Prevention
Provide education regarding sick-day management to patients with type 1 diabetes to prevent diabetic ketoacidosis. On sick days instruct patients to increase the frequency of home blood glucose monitoring; measure urinary or fingerstick ketones; continue insulin and maintain fluids; and proceed to an emergency depart- ment if nausea and vomiting persist or if home ketone testing is positive. Ensure that patients understand the need to continue insulin therapy even when they are unable to eat.
Screening
All type 1 diabetics should be screened for ketosis when blood sugars are >350 mg/dL or there is the presence of an anion-gap acidosis, regardless of the blood sugar.
Diagnosis
Over 10% of patients with a new diagnosis of type 1 diabetes pre- sent with diabetic ketoacidosis. Diabetic ketoacidosis occurs when insufficient insulin is present and excess glucose is metabolized via the fatty acid degradation pathway, producing metabolic ketoaci- dosis and ketonuria. Diabetic ketoacidosis is life-threatening and
Diabetes Mellitus and Diabetic Ketoacidosis • 39
Table 3. Glycemic Targets for All Patients with Diabetes
Parameter Target Value
Hemoglobin A1c(normal range 4%–6%) <7%* Preprandial plasma glucose 90–130 mg/dL Postprandial plasma glucose (1–2 hr after a meal) <180 mg/dL
*More stringent goals (i.e., <6%) can be considered in individual patients, although currently no evidence supports that this approach offers additional benefit. Adapted from American Diabetes Association, Standards of Medical Care in Diabetes. Diabetes Care. 2005;28:S10-S11; with permission.
is treated immediately in a hospital setting. The diagnosis is based upon a triad of hyperglycemia (blood glucose >250 mg/dL), arte- rial pH <7.30, and ketoacidosis (serum bicarbonate <15 meq/L and positive serum ketones).
Therapy
Patients are usually severely dehydrated and have hyperkalemia and hypophosphatemia. Infusion of 0.9% sodium chloride is start- ed immediately, along with an intravenous insulin drip; several liters of intravenous fluid may ultimately be required. Once serum glucose concentrations are <250 mg/dL, 5% or 10% intravenous dextrose solution is administered to avoid hypoglycemia as insulin infusion is continued.
Insulin is delivered via intravenous infusion; an initial bolus of regular insulin (0.15 U/kg) is followed by a constant infusion of 0.1 U/kg. Blood glucose is monitored hourly to ensure reduction to normal values. During this time, insulin will cause substantial shifts in potassium from the extracellular to the intracellular space, placing the patient at risk for hypokalemia and arrhythmias. Measure serum potassium every 1-2 hours during initial treatment and replace potassium via intravenous infusion. The goal of insulin therapy is full suppression of ketosis, not control of hyperglycemia. Premature discontinuation of insulin results in relapse of ketosis.
Follow-Up
Once stabilized, patients are converted to subcutaneous insulin. Because diabetic ketoacidosis is often precipitated by coexistent
illness, all patients are evaluated for signs of infection or other ill- ness. Patient education is paramount to promote recognition of early signs of diabetes ketoacidosis in the future.
Book Enhancement
Go to www.acponline.org/essentials/endocrinology-section.html to view a foot exam tutorial; access a foot exam worksheet, self- management checklist, and screening guidelines; and view an early diabetic foot, callus, pre-ulcer, and retinopathy. In MKSAP for
Students 4, assess yourself with items 2-17 in the Endocrinology
and Metabolismsection.
Bibliography
Campos C.Treating the whole patient for optimal management of type 2 diabetes: considerations for insulin therapy. South Med J. 2007; 100: 804-11. [PMID: 17713307]
Lochnan H.Diabetic Ketoacidosis. http://pier.acponline.org/physicians/ diseases/d644. [Date accessed: 2008 Jan 10] In: PIER [online data- base]. Philadelphia: American College of Physicians; 2008.
Passaro MD, Ratner RE.Diabetes Mellitus, Type 1. http://pier.acponline .org/ physicians/diseases/d257. [Date accessed: 2008 Jan 10] In: PIER [online database]. Philadelphia: American College of Physicians; 2008.
