summary of Glucose-Lowering Interventions
Modified with permission from Nathan DM, Buse JB, Davidson MB, et al. Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for initiation and adjustment of therapy: a consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 2009;32:193–203. Copyright © 2009 American Diabetes Association.
| Intervention | Expected Decrease in A 1c With Monotherapy (%) | Advantages | Disadvantages |
|---|---|---|---|
| Initial Therapy | |||
| Lifestyle change to decrease weight and increase activity | 1.0–2.0 | Broad benefits | Insufficient for most within first year owing to inadequate weight loss and weight regain |
| Metformin | 1.0–2.0 | Weight neutral | GI side effects, contraindicated with renal insufficiency (eGFR <30 mL/min) a |
| Additional Therapy | |||
| Insulin (usually with a single daily injection of intermediate- or long-acting insulin initially) | 1.5–3.5 | No dose limit, rapidly effective, improved lipid profile | One to four injections daily, monitoring weight gain, hypoglycemia, analogs are expensive |
| Sulfonylurea (shorter-acting agents preferred) | 1.0–2.0 | Rapidly effective | Weight gain, hypoglycemia (especially with glibenclamide or chlorpropamide) |
| GLP-1 receptor agonist (daily to weekly injections) | 0.5–1.5 | Weight loss, reduction in major adverse cardiovascular events (liraglutide, semaglutide, dulaglutide) in patients with established CVD and potentially for those at high risk for CVD | Requires injection, frequent GI side effects, expensive |
| Thiazolidinedione | 0.5–1.4 | Improved lipid profile (pioglitazone), potential decrease in MI (pioglitazone) | Fluid retention, HF, weight gain, bone fractures, potential increase in MI (rosiglitazone) and bladder cancer (pioglitazone) |
| Glinide | 0.5–1.5 Δ | Rapidly effective | Weight gain, 3 times/day dosing, hypoglycemia |
| SGLT-2 inhibitor | 0.5–0.7 | Weight loss, reduction in systolic blood pressure, reduced cardiovascular mortality in patients with established CVD, improved renal outcomes in patients with nephropathy | Vulvovaginal candidiasis, urinary tract infections, bone fractures, lower limb amputations, acute kidney injury, DKA, long-term safety not established |
| DPP-4 inhibitor | 0.5–0.8 | Weight neutral | Possible increased risk of HF with saxagliptin, expensive |
| α-glucosidase inhibitor | 0.5–0.8 | Weight neutral | Frequent GI side effects, 3 times/day dosing |
| Pramlintide | 0.5–1.0 | Weight loss | Three injections daily, frequent GI side effects, long-term safety not established, expensive |
A 1c : Glycated hemoglobin; CVD: cardiovascular disease; DPP-4: dipeptidyl peptidase-4; DKA: diabetic ketoacidosis; eGFR: estimated glomerular filtration rate; GI: gastrointestinal; GLP-1: glucagon-like peptide-1; HF: heart failure; MI: myocardial infarction; SGLT-2: sodium-glucose cotransporter 2.
The order of listing of additional therapies does not indicate a preferred order of selection. Δ Repaglinide is more effective in lowering A 1c than nateglinide.
a Initiation is contraindicated with eGFR <30 mL/min/1.73 m 2 and not recommended with eGFR 30–45 mL/min/1.73 m 2 .
Insulin
Insulin is necessary to manage all cases of type 1 diabetes and many cases of type 2 diabetes ( Table 22.5 ). In the United States, 30% of patients with type 2 diabetes are treated with insulin. The various forms of insulin include basal insulins, which are intermediate acting (NPH, Lente, lispro protamine, aspart protamine) administered twice daily or long acting (Ultralente, glargine) administered once daily; and insulins that are short acting (regular) or rapid acting (lispro, aspart), which provide glycemic control at mealtimes. Conventional insulin therapy usually requires twice-daily injections of combinations of intermediate-acting and short- or rapid-acting insulins. Intensive insulin therapy requires three or more daily injections or a continuous infusion ( Fig. 22.2 ).
