OBJECTIVES

After completing this chapter, the reader should be able to

  • Describe the use of glycated hemoglobin, fasting plasma glucose, and oral glucose tolerance tests as diagnostic tools for type 1 and type 2 diabetes mellitus

  • Explain the major differences between laboratory values found in patients with diabetic ketoacidosis and those in a hyperosmolar hyperglycemic state

  • Describe the actions of thyroxine, triiodothyronine, and thyroid-stimulating hormone and the feedback mechanisms regulating them

  • Given a case description including thyroid function test results, identify the type of thyroid disorder and describe how tests are used to monitor and adjust related therapy

  • Describe the relationship between urine osmolality, serum osmolality, and antidiuretic hormone as they relate to diabetes insipidus

  • Describe the laboratory tests used to diagnose Addison disease and Cushing syndrome

The endocrine system consists of hormones that serve as regulators, which stimulate or inhibit a biological response to maintain homeostasis within the body. Endocrine disorders often result from a deficiency or an excess of a hormone, leading to an imbalance in physiologic functions of the body. Usually, negative feedback mechanisms regulate hormone concentrations (Figure 9-1). Therefore, laboratory assessment of an endocrine disorder is based on the concentrations of a plasma hormone and integrity of the feedback mechanism regulating that hormone. In this chapter, the relationship between a hormone (insulin) and a target substrate (glucose) serves as an example of these concepts. Evaluations of the functions of the thyroid and adrenal glands are also described. The relationships between vasopressin (antidiuretic hormone [ADH]) and serum and urine osmolality are used to demonstrate the basis for the water deprivation test in diagnosing diabetes insipidus.

FIGURE 9-1.
FIGURE 9-1.

The hypothalamus may secrete a releasing hormone in response to low levels of stimulating, inhibitory, or target organ hormone. This releasing hormone causes the release of a stimulating or inhibitory hormone that, in turn, controls the release of target organ hormone.

GLUCOSE HOMEOSTASIS

Glucose serves as the fuel for most cellular functions and is necessary to sustain life. Carbohydrates ingested from a meal are metabolized in the body into glucose. Glucose is absorbed from the gastrointestinal (GI) tract into the bloodstream, where it is used in skeletal muscle and the brain for energy. Excess glucose is stored in the liver in the form of glycogen (glycogenesis) and is converted in adipose tissue to fats and triglycerides (lipogenesis). Insulin, which is produced, stored, and released from β cells of the pancreas, facilitates these anabolic processes. The liver, skeletal muscle, brain, and adipose tissue are the main tissues affected by insulin. To induce glucose uptake, insulin must bind to specific cell-surface receptors. Most secreted insulin is taken up by the liver, while the remainder is metabolized by the kidneys.

In the fasting state, insulin levels decrease, resulting in an increase in glycogen breakdown by the liver (glycogenolysis) and an increase in the conversion of free fatty acids to ketone bodies (lipolysis).1 When glucose concentrations fall below 70 mg/dL, an event known as hypoglycemia occurs, resulting in the release of glucagon by the pancreatic α cell. Glucagon stimulates the formation of glucose in the liver (gluconeogenesis) and glycogenolysis. Glucagon also facilitates the breakdown of stored triglycerides in adipose tissue into fatty acids (lipolysis), which can be used for energy in the liver and skeletal muscle. In addition to glucagon secretion, hypoglycemia leads to secretion of counterregulatory hormones such as epinephrine, cortisol, and growth hormone. Epinephrine release in response to hypoglycemia results in neurogenic symptoms such as sweating, palpitations, tremulousness, anxiety, and hunger. Glucagon and, to a lesser degree, epinephrine promote an immediate breakdown of glycogen and the synthesis of glucose by the liver. Cortisol increases glucose levels by stimulating gluconeogenesis. Growth hormone inhibits the uptake of glucose by tissues when glucose levels fall below 70 mg/dL.1

In individuals without diabetes, once plasma glucose concentrations exceed 180 mg/dL (the renal threshold), renal glucose reabsorption is saturated and glucose starts to appear in the urine. In individuals with hyperglycemia, large amounts of glucose may be excreted into the urine. However, in diabetes mellitus (DM), the renal glucose threshold may increase up to 240 mg/dL, causing reabsorption of more glucose, which further contributes to hyperglycemia.1

In summary, glucose concentrations are affected by any factor that can influence glucose production or utilization, glucose absorption from the GI tract, glycogen catabolism, or insulin production or secretion. Fasting suppresses the rate of insulin secretion, and eating generally increases insulin secretion. Increased insulin secretion lowers serum glucose concentrations, whereas decreased secretion raises glucose concentrations.1

DIABETES MELLITUS

The three most commonly encountered types of DM are as follows:

  1. Type 1 DM, formally known as insulin-dependent DM

  2. Type 2 DM, formerly known as adult-onset or noninsulin-dependent DM2

  3. Gestational DM (GDM)

Type 1 DM is characterized by a lack of endogenous insulin, a predisposition to ketoacidosis, and abrupt onset. Some patients present with ketoacidosis after experiencing polyuria, polyphagia, and polydipsia for several days. Typically, this type of DM is diagnosed in children and adolescents but may also occur at a later age. In contrast, patients with type 2 DM do not normally depend on exogenous insulin to sustain life and are not usually ketosis prone, but they are usually obese and >40 years old. There is an alarming increase in the number of children and adolescents diagnosed with type 2 DM. Although there is a genetic predisposition to the development of type 2 DM, environmental factors such as high-fat diet and sedentary lifestyle contribute to the disorder. Patients with type 2 DM are both insulin deficient and insulin resistant (Table 9-1).1

TABLE 9-1.

General Characteristics of Type 1 and Type 2 Diabetes Mellitus

CHARACTERISTICS

TYPE 1

TYPE 2

Usual age of onset

Childhood or adolescence

>40 yr old

Rapidity of onset

Abrupt

Gradual

Family studies

Increased prevalence of type 1 DM

Increased prevalence of type 2 DM

Body weight

Unusually thin

Obesity is common

Islet cell antibodies and pancreatic cell-mediated immunity

Yes

No

Ketosis

Possible

Unlikely; if present, associated with severe stress or infection

Insulin

Markedly diminished early in disease or totally absent

Levels may be low, normal, or high (indicating insulin resistance)

Symptoms

Polyuria, polydipsia, polyphagia, weight loss

May be asymptomatic; polyuria, polydipsia, polyphagia may be present

Source: Adapted from American Diabetes Association. Classification and diagnosis of diabetes: standards of medical care in diabetes: 2021. Diabetes Care 2021;44(suppl 1):S152S33.

Many patients with type 2 DM are asymptomatic, so diagnosis often depends on laboratory studies. Concentrations of ketone bodies in the blood and urine are typically low or absent, even in the presence of hyperglycemia. This finding is common because the lack of insulin is not severe enough to lead to abnormalities in lipolysis and significant ketosis or acidosis.

Because of the chronicity of asymptomatic type 2 DM, many patients with type 2 DM present with evidence of microvascular complications (neuropathy, nephropathy, and retinopathy) and macrovascular complications (coronary artery, cerebral vascular, and peripheral arterial disease) at the time of diagnosis. Type 2 DM is often discovered incidentally during glucose screening sponsored by hospitals and other healthcare institutions.1

Gestational DM, a third type of glucose intolerance, develops during the third trimester of pregnancy. Patients with GDM have a 30% to 50% chance of developing type 2 DM later in life.2 Women with diabetes who become pregnant or women diagnosed with diabetes early in pregnancy are not included in this category.

Diagnostic Laboratory Tests

C-Peptide

Categories of C-peptide values are as follows:

  • Fasting range: 0.78 to 1.89 ng/mL (0.26 to 0.62 nmol/L)

  • Range 1 hour after a glucose load: 5 to 12 ng/mL

  • During a glucose tolerance test: 1.66 to 3.97 nmol/L

Insulin is synthesized in the β cells of the islets of Langerhans as the precursor, proinsulin. Proinsulin is cleaved to form C-peptide and insulin, which are both secreted in equimolar amounts into the portal circulation. By measuring the levels of C-peptide, the level of insulin can also be calculated. C-peptide levels are also used to evaluate residual β-cell function. High levels of C-peptide generally indicate high levels of endogenous insulin production, which may be a response to high levels of blood glucose caused by glucose intake and insulin resistance. Also, high levels of C-peptide also are seen with insulinomas (insulin-producing tumors) and may be seen with hypokalemia, pregnancy, Cushing syndrome, and renal failure. Low levels of C-peptide are associated with low levels of insulin production, which can occur when insufficient insulin is produced due to a decrease in the number of functional insulin-producing β cells associated with type 1 DM or long-term type 2 DM or with suppression tests that involve substances such as somatostatin.3

A C-peptide test can be performed to distinguish between type 1 and type 2 DM. A patient with type 1 DM has a low level of insulin and C-peptide. A patient with newly diagnosed type 2 DM typically has a normal or high level of C-peptide. When a patient has newly diagnosed type 1 or type 2 DM, C-peptide can be used to help determine how much insulin the patient’s pancreas is still producing. With type 2 DM, the test may be ordered to monitor the status of β-cell function and insulin production over time and determine if insulin injections may be required.

A C-peptide test may differentiate the cause of hypoglycemia, such as excessive use of medicine to treat diabetes or a noncancerous growth (tumor) in the pancreas (insulinoma). Because man-made (synthetic) insulin does not have C-peptide, a person with a low blood sugar level from taking too much insulin has a low C-peptide level but a high level of insulin. Insulinomas are the most common cause of hypoglycemia resulting from endogenous hyperinsulinism. A person with an insulinoma has a high level of C-peptide in the blood when the he or she has a high level of insulin.

Although they are produced at the same rate, C-peptide and insulin leave the body by different routes. Insulin is processed and eliminated by the liver and kidneys, whereas C-peptide is removed primarily by the kidneys. The half-life of C-peptide is 30 minutes as compared with the half-life of insulin, which is 5 minutes. Thus, there is usually about five times as much C-peptide in the bloodstream as endogenous insulin.3

Diabetes-Related Autoantibody Testing

Diabetes-related (islet) autoantibody testing is used to distinguish between autoimmune type 1 DM and type 2 DM, allowing for early initiation of the most appropriate treatment, which may minimize disease complications. The four most commonly used autoantibody tests are islet cell cytoplasmic autoantibodies (ICA), glutamic acid decarboxylase autoantibodies (GADA), insulinoma-associated-2 autoantibodies (IA-2A), and insulin autoantibodies (IAA). Of these, ICA and GADA, which are autoantibodies directed against islet cell proteins or β-cell antigen, are present in 70% to 80% of adult patients with type 1 DM. IA-2A autoantibodies are present in approximately 60% of adult patients with type 1 DM. The majority of people, 95% or more, with new-onset type 1 DM will have at least one islet autoantibody.2 Some people who have type 1 DM will never develop detectable amounts of islet autoantibodies, but this is rare.

The autoantibodies seen in children are often different than those seen in adults. IAA is usually the first marker to appear in young children. As the disease evolves, IAA may disappear and ICA, GADA, and IA-2A become more important. Approximately 50% of children with new-onset type 1 DM will be IAA positive.

A combination of these autoantibodies may be ordered when a person is newly diagnosed with diabetes and the healthcare provider wants to distinguish between type 1 and type 2 DM. In addition, these tests may be used when the diagnosis is unclear in persons with diabetes who have been diagnosed as type 2 DM, but who have great difficulty in controlling their glucose levels with oral medications. If ICA, GADA, and IA-2A are present in a person with symptoms of DM, the diagnosis of type 1 DM is confirmed. Likewise, if IAA is present in a child with DM who is not insulin-treated, type 1 DM is the cause. If no diabetes-related autoantibodies are present, then it is unlikely that the diabetes is type 1 DM.2

Latent autoimmune diabetes in adults (LADA) is a slow-progressing form of autoimmune diabetes. Patients may present with characteristics of both type 1 and type 2 DM.4,5 The clinical features of type 1 diabetes seen in LADA include a lower body mass index (BMI) compared with what is typical in type 2 DM and autoimmunity against one or more of the following antibodies: ICA, autoantibodies to glutamic acid decarboxylase (GAD), IA-2, and IAA6,7 The characteristics of type 2 DM that may present in LADA include older age at onset and insulin resistance or deficiency. Characteristics of LADA tend to include an intermediate level of β-cell dysfunction between those in type 1 and type 2 DM, faster decline of C-peptide compared with type 2 DM, and a level of insulin resistance that is comparable to type 1 DM.8 β-cell decline is variable in LADA, as measured by C-peptide levels.8,9

Laboratory Tests to Assess Glucose Control

The two most common methods used for evaluating glucose homeostasis are the fasting plasma glucose (FPG) and glycated hemoglobin (A1c) tests. The oral glucose tolerance test (OGTT) is most commonly used to diagnosis GDM.2

With all blood tests, proper collection and storage of the sample and performance of the procedure are important. Improper collection and storage of samples for glucose determinations can lead to false results and interpretations. After collection, red blood cells (RBCs) and white blood cells (WBCs) continue to metabolize glucose in the sample tube. This process occurs unless (1) the RBCs can be separated from the serum using serum separator tubes or (2) the metabolism is inhibited using sodium fluoride–containing (gray-top) tubes or refrigeration of the specimen. Without such precautions, the glucose concentration drops by 5 to 10 mg/dL (0.3 to 0.6 mmol/L) per hour, and the measured glucose level does not reflect the patient’s FPG at collection time. In vitro, metabolic loss of glucose is hastened in samples of patients with leukocytosis or leukemia.1015

Fasting Plasma Glucose and Two-Hour Postprandial Glucose

The categories of FPG values are as follows:

  • FPG <100 mg/dL (5.6 mmol/L) represents normal fasting glucose

  • FPG ≥100 (5.6 mmol/L) and <126 mg/dL (7 mmol/L) represents prediabetes (previously termed impaired fasting glucose)

  • FPG ≥126 mg/dL (7 mmol/L) represents provisional diagnosis of diabetes (the diagnosis must be confirmed as described in Table 9-2)2

TABLE 9-2.
Diagnosis of DM Based on Fasting Plasma Glucose Concentration, Oral Glucose Tolerance Test, or Glycosylated Hemoglobin

LEVEL OF GLUCOSE TOLERANCE

FPG

VENOUS PLASMA GLUCOSE AFTER 75-g OGTTa (mg/dL)

A1c

30, 60, or 90 min

2 hr

“Normal”

<100

NA

<140

<5.7%

Prediabetes

100–125

NA

140–199

5.7%–6.4%

DM

≥126

NA

>200

≥6.5%

GDM

>92

>180 (1 hr)

>153

NA = not applicable.

aMultiply number by 0.056 to convert glucose to International System (SI) units (mmol/L).

Source: Adapted from American Diabetes Association. Classification and diagnosis of diabetes: standards of medical care in diabetes-2021. Diabetes Care 2021;44(suppl 1):S152S33.

An FPG concentration measures the ability of endogenous or exogenous insulin to prevent fasting hyperglycemia by regulating glucose anabolism and catabolism. FPG may be used to monitor therapy in patients being treated for glucose abnormalities. For this test, the patient maintains his or her usual diet, and the assay is performed on awakening (before breakfast). This timing allows for an 8-hour fast. An FPG >126 mg/dL (>7 mmol/L), in abnormal test results from the same sample or in two separate test samples, is diagnostic for DM. If the initial single test is an abnormal FPG result, either the same or a different test can be taken on a different day to confirm the diagnosis for DM.

Testing in asymptomatic people should be considered in adults of any age who are overweight or obese (BMI ≥25 kg/m2 or ≥23 kg/m2 for individuals of Asian-Pacific descent) with one or more risk factors2:

  • First-degree relative with diabetes

  • High-risk ethnic groups (eg, high-risk ethnic groups: Hispanic, African American, Native American, South or East Asian, or Pacific Island descent)

  • History of cardiovascular disease

  • Hypertension (≥140/90 mm Hg or on therapy for hypertension)

  • High-density lipoprotein cholesterol level of 35 mg/dL (0.90 mmol/L) and/or a triglyceride level of 250 mg/dL (2.82 mmol/L)

  • Women with polycystic ovary syndrome

  • Physical inactivity• A1c ≥5.7%, impaired glucose tolerance, or elevated fasting glucose on a previous testing (should be tested annually)

  • Polycystic ovary syndrome

  • Other clinical conditions associated with insulin resistance (eg, severe obesity, acanthosis nigricans)

Patients with prediabetes (A1C ≥5.7% [39 mmol/mol], impaired glucose tolerance [IGT]; impaired fasting glucose [IFG]) should be tested yearly. Women who were diagnosed with GDM should have lifelong testing at least every 3 years. Individuals without these risk factors should be screened no later than 45 years of age. If results are normal, testing should be repeated at a minimum of 3-year intervals, with consideration of more frequent testing depending on initial results and risk status. The American Diabetes Association (ADA) also recommends that individuals from high-risk groups aged >30 years be screened for DM every 3 years.2

Oral Glucose Tolerance Test

The categories for the 75-g OGTT are as follows:

  • 2-hour postload glucose (PG), <140 mg/dL (7.8 mmol/L) represents normal glucose tolerance

  • 2-hour PG 140 to 199 mg/dL (7.8 to 11 mmol/L) represents prediabetes (previously termed impaired glucose tolerance)

  • 2-hour PG ≥200 mg/dL (≥11.1 mmol/L) represents provisional diagnosis of diabetes

The OGTT can be used to assess patients who have signs and symptoms of DM but whose FPG is normal or suggests prediabetes (<126 mg/dL or <7 mmol/L). The OGTT measures both the ability of the pancreas to secrete insulin following a glucose load and the body’s response to insulin. Interpretation of the test is based on the plasma glucose concentrations drawn before and during the exam. This exam may also be used in diagnosing DM with onset during pregnancy if the disease threatens the health of the mother and fetus.