Vijan S.Diabetes Mellitus, Type 2. http://pier.acponline.org/physicians/ diseases/d296. [Date accessed: 2008 Jan 10] In: PIER [online data- base]. Philadelphia: American College of Physicians; 2008.
L
ipoproteins are lipids in the blood bound to proteins. Low- density lipoprotein (LDL) makes up 60%-70% of total serum cholesterol, is the major atherogenic component, and is the main target for therapy. High-density lipoprotein (HDL) accounts for 20%-30% of total cholesterol and levels are inversely related to coronary heart disease (CHD) risk. Very-low-density lipoproteins (VLDL) are triglyceride-rich lipoproteins produced by the liver, are precursors of LDL, and contain highly atherogenic remnant particles. Intermediate-density lipoprotein (IDL) is also athero- genic and is included in the LDL measurement. Chylomicrons are formed in the intestine, are rich in triglyceride, and when partial- ly degraded are atherogenic.Other lipoproteins are likely involved in the formation of an atheroma. Lipoprotein a [Lp(a)] is associated with increased risk for CHD, but treatment with statins does not lower LP(a) lev- els or risk. Small LDL particles and HDL subfractions are relat- ed to CHD but are not superior to LDL or HDL in predicting risk. Measurement of these other lipoproteins is not routinely indicated.
Prevention
All patients should be advised about lifestyle measures that will reduce lipid levels. These include healthy diet, regular exercise, weight control, avoidance of tobacco, and moderation of alcohol intake. The components of a healthy diet include one that does not exceed caloric needs and contains less than 25%-35% of calo- ries from all fat sources, less than 7% from saturated fat, and less than 200 mg of cholesterol/day. Increasing dietary intake of veg- etables, fruits, and high-fiber foods will help lower cholesterol. In particular, low density lipoprotein (LDL) cholesterol will be low- ered by eating foods with high levels of plant stanols (2 g/day) and increased amounts of soluble fiber (10-25 g/day). Aerobic exer- cise has beneficial effects on lipid profiles and should be done most days for at least 30 minutes per session. However, any amount of exercise is of benefit and more is better. Body weight should be brought as close as possible to the ideal body mass index. All forms of tobacco should be avoided, and alcohol intake should be mod- erated to ≤2 drinks per day for men and ≤1 drink for women.
Screening
Initiate screening for lipid disorders between the ages of 20 and 35 (20 to 40 for women) using fasting lipid profiles. Repeat screening of average-risk patients with normal lipids at initial
screening every 5 years and more frequently in patients with other risk factors or whose diet and/or weight have changed significantly. Screening for lipid disorders should be continued into advanced ages unless patients have a short (<1-2 years) life expectancy. Lipid disorders are more common in the elderly and, due to the higher burden of disease, carry as high a CHD attributable risk as it does in middle-aged patients, even if the relative risk change is not as great. Lowering lipids also prevents stroke, an important problem in the elderly.
If a fasting lipid profile is not feasible, total and HDL choles- terol levels can be used for initial screening. If either of these is abnormal, a fasting lipid profile should be obtained. A fasting lipid profile consists of measurements of total and HDL cholesterol, triglycerides, and calculated LDL cholesterol. LDL cholesterol is calculated using the Friedewald formula:
LDL = total cholesterol ⫺ HDL ⫺ (triglycerides/5) Triglyceride levels >400 mg/dL invalidate the Friedewald for- mula. In this case, LDL cholesterol can be directly measured.
Diagnosis
Perform a thorough history to identify other cardiovascular risk factors, such as cigarette smoking, hypertension, and a family his- tory of premature heart disease. A variety of drugs can cause dys- lipidemia including estrogens, corticosteroids, thiazide diuretics, beta-blockers, and androgenic steroids. History can determine coronary disease equivalent status, such as diabetes mellitus, peripheral vascular disease (aortic aneurysm, claudication), stroke, or a 10-year risk of CHD >20%. The physical examination can iden- tify CHD risks or CHD equivalents. The exam should include measurement of blood pressure and body mass index. Patients with existing cardiovascular disease may have abnormal cardiac exams, diminished pulses, bruits, or other signs of peripheral vascular dis- ease. Patients with very high lipids will often have cutaneous xan- thomas on extensor surfaces and xanthelasmas near the eyelids. Secondary causes of dyslipidemia, important because often treat- able (Table 1), include hypothyroidism, obstructive liver disease, nephrotic syndrome, alcoholism, uncontrolled diabetes, smoking, and renal failure.