TABLE 22.5
Insulin Preparations
| Insulin | Onset | Peak | Duration |
|---|---|---|---|
| Short Acting | |||
| Human regular | 30 min | 2–4 hr | 5–8 hr |
| Lispro (Humalog) | 10–15 min | 1–2 hr | 3–6 hr |
| Aspart (NovoLog) | 10–15 min | 1–2 hr | 3–6 hr |
| Intermediate | |||
| Human NPH | 1–2 hr | 6–10 hr | 10–20 hr |
| Lente | 1–2 hr | 6–10 hr | 10–20 hr |
| Long Acting | |||
| Ultralente | 4–6 hr | 8–20 hr | 24–48 hr |
| Glargine (Lantus) | 1–2 hr | – | 24 hr |
Hypoglycemia is the most frequent and dangerous complication of insulin therapy. The hypoglycemic effect can be exacerbated by simultaneous administration of alcohol, sulfonylureas, biguanides, thiazolidinediones, angiotensin-converting enzyme (ACE) inhibitors, monoamine oxidase inhibitors, and nonselective β blockers. β blockers may exacerbate hypoglycemia by inhibiting lipolysis of adipose tissue, which serves as an alternate fuel when patients become hypoglycemic. Defective counterregulatory responses by glucagon and epinephrine to reduce plasma glucose levels contribute to this complication.
Repetitive episodes of hypoglycemia, especially at night, can result in hypoglycemia unawareness, a condition in which the patient does not respond with the appropriate autonomic warning symptoms before neuroglycopenia. The diagnosis in adults requires a plasma glucose level of less than 55 mg/dL. Symptoms are adrenergic (sweating, tachycardia, palpitations, restlessness, pallor) and neuroglycopenic (fatigue, confusion, headache, somnolence, convulsions, coma). Treatment includes the administration of sugar in the form of sugar cubes, glucose tablets, or soft drinks if the patient is conscious, and glucose 0.5 g/kg IV or glucagon 0.5 to 1.0 mg intravenously, intramuscularly, or subcutaneously if the patient is unconscious.
Complications
Diabetic ketoacidosis
Diabetic ketoacidosis (DKA) is a complication of decompensated diabetes mellitus. Episodes of DKA occur more commonly in patients with type 1 diabetes and are precipitated by infection or acute illness. High glucose levels exceed the threshold for renal tubular absorption, which creates a significant osmotic diuresis with marked hypovolemia. A tight metabolic coupling between hepatic gluconeogenesis and ketogenesis leads to an overproduction of ketoacids by the liver. DKA results in an excess of glucose counterregulatory hormones, with glucagon activating lipolysis and free fatty acids providing the substrate for ketogenesis. An increase in production of ketoacids (β hydroxybutyrate, acetoacetate, acetone) creates an anion gap metabolic acidosis ( Table 22.6 ). Substantial deficits of water, potassium, and phosphorus exist, although laboratory values of these electrolytes may be normal or increased. Hyponatremia results from the effect of hyperglycemia and hyperosmolarity on water distribution. The deficit of potassium is usually substantial (3–5 mEq/kg), and the deficit of phosphorus, and can lead to diaphragmatic and skeletal muscle dysfunction and impaired myocardial contractility.
TABLE 22.6
Diagnostic Features of Diabetic Ketoacidosis
| Serum glucose level (mg/dL) | ≥300 |
| pH | ≤7.3 |
| HCO 3 − (mEq/L) | ≤18 |
| Serum osmolarity (mOsm/L) | <320 |
| Serum and urine ketone levels | Moderate to high |
The treatment of DKA consists of large amounts of normal saline and effective doses of insulin, and electrolyte supplementation. An intravenous loading dose of 0.1 unit/kg of regular insulin plus a low-dose insulin infusion of 0.1 unit/kg/hr is initiated. Insulin administration must be continued until a normal acid-base status is achieved. The insulin rate is reduced when hyperglycemia is controlled, the blood pH is higher than 7.3, and bicarbonate level exceeds 18 mEq/L. Potassium, phosphate, and magnesium are replaced as needed. Sodium bicarbonate is administered if the blood pH is less than 7.0. The infrequent but devastating development of cerebral edema can result from correction of hyperglycemia without simultaneous correction of serum sodium level. The overall mortality rate from DKA is 1% to 2% but is significantly higher in patients older than 65 years of age and in those who are comatose at presentation. Mortality rate has fallen significantly over the past 20 years.
