II. FINDINGS AND THEIR SIGNIFICANCE

CHAPTER 12 — OBESITY   83



(i.e., both lean and overweight patients have increased mortality), but the

increased risk of lean individuals is related to their age, cigarette use, and

illness-related weight loss.9,10

B. SKINFOLD THICKNESS

Another measure of obesity is “total skinfold thickness,” which is estimated

by adding together the skinfold thickness (measured with calipers) of multiple sites (mid-biceps, mid-triceps, subscapular, and suprailiac areas). These

sums are then converted by formulas into estimates of total body fat, which

correlate well with more precise measures (r = 0.7 to 0.8).6 Skinfold measurements are rarely used today, partly because they are too complex but mostly

because relatively few studies show that the number is clinically significant.

C. WAIST-TO-HIP RATIO

1. Findings

The waist-to-hip ratio (WHR) is the circumference of the waist divided by

that of the hips. It is based on the premise that the most important characteristic of obesity is its distribution, not its quantity. Abdominal obesity

(also called android, upper body, or apple-shaped obesity; Fig. 12-1) has

a much worse prognosis than gluteal-femoral obesity (also called gynoid,

lower body, or pear-shaped obesity).

Most authorities measure the waist circumference at the midpoint

between the lower costal margin and the iliac crest and the hip circumference at the widest part of the gluteal region. Adverse health outcomes

increase significantly when the WHR exceeds 1 in men and 0.85 in women,

values that are close to the top quintiles in epidemiologic studies.13

The French diabetologist Jean Vague is usually credited with making the

observation in the 1940s that abdominal obesity, common in men, is associated with worse health outcomes than obesity over the hips and thighs,

more common in women. (American life insurance companies, however,

made the same observation in the late 1800s.14) Vague’s original “index

of masculine differentiation,” a complicated index based on skinfold and

limb circumferences,12 is no longer used, having been replaced by the much

simpler WHR in the 1980s.

2. Clinical Significance

Even after controlling for the effects of BMI, the WHR correlates significantly with blood pressure, cholesterol level, incidence of diabetes mellitus,

stroke, coronary events, and overall mortality.8,13,15

3. Pathogenesis

The main contributor to abdominal obesity is visceral fat (i.e., omental,

mesenteric, and retroperitoneal fat), not subcutaneous fat. Visceral fat is

metabolically active, constantly releasing free fatty acids into the portal

circulation, which probably contributes to hyperlipidemia, atherogenesis,

and hyperinsulinemia.16 Gluteal-femoral fat, on the other hand, is metabolically inactive except during pregnancy and the postpartum period,



84   PART 3 — GENERAL APPEARANCE OF THE PATIENT



Abdominal obesity



Gluteal-femoral obesity



FIGURE 12-1  Comparison of abdominal and gluteal-femoral obesity. Abdominal obesity is depicted in the top row; gluteal-femoral obesity in the bottom row. The drawings in this figure

are adapted from photographs published by Jean Vague,12 who is credited with first associating

adverse health outcomes with abdominal obesity.



which has led some to suggest that the role of lower body fat is to help guarantee the survival of the species by providing a constant source of energy to

the lactating female even when external nutrients are unavailable.

D. WAIST CIRCUMFERENCE

Waist circumference is simply the numerator of the WHR calculation. It

has the advantages of being simpler to measure and of avoiding attention to

the hips, which, because they encompass bone and skeletal muscle as well

as fat, should have no biologically plausible relationship to diabetes, hypertension, and atherosclerosis. Recommended cutoffs for increased health

risk are a waist circumference of more than 102 cm (>40 inches) for men

and more than 88 cm (>35 inches) for women.4



CHAPTER 12 — OBESITY   85



Waist circumference is strongly associated with risk of death, independent of BMI.8,17 Waist circumference is also a criterion for the metabolic

syndrome (defined as the presence of three or more of the following five

variables: large waist circumference, hypertension, elevated triglyceride

levels, low high-density lipoprotein [HDL] cholesterol levels, and elevated

fasting glucose levels).18

E. SAGITTAL DIAMETER

Because waist circumference encompasses both subcutaneous and visceral

fat, investigators have looked for better anthropometric measures of just

visceral fat. One proposed measure is the sagittal diameter, which is the

total anteroposterior distance between the anterior abdominal wall of the

supine patient and the surface of the examining table. Theoretically, visceral fat maintains the abdominal depth in the supine patient, whereas

subcutaneous fat allows the abdominal depth to partially collapse from the

force of gravity.19 Even so, there are few studies of this measure, and most

correlate it with variables of uncertain clinical significance such as cardiovascular risk factors or the amount of visceral fat visualized on body

imaging.16

The references for this chapter can be found on www.expertconsult.com.