Before making the diagnosis of hyperlipidemia, obtain at least two measures of LDL cholesterol at least 1 week apart. LDL lev- els are the primary targets of therapy. Goals for LDL cholesterol are <100 mg/dL for those with CHD or CHD equivalent disease and <130 mg/dL for patients with ≥2 risk factors. These risk factors are
Chapter 9
Dyslipidemia
D. Michael Elnicki, MD
Gary Tabas, MD
remembered as the first five letters of the word CHOLEsterol: Cigarette use, Hypertension, Older age (45 in men, 55 in women), Low HDL, and Elders with CHD (male first-degree rel- atives <55 years of age and females <65 years). Further stratifi- cation of risk in patients who are above their goal of 130 mg/dL can be calculated using the Framingham risk equation (see Book Enhancement section below), which predicts 10-year risk of CHD. Patients are classified as low risk (<10% 10-year risk), mod- erate risk (10%-20%), and CHD risk equivalent (>20%). For the lowest-risk patients (<2 risk factors), the LDL goal is <160 mg/dL.
Triglyceride levels are a secondary target for therapy. Levels are classified as normal (<150 mg/dL), borderline (150-199 mg/dL), high (200-499 mg/dL), and very high (>500 mg/ dL). Very high triglyceride levels convey a risk of pancreatitis and are treated regardless of cardiovascular risk. Low HDL cho- lesterol (<40 mg/dL) is a CHD risk factor and is treated in patients with CHD.
Therapy
In patients with moderate-to-low risk for CHD, dietary interven- tions to reduce LDL cholesterol are appropriate. Dietary and exer- cise habit modifications may be able to normalize lipid levels. A diet low in saturated fat can result in a 5%-15% reduction in LDL cholesterol. Switching to high-fiber foods can result in a 5% reduc- tion in LDL. Furthermore, diets rich in fruits, vegetables, nuts, whole grains, and mono-unsaturated oils (olive oil, canola oil), and diets low in animal fat reduce cardiovascular risk even with- out changing lipid levels. Diets rich in n-3 fatty acids, from fish intake or supplements, improve lipid profiles and reduce risk of CHD by 20%-30%.
Patients should be encouraged to lose weight by reducing calories, particularly calories from fats and simple carbohydrates. Regular physical activity is encouraged, and both weight loss and exercise are particularly encouraged for patients with a body mass index >25. Regular aerobic exercise facilitates weight loss and improves lipid profiles. The beneficial effects are related to the
amount of exercise, rather than intensity or overall fitness. Patients should begin structured exercise programs lasting at least 30 min- utes on most days. Smoking cessation improves lipid ratios and reduces CHD and should be an integral part of lifestyle therapy.
Drug therapy is initiated in high-risk patients who are not responsive to lifestyle interventions, at least to the point of reach- ing National Cholesterol Education Program (NCEP) target cho- lesterol levels. Several drug classes for lipid lowering are available. These include HMG-CoA reductase inhibitors (statins), fibrates, niacin, bile acid binding resins, and intestinal cholesterol absorp- tion blockers (Table 2). Statins, the most effective drugs for low- ering LDL cholesterol, can cause hepatotoxicity and myopathy, particularly when used in combination with other lipid-lowering drugs. Patients should routinely be asked about symptoms such as nausea, abdominal pain, or myalgias. Serum transaminase lev- els are measured at baseline, after 3 months, and every 6-12 months when patients are on statins. If a statin-induced myopa- thy is suspected, confirm the diagnosis by measuring serum crea- tine phosphokinase. In low-risk patients, 6 months of diet and exercise are appropriate before starting drugs. Drug therapy is started earlier in patients with higher overall CHD risk and in those patients whose LDL cholesterol is more than 30 mg/dL above their goal because lowering LDL cholesterol pharmaco- logically has been shown to reduce CHD and stroke in primary and secondary prevention.