The OGTT is performed by giving a standard 75-g dose of an oral glucose solution over 5 minutes after an overnight fast. The pediatric dose is 1.75 g/kg up to a maximum of 75 g. Blood samples commonly are drawn before the glucose load and at 120 minutes after the glucose load. The samples should be collected into tubes containing sodium fluoride unless the assay will be performed immediately.2 If the patient vomits the test dose, the exam is invalid and must be repeated.

Pregnant women with risk factors such as overweight or obese with a BMI >25; family history of type 2 DM; hypertension; hyperlipidemia; and high-risk ethnic groups (eg, Hispanic, African American, Native American, South or East Asian, or Pacific Island descent) should be screened at the first prenatal visit using standard diagnostic criteria for type 2 DM. Pregnant women not previously known to have DM or risk factors can be screened for GDM at 24 to 28 weeks’ gestation. GDM diagnosis can be accomplished with either of two strategies:

  1. The “one-step” 75-g OGTT

  2. The older “two-step” approach with a 50-g (nonfasting) screen followed by a 100-g OGTT for women who screen positive

One-Step Strategy

A 75-g OGTT is performed with plasma glucose measurement when the patient is fasting and at 1 and 2 hours.2 The OGTT should be performed in the morning after an overnight fast of at least 8 hours. The diagnosis of GDM is made when any of the following plasma glucose values are met or exceeded:

  • FPG ≥92 mg/dL (5.1 mmol/L)

  • OGTT value at 1 hour ≥180 mg/dL (10 mmol/L)

  • OGTT value at 2 hours ≥153 mg/dL16 (8.5 mmol/L)

Two-Step Strategy

Step 1: Perform a 50-g OGTT (nonfasting), with plasma glucose measurement at 1 hour. If the plasma glucose level measured 1 hour after the load is ≥130, 135, or 140 mg/dL (7.2, 7.5, or 7.8 mmol/L, respectively), proceed to a 100-g OGTT. Cutoff values of 130, 135, and 140 are all used clinically for screening. The lower values are more sensitive but less specific for GDM.

Step 2: The 100-g OGTT should be performed when the patient is fasting.2 The diagnosis of GDM is made when at least two of the following four plasma glucose levels are met or exceeded (measured fasting and at 1, 2, and 3 hours during OGTT):

  • Fasting: 95 mg/dL (5.3 mmol/L)

  • 1 hour: 180 mg/dL (10.0 mmol/L)

  • 2 hours: 155 mg/dL (8.6 mmol/L)

  • 3 hours: 140 mg/dL (7.8 mmol/L)

Glycated Hemoglobin

Normal range: 4% to 5.6%

Glycated hemoglobin (A1c), also known as glycosylated A1c, is a component of the hemoglobin molecule. During the 120-day lifespan of an RBC, glucose is irreversibly bound to the hemoglobin moieties in proportion to the average serum glucose. The process is called glycosylation. Measurement of A1c is, therefore, indicative of glucose control during the preceding 3 months. The entire hemoglobin A1 molecule—composed of A1a, A1b, and A1c—is not used because subfractions A1a and A1b are more susceptible to nonglucose adducts in the blood of patients with opiate addiction, lead poisoning, uremia, and alcoholism.14 Because the test measures a component of hemoglobin, the specimen analyzed is RBC and not serum or plasma.

Results are not affected by daily fluctuations in the blood glucose concentration, and a fasting sample is not required. Results can reflect overall patient compliance to various treatment regimens. With most assays, 95% of a normal individual’s hemoglobin is 4% to 5.6% glycated; a level of 5.7% to 6.4% indicates prediabetes, and a level of ≥6.5% indicates diabetes. An A1c ≥7% suggests less-than-ideal glucose control for most patients. Patients with A1c of ≥9% are considered to have poorly controlled glucose levels.16

For years, the A1c has been used to monitor glucose control in people already diagnosed with DM. Initially, it was not recommended for diagnosis because the test variability from laboratory to laboratory was too great for a diagnostic test. The A1c cut-point of ≥6.5% identifies one-third fewer cases of undiagnosed DM than a fasting glucose cut-point of ≥126 mg/dL. However, the lower sensitivity of the test at the cut-point is offset by the test’s greater practicality, and wider use of this more convenient test may result in an increase in the number of diagnoses.2

A few situations confound interpretation of test results. False elevations in A1c may be noted with uremia, chronic alcohol intake, and hypertriglyceridemia.16 Recent blood transfusion, use of drugs that stimulate erythropoiesis, and end-stage kidney disease may also compromise the accuracy of the A1C result.2 Patients who have diseases with chronic or episodic hemolysis (eg, sickle cell disease and thalassemia) generally have spuriously low A1c concentrations caused by the predominance of young RBCs (which carry less A1c) in the circulation. In splenectomized patients and those with polycythemia, A1c is increased. If these disorders are stable, the test still can be used, but values must be compared with the patient’s previous results rather than published normal values. Both falsely elevated and falsely lowered measurements of A1c may also occur during pregnancy. Therefore, A1c should not be used to screen for GDM.16

The A1C test should be performed using a method that is certified by the NGSP (www.ngsp.org). Although point-of-care (POC) A1C assays may be NGSP certified and cleared by the U.S. Food and Drug Administration (FDA) for use in monitoring glycemic control in people with diabetes in both Clinical Laboratory Improvement Amendments (CLIA)-regulated and CLIA-waived settings, only those POC A1C assays that are also cleared by the FDA for use in the diagnosis of diabetes should be used for this purpose, and only in the clinical settings for which they are cleared. POC A1C assays may be more generally applied for the assessment of glycemic control in the clinic. Portable analyzers are available that can provide A1c results at the POC within 5 to 8 minutes.16 The ADA recommends A1c testing one to two times a year for patients with good glycemic control and quarterly in patients with poor control or whose therapy has changed.2

Fructosamine

Normal range: 170 to 285 µmol/L

Fructosamine is a general term that is applied to any glycosylated protein. Unlike the A1c test, only glycosylated proteins in the serum or plasma (eg, albumin)—not erythrocytes—are measured. In patients without diabetes, the unstable complex dissociates into glucose and protein. Therefore, only small quantities of fructosamine circulate. In patients with DM, higher glucose concentrations favor the generation of more stable glycation, and higher concentrations of fructosamine are found.

Fructosamine has no known inherent toxicological activity but can be used as a marker of medium-term glucose control. Fructosamine correlates with glucose control over 2 to 3 weeks based on the half-lives of albumin (14 to 20 days) and other serum proteins (2.5 to 23 days). As a result, high-fructosamine concentrations may alert caregivers to deteriorating glycemic control earlier than increases in A1c.

Falsely elevated results may occur for the following reasons:

  • Serum (not whole blood) hemoglobin concentrations are >100 mg/dL (normally <15 mg/dL)

  • Serum bilirubin is >4 mg/dL

  • Serum ascorbic acid is >5 mg/dL17

Methyldopa and calcium dobesilate (the latter is used outside the United States to minimize myocardial damage after an acute infarction) may also cause falsely elevated results. Serum fructosamine concentrations are lower in obese patients with DM as compared with lean patients with DM.18 Falsely low fructosamine levels can be observed in patients with low serum protein or albumin levels. Some clinicians advocate the use of fructosamine concentrations as a monitoring tool for short-term changes in glycemic control (eg, GDM, recent addition of medication). A fructosamine test can be used as an alternative test in cases in which the A1C may be unreliable, such as blood loss or hemolytic anemia, sickle cell anemia, or other hemoglobin variants. The hemoglobin A1c test is also less reliable and the fructosamine test may be preferred.18

Urine Glucose

Normal range: negative

Glucose “spills” into the urine when the serum glucose concentration exceeds the renal threshold for glucose reabsorption (normally 180 mg/dL). However, a poor correlation exists between urine glucose and concurrent serum glucose concentrations. This poor correlation occurs because urine is “produced” hours before it is tested unless the inconvenient double-void method (urine is collected 30 minutes after emptying of the bladder) is used. Furthermore, the renal threshold varies among patients and tends to increase in diabetes over time, especially if renal function is declining. Urine testing gradually has been replaced by convenient fingerstick blood sugar testing. Urine glucose testing should be recommended only if a patient is unable or unwilling to perform blood glucose monitoring.19

Self-Monitoring Tests for Blood Glucose

Blood glucose meters and reagent test strips are commercially available so that patients may perform blood glucose monitoring at home. These systems are also used in hospitals, where healthcare providers rely on quick results for determining insulin requirements. The meters currently marketed are lightweight, relatively inexpensive, accurate, and user friendly.20

The first generation of self-monitoring blood glucose (SMBG) meters relied on a photometric analysis that was based on a dye-related reaction. This method, also termed reflectance photometry, light reflectance, or enzyme photometry, involves a chemical reaction between capillary blood and a chemical on the strip that produces a change in color. The amount of color reflected from the strip is measured photometrically. The reflected color is directly related to the amount of glucose in the blood. The darker color the test strip, the higher the glucose concentration. The disadvantages of this method are that the test strip has to be developed after a precise interval (after the blood is washed away), a large sample size of blood (>12 μL) is required, and the meter requires frequent calibration.21

Most SMBG meters today utilize an electrochemical or enzyme electrode process, which determines glucose levels by measuring an electrical charge produced by the glucose-reagent reaction. These second-generation glucose meters can further be subdivided according to the electrochemical principle used: amperometry or colorimetry.21

Amperometry biosensor technology requires a large sample size (4 to 10 μL). Amperometric technology measures only a small percentage of the glucose and uses a multiplier to convert it to a numerical value. Therefore, blood glucose readings may be affected by environmental temperature, hematocrit (Hct), medications, and other factors. Also, small samples may result in inaccurate readings because of a weak signal being generated.22

The colorimetry method involves converting the glucose sample into an electrochemical charge, which is then captured for measurement. An advantage of this system is that a small amount of blood (eg, 0.3 mL) is enough to determine the blood glucose level. The colorimetry method is not influenced by changes in temperature and Hct levels. These monitors can use blood samples extracted from the arm and thigh, too. At these alternative sites, there are fewer capillaries and nerve endings, allowing for a less painful needle stick. Some examples of second-generation glucometers that use the colorimetry method include Nova Max Plus, OneTouch Verio, and FreeStyle Lite. A chart that lists the current glucose meters and their features can be found at http://main.diabetes.org/dforg/pdfs/2020/2020-cg-blood-glucose-meters.pdf.22

Although new SMBG meters report results as plasma values, older meters may report results as whole blood values, which are approximately 10% to 15% lower than plasma values. The ADA recommends whole blood fasting readings of 80 to 130 mg/dL (4.4 to 6.7 mmol/L) and postprandial readings of <180 mg/dL.2

Special features of glucose meters

Blood glucose testing can be challenging for adults with poor vision or limited dexterity and children with small hands. Patients should try several meters by checking their ease of use with the lancing device and lancets, test strips, packaging, and meter features before committing to one. Many meters like the Glucocard Shine Express, Advocate Redi-Code Plus Speaking Meter, and For a Test N’GO Advance Voice offer an audio function that is available in several different languages. Individuals with visual impairment may benefit from larger display screen, screen backlight, or test strip port light. Examples of meters that offer a screen backlight include the FreeStyle Lite, Presto, Presto Pro, OneTouch Ultra 2, and Contour Next Link USB.22

Some children are more comfortable monitoring their blood glucose than others. Some children may like glucometers that come in bright or “cool” colors. Many “auto-code” or “no-code” meters, which do not require manually programming the meter to recognize a specific group of test strips, are ideal choices for children who are learning how to monitor their blood glucose levels. Parents should select a meter that requires a small blood sample size.

Most meters hold from 100 to 450 test results, although a few save over 1,000. This makes it easier to track blood glucose control over time. Many meters on the market have computer-download capabilities through a USB connection.22

Generally, blood glucose concentrations determined by these methods are clinically useful estimates of corresponding plasma glucose concentrations measured by the laboratory. Therefore, at-home blood glucose monitoring is preferred to urine testing.22 At-home blood testing clarifies the relationship between symptomatology and blood glucose concentrations. The best meter for a patient is an individual decision. Patients should be encouraged to try different brands of meters to find the device with which they are most comfortable.20

The use of continuous glucose monitoring (CGM) is recognized as the standard of care for individuals with type 1 diabetes and a subset of those with type 2 diabetes requiring insulin therapy.23 CGM provides readings every few minutes throughout the day. This method allows patients and providers an opportunity to observe trends in glucose levels throughout the day and make the appropriate adjustments to medication, meal, or exercise regimens. A small, sterile, disposable glucose-sensing device called a sensor is inserted into the subcutaneous tissue. This sensor measures the change in glucose levels in interstitial fluid and sends the information to a reader that can store from 3 to 90 days of data. Real-time CGM systems include Dexcom G5 and Dexcom G6 sensors (manufactured by Dexcom); Eversense CGM System (manufactured by Senseonics) and Guardian Connect CGM System (manufactured by Medtronic Diabetes). Monitors are typically calibrated daily by entering at least two blood glucose readings obtained at different times using a standard blood glucose meter. The monitors have an alert system to warn patients if their blood glucose level is dangerously low or high. The monitor may be part of an insulin pump or a separate device that can be carried in a pocket or purse. Smartphone apps are also used in conjunction with CGMs. The FreeStyle Libre Flash Glucose Monitoring System and FreeStyle Libre 2 System (Abbott Diabetes Care) are the only intermittently scanned system currently available. After the sensor is inserted, there is a 12-hour warm-up time, and no initial or daily calibration is required during the 14-day wear period. Unlike with the real-time CGM system, the patient has to purposely scan the sensor to obtain changes in glucose levels.23,24

Quality control, which consists of control solution testing, calibration, and system maintenance, is a necessary component of accurate glucose testing. Control solutions can be purchased to assess the accuracy of the test strip. Control solutions should be used every time a new container of test strips is opened, when the blood glucose meter is mishandled or dropped, or whenever the accuracy of the results is questioned. The technique of verifying accuracy operates the same way that the patient analyzes a drop of blood. A few meters require manual calibration prior to use, but most have an automatic calibration mode for ease of use. In photometric meters, the blood sample intended for the strip may come in contact with the meter and soil the optic window resulting in inaccurate results.21 Pharmacists should guide patients through the instructions for cleaning the meter that is usually provided by the manufacturer.20

Factors affecting glucose readings

User error is the most common reason for inaccurate results. Some of the most common errors include not putting enough blood on the reagent portion of the strip. Patients should be asked periodically to demonstrate how they operate the meter.25

Environmental factors such as temperature, humidity, altitude, and light may influence the accuracy of glucose readings. Exposing glucometers to extremes of temperature can alter battery life and performance. Therefore, glucometers should be stored at room temperature to ensure accuracy (most will function at temperatures between 50°F and 104°F). Temperature changes and humidity may decrease the shelf life of test strips, resulting in inaccurate test results. Test strips should not be stored in areas of high humidity, such as a bathroom, or in areas with notable temperature changes, such as the car. Individuals should check the expiration date of the test strips. Because test strips are costly, patients are often tempted to use expired strips, which result in inaccurate readings.26,27 Most test strips expire within 90 to 180 days after being opened.

At higher altitudes, changes in oxygen content and temperature alter glucose testing results. Results of studies evaluating the accuracy of glucometers at altitudes >10,000 feet have revealed major alterations in blood glucose levels. These changes are attributed to variations in metabolic rate, hydration, diet, physical exercise, Hct, and temperature associated with higher altitudes. Patients should be educated on how to use glucometers at high altitudes. Changes in light exposure can also alter results with photometric glucometers.26 Additional variables such as hypotension, hypoxia, high triglyceride concentrations, and various drugs can alter readings; each patient should be evaluated for the presence of such variables and medication-related effects.2527

Accuracy of glucose readings

The FDA requires 95% of all meter test results to be within 20% of the actual blood glucose level for results ≥75 mg/dL (4.2 mmol/L). An actual blood glucose that is 100 mg/dL (5.6 mmol/L) could show on a meter as being between 80 and 120 mg/dL (4.4 to 6.7 mmol/L) and still be considered accurate. The FDA is currently reviewing more stringent standards that will require 98% of meter test results to be within 15% of the actual blood glucose level for results ≥75 mg/dL (4.2 mmol/L). For example, an actual blood glucose result of 100 mg/dL (5.6 mmol/L) could potentially show on a meter as any value between 85 and 115 mg/dL (4.7 to 6.4 mmol/L) and meet the standard.28

The guidelines for results in the hypoglycemic range, defined as a blood glucose level <72mg/dL (4.2 mmol/L), stipulate that 98% of test results must be within ±15 mg/dL of the actual blood glucose level. Therefore, if an actual blood glucose level is 60 mg/dL, the guidance says the reading would need to be between 45 and 75 mg/dL (2.5 to 4.2 mmol/L) to meet accuracy standards.28,29

The FDA guidance also recommends that meter boxes and test strip vials include easy-to-understand accuracy data—both on the outside of the package and on the insert inside. The FDA does not regularly monitor blood glucose meters or strips once they enter the commercial market. This means some companies may not maintain the same level of quality and accuracy as when the products were initially approved.28,29

Frequency of glucose monitoring

Glucose monitoring requirements may vary based on the pharmacologic therapy administered. It is generally unnecessary in patients who manage their diabetes with diet alone or who take oral medications that do not cause hypoglycemia. Patients taking insulin injections twice a day should check blood glucose levels at least twice a day. Patients on intensive insulin therapy should monitor blood glucose levels three to four times a day. Patients on insulin pumps need monitoring four to six times a day to determine the effectiveness of the basal and bolus doses. In general, premeal glucose measurements are needed to monitor the effectiveness of the basal insulin dose (eg, glargine or detemir) dose. Two-hour postprandial glucose (PPG) readings are needed to monitor rapid-acting insulins (eg, lispro, glulisine, aspart, and Afrezza inhaled). Oral blood glucose–lowering agents, such as metformin, thiazolidinediones, sitagliptin, and glipizide, are evaluated using 2-hour postprandial readings. Pregnancy requires frequent monitoring of blood glucose levels four to six times a day to ensure tight control. Premeal testing is required during acute illness to determine the need for supplemental insulin.3037

Diagnosis of Hyperglycemia

The diagnosis of patients with hyperglycemia commonly falls into one of three categories: (1) DM or prediabetes, (2) diabetic ketoacidosis (DKA), and (3) hyperosmolar hyperglycemia state (HHS).2

Diabetes Mellitus or Prediabetes

Goals of therapy

Once DM is diagnosed, the clinician needs to establish a therapeutic goal with respect to glucose control. The ADA recommends that an A1C goal for many nonpregnant adults of <7% (53 mmol/mol) is appropriate. On the basis of provider judgment and patient preference, achieving lower A1C levels (eg, <6.5%) may be acceptable if it can be achieved safely without significant hypoglycemia or other adverse effects of treatment. Less stringent A1C goals (eg, <8% [64 mmol/mol]) may be appropriate for patients with a history of severe hypoglycemia, limited life expectancy, advanced microvascular or macrovascular complications, extensive comorbid conditions, or long-standing diabetes in whom the goal is difficult to achieve despite diabetes self-management education, appropriate glucose monitoring, and effective doses of multiple glucose-lowering agents, including insulin.