Hyperglycemic hyperosmolar syndrome
Hyperglycemic hyperosmolar syndrome is characterized by severe hyperglycemia, hyperosmolarity, and dehydration. It usually occurs in patients with type 2 diabetes who are older than 60 years of age in the context of an acute illness. The syndrome evolves over days to weeks with a persistent glycosuric diuresis. When the glucose load exceeds the renal tubular maximum for glucose reabsorption, a massive solute diuresis occurs with total body water depletion. The patient experiences polyuria, polydipsia, hypovolemia, hypotension, tachycardia, and organ hypoperfusion. Hyperosmolarity (>340 mOsm/L) is responsible for mental obtundation or coma ( Table 22.7 ). Patients may have some degree of metabolic acidosis but do not demonstrate ketoacidosis. Vascular occlusions secondary to low-flow states and diffuse intravascular coagulation are important complications of hyperglycemic hyperosmolar syndrome.
TABLE 22.7
Diagnostic Features and Symptoms of Hyperglycemic Hyperosmolar Syndrome
| Glucose level (mg/dL) | ≥600 |
| pH | ≥7.3 |
| HCO 3 − (mEq/L) | ≥15 |
| Serum osmolarity (mOsm/L) | ≥350 |
|
Treatment includes significant fluid resuscitation, insulin administration, and electrolyte supplementation. If the plasma osmolarity is greater than 320 mOsm/L, large volumes of hypotonic saline (1000–1500 mL/hr) should be administered until the osmolarity is less than 320 mOsm/L, at which time large volumes of isotonic saline (1000–1500 mL/hr) can be given. Insulin therapy is initiated with an intravenous bolus of 0.1 unit/kg of regular insulin followed by a 0.1 unit/kg/hr infusion. The insulin infusion is decreased to 0.02 to 0.05 unit/kg/hr when the glucose level decreases to approximately 250 to 300 mg/dL. Electrolyte deficits are significant but usually less severe than in DKA. The mortality rate of hyperglycemic hyperosmolar syndrome is 10% to 20%.
Microvascular complications
Microvascular dysfunction is unique to diabetes and is characterized by nonocclusive, microcirculatory disease and impaired autoregulation of blood flow and vascular tone. Hyperglycemia is essential for the development of these changes, and intensive glycemic control delays the onset and slows the progression of microvascular effects.
Nephropathy
Approximately 30% to 40% of individuals with type 1 diabetes and 5% to 10% of those with type 2 diabetes develop end-stage renal disease. The kidneys demonstrate glomerulosclerosis with glomerular basement membrane thickening, arteriosclerosis, and tubulointerstitial disease. The clinical course is characterized by hypertension, albuminuria, peripheral edema, and a progressive decrease in glomerular filtration rate. When the glomerular filtration rate decreases to less than 15 to 20 mL/min, the ability of the kidneys to excrete potassium and acids is impaired and patients develop hyperkalemia and metabolic acidosis. Hypertension, hyperglycemia, hypercholesterolemia, and microalbuminuria accelerate the decrease in the glomerular filtration rate. Treatment of hypertension can markedly slow the progression of renal dysfunction. ACE inhibitors are particularly beneficial in diabetic patients because they slow the progression of proteinuria and the decrease in glomerular filtration rate. If end-stage renal disease develops, there are four options: hemodialysis, peritoneal dialysis, continuous ambulatory peritoneal dialysis, and transplantation. Patients who receive a kidney transplant, especially if the organ is from a living human leukocyte antigen (HLA)–identical donor, demonstrate a longer survival than those who undergo dialysis. Combined kidney-pancreas transplantation results in lower mortality than dialysis or renal transplantation alone and may prevent recurrence of diabetic nephropathy in the transplanted kidney.