REFERENCES    85.e1



REFERENCES

1. Brown WV, Fujioka K, Wilson PWF, Woodworth KA. Obesity: why be concerned? Am J

Med. 2009;122:S4-S11.

2. Hippocrates. Hippocratic Writings. Harmondsworth, Middlesex, England: Penguin Books;

1978.

3. Ogden CL, Carroll MD, Curtin LR, et al. Prevalence of overweight and obesity in the

United States, 1999-2004. JAMA. 2006;295(13):1549-1555.

4. U.S. Preventive Services Task Force. Screening for obesity in adults: recommendations

and rationale. Ann Intern Med. 2003;139:930-932.

5. Jelliffe DB, Jeliffe EF. Underappreciated pioneers: Quetelet: man and index. Am J Clin

Nutr. 1979;32:2519-2521.

6. Womersley J, Durnin JVGA. A comparison of the skinfold method with extent of “overweight” and various weight-height relationships in the assessment of obesity. Br J Nutr.

1977;38:271-284.

7. Haslam DW, James WPT. Obesity. Lancet. 2005;366:1197-1209.

8. Pischon T, Boeing H, Hoffmann K, et al. General and abdominal adiposity and risk of

death in Europe. N Engl J Med. 2008;359:2105-2120.

9. Prospective Studies Collaboration. Body-mass index and cause-specific mortality in

900,000 adults: collaborative analyses of 57 prospective studies. Lancet. 2009;373:

1083-1096.

10. Calle EE, Thun MJ, Petrelli JM, et al. Body-mass index and mortality in a prospective

cohort of U.S. adults. N Engl J Med. 1999;341:1097-1105.

11. de Gonzalez AB, Hartge P, Cerhan JR, et al. Body-mass index and mortality among 1.46

million white adults. N Engl J Med. 2010;363:2211-2219.

12. Vague J. The degree of masculine differentiation of obesities: a factor determining predisposition to diabetes, atherosclerosis, gout, and uric calculous disease. Am J Clin Nutr.

1956;4(1):20-34.

13. Bjorntorp P. Obesity. Lancet. 1997;350(9075):423-426.

14. Kahn HS, Williamson DF. Abdominal obesity and mortality risk among men in nineteenth-century North America. Int J Obes Relat Metab Disord. 1994;18(10):686-691.

15. Egger G. The case for using waist to hip ratio measurements in routine medical checks.

Med J Aust. 1992;156(4):280-285.

16. Snijder MB, van Dam RM, Visser M, Seidell JC. What aspects of body fat are particularly

hazardous and how do we measure them? Int J Epidemiol. 2006;35:83-92.

17. Jacobs EJ, Newton CC, Wang Y, et al. Waist circumference and all-cause mortality in a

large US cohort. Arch Intern Med. 2010;170(15):1293-1301.

18. Expert panel on detection, evaluation, and treatment of high blood cholesterol in adults:

Executive summary of the third report of the National Cholesterol Education Program

(NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol

in adults (Adult Treatment Panel III). JAMA. 2001;285:2486-2497.

19. van der Kooy K, Seidell JC. Techniques for the measurement of visceral fat: a practical

guide. Int J Obes Relat Metab Disord. 1993;17(4):187-196.



CHAPTER



13



Cushing Syndrome

I.  INTRODUCTION

Cushing syndrome refers to clinical findings—such as hypertension,

central obesity, weakness, hirsutism (in women), depression, skin striae,

and bruises—induced by excess circulating glucocorticoids. The most

common cause is exogenous administration of corticosteroid hormones.1

Endogenous Cushing syndrome results from pituitary tumors producing

adrenocorticotropic hormone (ACTH) (i.e., Cushing disease; 70% of

endogenous cases), ectopic production of ACTH (usually by small cell carcinoma of the lung or carcinoid tumors of the lung or mediastinum; 10%

of cases), adrenal adenomas (10% of cases), or adrenal carcinomas (5% of

cases).1 Cushing disease and ectopic ACTH syndrome are referred to as

ACTH-dependent disease because the elevated cortisol levels are accompanied by inappropriately high ACTH levels. Adrenal tumors are referred

to as ACTH-independent disease.