Diabetic Ketoacidosis

Insulin deficiency can result in impaired glucose use by peripheral tissues and the liver. Prolonged insulin deficiency results in protein breakdown and increased glucose production (gluconeogenesis) by the liver and an increased release of counterregulatory hormones such as glucagon, catecholamines (eg, epinephrine and norepinephrine), cortisol, and growth hormones. In the face of lipolysis, free fatty acids are converted by the liver to ketone bodies (β-hydroxybutyric acid and acetoacetic acid), which can result in metabolic acidosis. DKA, which occurs most commonly in patients with type 1 DM, is initiated by insulin deficiency (Minicase 1). The most common causes of DKA include the following38:

  • Infections, illness, and emotional stress

  • Nonadherence or inadequate insulin dosage

  • Undiagnosed type 1 DM

  • Unknown or no precipitating event

Clinically, patients with DKA typically present with dehydration, lethargy, acetone-smelling breath, abdominal pain, tachycardia, orthostatic hypotension, tachypnea, and, occasionally, mild hypothermia and lethargy or coma. Because of a patient’s tendency toward low body temperatures, fever strongly suggests infection as a precipitant of DKA. DKA is typically associated with a high glucose concentration. This concentration is typically >250 mg/dL or 13.9 mmol/L; however, in the setting of sodium-glucose cotransporter-2 (SGLT2) inhibitors use and other uncommon conditions, the blood glucose can be in the normal range (euglycemic DKA).39

Diabetic Ketoacidosis

Rena M. is a 40-year-old woman with a 2-year history of type 2 DM. She presents to the ED with a pH of 7.25, HCO3 of 9, and blood glucose of 180 mg/dL. Her husband brought her to the ED after finding her “out of it” when attempting to wake her. She was vomiting and unable to eat over the last 24 hours, and she experienced labored breathing, fever, chills, and unusual fatigue.

Approximately 1 year ago, her provider started her on Janumet (sitagliptin–metformin, 50 mg/1,000 mg) at breakfast and dinner. At her most recent clinic appointment 1 month ago, her laboratory results indicated that her HbA1c has dropped from 9.2 to 7.8 since starting sitagliptin–metformin. Her doctor decided to add dapagliflozin 10 mg to her regimen to obtain an HbA1c below 7%. Rena M. also takes atorvastatin 40 mg at bedtime for elevated cholesterol and lisinopril 10 mg daily and hydrochlorothiazide 25 mg daily for hypertension. She has tolerated all of her medications and adheres to the indicated daily schedule. Physical examination reveals a lethargic woman with vital signs including BP 116/68 mm Hg (which dropped to 95/50 when standing); HR 105 beats/min; respiratory rate (RR) 30 breaths/min (deep and regular); and an oral temperature 101.4°F (38.6°C). Her skin turgor is poor, her mucous membranes are dry, and she is disoriented and confused. Her laboratory results are as follows:

  • Sodium, 142 mEq/L (136 to 142 mEq/L)

  • Potassium, 5 mEq/L (3.8 to 5 mEq/L)

  • Chloride, 99 mEq/L (95 to 103 mEq/L)

  • BUN, 28 mg/dL (8 to 23 mg/dL)

  • SCr, 1.8 mg/dL (0.6 to 1.2 mg/dL)

  • Phosphorus, 2.7 mg/dL (2.3 to 4.7 mg/dL)

  • Amylase, 200 International Units/L (30 to 220 International Units/L)

  • pH, 7.25 (7.38 to 7.44)

  • Bicarbonate, 9 mEq/L (21 to 28 mEq/L)

  • Hct, 52% (36% to 45%)

  • WBC count, 16 × 103 cells/mm3 (4.8 to 10.8 × 103 cells/mm3)

  • Calcium, 9 mg/dL (9.2 to 11 mg/dL)

  • Glucose, 180 mg/dL (70 to 110 mg/dL)

  • Ketones, 3+ at 1:8 serum dilution (normal = 0)

  • Osmolality, 304 mOsm/kg (280 to 295 mOsm/kg)

  • Triglycerides, 174 mg/dL (10 to 150 mg/dL)

  • Lipase, 1.4 units/mL (<1.5 units/mL)

  • Magnesium, 2 mEq/L (1.3 to 2.1 mEq/L)

A urine screen with Multistix indicates a large (160 mg/dL) amount of ketones (the highest designation on the strip).

QUESTION: Based on clinical and laboratory findings, what is the most likely diagnosis for this patient? What precipitated this metabolic disorder? Can an interpretation of any results be influenced by her acidosis or hyperglycemia? Are there potential medication interferences with any laboratory tests?

DISCUSSION: The patient has type 2 DM and presents with DKA, which is less commonly observed in patients with type 2 DM compared with type 1 DM. Since 2014, the FDA has received many reports of DKA in patients treated with SGLT2 inhibitors. The FDA reports that DKA case presentations associated with SGLT2 inhibitors are atypical in that glucose levels can be normal or mildly elevated, whereas patients with a typical DKA presentation (type 1 DM or type 2 DM) typically have glucose levels >300 mg/dL. This patient has a fever, which suggest a potential infection. She should be examined for infection by obtaining a urinalysis and blood culture. The cause of preserved euglycemia could be greater urinary loss of glucose triggered by counterregulatory hormones, hepatic glucose production observed during a fasting state, or the SGLT2 inhibitor. A key physiologic determinant is the quantity of food she ingested before development of DKA. That is, when patients are well fed, their liver contains large amounts of glycogen, which primes the liver to produce glucose and suppress ketogenesis. However, when patients have been vomiting and unable to eat, the liver is depleted of glycogen and primed to produce ketones. Thus, patients such as Rena M. with euglycemic ketoacidosis are usually in the fasting state before they become ill.

Clinically, Rena M. presents with typical signs of ketoacidosis, which include difficulty breathing, nausea, vomiting, abdominal pain, confusion, and unusual fatigue and sleepiness. Her decreased skin turgor, dry mucous membranes, tachycardia (HR 105 beats/min), and orthostatic hypotension are consistent with dehydration, a common condition in patients with DKA. Her breathing is rapid and deep. Although she is not comatose, she is lethargic, confused, and disoriented. Chemically, she probably has a total body deficit of sodium and potassium despite serum concentration results within normal limits.

The decreased intravascular volume associated with DKA causes hemoconcentration on electrolytes. Therefore, these values do not reflect total body stores, and the clinician can expect them to decline rapidly if unsupplemented fluids are infused. Although her phosphorus concentration is in the normal range (lower end), it likely will decrease after rehydration and insulin. Serial electrolyte testing should be done every 3 to 4 hours during the first 24 hours.

Serial glucose, ketones, and acid-base measurements, typical of DKA, should show gradual improvement with proper therapy. Potassium balance is altered in patients with DKA because of combined urinary and GI losses. Although total potassium is depleted, the serum potassium concentration may be high, normal, or low, depending on the degree of acidosis. Her metabolic acidosis has resulted in an extracellular shifting of potassium, causing an elevated serum potassium concentration. Potassium supplementation may be withheld for the first hour or until serum levels begin to drop. Potassium replacement should begin when potassium levels reach normal. Low serum potassium in the face of pronounced acidosis suggests severe potassium depletion that requires early, aggressive therapy to prevent life-threatening hypokalemia during treatment.

Decreased intravascular volume has led to a hemoconcentrated Hct and BUN, which is also elevated by decreased renal perfusion (prerenal azotemia), although intrinsic renal causes should be considered if SCr is also elevated. Fortunately, as is probably the case with this patient, high SCr may be an artifact caused by the influence of ketone bodies on the assay. If so, SCr concentrations should decline with ketone concentrations.

She may be exhibiting leukocytosis unrelated to infection, but no lab data were provided in the case to actually rule out infection. Her estimated plasma osmolarity based on the osmolarity estimation formula would be (2 × 142) + (180/18) + (28/2.8) = 304 mOsm/L, which is approximately equal to the actual measured laboratory result.

The serum ketone results still would have to be interpreted as real and significant, given all of the other signs and symptoms. A urine screen also indicated the presence of ketones.

DKA is also characterized by low venous bicarbonate (0 to 15 mEq/L), a decreased arterial pH (<7.0 to 7.2), and the presence of an anion gap (>12) (see Chapter 13 for more information on anion gap). Glucose spilling in the urine can lead to osmotic diuresis, resulting in hypotonic fluid losses, dehydration, and electrolyte loss. Sodium and potassium concentrations may be low, normal, or high on initial presentation. Sodium concentrations are reflective of the amount of total body water and sodium lost and replaced. In the presence of hyperglycemia, sodium concentrations may be decreased because of the movement of water from the intracellular space to the extracellular space. The potassium level reflects a balance between the amount of potassium lost in the urine and insulin deficiency, which causes higher concentrations of serum potassium as potassium shifts from intracellular spaces to extracellular fluid. Hypertonicity and acidosis can cause potassium to move from the intracellular space to the extracellular space, resulting in elevated potassium levels. Patients with low or normal potassium levels on presentation should be placed on intravenous (IV) potassium replacement and monitored closely because DKA and its subsequent treatment can result in a low serum potassium and total body potassium levels that may place the patient at risk for cardiac dysrhythmia.38,39

The phosphate level is usually normal or slightly elevated but may decrease during treatment and should be monitored.38 Creatinine and blood urea nitrogen (BUN) are usually elevated due to dehydration with an increased BUN to Scr ratio. These levels usually return to normal after rehydration unless there was preexisting renal insufficiency. Hemoglobin, Hct, and total protein levels are mildly elevated due to decreased plasma volume and dehydration. Amylase levels may be increased due to increased secretion by the salivary glands. Liver function tests are usually elevated but return to normal in 3 to 4 weeks.

Serum osmolality is typically elevated at 300 to 320 mOsm/kg (normally, 280 to 295 mOsm/kg). Serum osmolarity (milliosmoles/liter), which is practically equivalent to osmolality (milliosmoles/kilogram), can be estimated using the following formula:
serum osmolaritymOsm/L=2sodium+glucose/18+BUN/2.8

where glucose and BUN units are expressed as milligrams/deciliter.

Blood and urine ketones

Ketones are present in the blood and urine of patients with DKA, as the name of this disorder implies. Formation of ketone bodies results from fat metabolism. Three principal ketone bodies include acetoacetate, acetone, and β-hydroxybutyrate, which is the predominant ketone in the blood of patients with DKA.38 DKA can be prevented if patients are educated about detection of hyperglycemia and ketonuria. It is recommended that all patients with DM test their urine for ketones during acute illness or stress when blood glucose levels are consistently >250 mg/dL (14 mmol/L), during pregnancy, or when any symptoms of ketoacidosis—such as nausea, vomiting, or abdominal pain—are present.40

All of the commercially available urine testing methods are based on the reaction of acetoacetic acid with sodium nitroprusside (nitroferricyanide) in a strongly basic medium. The colors range from beige or buff-pink for a “negative” reading to pink and pink-purple for a “positive” reading (Acetest, Ketostix, Laboratorystix, and Multistix). These nitroprusside-based (nitroferricyanide) assays do not detect β-hydroxybutyric acid and are 15 to 20 times more sensitive to acetoacetate than to acetone. In a few situations (eg, severe hypovolemia, hypotension, low partial pressure of oxygen [pO2], and alcoholism) where β-hydroxybutyrate predominates, assessment of ketones may be falsely low. As DKA resolves, β-hydroxybutyric acid is converted to acetoacetate, the assay-reactive ketone body. Therefore, a stronger reaction may be encountered in laboratory results. However, this reaction does not necessarily mean a worsening of the ketoacidotic state.41

Clinicians must keep in mind that ketonuria may also result from starvation, high-fat diets, fever, and anesthesia, but these conditions are not associated with hyperglycemia. Levodopa, mesna, acetylcysteine (irrigation), methyldopa, phenazopyridine, pyrazinamide, valproic acid, captopril, and high-dose aspirin may cause false-positive results with urine ketone tests.4244 The influence of these drugs on serum ketone tests has not been studied extensively. If the ketone concentration is increased, a typical series of dipstick results includes the following results:

  1. Negative

  2. Trace (5 mg/dL)

  3. Small (15 mg/dL)

  4. Moderate (40 mg/dL)

  5. Large (80 mg/dL)

  6. Very large (160 mg/dL)

False-negative readings have been reported when test strips have been exposed to air for an extended period of time or when urine specimens have been highly acidic, such as after large intakes of ascorbic acid.40 Urine ketone tests should not be used for diagnosing or monitoring the treatment of DKA. Acetoacetic and β-hydroxybutyric acids concentrations in urine greatly exceed blood concentrations. Therefore, the presence of ketone bodies in urine cannot be used to diagnose DKA. Conversely, during recovery from ketoacidosis, ketone bodies may be detected in urine long after blood concentrations have fallen.43,45 In addition, urine testing only provides an estimate of blood ketone levels 2 to 4 hours before testing and depends on the person being able to pass urine.40,41

Blood β-ketone testing can provide a patient with an early warning of impending DKA.45,46 While blood β-ketone testing is routinely conducted in a medical setting, patients may also use an at-home kit to test for ketones in blood. While instructions may vary, kits will include some kind of device for the patient to prick their finger (similar to blood glucose testing). The brands of meters currently marketed are CareTouch, Keto-Mojo, Nova Max Plus, and Precision Xtra. All of these meters can also be used to measure blood glucose levels. Patients should purchase the glucose strips made for their meter to use this feature. In addition, each meter can be tested against control. A β-hydroxybutyric acid level <0.6 mmol/L is considered normal. Patients with levels between 0.6 and 1 mmol/L should take additional insulin and increase their fluid intake to flush out the ketones. Patients should contact their physician if levels are between 1 and 3 mmol/L. Patients should be advised to report to the emergency department (ED) immediately if their levels are >3 mmol/L.46

Hyperosmolar Hyperglycemia State

Hyperosmolar hyperglycemia state (HHS) is a condition that occurs most frequently in elderly patients with type 2 DM, and it is usually precipitated by stress or illness when such patients do not drink enough to keep up with osmotic diuresis. Patients usually present with severe hyperglycemia (glucose concentrations >600 mg/dL or >33.3 mmol/L); decreased mentation (eg, lethargy, confusion, dehydration); neurologic manifestations (eg, seizures and hemisensory deficits); and an absence of ketosis. Insulin deficiency is not as severe in HHS as in DKA. Therefore, lipolysis, which is necessary for the formation of ketone bodies, does not occur (Minicase 2). The absence of ketosis results in significantly milder GI symptoms than patients with DKA. Therefore, patients often fail to seek medical attention. Patients with HHS tend to have much higher blood glucose concentrations than in DKA and are usually more dehydrated on presentation than patients with DKA due to impairment in the thirst mechanism, which results in prolonged diuresis and dehydration.4648

In some cases, patients are taking medications that cause glucose intolerance (eg, diuretics, steroids, and phenytoin). Stroke and infection are disease-related predisposing factors. Initially, electrolytes are within normal ranges, but BUN routinely is elevated. Serum osmolalities characteristically are higher than those in DKA—in the range of 320 to 400 mOsm/kg. Serum electrolytes (eg, magnesium, phosphorus, and calcium) are typically abnormal and should be monitored until they return to normal range.47,48

Hypoglycemia

Hypoglycemia is defined as a blood glucose level of 70 mg/dL (3.9 mmol/L) or lower.

  • Level 1 (mild) hypoglycemia: blood glucose is <70 mg/dL but ≥54 mg/dL.

  • Level 2 (moderate) hypoglycemia: Blood glucose is <54 mg/dL.

  • Level 3 (severe) hypoglycemia: A person is unable to function because of mental or physical changes. They need help from another person. In this case, blood glucose is often <40 mg/dL.