Follow-Up
Patients are seen at regular intervals even after lipids are normal- ized. Patients who are on drug therapy need to be seen regularly at 4-6 month intervals. A fasting lipid profile should be obtained at least yearly, with monitoring for drug toxicity.
Book Enhancement
Go to www.acponline.org/essentials/endocrinology-section .html to access a tool to calculate the Framingham risk score and to view tables on the classification of lipid levels, goals of
42 • Endocrinology and Metabolism
Table 1. Laboratory Tests for Evaluation of Dyslipidemia Test Notes
Fasting lipid profile with Obtain two measurements at least 1 week apart to confirm diagnosis. Results unreliable >24 hr after myocardial calculated LDL cholesterol infarction, major surgery, or trauma, and for 6-8 wk after event onset.
Direct LDL cholesterol Obtain if triglycerides >400 mg/dL, which makes Friedewald equation unreliable for calculating LDL cholesterol. measurement
TSH Identify hypothyroidism as a secondary cause.
Fasting blood glucose (FBG) Identify uncontrolled diabetes as a secondary cause with fasting blood glucose >126 mg/dL on two fasting samples. Direct bilirubin Identify obstructive jaundice as a secondary cause if bilirubin >50% above normal.
Alkaline phosphatase AST/ALT Identify liver disease as a contraindication to some lipid-lowering drugs. Verify absence of liver disease before starting a statin.
Urine for protein Begin with a urine dipstick for overt proteinuria to identify nephrotic syndrome as a secondary cause.
therapy using LDL cholesterol, and nutrient composition of the Therapeutic Lifestyle Change Diet. In MKSAP for Students 4, assess yourself with items 15-22 in the Endocrinology and
Metabolismsection.
Bibliography
Forrester JS, Libby P.The inflammation hypothesis and its potential rele- vance to statin therapy. Am J Cardiol. 2007;99:732-8. [PMID: 17317382]
Kopin LA, Pearson TA.In the clinic. Dyslipidemia. Ann Intern Med. 2007;147:ITC9-1-ITC9-16. [PMID: 17785482]
Dyslipidemia • 43
Table 2. Drugs for Treating Lipid Disorders
Agent (Examples) Mechanism of Action and Indications
Colestipol hydrochloride Interrupts bile acid reabsorption and reduces LDL cholesterol by 10%-15%. Often used as second-line drug with statins Colesevelam hydrochloride because it acts synergistically to induce LDL receptors. Do not use in patients with triglycerides >300 mg/dL or in those
with gastrointestinal motility disorders. Can interfere with absorption of other drugs given at the same time. Atorvastatin Partially inhibits HMG-CoA reductase, inducing LDL receptor formation; lowers LDL cholesterol 20%-60%, raises HDL Lovastatin cholesterol 5%-10%, and lowers triglycerides 15%-25%. Drug of choice for elevated LDL cholesterol. Side effects include Pravastatin elevated aminotransaminase levels, myositis/myalgias. Use in combination with bile acid binding resins to synergistically Simvastatin lower LDL cholesterol. Use in combination with niacin and fibrates in patients with combined hyperlipidemia. Use
cautiously in patients on fibrates due to increased risk of myalgia/myositis. Pravastatin is least likely to cause myalgia. Gemfibrozil Reduces VLDL synthesis and induces lipoprotein lipase. Lowers triglycerides 50%, raises HDL 15% but does not lower LDL Fenofibrate cholesterol reliably. Use in combination with statins cautiously due to increased incidence of myositis/myalgias. Use with
caution in patients with renal insufficiency and gallbladder disease.
Niacin Reduces hepatic production of β-containing lipoproteins and increases HDL cholesterol production. Lowers LDL cholesterol and triglycerides 10%-30%. Most effective drug at raising HDL cholesterol (25%-35%). Drug of choice for combined hyperlipidemia and in patients with low HDL cholesterol. Extended-release preparations limit flushing and
aminotransaminase abnormalities. Can cause nausea, glucose intolerance, gout, and elevated uric acid levels. Over-the-counter, long-acting niacin preparations are not recommended because they increase the incidence of hepatotoxicity. Use in combination with statins or bile acid binding resins in combined hyperlipidemia. To minimize flushing, aspirin can be taken 1 hour before dose.