Peripheral neuropathy
More than 50% of patients who have had diabetes for longer than 25 years develop a peripheral neuropathy. A distal symmetric diffuse sensorimotor polyneuropathy is the most common form. Sensory deficits usually overshadow motor abnormalities and appear in the toes or feet and progress proximally toward the chest in a “stocking and glove” distribution. Loss of large sensory and motor fibers produces loss of light touch and proprioception as well as muscle weakness. Loss of small fibers decreases the perception of pain and temperature and produces dysesthesias, paresthesias, and neuropathic pain. Foot ulcers develop from mechanical and traumatic injury as a result of loss of cutaneous sensitivity to pain and temperature and impaired perfusion. Significant morbidity results from recurrent infection, foot fractures (Charcot joint), and subsequent amputations. The treatment of peripheral neuropathy includes optimal glucose control and use of nonsteroidal antiinflammatory drugs (NSAIDs), antidepressants, and anticonvulsants for pain control.
Retinopathy
Diabetic retinopathy results from a variety of microvascular changes, including blood vessel occlusion, dilation, increased permeability, and microaneurysm formation resulting in hemorrhage, exudation, and growth of abnormal blood vessels and fibrous tissue. Visual impairment can range from minor changes in color vision to total blindness. Strict glycemic blood pressure control reduces the risk of development and progression of retinopathy.
Autonomic neuropathy
Diabetic autonomic neuropathy can affect any part of the autonomic nervous system and is the result of damaged vasoconstrictor fibers, impaired baroreceptor function, and ineffective cardiovascular reactivity. Cardiovascular signs of autonomic neuropathy include abnormalities in heart rate control as well as central and peripheral vascular dynamics. Resting tachycardia and loss of heart rate variability during deep breathing are early signs. A heart rate that fails to respond to exercise is indicative of significant cardiac denervation and is likely to result in substantially reduced exercise tolerance. The heart may demonstrate systolic and diastolic dysfunction with a reduced ejection fraction. Dysrhythmias may be responsible for sudden death. In advanced stages, severe orthostatic hypotension is present.
Diabetic autonomic neuropathy may also impair gastric secretion and gastric motility, eventually causing gastroparesis diabeticorum. Although it is often clinically silent, symptomatic patients will have nausea, vomiting, early satiety, bloating, and epigastric pain. Treatment of gastroparesis includes strict blood glucose control, consumption of multiple small meals, reduction of the fat content of meals, and use of prokinetic agents such as metoclopramide. Diarrhea and constipation are also common. In addition, patients with diabetic autonomic neuropathy may demonstrate altered respiratory reflexes and impaired ventilatory responses to hypoxia and hypercapnia.
Macrovascular complications
Cardiovascular disease is a major cause of morbidity and the leading cause of mortality in diabetic individuals. Between 20% and 30% of patients coming to the hospital with a myocardial infarction have diabetes. Patients with poorly controlled diabetes demonstrate elevated triglyceride levels, low levels of high-density lipoprotein cholesterol, and an abnormally small, dense, more atherogenic low-density lipoprotein cholesterol. This dyslipidemia is caused by lack of appropriate insulin signaling and is exacerbated by poor glucose control. Measures to prevent coronary artery disease include maintaining lipid levels, glucose level, and blood pressure within normal limits. Aspirin and statin therapy should be considered for all diabetic patients.
Management of anesthesia
Preoperative evaluation
The preoperative evaluation should emphasize the cardiovascular, renal, neurologic, and musculoskeletal systems. The index of suspicion should be high for myocardial ischemia and infarction. Silent ischemia is possible if autonomic neuropathy is present, and stress testing should be considered in patients with multiple cardiac risk factors and poor or indeterminate exercise tolerance. Meticulous attention to hydration status, avoidance of nephrotoxins, and preservation of renal blood flow are also essential. The presence of autonomic neuropathy predisposes the patient to perioperative dysrhythmias and intraoperative hypotension. In addition, loss of compensatory sympathetic responses interferes with the detection and treatment of hemodynamic insults. Preoperative evaluation of the musculoskeletal system should look for limited joint mobility caused by nonenzymatic glycosylation of proteins and abnormal cross-linking of collagen. Firm, woody, nonpitting edema of the posterior neck and upper back (scleredema of diabetes) coupled with impaired joint mobility may limit range of motion of the neck and render endotracheal intubation difficult. Gastroparesis may increase the risk of aspiration, regardless of nothing-by-mouth status.