The bedside findings of Cushing syndrome were originally described by

Harvey Cushing in 1932.2 Corticosteroid hormones were first used as therapeutic agents to treat patients with rheumatoid arthritis in 1949; within

2 years, clear descriptions of exogenous Cushing syndrome appeared.3



II.  FINDINGS AND THEIR PATHOGENESIS

Table 13-1 presents the physical signs of more than 1000 patients with

Cushing syndrome.

A.  BODY HABITUS

Patients with Cushing syndrome develop central obesity (also known as

truncal obesity or centripetal obesity), a term describing the accumulation

of fat centrally on the neck, chest, and abdomen, which contrasts conspicuously with the muscle atrophy affecting the extremities.

There are three definitions of central obesity.

1.Obesity sparing the extremities (a subjective definition and also the

most common one)4,12

2.Obesity as defined by the central obesity index, a complicated ratio

of the sum of three truncal circumferences (neck, chest, and abdomen) divided by the sum of six limb circumferences (bilateral arms,

thighs, and lower legs); values higher than 1 are abnormal13

86



CHAPTER 13 — CUSHING SYNDROME   87

TABLE 13-1 Frequency

Physical Finding†



of Individual Findings in Cushing Syndrome*

Frequency (%)‡



vital signs



Hypertension



64-88



body habitus



Moon facies

Central obesity

Buffalo hump



67-92

44-97

34-75



skin findings



Thin skin

Plethora

Hirsutism, women

Ecchymoses

Red or purple striae

Acne



27

28-94

48-81

23-75

46-68

21-52



extremity findings



Proximal muscle weakness

Edema



39-68

15-66



other findings



Significant depression



12-40



*Information is based on 1056 patients from references 4 to 11. Each study enrolled more than

50 patients with disease.

†Diagnostic standard: For Cushing syndrome, elevated daily cortisol or corticosteroid metabolites,

or both, with loss of circadian rhythm and with abnormal dexamethasone suppression tests.

‡Results are overall mean frequency or, if statistically heterogeneous, the range of values.



3.Obesity as defined by an abnormal waist-to-hip circumference ratio

(i.e., >1 in men and >0.85 in women; see Chapter 12)14

Defining central obesity based on the abnormal waist-to-hip circumference

is not recommended, because there are many false-positive results (i.e., for

Cushing syndrome).

Other characteristic features of the body habitus in Cushing syndrome

are accumulation of fat in the bitemporal region (moon facies),15 between

the scapulae and behind the neck (buffalo hump), in the supraclavicular

region (producing a “collar” around the base of the neck),14 and in front

of the sternum (dewlap, named for its resemblance to the hanging fold

of skin at the base of the bovine neck [Fig.13-1]).16 Many experts state

that the buffalo hump is not specific for Cushing syndrome but accompanies weight gain from any cause17,18; this hypothesis has not been formally

tested. Morbid obesity is rare in Cushing syndrome.19

The truncal obesity of Cushing syndrome reflects increased intraabdominal visceral fat, not subcutaneous fat,20 probably from glucocorticoid-induced reduction in lipolytic activity and activation of lipoprotein

lipase, which allows tissues to accumulate triglyceride.



88   PART 3 — GENERAL APPEARANCE OF THE PATIENT



Temporal

Supraclavicular

Dorsal scapular

Episternal



FIGURE 13-1  Distribution of adipose tissue in Cushing syndrome. Rounding of cheeks

and prominent bitemporal fat produce the characteristic moon facies. Fat also may accumulate

bilaterally above the clavicles (supraclavicular collar), in front of the sternum (episternal area, or

dewlap), and over the back of the neck (dorsal cervical fat pad, or buffalo hump). In these drawings,

the dotted line depicts normal contours of patients without Cushing syndrome.



B.  HYPERTENSION

Hypertension affects three of four patients with Cushing syndrome.

Proposed mechanisms are suppressed vasodepressor systems (prostaglandins,

kallikrein-kinin), exaggerated pressor responses to vasoactive substances,

and possible activation of the renin-angiotensin system.21 Most patients do

not have a positive salt and water balance.14

C.  SKIN FINDINGS

The characteristic skin findings are thin skin, striae, plethora, hirsutism (in

women), acne, and ecchymoses.