The classification of hypoglycemia is based on an individual’s ability to self-treat. Mild hypoglycemia is characterized by symptoms such as sweating, trembling, shaking, rapid heartbeat, heavy breathing, and difficulty concentrating. The symptoms associated with mild hypoglycemia vary in severity and do not imply that the symptoms experienced by the individual are minor or easily tolerated. Although patients may experience profuse sweating, dizziness, and lack of coordination, they still may be able to self-treat. These symptoms resolve after consuming readily absorbable carbohydrates (eg, fruit juice, milk, or hard candy).16,49

Other Laboratory Tests Used in the Management of Diabetes Mellitus

The 2021 ADA standards recommend urinalysis for detection of proteinuria should be obtained in patients with DM on a yearly basis.50 This should begin at the time of diagnosis in patients with type 2 DM and 5 years after diagnosis in patients with type 1 DM.50 A quantitative test for urine protein should follow a positive result on urinalysis. If urinalysis is negative for proteinuria, testing for increased albumin excretion (previously termed microalbuminuria) should be obtained. Increased albumin excretion indicates glomerular damage and is predictive of clinical nephropathy.50

Three methods are available to screen for increased albumin excretion. One method is measurement of the urine albumin to creatinine ratio in a spot urine sample. This method is convenient in the clinical setting because it requires only one urine sample. A morning sample is preferred to take into account the diurnal variation of albumin excretion. A second method is a 24-hour urine collection for determination of albumin excretion. This method may be tedious and accuracy relies on proper collection techniques. An advantage of this method is that renal function can simultaneously be quantified. A third alternative method to the 24-hour collection is a timed urine collection for albumin. Moderately increased albuminuria is defined as a urinary albumin excretion of 30 to 299 mcg/mL on a spot urine sample, 30 to 299 mg/24 hr on a 24-hour urine collection, or 20 to 199 mcg/min on a timed urine collection. Transient rises in albumin excretion can be associated with exercise, hyperglycemia, hypertension, urinary tract infection, heart failure, and fever. Therefore, if any of these conditions are present, they may result in false-positive results on screening tests. Variability exists in the excretion of albumin; thus, moderately increased albuminuria must be confirmed in two repeated tests in a 3- to 6-month period. Two of three positive screening tests for moderately increased albuminuria confirm the diagnosis.50

Hyperosmolar Hyperglycemia State Secondary to Uncontrolled Type 2 Diabetes Mellitus

Jimmy C. is a 63-year-old African American man with a 19-year history of type 2 DM, hypertension, and dyslipidemia. He lives alone. His medication list includes metformin 1,000 mg BID, simvastatin 20 mg daily at bedtime, lisinopril 20 mg daily, hydrochlorothiazide 25 mg daily, and ASA 325 mg daily. He monitors his blood glucose once a day, and his results have ranged from 215 to 400 mg/dL. His fasting blood glucose has averaged 200 mg/dL over the last week. He reports frequent urination throughout the day and night, which has increased over the last 6 days. He denies any nausea or vomiting but states he has not had much of an appetite lately. His daughter accompanies him to the doctor’s office because she thinks he has not been his usual self lately.

The physical examination reveals a disoriented and confused man with vital signs including BP 120/60 mm Hg (which decreased to 100/60 when standing); HR 100 beats/min; RR 20 breaths/min (deep and regular); and oral temperature 101.4°F (38.6°C). His skin turgor is poor, and his mucous membranes are dry. His laboratory results are as follows:

  • Sodium, 139 mEq/L (136 to 142 mEq/L)

  • Potassium, 4.6 mEq/L (3.8 to 5 mEq/L)

  • Chloride, 102 mEq/L (95 to 103 mEq/L)

  • BUN, 50 mg/dL (8 to 23 mg/dL)

  • SCr, 1.2 mg/dL (0.6 to 1.2 mg/dL)

  • Phosphorus, 2.7 mg/dL (2.3 to 4.7 mg/dL)

  • pH, 7.38 (7.36 to 7.44)

  • Bicarbonate, 26 mEq/L (21 to 28 mEq/L)

  • Hct, 39% (42% to 50%)

  • WBC count, 9.4 × 103 cells/mm3 (4.8 to 10.8 × 103 cells/mm3)

  • Calcium, 9 mg/dL (9.2 to 11 mg/dL)

  • Glucose, 715 mg/dL (70 to 110 mg/dL)

  • Ketones, 0 (normal = 0)

  • Osmolality, 335 mOsm/kg (280 to 295 mOsm/kg)

  • Triglycerides, 174 mg/dL (10 to 150 mg/dL)

  • Lipase, 1.4 units/mL (<1.5 units/mL)

  • Magnesium, 2 mEq/L (1.3 to 2.1 mEq/L)

  • Hemoglobin A1c, 9.5 (4% to 5.6%)

QUESTION: Based on the subjective and objective data provided, what is the most likely diagnosis for this patient? What signs and symptoms support the diagnosis? What could have precipitated this disorder?

DISCUSSION: Jimmy C. is older than 60 years. HHS occurs most frequently in patients older than 60 years. He reports symptoms for more than 5 days. He has decreased skin turgor, dry mucous membranes, tachycardia (HR 100 beats/min), and orthostatic hypotension (a fall of systolic BP 20 mm Hg after 1 minute of standing), which are consistent with dehydration. He is lethargic, confused, and disoriented. Patients with HHS are generally more dehydrated than patients with DKA; therefore, mentation changes are more commonly seen in patients with HHS than in DKA. Elderly persons often have an impaired thirst mechanism that increases the risk of HHS. Jimmy C.’s plasma glucose level is >600 mg/dL; bicarbonate concentration is normal; and pH is normal. Negative ketone bodies <2+ in 1:1 dilution confirms the diagnosis of HHS (and not DKA, in which ketones are present in the blood and urine of patients). Insulin deficiency is less profound in HHS; therefore, lipolysis resulting in the production of ketone bodies does not occur. His plasma osmolarity can be estimated using a formula:
pOsm=2×serum sodium+glucose/18+BUN/2.8

The estimated osmolality is (2 × 139) + (715/18) + 50/2.8 = 335 mOsm/kg, which is the same as the actual laboratory value. Massive fluid loss due to prolonged osmotic diuresis secondary to hyperglycemia may have precipitated the onset of HHS.

The patient should be given IV fluids for hydration because of the mental status changes. An IV insulin drip should also be administered. Although his sodium and potassium are within normal limits, the presence of orthostatic hypotension is consistent with decreased intravascular volume, causing hemoconcentration of sodium and potassium. These levels may decline when the patient is rehydrated with fluids. Potassium replacement is required. Phosphorus is also within normal limits but may decrease after rehydration and insulin. Decreased intravascular volume has led to hemoconcentration of Hct and BUN, which is also elevated because of decreased renal perfusion (prerenal azotemia), although intrinsic renal causes should be considered if SCr is also elevated.

Given the patient’s symptoms and diagnosis of HHS, metformin in combination with a once-daily injection of long-acting insulin administered at breakfast or bedtime is a reasonable option because he did not obtain glycemic control on oral agent(s). Metformin can be continued if glomerular filtration rate >30 mL/min/1.73m2 and long-acting insulin can be administered at bedtime.

Based on results of landmark studies, the ADA recommends angiotension-converting enzyme (ACE) inhibitors or angiotension receptor blockers (ARBs) for the treatment of both moderately increased albuminuria (previously termed microalbumuria and defined as a urinary albumin excretion 30 to 299 mg/day) and severely increased albuminuria (previously termed macroalbuminuria and defined as a urinary albumin excretion >300 mg/day). If one class is not tolerated, the other should be substituted.

The leading cause of death in patients with DM is cardiovascular disease. Control of hypertension and dyslipidemia is necessary to decrease the risk of macrovascular complications. Under the new American College of Cardiology and American Heart Association lipid guidelines, patients should be placed on statin medications based on risk stratification and treated with varying intensity statin dosing regimens.51,52

Patients with DM and hypertension should be treated with pharmacologic therapy regimen that includes either an ACE inhibitor or an ARB.50 Although ARBs have been shown to delay the progression of nephropathy in patients with type 2 DM, hypertension, moderately increased albuminuria, and renal insufficiency, ACE inhibitors are the initial agents of choice in patients with type 1 DM with hypertension and any degree of albuminuria. Thiazide diuretics, β-blockers, or calcium channel blockers should be used as an add-on agent to further decrease BP (blood pressure). Avoidance of nephrotoxic drugs and use of SGLT2i therapy is also recommended.50

THYROID

Anatomy and Physiology

The thyroid gland is a butterfly-shaped organ composed of two connecting lobes that span the width of the trachea. The thyroid produces the hormones thyroxine (T4) and triiodothyronine (T3). Approximately 80 and 30 mcg of T4 and T3, respectively, are produced daily in normal adults. Although T4 is produced solely by the thyroid gland, only about 20% to 25% of T3 is directly secreted by this gland. Approximately 80% of T3 is formed by hepatic and renal deiodination of T4.53

T4 has a longer half-life than T3, approximately 7 days versus 1 day, respectively. At the cellular level, however, T3 is three to four times more active physiologically than T4.49 When the conversion of T4 to T3 is impaired, a stereoisomer of T3, known as reverse T3, is produced; reverse T3 has no known biological effect.

Thyroid hormones have many biological effects, both at the molecular level and on specific organ systems. These hormones stimulate the basal metabolic rate and can affect protein, carbohydrate, and lipid metabolism. They are also essential for normal growth and development. Thyroid hormones act to do the following tasks:

  • Stimulate neural and skeletal development during fetal life

  • Stimulate oxygen consumption at rest

  • Stimulate bone turnover by increasing bone formation and resorption

  • Promote conversion of carotene to vitamin A

  • Promote chronotropic and inotropic effects on the heart

  • Increase number of catecholamine receptors in heart muscle cells

  • Increase basal body temperature

  • Increase production of RBCs

  • Increase metabolism and clearance of steroid hormones

  • Alter metabolism of carbohydrates, fats, and protein

  • Control normal hypoxic and hypercapnic respiratory drives

The synthesis of thyroid hormones depends on iodine and the amino acid tyrosine. The thyroid gland, using an energy-requiring process, transports dietary iodide (I) from the circulation into the thyroid follicular cell. Iodide is oxidized to iodine (I2), and then combined with tyrosyl residues within the thyroglobulin molecule to form thyroid hormones (iodothyronine). Thus, thyroid hormones are formed and stored within the thyroglobulin protein for release into the circulation.54,55

Both T4 and T3 circulate in human serum bound to three proteins: thyroxine-binding globulin (TBG); transthyretin, previously known as thyroid-binding prealbumin; and albumin. Of the three proteins, 80% of T4 and T3 is bound to TBG. Only 0.02% of T4 and 0.2% of T3 circulate unbound, free to diffuse into tissues. The “free” fraction is the physiologically active component. Total and free hormones exist in an equilibrium state in which the protein-bound fraction serves as a reservoir for making the free fraction available to tissues.55

Thyroid hormone secretion is regulated by a feedback mechanism involving the hypothalamus, anterior pituitary, and thyroid gland itself (Figure 9-2). The release of T4 and T3 from the thyroid gland is regulated by thyrotropin, also called thyroid stimulating hormone (TSH), which is secreted by the anterior pituitary. The intrathyroidal iodine concentration also influences thyroid gland activity, and TSH secretion primarily is regulated by a dual negative feedback mechanism:

Thyrotropin-releasing hormone (TRH), or protirelin, is released by the hypothalamus, which stimulates the synthesis and release of TSH from the pituitary gland. Basal TSH concentrations in persons with normal thyroid function are 0.3 to 5 milliunits/L. The inverse relationship between TSH and free T4 is logarithmic. A 50% decrease in free T4 concentrations leads to a 50-fold increase in TSH concentrations and vice versa.49 Unbound T4 and T3 (mainly the concentration of intracellular T3 in the pituitary) directly inhibit pituitary TSH secretion. Consequently, increased concentrations of free thyroid hormones cause decreased TSH secretion, and decreased concentrations of T4 and T3 cause increased TSH secretion.55

FIGURE 9-2.
FIGURE 9-2.

The hypothalamic-pituitary-thyroid axis.

Prolonged exposure to cold and acute psychosis may activate the hypothalamic-pituitary-thyroid axis, whereas severe stress may inhibit it. Although TRH stimulates pituitary TSH release, somatostatin, corticosteroids, and dopamine inhibit it. Small amounts of iodide are needed for T4 and T3 production, but large amounts inhibit their production and release. Evidence from the most sensitive assays suggests that no physiologically relevant change in serum TSH concentrations occurs in relation to age.54

Thyroid Disorders

Patients with a normally functioning thyroid gland are said to be in a euthyroid state. When this state is disrupted, thyroid disease may result, which occurs four times more often in women than in men. Thyroid disease may occur at any age but peaks between the third and sixth decades of life. A family history of this disease often is present, especially for autoimmune thyroid diseases. Diseases of the thyroid usually involve an alteration in the quantity or quality of thyroid hormone secretion and may manifest as hypothyroidism or hyperthyroidism. In addition to the signs and symptoms discussed next, thyroid disease may produce an enlargement of the thyroid gland known as goiter.51

Hypothyroidism

Hypothyroidism results from a deficiency of thyroid hormone production, causing the body metabolism to slow down. This condition affects about 2% of women and 0.2% of men, and the incidence increases with age. Symptoms include lethargy; constipation; dry, coarse skin and hair; paresthesias and slowed deep tendon reflexes; facial puffiness; cold intolerance; decreased sweating; impaired memory, confusion, and dementia; slow speech and motor activity; and anemia and growth retardation in children. Interestingly, these typical signs and symptoms have been observed in as little as 25% of elderly hypothyroid patients.57

Hypothyroidism is usually caused by one of three mechanisms. Primary hypothyroidism is a failure of the thyroid to produce thyroid hormone; secondary hypothyroidism is failure of the anterior pituitary to secrete TSH; and tertiary hypothyroidism is failure of the hypothalamus to produce TRH. The classification is commonly referred to as primary (problem originating within the thyroid gland) or secondary (disease originating from the pituitary or hypothalamus).

Most patients with symptomatic primary hypothyroidism have TSH concentrations >20 milliunits/L. Patients with mild signs or symptoms (usually not the reason for the visit to the doctor) have TSH values of 10 to 20 milliunits/L. Patients with secondary and tertiary hypothyroidism may have a low or normal TSH. In such patients, other pituitary hormones (eg, adrenocorticotropic hormone [ACTH], antidiuretic hormone [ADH], prolactin, growth hormone, and luteinizing hormone/follicle-stimulating hormone [LH/FSH]) should be measured to rule out other pituitary hormone deficiencies. Table 9-3 outlines the numerous etiologies of hypothyroidism.57

TABLE 9-3.
Classification of Hypothyroidism by Etiology

Primary

  • Iodine deficiency

  • Excessive iodide intake (eg, kelp and contrast dyes)

  • Thyroid ablation: surgical removal of the thyroid, post 131I (radioactive iodine 131I) treatment of thyrotoxicosis, radiation of neoplasm

  • Hashimoto (autoimmune) thyroiditis

  • Subacute thyroiditis

  • Genetic abnormalities of thyroid hormone synthesis

  • Medications: propylthiouracil, methimazole, thiocyanate, lithium, amiodarone, alfa-interferon, some antineoplastic agents (ipilimumab, bexarotene, sunitinib, nivolumab)

  • Food: excessive intake of goitrogenic foods (eg, cabbage and turnips)

Secondary

  • Hypopituitarism: adenoma, ablative therapy, pituitary destruction, sarcoidosis hypothalamic dysfunction

Other

  • Abnormalities of T4 receptor

T4 = thyroxine.

Source: Adapted from Cryer PE. Hypoglycemia: pathophysiology, diagnosis and treatment. New York: Oxford University Press; 1997; Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation. 2019;139(25):e1082–e1143.

Thyrotoxicosis

Thyrotoxicosis results when excessive amounts of thyroid hormones are circulating and is usually due to hyperactivity of the thyroid gland (hyperthyroidism). Signs and symptoms include nervousness; fatigue; weight loss; heat intolerance; increased sweating; tachycardia or atrial fibrillation; muscle atrophy; warm, moist skin; and, in some patients, exophthalmos.58 These signs and symptoms occur much less frequently in elderly persons, except for atrial fibrillation, which occurs three times more often.59 Table 9-4 summarizes the specific causes of hyperthyroidism.

TABLE 9-4.
Classification of Hyperthyroidism by Etiology

Overproduction of thyroid hormone

 Graves diseasea

 TSH-secreting pituitary adenomas

 Hydatidiform moles/choriocarcinomasb

 Multinodular goiter

 “Leaking” thyroid hormone due to thyroid destruction

 Lymphocytic thyroiditis

 Granulomatous thyroiditis

 Subacute thyroiditis

 Radiation

Medications: thyroid-replacement drugs (excessive), amiodarone, iodinated radiocontrast agents, iodine excess, kelpc

Ovarian teratomas with thyroid elements

Metastatic thyroid carcinoma

aMost frequent cause. The mechanism is production of thyroid-stimulating antibodies; usually associated with diffuse goiter and ophthalmopathy.

bTumor production of chorionic gonadotropin, which stimulates the thyroid.

cPatients at risk for hyperthyroidism from these agents usually have some degree of thyroid autonomy.

Source: Adapted from Cryer PE. Hypoglycemia: Pathophysiology, Diagnosis and Treatment. New York: Oxford University Press; 1997; American Diabetes Association. Cardiovascular disease and risk management: standards of medical care in diabetes: 2020. Diabetes Care. 2020;43(suppl 1):S111–S134.

Nonthyroid Laboratory Tests in Patients with Thyroid Disease

Thyroid disease may present with a wide range of signs, symptoms, and abnormal laboratory results. Table 9-5 lists nonthyroid laboratory tests that may indicate a thyroid disorder. The influence on these tests reflects the widespread effects of thyroid hormones on peripheral tissues. Findings from these tests cannot be used alone to diagnose a thyroid disorder. However, they may support a diagnosis of thyroid dysfunction when used with specific thyroid function tests and the patient’s presenting signs and symptoms.60

TABLE 9-5.