Patients who take oral hypoglycemic drugs or noninsulin injectables can continue their usual antidiabetic medications until the morning of surgery, when oral hypoglycemic and noninsulin injectable drugs should be held. Sulfonylureas increase the risk of hypoglycemia and inhibit the myocardial potassium adenosine triphosphate (ATP) channels that are responsible for myocardial preconditioning, which may theoretically increase the risk of myocardial infarction or increase infarct size. Management of insulin in the preoperative period depends on the type of insulin that the patient takes and the timing of dosing. Several strategies exist, and there is no consensus on the optimal strategy. Between one-third and one-half of the usual morning NPH dose should be given on the day of surgery. The daily morning dose of regular insulin or rapid-acting (e.g., lispro, aspart, glulisine) insulin should be held. For patients who take long-acting insulin (e.g., glargine) once per day or who use a continuous insulin infusion via an insulin pump, the basal rate can continue unchanged as long as the basal insulin dose is appropriately calculated. If there is a concern for preoperative hypoglycemia, for example with a patient who has a history of low glucose measurements, the basal rate can be reduced by 10% to 25%.
Intraoperative management
Aggressive glycemic control is important intraoperatively. For long and complex procedures, intravenous insulin is usually required, and dosing may be guided by trial and error or with an algorithm such as EndoTool. Ideally, a continuous infusion of insulin should be initiated at least 2 hours before surgery. Intraoperative serum glucose levels should be maintained between 120 and 180 mg/dL. Levels above 200 mg/dL are likely to cause glycosuria and dehydration and to inhibit phagocyte function and wound healing. Typically, 1 unit of insulin lowers glucose approximately 25 to 30 mg/dL. A typical rate is 0.02 unit/kg/hr, or 1.4 units/hr in a 70-kg patient. Insulin infusion requirements are higher for patients undergoing coronary bypass graft surgery, receiving steroids, with severe infections, and receiving hyperalimentation or vasopressor infusions. An insulin infusion should be accompanied by an infusion of 5% dextrose in half-normal saline with 20 mEq KCl at 100 to 150 mL/hr to provide enough carbohydrate (at least 150 g/day) to inhibit hepatic glucose production and protein catabolism. Serum glucose levels should be monitored at least every hour. Shorter intervals may be needed if blood glucose levels are less than 100 mg/dL, if rate of fall is rapid, or for patients undergoing coronary artery bypass graft surgery or patients with high insulin requirements.
Avoidance of hypoglycemia is especially critical since recognition of hypoglycemia may be delayed in patients receiving anesthetics, sedatives, analgesics, β blockers, or sympatholytics, and in those with autonomic neuropathy. If hypoglycemia does occur, treatment consists of 50 mL of 50% dextrose in water, which typically increases the glucose level 100 mg/dL or 2 mg/dL/mL.
Postoperative care
The postoperative management of diabetic patients requires meticulous monitoring of insulin requirements. Hyperglycemia has been associated with poor outcomes in postoperative and critically ill patients. However, the optimal target for blood glucose level in the perioperative period has not yet been defined. In addition, this target may be different for patients with newly diagnosed hyperglycemia than for those with preexisting diabetes. The risks of hypoglycemia must also be considered. Currently, the American Diabetes Association recommends that glucose levels be maintained between 140 and 180 mg/dL in critically ill patients and that insulin treatment be initiated if serum glucose levels exceed 180 mg/dL.
Insulinoma
Insulinomas are rare, benign insulin-secreting pancreatic islet cell tumors. They usually occur as an isolated finding but may present as part of multiple endocrine neoplasia syndrome type I (insulinoma, hyperparathyroidism, and a pituitary tumor). They occur in women twice as often as in men and usually in the fifth or sixth decade of life. The diagnosis is made by demonstrating Whipple triad:
- 1.
Symptoms of hypoglycemia with fasting
- 2.
Glucose level <50 mg/dL with symptoms
- 3.
Relief of symptoms by administration of glucose
An inappropriately high insulin level (>5–10 microunits/mL) during a 48- to 72-hour fast confirms the diagnosis.