Ezetimibe Selectively inhibits the intestinal absorption of cholesterol. Reduces LDL by 18%, triglycerides by 8%. When used in combination with statins, yields an additional LDL reduction of 12% (total reduction 26% to 60%), an increase in HDL of 3%, and a triglyceride reduction of 8%. Do not use in combination with resins or fibrates. Contraindicated in patients with active liver disease or elevated aminotransaminase levels.
44
T
he thyroid gland releases two forms of thyroid hormone: thyroxine (T4) and triiodothyronine (T3). All of the T4inthe body is made within the thyroid gland, whereas 80% of T3is derived from the peripheral tissues. T3affects the physiologic
function of almost all bodily tissues through binding with a spe- cific nuclear receptor and thereby regulates the transcription of thyroid-dependent genes. The peripheral conversion of T4to
T3is decreased by various medications, including propranolol,
corticosteroids, propylthiouracil, and amiodarone, and is down- regulated during the course of nonthyroidal illness. The synthesis and release of thyroid hormone are controlled by the pituitary- derived thyroid-stimulating hormone (TSH) under the influence of thyrotropin-releasing hormone from the hypothalamus. TSH stimulates basic thyrocyte functions such as iodine uptake and organification and the synthesis and release of thyroid hormone. Both T3and T4are bound to protein in the circulation that serves
the dual purpose of preventing excessive tissue uptake and main- taining a readily accessible reserve of hormone. Several common medications affect levels of thyroxine-binding globulin without generally affecting the free-thyroid hormone levels.
Screening
Screening for hypothyroidism and hyperthyroidism is not recom- mended for the general population, but it is considered for certain higher-risk populations. It is reasonable to screen women aged >50 years using a sensitive TSH test given the increased prevalence of hypothyroidism in this population. Screening other high-risk populations is also appropriate. In particular, measuring TSH is appropriate in the following patients:
• Patients with evidence of Hashimoto’s disease or Graves’ dis- ease in a first-degree relative
• Patients with other autoimmune diseases such as type 1 dia- betes
• Patients with a history of any prior thyroid dysfunction, even if self-limited
• Patients living in an iodine-deficient region of the world • Patients anticipating a pregnancy or currently pregnant • Patients with conditions (e.g., cardiac arrhythmias, weight
loss, osteoporosis, anxiety) that may be explained or aggra- vated by hyperthyroidism
Of particular note is the population of young women with hypothyroidism receiving adequate levothyroxine replacement therapy who desire to be (or are currently) pregnant. During
pregnancy, the daily thyroid hormone requirement increases by approximately 40% above baseline beginning very early in gesta- tion. In patients with hypothyroidism, the dose of levothyroxine must be increased. Failure to do so results in maternal (and pos- sibly fetal) hypothyroidism, which can be associated with sub- stantial morbidity to both mother and fetus. For this reason, pre- pregnancy or pregnancy screening of women for hypothyroidism is important. Patients on thyroid replacement should be coun- seled to contact their physician as soon as pregnancy is confirmed so that levothyroxine dose adjustment can be made early to main- tain a euthyroid state throughout gestation.
Diagnosis
Consider the diagnosis of hyperthyroidism in patients with signs or symptoms of thyrotoxicosis (Table 1) or in those with diseases known to be caused or aggravated by thyrotoxicosis (e.g., atrial fibrillation). In hyperthyroidism, the TSH is low or undetectable and a free-T4concentration is elevated. If the TSH is suppressed
and the free-T4is normal, measure the serum T3concentration.
T3thyrotoxicosis (suppressed TSH, normal T4, elevated T3) is
seen with increased frequency in patients with toxic multinodular goiter and autonomously functioning thyroid nodules. Look for “apathetic thyrotoxicosis” in elderly patients characterized by a lower frequency of goiter (found in 50%), fewer hyperadrenergic