Nonthyroid Laboratory Tests Consistent with Thyroid Disorders

HYPOTHYROIDISM

HYPERTHYROIDISM

Decreased

  • Hgb/Hcta

  • Serum glucose

  • Serum sodium

  • Urinary excretion of 17-hydroxysteroids

  • Urinary excretion of 17-ketosteroids

Granulocytes

Serum cholesterol

Serum triglycerides

Increased

  • AST/SGOT

  • Capillary fragility

  • Cerebrospinal fluid protein

  • LDH

  • pCO2

  • Serum carotene

  • Serum cholesterol

  • CPK

  • Serum prolactin

  • Serum triglycerides

Alkaline phosphatase

Lymphocytes

Serum ferritin

Urinary calcium excretion

AST = aspartate aminotransferase; CPK = serum creatine phosphokinase; Hgb = hemoglobin; LDH = lactate dehydrogenase; pCO2 = partial pressure of carbon dioxide; SGOT = serum glutamic-oxaloacetic transaminase.

aAssociated with normocytic and macrocytic anemias.

Source: Adapted from Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation. 2019;139(25):e1082–e1143; American Diabetes Association. Cardiovascular disease and risk management: standards of medical care in diabetes: 2020. Diabetes Care. 2020;43(suppl 1):S111–S134.

Thyroid Function Tests

Tests more specific for thyroid status or function can be categorized as those that (1) measure the concentration of products secreted by the thyroid gland, (2) evaluate the integrity of the hypothalamic-pituitary-thyroid axis, (3) assess intrinsic thyroid gland function, and (4) detect antibodies to thyroid tissue.60 Tests that directly or indirectly measure the concentrations of T4 and T3 include the following:

  • Free T4

  • Total serum T4

  • Serum T3 resin uptake

  • Free T4 index

  • Total serum T3

Test results that are higher than normal are consistent with hyperthyroidism, whereas test results that are lower than normal indicate hypothyroidism.

The integrity of the hypothalamic-pituitary-thyroid axis is assessed by measuring TSH and TRH. A radioactive iodine uptake test assesses intrinsic thyroid gland function, and an antithyroid antibodies test detects antibodies to thyroid tissue.

Free T4

Normal range: 0.9 to 2.3 ng/dL (11.6 to 29.6 pmol/L)

This test measures the unbound T4 in the serum and is the most accurate reflection of thyrometabolic status (Tables 9-6 and 9-7). Several methods are available to determine free T4 concentrations. Some methods perform well only in otherwise healthy hypothyroid and hyperthyroid patients and in euthyroid patients with mild abnormalities of TBG. However, in patients with severe alterations of T4 binding to carrier proteins (eg, severe nonthyroidal illness), only the direct equilibrium dialysis method maintains accuracy (Table 9-7).61

TABLE 9-6.
Free T4 and TSH in Thyroidal and Nonthyroidal Disorders

DIAGNOSIS

FREE T4 INDEX OR DIRECT EQUILIBRIUM DIALYSIS FREE T4

TSH (milliunits/L)

Hypothyroidism

 Primary Normal

 On dopamine or glucocorticoids

 Secondary or tertiary: functional hypopituitarism

 Recent thyroid supplement withdrawal

<0.1

 Recently treated hyperthyroidism

<0.1

Hyperthyroidism

<0.1a

 With severe nonthyroidal illness

↓/WNL/↑b

<0.1a

Euthyroid states

WNL

WNL

 Low total T4 of nonthyroidal illness

↓/WNL/↑c

WNL/↑

 After T3 therapy

WNL/↓

 After T4 therapy

WNL

WNL

 High total T4 of nonthyroidal illness

WNL/↑

 High total T4 from amiodarone or iodinated contrast media

 Decreased T4-binding proteins

↑/WNLd

WNL

↑ = increased; ↓ = decreased; T3 = triiodothyronine; T4 = thyroxine; WNL = within normal limits.

aUsually absent TSH response to TRH; also may be normal with hyperthyroidism from TSH-secreting tumors.

bNormal or low using free T4 index estimation; increased using the direct equilibrium dialysis free T4 assay.

cDecreased using free T4 index estimation; normal to high using the direct equilibrium dialysis free T4 assay.

dDecreased using free T4 index estimation; normal using the direct equilibrium dialysis free T4 assay.

Source: Adapted from Jenklass J, Talbert RL. Thyroid disorders. In: DiPiro JT, Talbert RL, Yee GC, eds. Pharmacotherapy: A Pathophysiologic Approach. 9th ed. New York, NY: McGraw-Hill; 2014:1191–1216; Mokshagundam S, Barzel US. Thyroid disease in the elderly. J Am Geriatr Soc. 1993;41(12):1361–1369.
TABLE 9-7.
Performance and Availability of Free T4 Methods

ASSAY

% OF EUTHYROID PATIENTS WITH SEVERE TBG DEPRESSION OR SEVERE NONTHYROIDAL ILLNESS IN WHICH ASSAY UNDERESTIMATES FREE T4

COMMENTS

Free T4 indexa or single-step

50%–80%

Available in most clinical laboratory tests

Immunoextraction or RIAb

10%–30%

Available in some clinical laboratory tests

Direct equilibrium dialysisc

0%–5%

Available in reference laboratory tests and large medical center laboratory tests; gold standard

Ultrafiltrationd

0%–5%

Available only in research laboratory tests

aCorrects total T4 values using an assessment of T4-binding proteins.

bUses a T4 analog or two-step-back titration with solid-phase T4 antibody but does not use membranes to separate free from bound hormone.

cUses minimally diluted serum that separates free T4 from bound T4 using a semipermeable membrane.

dMay be underestimated in 25% of patients on dopamine. A decreased direct equilibrium dialysis free T4 with an elevated TSH is diagnostic of primary hypothyroidism, even in patients with severely depressed TBG. Conversely, an increased direct equilibrium dialysis free T4 with a TSH of <0.10 milliunit/L is consistent with nonpituitary hyperthyroidism.53 Decreased direct equilibrium dialysis free T4 with normal or decreased TSH concentrations may be seen in patients on T3 therapy (Table 9-8). Although free T4 assays are becoming widely available (Table 9-12), most clinicians initially rely on the traditional total serum T4 measurement by RIA.

Source: Adapted from Walsh JP. Managing thyroid disease in general practice. Med J Aust. 2016;205(4):179–184; Kaptein EM. Clinical application of free thyroxine determinations. Clin Lab Med. 1993;13:653–672.

Total Serum T4

Normal range: 5.5 to 12.5 mcg/dL (71 to 161 nmol/L)

In most patients, the total serum T4 level is a sensitive test for the functional status of the thyroid gland. It is high in 90% of patients with hyperthyroidism and low in 85% of patients with hypothyroidism. This test measures both bound and free T4 and is, therefore, influenced by any alteration in the concentration or binding affinity of thyroid-binding protein.56

Conditions that increase or decrease thyroid-binding protein result in an increased or decreased total serum T4, respectively, but do not affect the amount of metabolically active free T4 in the circulation. Therefore, thyrometabolic status may not always be truly represented by the results. Table 9-8 lists factors that alter thyroid-binding protein.61

TABLE 9-8.
Factors Altering Thyroid-Binding Protein

FACTORS THAT INCREASE THYROID-BINDING PROTEIN

FACTORS THAT DECREASE THYROID-BINDING PROTEIN

Acute infectious hepatitis

Acute intermittent porphyria

Chronic active hepatitis

Clofibrate

Estrogen-containing oral contraceptives

Estrogen-producing tumors

Estrogen therapy

5-fluorouracil

Genetic excess of total binding protein

Heroin

Methadone maintenance

Perphenazine

Pregnancy

Tamoxifen

Acromegaly

Androgen therapy

l-asparaginase

Cirrhosis

Danazol

Salsalate

Genetic deficiency of TBG

Glucocorticoid therapy (high dose)

Furosemide (high dose)

Hypoproteinemia

Malnutrition

Nephrotic syndrome

Phenytoin

Salicylates

Testosterone-producing tumors

Source: Adapted from Walsh JP. Managing thyroid disease in general practice. Med J Aust. 2016;205(4):179–184; Mokshagundam S, Barzel US. Thyroid disease in the elderly. J Am Geriatr Soc. 1993;41(12):1361–1369; Klee GG, Hay ID. Role of thyrotropin measurements in the diagnosis and management of thyroid disease. (review). Clin Lab Med. 1993;13(3):673–682.
Increased total serum T4

An increased total serum T4 may indicate hyperthyroidism, elevated concentrations of thyroid-binding proteins (as seen in pregnancy or in women receiving oral contraceptive therapy), or nonthyroid illness. Total serum T4 elevations have been noted in patients, particularly elderly persons, with relatively minor illnesses. These transient elevations may be due to increased TSH secretion stimulated by a low T3 concentration. Similarly, up to 20% of all patients admitted to psychiatric hospitals have had transient total serum T4 elevations on admission.61 Thus, the differential diagnosis for a patient with this elevation must include nonthyroid illness versus hyperthyroidism if other signs and symptoms of thyroid disease are absent or inconsistent.61

Decreased total serum T4

A decreased total serum T4 may indicate hypothyroidism, decreased concentrations of thyroid-binding proteins, or nonthyroid illness (also called euthyroid sick syndrome). Nonthyroid illness may lower the total serum T4 concentration with no change in thyrometabolic status. Typically in this syndrome, total serum T4 is decreased (or normal), total serum T3 is decreased, reverse T3 is increased, and TSH is decreased (or normal). Neoplastic disease, DM, burns, trauma, liver disease, renal failure, prolonged infections, and cardiovascular disease are nonthyroid illnesses that can lower total serum T4 concentrations.61

Several mechanisms probably contribute to this low T4 state. Diminished T4 in nonthyroid illness may be due to low TBG concentrations caused by protease cleavage at inflammatory sites during acute inflammatory illness. In some, but not all, patients with chronic illness, a desialylated form of TBG is synthesized by the liver, which has one-tenth the binding capacity of that of normal TBG. This results in a fall in the circulating levels of total thyroid hormone as a consequence of the diminished thyroid hormone-binding capacity. In addition, peripheral deiodination of T4 to T3 is impaired because of diminished activity of type I deiodinase enzyme. Diminished enzyme activity accounts for decreased deiodination of T4 to T3 and an increase in the production of reverse T3.60,61

In general, a correlation exists between the degree of total serum T4 depression and the prognosis of the illness (ie, the lower the total serum T4, the poorer the disease outcome). Because severely ill patients may appear to be hypothyroid, it is important to differentiate between patients with serious nonthyroid illnesses and those who are truly hypothyroid.61 After recovery from a nonthyroid illness, thyroid function test result abnormalities should be completely reversible.

Drugs causing true alterations in total serum thyroxine

Medications can cause a true alteration in total serum T4 and a corresponding change in free T4 concentrations (Tables 9-9 and 9-10).62 In such cases, the total serum T4 (and free T4) result remains a true reflection of thyrometabolic status. High-dose salicylates and phenytoin also may lower total serum T4 significantly via decreased protein binding in vivo. Salicylates inhibit binding of T4 and T3 to TBG. An initial increase in serum free T4 is followed by return of free T4 to normal levels with sustained therapeutic serum salicylate concentrations, although total T4 levels may decrease by as much as 30%. Phenytoin displaces T4 and T3 from serum binding proteins, resulting in an initial increase in free T4 and T3 and a decrease in total T4 levels.62,63

TABLE 9-9.
Medications That Cause a True Alteration in Total Serum T4 and Free T4 Measurementsa

MECHANISM

INCREASE TOTAL SERUM T4 AND FREE T4

DECREASE TOTAL SERUM T4 AND FREE T4

Interference in central regulation of TSH secretion at hypothalamic-pituitary level

Amphetamines

Glucocorticoids (acutely)

Octreotide

Dobutamine

Dopamine

Interference with thyroid hormone synthesis or release from thyroid gland

Amiodarone,b lithiumb

Aminoglutethimide, amiodarone,b 6-mercaptopurine, sulfonamides

Iodidesb

Thionamides

Lithiumb

Altered thyroid hormone metabolism

Amiodarone, iopanoic acid, ipodate, propranolol (high dose)

Phenobarbital

Carbamazepine

Rifampin

Phenytoin

Inhibition of GI absorption of exogenous thyroid hormone

Antacids, orlistat cholestyramine, colestipol, iron, sodium polystyrene sulfonate, soybean flour (infant formulas), sucralfate

Omeprazole

lansoprazole

aIn true alterations, the concentration change is not due to assay interference or alteration in thyroid-binding proteins. As noted in Table 9-10, iodides can significantly alter thyroid status. They have the potential to inhibit thyroid hormone release and impair the organification of iodine. In healthy individuals, this effect lasts only 1 to 2 weeks. However, individuals with subclinical hypothyroid disease may develop clinical hypothyroidism after treatment with iodides. Iodide-induced hypothyroidism has also been noted in patients with cystic fibrosis and emphysema.57

bMay increase or decrease total serum T4 and free T4.

Source: Compiled, in part, from references 55,57,58.
TABLE 9-10.
Iodine-Containing Compounds That May Influence Thyroid Status

Oral radiopaque agents

 Diatrizoate

 Iocetamic acid

 Iopanoic acid

 Ipodate

 Tyropanoate

Expectorants

 Iodinated glycerola

 Potassium iodide solution

 SSKI

Parenteral radiopaque agents

 Diatrizoate meglumine

 Iodamide meglumine

 Iopamidol

 Iothalamate meglumine

 Metrizamide

Miscellaneous compounds

Amiodarone

Kelp-containing nutritional supplements

SSKI = supersaturated potassium iodide.

aNo longer available; most products reformulated with guaifenesin.

Source: Compiled, in part, from references 58 and 59.

Iodides may also increase thyroid function. A previously euthyroid patient may develop thyrotoxicosis from exposure to increased quantities of iodine. Supplemental iodine causes autonomously functioning thyroid tissue to produce and secrete thyroid hormones, leading to a significant increase in T4 and T3 concentrations. This phenomenon commonly occurs during therapeutic iodine replacement in patients who live in areas of endemic iodine deficiency.

Similarly, patients with underlying goiter who live in iodine-sufficient areas may develop hyperthyroidism when given pharmacological doses of iodide. The heavily iodinated antiarrhythmic medication amiodarone may induce hyperthyroidism (1% to 5% of patients) as well as hypothyroidism (6% to 10% of patients).64 Propylthiouracil and methimazole are used in patients with hyperthyroidism to decrease hormone concentrations. Both T4 and T3 concentrations decrease more rapidly with methimazole than propylthiouracil.65

Serum T3 Resin Uptake

Normal range: 25% to 38%

Although rarely used, the serum T3 resin uptake test indirectly estimates the number of binding sites on thyroid-binding protein occupied by T3. This result is also referred to as the thyroid hormone-binding ratio. The T3 resin uptake is usually low when the concentration of thyroid-binding proteins is high.60

In this test, radiolabeled T3 is added to a specimen that contains endogenous hormone. An aliquot of this mixture is then added to a resin that competes with endogenous thyroid-binding proteins for the free hormone. Radiolabeled T3 binds to any free endogenous thyroid-binding protein; at the saturation point, the remainder binds to the resin. The amount of thyroid-binding protein can be estimated from the amount of radiolabeled T3 taken up by the resin. The T3 resin uptake result is expressed as a percentage of the total radiolabeled T3 that binds to the resin. The T3 resin uptake can verify the clinical significance of measured total serum T4 and T3 concentrations because it is an indicator of thyroid-binding protein-induced alterations of these measurements; however, it is rarely used in contemporary practice because of the availability of the free T4 test.60

Elevated T3 resin uptake concentrations are consistent with hyperthyroidism, whereas decreased concentrations are consistent with hypothyroidism. However, this test is never used alone for diagnosis. The T3 resin uptake is low in hypothyroidism because of the increased availability of binding sites on the TBG. However, in nonthyroidal illnesses with a low T4, the T3 resin uptake is elevated. Therefore, the test may be used to differentiate between true hypothyroidism and a low T4 state caused by nonthyroid illness.60

All of the disease states and medications listed in Table 9-11 can influence thyroid-binding protein and, consequently, alter T3 resin uptake results. Radioactive substances taken by the patient also interfere with this test. In practice, the T3 resin uptake test is used only to calculate the free T4 index.61,62

TABLE 9-11.
Test Results Seen in Common Thyroid Disorders and Drug Effects on Test Results

DISEASE

TOTAL SERUM T4

TOTAL SERUM T3

T3 RESIN UPTAKE

FREE T4 INDEX

RAIU

TSH

COMMENT

Hypothyroidism

↑/↓ a

Hyperthyroidism

T3 thyrotoxicosis

No change

No change

No change

No change

T3 resin uptake may be slightly increased

Euthyroid sick

No change/↓

Variable

No change

No change syndrome

Corticosteroids

No change/↓

No change

No change/↓

Phenytoin/aspirin

No change

No change

Large salicylate dose

Radiopaque media

No change/↑

No change/↓

No change

No change/↑

No change

↑ = increased; ↓ = decreased; RAIU = radioactive iodine uptake test.

aIncreased TSH diagnostic of primary hypothyroidism. TSH is decreased in secondary and tertiary types.

Source: Adapted from Surks MI, Sievert R. Drugs and thyroid function. N Engl J Med. 1995;333(25):1688–1694; Kaptein EM. Clinical application of free thyroxine determinations. Clin Lab Med. 1993;13(3):653–672.