Preoperatively, patients are often managed with diazoxide, an agent that directly inhibits insulin release from β cells. Other medical therapies include verapamil, phenytoin, propranolol, glucocorticoids, and the somatostatin analogues octreotide and lanreotide. Surgical treatment is curative. Ninety percent of insulinomas are benign, and tumor enucleation is the procedure of choice. Laparoscopic resection is used in some centers.
Profound hypoglycemia can occur intraoperatively, particularly during manipulation of the tumor; however, marked hyperglycemia can follow removal of the tumor. In a few medical centers, an artificial pancreas that continuously analyzes the blood glucose concentration and automatically infuses insulin or glucose has been used for intraoperative management of these patients. In most cases, serial blood glucose measurements (every 15 minutes) are taken using a standard glucometer. Since evidence of hypoglycemia may be masked under anesthesia, intravenous fluids containing glucose should be considered.
Thyroid disease
The thyroid gland weighs approximately 20 g and is composed of two lobes joined by an isthmus. The gland is closely affixed to the anterior and lateral aspects of the trachea, with the upper border of the isthmus located just below the cricoid cartilage. A pair of parathyroid glands is located on the posterior aspect of each lobe. A rich capillary network permeates the entire gland. The gland is innervated by the adrenergic and cholinergic nervous systems. The recurrent laryngeal nerve and external motor branch of the superior laryngeal nerve are in intimate proximity to the gland. Histologically, the thyroid is composed of numerous follicles filled with proteinaceous colloid. The major constituent of colloid is thyroglobulin, an iodinated glycoprotein that serves as the substrate for thyroid hormone synthesis. The thyroid gland also contains parafollicular C cells, which produce calcitonin.
Production of normal quantities of thyroid hormones depends on the availability of exogenous iodine. The diet is the primary source of iodine. Iodine is reduced to iodide in the gastrointestinal tract, rapidly absorbed into the blood, then actively transported from the plasma into thyroid follicular cells. Binding of iodine to thyroglobulin (i.e., organification) is catalyzed by an iodinase enzyme and yields inactive monoiodotyrosine and diiodotyrosine. Approximately 25% of the monoiodotyrosine and diiodotyrosine undergo coupling via thyroid peroxidase to form the active compound triiodothyronine (T 3 ) and thyroxine (T 4 ). The remaining 75% never becomes hormones, and eventually the iodine is cleaved and recycled. T 3 and T 4 remain attached to thyroglobulin and are stored as colloid until they are released into the circulation. Since the thyroid contains a large store of hormones and has a low turnover rate, there is protection against depletion if synthesis is impaired or discontinued.
The T 4 /T 3 ratio of secreted hormones is 10:1. Upon entering the blood, T 4 and T 3 reversibly bind to three major proteins: thyroxine-binding globulin (80% of binding), prealbumin (10–15%), and albumin (5–10%). Only the small amount of free fraction of hormone is biologically active. Although only 10% of thyroid hormone secretion is T 3 , T 3 is three to four times more active than T 4 per unit of weight and may be the only active thyroid hormone in peripheral tissues. Thyroid hormones stimulate virtually all metabolic processes. They influence growth and maturation of tissues, enhance tissue function, and stimulate protein synthesis and carbohydrate and lipid metabolism.
Thyroid hormone acts directly on cardiac myocytes and vascular smooth muscle cells. In the heart, T 3 is transported via specific proteins across the myocyte cell membrane and enters the nucleus, binding to nuclear receptors that in turn bind to specific target genes. T 3 -responsive genes code for structural and regulatory proteins in the heart that are important for systolic contractile function and diastolic relaxation. Thyroid hormone increases myocardial contractility directly, decreases systemic vascular resistance via direct vasodilation, and increases intravascular volume. Most recent studies emphasize the direct effects of T 3 on the heart and vascular smooth muscle as responsible for the exaggerated hemodynamic effects of hyperthyroidism. Even though hyperthyroid patients appear to have increased numbers of β-adrenergic receptors, these receptors demonstrate little or no increased sensitivity to adrenergic stimulation, and surprisingly these patients have normal or low serum concentrations of catecholamines.
Regulation of thyroid function is controlled by the hypothalamus, pituitary, and thyroid glands, which participate in a classic feedback control system. Thyrotropin-releasing hormone (TRH) is secreted from the hypothalamus, traverses the pituitary stalk, and promotes release of thyrotropin-stimulating hormone (TSH) from the anterior pituitary. TSH binds to specific receptors on the thyroid cell membrane and enhances all processes of synthesis and secretion of T 4 and T 3 . A decrease in TSH causes a reduction in synthesis and secretion of T 4 and T 3 , a decrease in follicular cell size, and a decrease in the gland’s vascularity. An increase in TSH yields an increase in hormone production and release and an increase in gland cellularity and vascularity. TSH secretion is also influenced by plasma levels of T 4 and T 3 via a negative feedback loop. In addition to the feedback system, the thyroid gland has an autoregulatory mechanism that maintains a consistent level of hormone stores.
Diagnosis
The third generation of the TSH assay is now the single best test of thyroid hormone action at the cellular level. Small changes in thyroid function cause significant changes in TSH secretion. The normal TSH level is 0.4 to 5.0 milliunits/L. Table 22.8 provides details on laboratory assessment of thyroid function.
TABLE 22.8
Laboratory Assessment of Thyroid Function
| TSH | Free T 3 /T 4 | |
|---|---|---|
| Subclinical hyperthyroidism | 0.1–0.4 milliunits/L | Normal |
| Overt hyperthyroidism | <0.03 milliunits/L | Increased |
| Subclinical hypothyroidism | 5.0–10 milliunits/L | Normal |
| Overt hypothyroidism | >20 milliunits/L | Reduced |
The TRH stimulation test assesses the functional state of the TSH-secreting mechanism in response to TRH and is used to test pituitary function. Other tests that may be helpful in detecting thyroid dysfunction include measurement of serum antimicrosomal antibodies, antithyroglobulin antibodies, and thyroid-stimulating immunoglobulins. Thyroid scans using iodine 123 ( 123 I) or technetium 99m evaluate thyroid nodules as “warm” (normally functioning), “hot” (hyperfunctioning), or “cold” (hypofunctioning). Ultrasonography is 90% to 95% accurate in determining whether a lesion is cystic, solid, or mixed.
Hyperthyroidism
Signs and symptoms
Hyperthyroidism refers to hyperfunctioning of the thyroid gland with excessive secretion of active thyroid hormones. The majority of cases of hyperthyroidism result from one of three pathologic processes: Graves disease, toxic multinodular goiter, or toxic adenoma. Regardless of the cause, the signs and symptoms of hyperthyroidism are those of a hypermetabolic state ( Table 22.9 ). The patient may demonstrate increased sweating and complain of heat intolerance. The patient usually complains of extreme fatigue but an inability to sleep. Increased bone turnover and osteoporosis may occur. Weight loss despite an increased appetite occurs secondary to increased calorigenesis. T 3 acts directly on the myocardium and peripheral vasculature to cause the cardiac responses.
TABLE 22.9
Signs and Symptoms of Hyperthyroidism and Cardiac Effects
| Signs and Symptoms | |
| General: | Anxious |
| HEENT: | Flushed face |
| Fine hair | |
| Exophthalmos/proptosis | |
| Cardiovascular: | Palpitations |
| Neurologic: | Wasting, weakness, fatigue of proximal limb muscles |
| Fine tremor of hands | |
| Hyperactive deep tendon reflexes | |
| GI: | Frequent bowel movements/diarrhea |
| Psych: | Emotionally unstable |
| Skin: | Warm, moist |
| Cardiac Effects | |
| Tachycardia, arrhythmias (commonly atrial) | |
| Hyperdynamic | |
| Increased cardiac output and contractility | |
| Cardiomegaly | |
Graves disease or toxic diffuse goiter occurs in 0.4% of the US population and is the leading cause of hyperthyroidism. The disease typically occurs in females (female:male ratio is 7:1) between the ages of 20 and 40 years. Although the etiology is unknown, Graves disease appears to be a systemic autoimmune disease caused by thyroid-stimulating antibodies that bind to TSH receptors in the thyroid, stimulating thyroid growth, vascularity, and hypersecretion of T 4 and T 3 . The thyroid is usually diffusely enlarged. An ophthalmopathy occurs in 30% of cases and may include upper lid retraction, a wide-eyed stare, muscle weakness, proptosis, and an increase in intraocular pressure. When severe, the condition is termed malignant opthalmos . Steroid therapy, bilateral tarsorrhaphy, external radiation therapy, or surgical decompression may be necessary in these cases. The diagnosis of Graves disease is confirmed by the presence of thyroid-stimulating antibodies in the context of low TSH and elevated T 4 and T 3 levels.