Free T4 Index

Normal range: 1 to 4 units

The free T4 index is the product of total serum T4 multiplied by the percentage of T3 resin uptake:
free T4index=total serum T4mcg/dL×T3resin uptake%

The free T4 index adjusts for the effects of alterations in thyroid-binding protein on the total serum T4 assay. The index is high in hyperthyroidism and low in hypothyroidism. Patients taking phenytoin or salicylates have low total serum T4 and high T3 resin uptake with a normal free T4 index. Pregnant patients have high total serum T4 and low T3 resin uptake with a normal free T4 index. Patients taking therapeutic doses of levothyroxine may have a high free T4 index because total serum T4 and T3 resin uptake are high. In addition to affecting total serum T4 and free T4, propranolol and nadolol block the conversion of T4 to T3, which may cause mild elevations in the free T4 index.60

Total Serum T3

Normal range: 80 to 200 ng/dL (1.2 to 3.1 nmol/L)

Using radioimmunoassay (RIA), highly active thyroid hormone T3 is measured. Like T4, almost all of T3 is protein bound. Therefore, any alteration in thyroid-binding protein influences this measurement. As with the total serum T4 test, changes in thyroid-binding protein increase or decrease total serum T3 but do not affect the metabolically active free T3 in the circulation. Therefore, the patient’s thyrometabolic status remains unchanged.60

Total serum T3 is primarily used as an indicator of hyperthyroidism (Minicase 3). This measurement is usually made to detect T3 toxicosis when T3, but not T4, is elevated. Generally, the serum T3 assay is not a reliable indicator of hypothyroidism because of the lack of reliability of the assay in the low to normal range. Drugs that affect T4 concentrations have a corresponding effect on T3 concentrations. Additionally, propranolol, propylthiouracil, and glucocorticoids inhibit the peripheral conversion of T4 to T3 and cause decreased T3 concentration (T4 usually stays normal).60

Total serum T3 concentrations can be low in euthyroid patients with conditions (eg, malnutrition, cirrhosis, and uremia) in which the conversion of T4 to T3 is suppressed. T3 is low in only half of hypothyroid patients because these patients tend to produce relatively more T3 than T4. A patient with a normal total serum T4, a low T3, and a patient with high reverse T3 has euthyroid sick syndrome.60

Thyroid-Stimulating Hormone

Normal range: 0.5 to 5.0 milliunits/L

Thyroid stimulating hormone (TSH) is a glycoprotein with two subunits: α and β. The α subunit is similar to those of other hormones secreted from the anterior pituitary: follicle-stimulating hormone, human chorionic gonadotropin (hCG), and luteinizing hormone. The β subunit of TSH is unique and renders its specific physiologic properties.61,62

A Patient with Hyperthyroidism

A 35-year-old nurse complains of nervousness, mood swings, weakness, and palpitations with exertion for the past 6 months. Recently, she noticed excessive sweating and wanted to sleep with fewer blankets than her husband. Menstrual periods had been regular, but there was less bleeding. She has lost 20 lb over the last 6 months despite eating twice as much as she did 1 year ago. Her HR is 92 beats/min and BP is 150/90 mm Hg. She appears anxious. She has smooth, warm, moist skin; she has a fine tremor; and she cannot rise from a deep knee bend without aid. Upon physical exam, her thyroid contains three nodules—two on the right and one on the left with a total gland size of 60 g (three times normal size). All nodules are of firm consistency, and there is no lymphadenopathy.

  • Sodium, 145 mEq/L (136 to 142 mEq/L)

  • Potassium, 4 mEq/L (3.8 to 5 mEq/L)

  • Chloride, 101 mEq/L (95 to 103 mEq/L)

  • Carbon dioxide, 26 mEq/L (21 to 28 mEq/L)

  • BUN, 10 mg/dL (8 to 23 mg/dL)

  • SCr, 0.8 mg/dL (0.6 to 1.2 mg/dL)

  • Hemoglobin, 12 g/dL (12 to 16 g/dL)

  • Hct, 36% (36% to 45%)

  • RBC count, 3.5 M/mm3 (4 to 5.2 M/mm3)

  • Antithyroid antibodies, 1:200

  • Mean cell (corpuscular) volume, 104 mm3 (80 to 100 mm3)

  • WBC count, 16 × 103 cells/mm3 (4.8 to 10.8 × 103 cells/mm3)

  • Calcium, 9 mg/dL (9.2 to 11 mg/dL)

  • Glucose, 96 mg/dL (70 to 110 mg/dL)

  • Free T4, 4.6 ng/dL (0.9 to 2.3 ng/dL)

  • T3, 250 ng/dL (80 to 200 ng/dL)

  • TSH, 0.3 microunits/mL (0.5 to 5 microunits/mL)

QUESTION: How should these results be interpreted? Are confirmatory tests needed?

DISCUSSION: This patient presents with many of the clinical features of hyperthyroidism, including rapid heart rate, weight loss, and heat intolerance. Her thyroid gland is visibly enlarged (goiter). She also has elevated BP and complains of nervousness, sweating, and hand tremors. The diagnosis of hyperthyroidism can be confirmed by her laboratory results of a high T4 and a below-normal TSH value. She has a toxic multinodular goiter that should be treated with radioactive iodine or surgery with antithyroid drug and iodine pretreatment.

Although the older “first-generation” TSH assays have been useful in diagnosing primary hypothyroidism, they have not been useful in diagnosing hyperthyroidism. Almost all patients with symptomatic primary hypothyroidism have TSH concentrations >20 milliunits/L; those with mild signs or symptoms have TSH values of 10 to 20 milliunits/L. Often, TSH concentrations become elevated before T4 concentrations decline. All assays can accurately measure high concentrations of TSH.61,66

The first-generation TSH assays, however, cannot distinguish low-normal from abnormally low values because their lower limit of detection is 1 milliunit/L, whereas the lower limit of basal TSH is 0.2 to 0.3 milliunits/L in most euthyroid persons. This distinction can usually be ascertained with the second-generation assays, which can accurately measure TSH concentrations as low as 0.05 milliunits/L. Occasionally, some euthyroid patients have levels of 0.05 to 0.5 milliunits/L. Therefore, supersensitive, third- and fourth-generation assays have been developed; they can detect TSH concentrations as low as 0.005 milliunits/L and 0.004 milliunits/L, respectively. Although third-generation assays are usually not required to make or confirm this diagnosis, they provide a wider margin of tolerance so that discrimination at 0.1 milliunit/L can be ensured even when the assay is not performing optimally. Concentrations <0.05 milliunits/L are almost always diagnostic of primary hyperthyroidism in patients <70 years.61

Use in therapy

In patients with primary hypothyroidism, TSH concentrations are also used to adjust the dosage of thyroid hormone replacement therapy. In addition to achieving a clinical euthyroid state, typically the goal should be to lower TSH into the midnormal range (Minicase 4). The exception is in patients with recently diagnosed papillary or follicular thyroid cancer, where the goal TSH level may be in the 0.1 to 0.2 milliunits/L range. Although TSH concentrations reflect long-term thyroid status, serum T4 concentrations reflect acute changes. Patients with long-standing hypothyroidism often notice an improvement in well-being two to three weeks after starting therapy. Significant improvements in heart rate (HR), weight, and puffiness are seen early in therapy, but hoarseness, anemia, and skin/hair changes may take many months to resolve.66

Unless undesirable changes in signs or symptoms occur, it is rational to wait at least 6 to 8 weeks after starting or changing therapy to repeat TSH and T4 concentrations to refine dosing.56 The hypothalamic-pituitary-axis requires this time to respond fully to changes in circulating thyroid hormone concentrations. For example, noncompliant patients with hypothyroidism who wait to take their thyroid hormone replacement therapy until days before their appointment may have elevated TSH concentrations despite a normal T4 concentration.61

Patients with thyroid cancer are often treated with TSH suppressive therapy, usually levothyroxine. The therapeutic endpoint is a basal TSH concentration of about 0.1 milliunit/L.Some clinicians suggest more complete suppression with TSH concentrations <0.005 milliunit/L, whereas others think that it leads to toxic effects of overreplacement (eg, accelerated bone loss, new onset atrial fibrillation).61,66

A Case of Possible Hypothyroidism

Diane G. is a 45-year-old homemaker who presents to clinic complaining of progressive weight gain of 20 lb in 1 year, fatigue, postural dizziness, loss of memory, slow speech, deepening of her voice, dry skin, constipation, and cold intolerance. Her HR is 58 beats/min, and her BP is 110/70 mm Hg. Her physical exam is normal, except for a mildly enlarged thyroid gland, pallor, and diminished tendon reflexes. She denies taking any medications or changing her diet. Diane G.’s chemistry results are as follows:

  • Sodium, 130 mEq/L (136 to 142 mEq/L)

  • Potassium, 3.8 mEq/L (3.8 to 5 mEq/L)

  • Carbon dioxide, 28 mEq/L (21 to 28 mEq/L)

  • Calcium, 9.5 mg/dL (9.2 to 11 mg/dL)

  • Magnesium, 2 mEq/L (1.3 to 2.1 mEq/L)

  • Glucose, 80 mg/dL (70 to 110 mg/dL)

  • BUN, 20 mg/dL (8 to 23 mg/dL)

  • SCr, 1.1 mg/dL (0.6 to 1.2 mg/dL)

  • Cholesterol, 255 mg/dL (<200 mg/dL)

The cholesterol concentration is elevated since a screening 6 months ago. A test for mononucleosis is negative. Hct is low at 36% (36% to 45%)—close to her usual. Her total serum T4 is 3.8 mcg/dL (5.5 to 12.5 mcg/dL), her T3 resin uptake is 15% (25% to 38%), her free T4 index is 1.0 (1 to 4), and her TSH is 65 milliunits/L (0.3 to 5 milliunits/L).

QUESTION: How should these results be interpreted?

DISCUSSION: Clinically, all of the history and physical findings point to hypothyroidism. The pallor and weakness are also consistent with anemia, but an Hct of 35% is unlikely to cause such significant symptoms. Her cholesterol recently became elevated, consistent with primary hypothyroidism.93 Both the total serum T4 and T3 resin uptake are low and TSH level is high.

QUESTION: Does this information help to elucidate the diagnosis?

DISCUSSION: An elevated TSH confirms primary hypothyroidism. Diane G. is started on levothyroxine 0.2 mg/day, and her TSH is 6 milliunits/L 3 weeks later. Clinically, she improves but is not fully back to normal. Six weeks after starting therapy, she complains of jitteriness, palpitations, and increased sweating. Her TSH is <0.3 milliunit/L. Her physician lowers the dose of levothyroxine to 0.1 mg/day, and she becomes asymptomatic after about 2 weeks. Eight weeks later, her TSH is 1.5 milliunits/L, and she remains asymptomatic. Her cholesterol is 200 mg/dL, sodium is 138 mEq/L, and Hct is 40%.

QUESTION: Which test(s) should be used to determine proper dosing of levothyroxine? How long after a dosage change should clinicians wait before repeating the test(s)?

DISCUSSION: Although total serum T4, T3 resin uptake, and free T4 index can be used to monitor and adjust doses of thyroid supplements in patients with a hypothyroid disorder, the highly sensitive TSH test is most reliable. Chemically, the goal is to achieve a TSH in the normal range, as was ultimately achieved in this patient (TSH of 1.5 milliunits/L).

The TSH is the standard for adjusting thyroid replacement therapy. The 0.2-mg levothyroxine dose is excessive for this patient, as evidenced by her “hyperthyroid” symptoms and the fully suppressed TSH. Eight weeks later, after T4 steady state has been reached on the 0.1-mg/day dose and after the hypothalamic-pituitary-thyroid axis reached homeostasis, TSH is within the desired range. Her cholesterol, sodium, and Hct also normalized when she became euthyroid.

Potential misinterpretation and drug interference

Some TSH assays may yield falsely elevated results whenever hCG concentrations are high (eg, pregnancy) due to the similarity in structure of these two proteins. Most patients who have secondary or tertiary hypothyroidism have low or normal TSH concentrations. In patients with nonthyroid illness, TSH may be suppressed by factors other than thyroid hyperfunction. As mentioned previously, the TSH concentration typically is normal in patients with euthyroid sick syndrome.62,66

Thyroid function tests are known to be altered in depressed patients. With the advent of the third-generation TSH assays, it was hoped that TSH concentrations could help to determine various types of depression and response to therapies. Unfortunately, TSH has not proven useful in this way.66 Because endogenous dopamine inhibits the stimulatory effects of TRH, any drug with dopaminergic activity can inhibit TSH secretion. Therefore, levodopa, glucocorticoids, bromocriptine, and dopamine are likely to lower TSH results. The converse is also true—dopamine antagonists (metoclopramide) may increase TSH concentrations.62,63

Radioactive Iodine Uptake Test

This test is used to detect the ability of the thyroid gland to trap and concentrate iodine and, thereby, produce thyroid hormone. In other words, this test assesses the intrinsic function of the thyroid gland. This test is not specific, and its reference range must be adjusted to the local population. Therefore, its use is declining. In patients with a normal thyroid gland, 12% to 20% of the radioactive iodine is absorbed by the gland after 6 hours and 5% to 25% is absorbed after 24 hours. The radioactive iodine uptake test is an indirect measure of thyroid gland activity and should not be used as a basic screening test of thyroid function. This test is most useful in distinguishing causes of hyperthyroidism, including that caused by subacute thyroiditis, which results in an absent or reduced uptake of iodine.56

A high radioactive iodine uptake is noted with the following conditions51:

  • Thyrotoxicosis

  • Iodine deficiency

  • Postthyroiditis

  • Withdrawal rebound after thyroid hormone or antithyroid drug therapy

A low test result occurs in the following persons51:

  • Individuals with acute thyroiditis

  • Euthyroid patients who ingest iodine-containing products

  • Patients on exogenous thyroid hormone therapy

  • Patients who are taking antithyroid drugs such as propylthiouracil

  • Individuals with hypothyroidism

The radioactive iodine uptake test is affected by the body’s store of iodine. Therefore, the patient should be carefully questioned about the use of iodine-containing products before the test. This test is contraindicated during pregnancy.

Antithyroid Antibodies

Normal range: varies with antibody

Antibodies that “attack” various thyroid tissue components can be detected in the serum of patients with autoimmune disorders such as Hashimoto thyroiditis and Graves disease. Thyroid microsomal antibody is found in 95% of patients with Hashimoto thyroiditis, 55% of patients with Graves disease, and 10% of adults without thyroid disease. In patients who have nodular goiters, high-antibody titers strongly suggest Hashimoto thyroiditis as opposed to cancer. In Graves disease, hyperthyroidism is caused by antibodies, which activate TSH receptors. In chronic autoimmune thyroiditis, hypothyroidism may be caused by antibodies competitively binding to TSH receptors, thereby blocking TSH from eliciting a response.66

Results are reported as titers. Titers in excess of 1:100 are significant and usually can be detected even during remission. Antibodies (>1:10) to thyroglobulin are present in 60% to 70% of adults with active Hashimoto thyroiditis but typically are not detected during remission. Titers above 1:1,000 are found only in Hashimoto thyroiditis or Graves disease (25% to 10%, respectively). Lower titers may be seen in 4% of the normal population, although the frequency increases with the age in female patients. The thyroid microsomal antibody and thyroglobulin antibody serological tests may be elevated or positive in patients with nonthyroidal autoimmune disease.

Anti-TSH receptor antibodies are present in virtually all patients with Graves disease, but the test is usually not necessary for diagnosis. These antibodies mostly stimulate TSH receptors (eg, thyroid-stimulating immunoglobulin) but also may compete with TSH and inhibit TSH stimulation of the thyroid gland. High titers allow a confirmation of Graves disease in asymptomatic patients, such as those whose only manifestation is exophthalmos.66,67

Laboratory Diagnosis of Hypothalamic-Pituitary-Thyroid Axis Dysfunction

The laboratory diagnosis of primary hypothyroidism can be made with a low free T4 index and an elevated TSH concentration. The presence of a low free T4 index and a normal or low serum TSH concentration indicates secondary or tertiary hypothyroidism or nonthyroid illness. In such patients, the T3 resin uptake may differentiate between hypothyroidism and a low T4 state due to nonthyroid illness. An elevated reverse T3 concentration also suggests nonthyroid illness. T3 is of limited usefulness in diagnosing hypothyroidism because it may be normal in up to one-third of patients with hypothyroidism.55,61 With the availability of ultrasensitive TSH assays, many clinicians begin their evaluations with this test.

The total serum T4 and free T4 or free T4 indexes are commonly used and are increased in almost all patients with hyperthyroidism. Usually, both T3 and T4 are elevated. However, a few (<5%) patients with hyperthyroidism exhibit normal T4 with elevated T3 (T3 toxicosis). Second-line tests such as antithyroid antibody serologies are necessary to diagnose autoimmune thyroid disorders.66

ADRENAL DISORDERS

The adrenal glands are located extraperitoneally at the upper poles of each kidney. The adrenal medulla, which makes up 10% of the adrenal gland, secretes catecholamines (eg, epinephrine and norepinephrine). The adrenal cortex, which comprises 90% of the adrenal gland, is divided into three areas.

  1. The outer layer of the adrenal gland, known as the zona glomerulosa, makes up 15% of the adrenal gland and is responsible for production of aldosterone, a mineralocorticoid that regulates electrolyte and volume homeostasis.

  2. The zona fasciculata, located in the center of the adrenal gland, occupies 60% of the gland and is responsible for glucocorticoid production. Cortisol, a principal end product of glucocorticoid production, regulates fat, carbohydrate, and protein metabolism. Glucocorticoids maintain the body’s homeostasis by regulating bodily functions involved in stress as well as normal activities.

  3. The zona reticularis makes up 25% of the adrenal gland and secretes mostly inactive androgen precursors that undergo peripheral conversion to adrenal androgens, such as dehydroepiandrosterone (DHEA), DHEA sulfate (DHEA-S), and androstenedione (the precursor to testosterone). These hormones influence the development of the reproductive system.68,69

Cushing Syndrome

Cushing syndrome, first described 70 years ago, is the result of excessive concentrations of cortisol. It is an extremely rare disease in children, with a peak in adults in the third or fourth decade. In most cases, hypercortisolism is the result of overproduction of cortisol by the adrenal glands due to an ACTH-secreting pituitary tumor. Long-term use of glucocorticoids, the most common cause of Cushing’s disease, and adrenal tumors can result in hypercortisolism.