Toxic multinodular goiter usually arises from long-standing simple goiter and occurs mostly in patients older than 50 years of age. It may present with extreme thyroid enlargement that can cause dysphagia, globus sensation, and possibly inspiratory stridor from tracheal compression. The latter is especially common when the mass extends into the thoracic inlet behind the sternum. In severe cases, superior vena cava obstruction syndrome may also be present. The diagnosis is confirmed by a thyroid scan demonstrating “hot” patchy foci throughout the gland or one or two “hot” nodules. Radioactive iodine uptake and serum T 4 and T 3 levels may only be slightly elevated. The goiter must be differentiated from a neoplasm, and a computed tomography (CT) scan and biopsy may be necessary.
Treatment
The first line of treatment for hyperthyroidism is an antithyroid drug, either methimazole or propylthiouracil (PTU). These agents interfere with the synthesis of thyroid hormones by inhibiting organification and coupling. PTU has the added advantage of inhibiting the peripheral conversion of T 4 to T 3 . A euthyroid state can almost always be achieved in 6 to 8 weeks with either drug if a sufficient dosage is used. Side effects occur in 3% to 12% of patients, with agranulocytosis being the most serious.
Iodide in high concentrations inhibits release of hormones from the hyperfunctioning gland. High concentrations of iodide decrease all phases of thyroid synthesis and release, and result in reduced gland size and possibly a decrease in vascularity. Its effects occur immediately but are short lived. Therefore iodide is usually reserved for preparing hyperthyroid patients for surgery, managing patients with actual or impeding thyroid storm, and treating patients with severe thyrocardiac disease. There is no need to delay surgery in a patient with otherwise well-controlled thyrotoxicosis to initiate iodide therapy.
Iodide is administered orally as a saturated solution of potassium iodide (SSKI). The radiographic contrast dye ipodate or iopanoic acid contains iodide and demonstrates beneficial effects similar to those of inorganic iodide. In addition, ipodate inhibits the peripheral conversion of T 4 to T 3 and may antagonize thyroid hormone binding to receptors. Antithyroid drug therapy should precede the initiation of iodide treatment because administration of iodide alone will increase thyroid hormone stores and exacerbate the thyrotoxic state. Lithium carbonate may be given in place of potassium iodide or ipodate to patients who are allergic to iodide.
β-adrenergic antagonists do not affect the underlying thyroid abnormality but may relieve signs and symptoms of increased adrenergic activity such as anxiety, sweating, heat intolerance, tremors, and tachycardia. Propranolol offers the added features of impairing the peripheral conversion of T 4 to T 3 .
Ablative therapy with radioactive 131 I or surgery is recommended for patients with Graves disease for whom medical management has failed, as well as for patients with toxic multinodular goiter or a toxic adenoma. Standard doses of 131 I deliver approximately 8500 rad to the thyroid and destroy the follicular cells. The remission rate is 80% to 98%. A major disadvantage of therapy is that 40% to 70% of treated patients become hypothyroid within 10 years.
Surgery (subtotal thyroidectomy) results in prompt control of disease and is associated with a lower incidence of hypothyroidism (10–30%) than radioactive iodine therapy. Subtotal thyroidectomy corrects thyrotoxicosis in more than 95% of patients; mortality rate for the procedure is less than 0.1%. Complications from surgery include hypothyroidism, hemorrhage with tracheal compression, unilateral or bilateral damage to the recurrent laryngeal nerve(s), damage to the motor branch of the superior laryngeal nerve, and damage to or inadvertent removal of the parathyroid glands.
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