Patients with hypercortisolism generally present with facial plethora (moon face) as a result of atrophy of the skin and underlying tissue. A common sign of hypercortisolism is fat accumulation in the dorsocervical area often referred to as “buffalo hump.” Other cardinal signs and symptoms include hypertension, osteopenia, glucose intolerance, myopathy, bruising, back pain, proximal muscle weakness, and depression. Hyperpigmentation is present in patients with ACTH-secreting pituitary tumors. Hair loss, acne, and oligomenorrhea are also the result of superfluous cortical secretion.70

Diagnostic Tests

It is important to rule out iatrogenic Cushing’s syndrome when there is long-term steroid therapy and assess pretest probability of Cushing’s syndrome based on relatively specific signs stated previously (Minicase 5).

In healthy individuals, the level of serum cortisol reaches a peak in the morning around 7 a.m. to 9 a.m. (5 to 23 mcg/dL) and reaches the lowest level between bedtime and 2 a.m. (usually <5 ug/dL).

One of the first signs of Cushing’s syndrome is the loss of this diurnal variation. Accordingly, the three first-line biochemical screening tests recommended for the diagnosis of endogenous hypercortisolism are to prove that the patients has lost this normal secretion of cortisol, and thus it is recommended that patients are screened with these tests. The following tests are used to identify patients with Cushing syndrome: 24-hour urine-free cortisol (UFC), midnight plasma cortisol, and the low-dose dexamethasone suppression test (DST) using 1 mg for the overnight test or 0.5 mg every 6 hours for the 2-day study. The most frequently used test to identify patients with hypercortisolism is the 24-hour UFC test, which measures free cortisol levels and creatinine in a urine sample that is collected over a 24-hour period. Laboratory tests in adults with Cushing syndrome include the following results:

  1. 24-hour UFC at least three times above normal

  2. Midnight plasma cortisol 5 mcg/dL (138 mmol/L) or more

  3. Low-dose DST plasma cortisol exceeds 2 mcg/dL (50 nmol/L) when drawn between 8:00 a.m. and 9:00 a.m. 71

Steroid-Induced Hypercortisolism

Teresa S. is a 35-year-old woman with a past medical history of type 2 diabetes that was diagnosed in her late 20s. She has been taking metformin 1,000 mg twice a day regularly since her diagnosis. Teresa S. was diagnosed with rheumatoid arthritis 6 months ago and started on regular treatment with prednisolone 30 mg daily. She reports to her primary care provider for general muscle weakness and low back pain. She has been having low back pain for a little over 4 months. The general muscle weakness has been getting progressively worse over the past month and is beginning to concern her. Teresa S. also reports having trouble making it through her Zumba class on Tuesdays and Thursdays. She says that lately she has little interest in her regular activities and has been experiencing fatigue without physical exertion. Lastly, Teresa S. reports having irregular menstrual cycles for the past 2 years accompanied by unexplained weight gain in her abdomen.

Physical exam reveals purple/pink stretch marks on arms, abdomen, and thighs. The patient has multiple cuts and bruises on her arms and hands, with an explanation of having thin skin. The patient is obese with noticeable fatty deposits in the upper back and midsection. Her BP is 154/76 mm Hg, and her heart rate is 74 beats/min.

The patient would like to have little to no back pain. She also would like to be able to increase her strength and endurance to resume her normal Zumba classes twice a week. Goals for her blood test results are as follows:

  • Sodium, 142 mEq/L (136 to 142 mEq/L)

  • Potassium, 3.3 mEq/L (3.8 to 5 mEq/L)

  • Chloride, 99 mEq/L (95 to 103 mEq/L)

  • BUN, 28 mg/dL (8 to 23 mg/dL)

  • SCr, 1.8 mg/dL (0.6 to 1.2 mg/dL)

  • Hct, 40% (36% to 45%)

  • WBC count, 6.2 × 103 cells/mm3 (4.8 to 10.8 × 103 cells/mm3)

  • Calcium, 10 mg/dL (9.2 to 11 mg/dL)

  • Glucose, 180 mg/dL (70 to 110 mg/dL)

  • Ketones, 0 at 1:8 serum dilution (normal = 0)

  • Osmolality, 285 mOsm/kg (280 to 295 mOsm/kg)

  • Triglycerides, 207 mg/dL (10 to 150 mg/dL)

  • Lipase, 1.0 units/mL (<1.5 units/mL)

  • Magnesium, 1.7 mEq/L (1.3 to 2.1 mEq/L)

  • Hemoglobin A1c, 6.1 (4% to 5.6%)

  • 8 a.m. Cortisol, 33.4 mcg/dL

QUESTION: Based on the subjective and objective data provided, what is the most likely diagnosis for this patient? What signs and symptoms support the diagnosis? What could have precipitated this disorder?

DISCUSSION: The patient complained of unusual fatigue, back pain, headaches, irregular menstrual cycles, generalized weakness, and a recent lack of interest in her normal hobbies/activities. Teresa S.’s reports are accompanied by objective findings of elevated BP, proximal weakness, purple/pink stretch marks, multiple bruises, and noticeable fatty deposits.

The diagnosis of hypercortisolism due to the chronic use of prednisolone is supported by her lab results of an elevated 8 a.m. serum cortisol of 33.4 mcg/dL, potassium level of 3.3 mmol/L, elevated fasting blood glucose level 180 mg/dL, and serum triglyceride levels of 207 mg/dL. Based on subjective and objective evidence, the patient is diagnosed as having Cushing syndrome caused by the chronic use of prednisolone. The prednisolone dose is tapered, alternative treatment options for rheumatoid arthritis are considered, and the serum cortisol level is measured after 3 months during a follow-up appointment. BP and cholesterol levels will be rechecked at the follow-up appointment.

Of the suppression tests, the overnight DST, is the least laborious test to perform. The patient is given 1 mg of dexamethasone at 11:00 p.m. A plasma cortisol levels is obtained at 8:00 a.m. the next morning. Patients with Cushing syndrome have high cortisol concentrations (>5 mcg/dL or >138 nmol/L) because of an inability to suppress the negative-feedback mechanism of the hypothalamic-pituitary-adrenal axis.63,64

Once hypercortisolism is confirmed, one of the following tests should be performed to identify the source of hypersecretion, which could include the pituitary gland, adrenal gland, or production from an ectopic site. Such tests include high-dose DST; plasma ACTH via immunoradiometric assay (IRMA) or RIA; adrenal vein catheterization; metyrapone stimulation test; adrenal, chest, or abdominal computed tomography; corticotropin-releasing hormone (CRH) stimulation test; inferior petrosal sinus sampling; and pituitary magnetic resonance imaging. Other possible tests and procedures include insulin-induced hypoglycemia, somatostatin receptor scintigraphy, desmopressin stimulation test, naloxone CRH stimulation test, loperamide test, hexarelin stimulation test, and radionuclide imaging. Additional tests should be performed to confirm the diagnosis because other factors (eg, starvation, topical steroid application, and acute stress) influence the results of the previously mentioned tests.69,70

Plasma ACTH concentrations can be measured by RIA procedures. Interpretation of the results is as follows:

  • ACTH levels <10 pg/mL indicate an ACTH-independent adrenal source, such as an adrenal tumor or long-term use of steroids

  • ACTH levels between 5 and 10 pg/mL should be followed by a CRH test

  • ACTH levels >10 pg/mL indicate an ACTH-dependent syndrome

The CRH test can be employed to determine if the source of hypercortisolism is pituitary or ectopic (extrapituitary). Baseline ACTH and CRH levels are obtained. Then, ACTH and cortisol levels are measured 15 to 30 and 45 to 60 minutes after the administration of a 100-mcg IV dose of CRH. A 50% increase from baseline in ACTH levels indicates an ACTH-dependent syndrome.70

Adrenal Insufficiency (Addison Disease)

Adrenal insufficiency (Addison disease or primary adrenal insufficiency) is the result of an autoimmune destruction of all regions of the adrenal cortex. Tuberculosis, fungal infections, acquired immunodeficiency syndrome, metastatic cancer, and lymphomas can also precipitate adrenal insufficiency. Adrenal insufficiency results in deficiencies in cortisol, aldosterone, and androgens. Patients usually present with weakness, weight loss, increased pigmentation, hypotension, GI symptoms, postural dizziness, and vertigo.

Secondary adrenal insufficiency can result from the use of high doses or extended duration of use of exogenous steroids, which suppress the hypothalamic-pituitary axis, resulting in a decrease in the release of ACTH. Patients with secondary adrenal insufficiency maintain normal aldosterone levels and do not exhibit signs of hyperpigmentation.71,72

Diagnostic tests

Measurement and interpretation of plasma corticotropin (ACTH) levels are recommended to distinguish between primary adrenal insufficiency and secondary adrenal insufficiency. A high normal or elevated ACTH concentration is consistent with primary adrenal insufficiency, whereas a low normal or undetectable level suggests secondary adrenal insufficiency.

The cosyntropin stimulation test is used to diagnose patients with low cortisol levels. Patients receive 250 mcg of synthetic ACTH or cosyntropin intravenously or intramuscularly. Serum cortisol levels are drawn at the time of injection and 30 minutes and 1 hour after injection. Cortisol levels >18 to 20 mcg/dL (497 to 552 nmol/L) indicate an adequate response from the adrenal gland, thus ruling out adrenal insufficiency. The cosyntropin stimulation test results may be normal in patients with secondary adrenal insufficiency or mild primary adrenal insufficiency due to the high dose of corticotropin given. Therefore, many endocrinologists recommend that higher cutoff values (≥22 to 25 mcg/dL or 607 to 690 nmol/L) be used. To distinguish primary from secondary adrenal insufficiency, ACTH, renin, and aldosterone levels are measured.71,72

DIABETES INSIPIDUS

Diabetes insipidus is a syndrome in which the body’s inability to conserve water manifests as excretion of large volumes of dilute urine. This section explores related pathophysiology, types of diabetes insipidus, and interpretation of test results to evaluate this disorder.73

Physiology

Normally, serum osmolality is maintained around 285 mOsm/kg and is determined by the amounts of sodium, chloride, bicarbonate, glucose, and urea in the serum. The excretion of these solutes along with water is a primary factor in determining urine volume and concentration. In turn, the amount of water excreted by the kidneys is determined by renal function and ADH (vasopressin). ADH reduces renal elimination of water and produces concentrated urine.

ADH is synthesized in the hypothalamus and stored in the posterior pituitary gland. This hormone is released into the circulation after physiologic stimulation, such as an increase in serum osmolality or blood volume detected by the osmoregulatory centers in the hypothalamus.73,74 Congestive heart failure lowers the osmotic threshold for ADH release, whereas nausea—but not vomiting—strongly stimulates ADH. In general, α-adrenergic agonists stimulate ADH release, whereas β-adrenergic agonists inhibit release and acts on the distal renal tubule and the collecting duct to cause water reabsorption. Chlorpropamide potentiates the effect of ADH on renal concentrating ability. When ADH is lacking or the renal tubules do not respond to the hormone, polyuria ensues. If the polyuria is severe enough, a diagnosis of diabetes insipidus is considered.73,74

Clinical Diagnosis

Diabetes insipidus should be differentiated from other causes of polyuria, such as osmotic diuresis (eg, hyperglycemia, mannitol, and contrast media), renal tubular acidosis, diuretic therapy, and psychogenic polydipsia. Patients usually excrete 16 to 24 L of dilute urine in 24 hours. The urine specific gravity is <1.005 and urine osmolality <300 mOsm/kg.73 As long as the thirst mechanism is intact and a patient can drink, no electrolyte problems result. However, if a patient is unable to replace fluids lost through excessive urine output, he or she can develop dehydration and hypernatremia.

Although diabetes insipidus is usually caused by a defect in the pituitary secretion (neurogenic, also called central) or renal activity (nephrogenic) of ADH, it can also be caused by a defect in thirst (dipsogenic) or psychological function (psychogenic), with resultant excessive intake of water. If left untreated, diabetes insipidus can lead to significant morbidity and mortality; therefore, the underlying cause should be sought to ensure proper diagnosis and therapy. The specific type of diabetes insipidus often can be identified by the clinical setting. If the diagnosis is equivocal, a therapeutic trial with an antidiuretic drug or measurement of plasma ADH is necessary (Table 9-12).74

TABLE 9-12.

Differential Diagnosis of Diabetes Insipidus Based on Water Deprivation Test

DIAGNOSIS

URINE SPECIFIC GRAVITY

AVERAGE URINE OSMOLALITY (mOsm/kg)

PLATEAU URINE OSMOLALITY (mOsm/kg)

AVERAGE SERUM OSMOLALITY (mOsm/kg)

CHANGE IN URINE OSMOLALITY AFTER VASOPRESSIN

Normal individuals

>1.015

300–800

<1,600

280–295

Little change

Central diabetes insipidus

<1.010

<300

<300

Normal or increased

Increases

Nephrogenic diabetes insipidus

<1.010

<300

<300

Normal or increased

Little change

Source: Sowers JR, Zieve FJ. Clinical disorders of vasopression. In: Lavin N, ed. Manual of Endocrinology and metabolism. Boston, MA: Little, Brown; 1986-65-74. Young DS. Effects of Drugs on Clinical Laboratory Tests. 3rd ed. Washington, DC: American Association for Clinical Chemistry Press; 1990.

Central Diabetes Insipidus

Central diabetes insipidus (ADH deficiency) may be the result of any disruption in the pituitary-hypothalamic regulation of ADH. Patients often present with a sudden onset of polyuria (in the absence of hyperglycemia) and preference for iced drinks. Tumors or metastases in or around the pituitary or hypothalamus, head trauma, neurosurgery, genetic abnormalities, Guillain-Barré syndrome, meningitis, encephalitis, toxoplasmosis, cytomegalovirus, tuberculosis, and aneurysms are some of the known causes. In addition, phenytoin and alcohol inhibit ADH release from the pituitary. In response to deficient secretion of ADH and subsequent hyperosmolality of the plasma, thirst is stimulated. The absence of effective ADH results in polyuria.73

Nephrogenic Diabetes Insipidus

In nephrogenic diabetes insipidus (ADH resistance), the secretion of ADH is normal, but the renal tubules do not respond to ADH.75 In the kidney, the actions of ADH on its type-2 receptor (V2R) induce increased water reabsorption in addition to polyphosphorylation and membrane targeting of the water channel aquaporin-2. Mutations in the V2R have been found to be associated with nephrogenic diabetes insipidus. Causes of nephrogenic diabetes insipidus include chronic renal failure, pyelonephritis, hypokalemia, hypercalciuria, malnutrition, genetic defects, and sickle cell disease. Additionally, lithium toxicity, colchicine, glyburide, demeclocycline, cidofovir, and methoxyflurane occasionally cause this disorder.74

Diabetes Insipidus of Pregnancy

A transient diabetes insipidus, originally thought to be a form of nephrogenic diabetes insipidus, may develop during late pregnancy from excessive vasopressinase (ADHase) activity. This kind of diabetes insipidus is associated with preeclampsia with liver involvement. Because vasopressinase does not metabolize desmopressin acetate, this is the treatment of choice.76

Laboratory diagnosis

Some clinicians avoid dehydration testing and rely on measuring plasma ADH concentrations to distinguish central from nephrogenic diabetes insipidus. In otherwise healthy adults, the average basal plasma ADH concentration is 1.3 to 4 pg/mL (1.2 to 3.7 pmol/L). Based on medical history, symptoms, and signs, an elevated basal plasma ADH level almost always indicates nephrogenic diabetes insipidus. If the basal plasma ADH concentration is low (<1 pg/mL) or immeasurable, the result is inconclusive and a dehydration test should be done.

The theory behind the water deprivation test is that in normal individuals, dehydration stimulates ADH release and the urine becomes concentrated. An injection of vasopressin at this point does not further concentrate the urine. In contrast, the urine of patients with central diabetes insipidus is not maximally concentrated after fluid deprivation but will be after vasopressin injection.77

To perform the test, patients are deprived of fluid intake (up to 18 hours) until the urine osmolality of three consecutive samples varies by no more than 30 mOsm/kg. Urine osmolality and specific gravity are measured hourly. At this time, 5 units of aqueous vasopressin is administered subcutaneously, and urine osmolality is measured 1 hour later. Plasma osmolality is measured before the test, when urine osmolality has stabilized, and after vasopressin has been administered.

In healthy individuals, fluid deprivation for 8 to 12 hours results in normal serum osmolality and a urine osmolality of 800 mOsm/kg. The urine osmolality plateaus after 16 to 18 hours. Patients with central diabetes insipidus have an immediate rise in urine osmolality to 600 mOsm/kg, with a corresponding decrease in urine output with vasopressin injection. Patients with nephrogenic diabetes insipidus are unable to increase urine osmolality above 300 mOsm/kg because vasopressin injection has little effect.77

In addition to being inconvenient and expensive, dehydration procedures are reliable only if the diabetes insipidus is severe enough that—even with induced dehydration—the urine still cannot be concentrated.

Accurate interpretation requires consideration of potential confounding factors. If the laboratory cannot ensure accurate and precise plasma (not serum) osmolality measurements, plasma sodium should be used. Patients should be observed for nonosmotic stimuli, such as vasovagal reactions, that may affect ADH release. Lastly, if the patient has previously received ADH therapy, ADH antibodies may cause false-positive results suggestive of nephrogenic diabetes insipidus.74,75

SUMMARY

Endocrine disorders typically result from a deficiency or excess of a hormone. Laboratory tests that measure the actual hormone, precursors, or metabolites can help to elucidate whether and why a hormonal or metabolic imbalance exists. Tests used to assess thyroid, adrenal, glucose, and water homeostasis or receptors have been discussed.

The FPG and the 2-hour PPG concentration tests are the most commonly performed tests for evaluation of glucose homeostasis. Glycated hemoglobin assesses average glucose control over the previous 2 to 3 months, whereas fructosamine assesses average control over the previous 2 to 3 weeks.

DKA and hyperosmolar nonketotic hyperglycemia are the most severe disorders along the continuum of glucose intolerance. Extreme hyperglycemia (600 to 2,000 mg/dL) with insignificant ketonemia/acidosis is consistent with hyperosmolar nonketotic hyperglycemia, whereas less severe or even absent hyperglycemia with ketonemia and acidosis is characteristic of DKA (350 to 650 mg/dL). Hyperglycemia with ketonemia and acidosis is characteristic of DKA.

Thyroid tests can be divided into those that (1) measure the concentration of products secreted by the thyroid gland (T3 and T4); (2) evaluate the integrity of the hypothalamic-pituitary-thyroid axis (TSH and TRH); (3) assess intrinsic thyroid gland function (radioactive iodine uptake test); and (4) detect antibodies to thyroid tissue (thyroid microsomal antibody). Although TSH concentrations are usually undetectable or <0.3 milliunit/L in patients with hyperthyroidism, T4 concentrations are usually high in patients with overt hyperthyroidism. The TSH concentrations are low or undetectable in patients with hypothyroidism from hypothalamic or pituitary insufficiency and in patients with nonthyroidal illness. In contrast, TSH concentrations are high and T4 concentrations are low in patients with primary hypothyroidism.

Glucocorticoids maintain the body’s homeostasis by regulating bodily functions involved in stress and normal activities. Sex hormone precursors are all produced in the adrenal glands. Cushing syndrome is the result of excessive cortisol in the body. Addison disease occurs when there is a deficiency in cortisol production.

Diabetes insipidus is a syndrome in which the body’s inability to conserve water manifests as excretion of large volumes of dilute urine. It most often is caused by a defect in the secretion (neurogenic, also called central) or renal activity (nephrogenic) of ADH. Urine and plasma osmolality are key tests. With the advent of high-performance assays, the use of plasma vasopressin concentrations to distinguish central from nephrogenic types may obviate the need for provocative iatrogenic dehydration testing procedures.

LEARNING POINTS

1. Which patients with diabetes benefit from self-monitoring of blood glucose and how can different test results (premeal, postmeal, and fasting) be used in diabetes management?

ANSWER: The ADA recommends self-monitoring of blood glucose for all people with diabetes who use insulin.78 Self-monitoring provides information that patients can use to adjust insulin doses, physical activity, and carbohydrate intake in response to high or low glucose levels. The goal of self-monitoring of blood glucose is to prevent hypoglycemia while maintaining blood glucose levels as close to normal as possible. Most people with type 1 DM must use self-monitoring of blood glucose to achieve this goal. Although patients with type 2 DM receiving insulin therapy benefit from self-monitoring of blood glucose, the benefit of self-monitoring of blood glucose for individuals with type 2 DM who do not use insulin is not firmly established.78 The ADA states that self-monitoring of blood glucose may be desirable in patients treated with sulfonylureas or other drugs that increase the risk of hypoglycemia.78 The frequency and timing of self-monitoring of blood glucose vary based on several factors, including an individual’s glycemic goals, the current level of glucose control, and the treatment regimen. The ADA recommends self-monitoring of blood glucose three or more times per day for most individuals who have type 1 DM and seven-point testing for pregnant women who use insulin.74 More frequent testing (four to six times per day) may be needed to monitor pump therapy.79,80 In patients with type 1 DM, self-monitoring of blood glucose is most commonly recommended four times a day: before meals and at bedtime. A periodic 2:00 a.m. test is recommended to monitor for nighttime hypoglycemia. These measurements are used to adjust insulin doses and attain the fasting glucose goal. However, there is evidence that blood glucose measurements taken after lunch, after dinner, and at bedtime have the highest correlation to A1c values.79,80 When premeal or fasting goals are reached but A1c values are not optimal, self-monitoring of blood glucose 2 hours after meals can provide guidance for further adjustment of insulin regimens. Postmeal measurements are also used to evaluate the effects of rapid-acting insulins (eg, lispro, aspart), which are injected just before meals. Patients with type 2 DM who use multiple daily injections of insulin should generally test as often as patients with type 1 (at least three times per day). Patients on once-daily insulin and oral medications may also benefit from testing before meals and at bedtime when therapy is initiated or if control is poor.81,82

2. What factors should a pharmacist consider when helping a patient select an SMBG meter?

ANSWER: Meters offer a variety of features that should be considered in the selection process. The key features are meter size; the amount of blood required for each test; ease of use; speed of testing; cleaning and calibration requirements; alternate site testing capability; meter and test strip cost; language choice; and the capability to store readings, average readings over time, and download data. Patient factors to consider include lifestyle (where they will be testing, importance of portability, and speed), preferences (importance of small sample size or alternate site capability), dexterity (whether they can they operate the meter), visual acuity, and insurance coverage.83

3. What are some of the advantages of CGM?

ANSWER: Continuous glucose monitoring can provide a near-continuous readout of interstitial glucose concentration, which adequately reflects blood glucose concentration and can help to identify trends and patterns in glucose control with only a single needle stick to place the sensor. In addition, in the case of real-time CGM, monitors can be programmed to alarm for either high or low glucose values, thus allowing the patient to treat for these abnormal values and potentially reduce the risks associated with hypoglycemia or hyperglycemia as well as diminish patient fear of such an occurrence.23,24

4. What factors may affect the accuracy of an A1c result?

ANSWER: False elevations in A1c may be noted with uremia, chronic alcohol intake, and hypertriglyceridemia. Patients who have diseases with chronic or episodic hemolysis (eg, sickle cell disease and thalassemia) generally have spuriously low A1c concentrations caused by the predominance of young RBCs (which carry less A1c) in the circulation. In splenectomized patients and those with polycythemia, A1c is increased. If these disorders are stable, the test still can be used, but values must be compared with the patient’s previous results rather than published normal values. Both falsely elevated and falsely lowered measurements of A1c may also occur during pregnancy. Therefore, it should not be used to screen for GDM.10,12,15

5. Which laboratory tests are recommended in the initial evaluation of thyroid disorders?

ANSWER: The principal laboratory tests recommended in the initial evaluation of a suspected thyroid disorder are the sensitive TSH and the free T4 levels. Free T4 is the most accurate reflection of thyrometabolic status. The free T4 is the most reliable diagnostic test for the evaluation of hypothyroidism and hyperthyroidism when thyroid hormone–binding abnormalities exist. If a direct measure of the free T4 level is not available, the estimated free T4 index can provide comparable information. Total serum T4 is still the standard initial screening test to assess thyroid function because of its wide availability and quick turnaround time. In most patients, the total serum T4 level is a sensitive test to evaluate the function of the thyroid gland. This test measures both bound and free T4 and is, therefore, less reliable than the free T4 or free T4 index when alterations in TBG or nonthyroidal illnesses exist. The serum TSH is the most sensitive test to evaluate decreased thyroid function. TSH secreted by the pituitary is elevated in early or subclinical hypothyroidism (when thyroid hormone levels appear normal) or when thyroid hormone replacement therapy is inadequate.56,60

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QUICKVIEW | Total Serum T3

PARAMETER

DESCRIPTION

COMMENTS

Common reference ranges

Adults and children

80–200 ng/dL

Affected by TBG changes

(1.2–3.1 nmol/L)

SI conversion factor = 0.0154 (nmol/L)

Critical value

Not established

Extremely high or low values should be reported quickly

Natural substance?

Yes

Only 0.2% of T3 is unbound

Inherent activity?

Only free portion

Total assumed to correlate with free T3 activity

Location

Production and storage

20%–25% secreted by thyroid gland, remainder produced by conversion of T4 to T3

Bound mostly to thyroglobulin

Secretion/excretion

From thyroid, liver, and kidneys to blood

Major causes of…

High results

Hyperthyroidism

Not truly a cause but a reflection of high result

T4 and T3 supplements

Other causes

Associated signs and symptoms

Signs and symptoms of hyperthyroidism

Nervousness, weight loss, heat intolerance, tachycardia, diaphoresis

Low results

Hypothyroidism

Not truly a cause but a reflection of low result

Other causes

Propranolol

Propylthiouracil

Glucocorticoids

Associated signs and symptoms

Signs and symptoms of hypothyroidism

Lethargy, constipation, dry skin, cold intolerance, slow speech, confusion

After insult, time to…

Initial elevation or depression

Weeks to months

Increases within hours in acute T4 or T3 overdose

Peak values

Weeks to months

Increases within hours in acute T4 or T3 overdose

Normalization

Usually same time as onset

Assumes insult removed or effectively treated

Drugs often monitored with test

T4 and T3

Other drugs

Causes of spurious results

Increased or decreased TBG leads to falsely increased or decreased total serum T3, respectively; nonthyroidal illness leads to falsely increased or decreased total serum T3

QUICKVIEW | Total Serum T4

PARAMETER

DESCRIPTION

COMMENTS

Common reference ranges

Adults and children

5.5–12.5 mcg/dL (71–161 nmol/L)

Affected by TBG changes with nonthyroidal illness

SI conversion factor = 12.87 (nmol/L)

Newborn/3–5 days

11–23/9–18 mcg/dL

Affected by TBG changes with nonthyroidal illness

Critical value

Not established

Extremely high or low values should be reported quickly, especially in newborns

Natural substance?

Yes

Only 0.02% of T4 is unbound

Inherent activity?

Only free portion

Total assumed to correlate with free T4 activity

Location

Production and storage

Thyroid gland

Bound mostly to thyroglobulin

Secretion/excretion

From thyroid to blood

About 33% converted to T3 outside thyroid

Major causes of…

High results

Hyperthyroidism

Not truly a cause but a reflection of high result

T4 supplements

Other causes (Tables 9-6 and 9-8)

Associated signs and symptoms

Signs and symptoms of hyperthyroidism

Nervousness, weight loss, heat intolerance, tachycardia, diaphoresis

Low results

Hypothyroidism

Not truly a cause but a reflection of low result

Other causes (Tables 9-5 and 9-8)

Signs and symptoms of hyperthyroidism

Lethargy, constipation, dry skin, cold intolerance, slow speech, confusion

After insult, time to…

Initial elevation or depression

Weeks to months

Increases within hours in acute T4 overdose

Peak values

Weeks to months

Increases within hours in acute T4 overdose

Normalization

Usually same time as onset

Assumes insult removed or effectively treated

Drugs often monitored with test

T4

Other drugs

Causes of spurious results

Increased or decreased TBG leads to falsely increased or decreased total serum T4, respectively; nonthyroidal illness leads to falsely increased or decreased total serum T4

QUICKVIEW | Free T4

PARAMETER

DESCRIPTION

COMMENTS

Common reference ranges

Adults and children

0.9–2.3 ng/dL (11.6–29.6 pmol/L)

Higher in infants <1 mo; direct equilibrium dialysis assay not affected by TBG changes or severe nonthyroidal illness

SI conversion factor = 12.87 (pmol/L)

Critical value

Not established

Extremely high or low values should be reported quickly

Natural substance?

Yes

Only 0.02% of T4 is unbound

Inherent activity?

Probably

Some influence on basal metabolic rate; T3 most active

Location

Production and storage

Thyroid gland

Bound mostly to thyroglobulin

Secretion/excretion

From thyroid to blood

33% converted to T3 outside thyroid

Major causes of…

High results

Hyperthyroidism

Not truly a cause but a reflection of high result

T4 supplements

Other causes (Table 9-8)

Associated signs and symptoms

Signs and symptoms of hyperthyroidism

Nervousness, weight loss, heat intolerance, tachycardia, diaphoresis

Low results

Hypothyroidism

Not truly a cause but a reflection of low result

Other causes (Table 9-8)

Associated signs and symptoms

Signs and symptoms of hypothyroidism

Lethargy, constipation, dry skin, cold intolerance, slow speech, confusion

After insult, time to…

Initial elevation or depression

Weeks to months

Increases within hours in acute T4 overdose

Peak values

Weeks to months

Increases within hours in acute T4 overdose

Normalization

Usually same time as onset

Assumes insult removed or effectively treated

Drugs often monitored with test

T4

Other drugs

Causes of spurious results

Rare with direct equilibrium dialysis assay (Table 9-9)

Decreased direct equilibrium dialysis assay for free T4 with decreased or normal TSH may occur in patients

QUICKVIEW | TSH

PARAMETER

DESCRIPTION

COMMENTS

Common reference ranges

Adults and children

0.5–5.0 milliunits/L

Critical value

Not established

Extremely high or low values should be reported quickly

Natural substance?

Yes

Inherent activity?

Yes

Stimulates thyroid to secrete hormone

Location

Production and storage

Anterior pituitary

Secretion/excretion

Unknown

Major causes of…

High results

Primary hypothyroidism

Antithyroid drugs

Causes of primary hypothyroidism

Other causes (Table 9-6)

Associated signs and symptoms

Signs and symptoms of hypothyroidism

Lethargy, constipation, dry skin, cold intolerance, slow speech, confusion

Low results

Primary hyperthyroidism

Must be ≤0.05 milliunit/L for definitive diagnosis of (primary hyperthyroidism); may be decreased or normal in secondary or tertiary hypothyroidism

Other causes (Tables 9-5 and 9-8)

Associated signs and symptoms

Signs and symptoms of hyperthyroidism

Nervousness, weight loss, heat intolerance, HR increase, diaphoresis

After insult, time to…

Initial elevation or depression

Weeks to months

Decreases within hours in acute T4 overdose

Peak values

Weeks to months

Decreases within hours in acute T4 overdose

Normalization

Usually same time as onset

Assumes insult removed or effectively treated

Drugs often monitored with test

T4 and T3

Also antithyroid drugs (methimazole and propylthiouracil)

Causes of spurious results

Increased TSH: dopamine antagonists

Decreased TSH: dopamine agonists

Above TSH measurements are accurate here

Metoclopramide and domperidone

Dopamine, bromocriptine, levodopa, glucocorticoids

These drugs decrease TSH, but the change is not reflective of primary hypothyroidism or hyperthyroidism; therefore, the results are not truly spurious

QUICKVIEW | Plasma Glucose

PARAMETER

DESCRIPTION

COMMENTS

Common reference ranges

Adults

Adult fasting: <100 mg/dL (5.6 mmol/L)

Adult 2-hr postprandial: <140 mg/dL (7.8 mmol/L)

Full-term infant normal: 20–90 mg/dL (1.11–5 mmol/L)

Multiply by 0.056 for SI units (mmol/L)

Critical value

Adult fasting, no previous history: >126 mg/dL (7 mmol/L)

Anytime: <50 mg/dL (<2.8 mmol/L)

In known patient with diabetes, increased glucose is not an immediate concern unless patient is symptomatic; an increased glucose is not critical if serial levels are decreasing over time

Natural substance?

Yes

Always present in blood

Inherent activity?

Yes

Major source of energy for cellular metabolism

Location

Production

Liver and muscle

Dietary intake

Storage

Liver and muscle

As glycogen

Secretion/excretion

Mostly metabolized for energy

Levels >180 mg/dL (10 mmol/L) spill into urine

Major causes of…

High results

Type 1 and 2 DM

Drugs (Table 9-2)

Excess intake

Associated signs and symptoms

Polyuria, polydipsia, polyphagia, weakness

Long term: damage to kidneys, retina, neurons, and vessels

Low results

Insulin secretion/dose excessive relative to diet

Most common in patients with diabetes

Sulfonylureas or other hypoglycemic agents

Insulinomas

Associated signs and symptoms

Hunger, sweating, weakness, trembling, headache, confusion, seizures, coma

From neuroglycopenia and adrenergic discharge

After insult, time to…

 Initial elevation

Type 1 DM: months to elevation

Type 2 DM: years to elevation

After insulin: minutes to decrease

After meal: 15–30 min to elevation

After epinephrine or glucagon: minutes

After steroids and growth hormone: hours

Normalization

After insulin: minutes

Depends on insulin type

After exercise: minutes to hours

Depends on intensity and duration

Drugs often monitored with test

Insulin, sulfonylureas, biguanides (eg, metformin), thiazolidinediones, or other hypoglycemic agents

Also, diazoxide, L-asparaginase, total parenteral nutrition

Causes of spurious results

High-dose vitamin C, acetaminophen

With some glucometers

Metronidazole

With some automated assays

QUICKVIEW | A1c

PARAMETER

DESCRIPTION

COMMENTS

Common reference ranges

Adults and children

4%–5.6%

Fasting not required; represents average glucose levels past 8 wk

Critical value

Not applicable

Reflects long-term glycemic control; >9% suggests poor control

Natural substance?

Yes

Subunit of Hgb

Inherent activity?

Yes

Oxygen carrier; also carries glucose

Location

Production

Bone marrow

In newborns in liver and spleen

Storage

Not stored

Circulates in blood

Secretion/excretion

Older cell removed by spleen

Converted to bilirubin

Major causes of…

High results

DM

Any cause of prolonged hyperglycemia

Chronic hyperglycemia

Signs and symptoms

Signs and symptoms of diabetes

Low results

Associated signs and symptoms

Not clinically useful

After insult, time to…

Initial elevation

2–4 mo

Initial insult is chronic hyperglycemia

Normalization

2–4 mo

Assumes sudden and persistent euglycemia

Drugs often monitored with test

biguanides (eg, metformin), sulfonylureas (eg, glimepiride), meglitinides (eg, repaglinide), thiazolidinediones (eg, pioglitazone), dipeptidyl peptidase IV inhibitors (eg, sitagliptin), and α-glucosidase inhibitors (eg, acarbose), insulin (eg, glargine)

Also diet and exercise

Causes of spurious results

High results: alcoholism, uremia, increased triglycerides, hypertriglyceridemia, hemolysis, polycythemia

Low results: sickle cell anemia, thalassemia

Also seen in pregnant and splenectomized patients