Significant thinning of the skin probably arises from corticosteroidinduced inhibition of epidermal cell division and dermal collagen synthesis.14 To measure skin thickness, many experts recommend using calipers

(either skinfold calipers or electrocardiograph calipers) on the back of the

patient’s hand, an area lacking significant subcutaneous fat and thus representing just epidermis and dermis.22,23 In women of reproductive age,

this skinfold should be thicker than 1.8 mm.22 Precise cutoffs have not

been established for men, in whom the skin is normally thicker than in

women, or for elderly patients, in whom the skin is normally thinner than

in younger patients.23

The striae of Cushing syndrome are wide (>1 cm) and deep red or purple, in contrast to the thinner, paler pink or white striae that occur normally during rapid weight gain of any cause.4,24 Striae are usually found on

the lower abdomen but may occur on the buttocks, hips, lower back, upper

thighs, and arms. In one of the original Cushing syndrome patients, wide

striae extended from the lower abdomen to the axillae.2 Pathologically,

striae are dermal scars, with collagen fibers all aligned in the direction

of stress, covered by an abnormally thin epidermis.25 The pathogenesis

of striae is not understood, but they may represent actual rupture of the



CHAPTER 13 — CUSHING SYNDROME   89



weakened connective tissue of the skin, under tension from central obesity, which leaves a thin translucent window to the red- and purple-colored

dermal blood vessels. Striae are more common in younger patients with

Cushing syndrome than in older patients.24,26

Plethora is an abnormal diffuse purple or reddish color of the face.4

Hirsutism and acne occur because of increased adrenal androgens.14,24

Ecchymoses probably appear because the blood vessels, lacking connective

tissue support and protection, are more easily traumatized.

The severity of striae, acne, and hirsutism correlates poorly with cortisol

levels, indicating that other factors—temporal, biochemical, or genetic—

play a role in these physical signs.24

D.  PROXIMAL WEAKNESS

Painless proximal weakness of the legs is common and prominent in

Cushing syndrome, especially in elderly patients.26 Because the weakness

is a true myopathy, patients lack fasciculations, sensory changes, or reflex

abnormalities. Chapter 59 discusses how to assess proximal muscle strength.

E.  DEPRESSION

Patients with Cushing syndrome may have crying episodes, insomnia,

impaired concentration, difficulty with memory, and suicide attempts.27,28

The severity of depression correlates with the cortisol level,27 and, unless

the depression antedates the endocrine symptoms by years, it usually

improves dramatically after treatment.28

F.  PSEUDO-CUSHING SYNDROME

Several disorders, including chronic alcoholism, depression, and human

immunodeficiency virus (HIV) infection, may mimic the physical findings and biochemical findings of Cushing syndrome and are referred to as

pseudo-Cushing syndrome. Patients with chronic alcoholism may develop

the physical findings or the biochemical abnormalities, or both, probably

because of overproduction of ACTH by the hypothalamic-pituitary axis, an

abnormality that resolves after several weeks of abstinence.29,30 Depressed

patients may have the biochemical abnormalities of Cushing syndrome,

but they usually lack the physical findings.31 Patients with HIV infection,

particularly if they are receiving protease inhibitors, may develop some of

the physical findings (especially the buffalo hump and truncal obesity) but

rarely the biochemical abnormalities.32-34



III.  CLINICAL SIGNIFICANCE

A.  DIAGNOSTIC ACCURACY OF FINDING

EBM Box 13-1 presents the diagnostic accuracy of individual physical signs

for Cushing syndrome, as applied to 247 patients with suspected disease.

The findings that significantly increase the probability of Cushing syndrome

are thin skinfold (likelihood ratio [LR] = 115.6), ecchymoses (LR = 4.5),

central obesity (LR = 3), and plethora (LR = 2.7). (The astronomical

LR for thin skinfold thickness [LR = 115.6] derives from young women



90   PART 3 — GENERAL APPEARANCE OF THE PATIENT



EBM BOX 13-1



Cushing Syndrome*

Likelihood Ratio‡

if Finding Is



Sensitivity

(%)



Specificity

(%)



Vital Signs

Hypertension4,12



25-38



83-94



2.3



0.8



Body Habitus

Moon facies12

Central obesity4,12,13

Generalized obesity4



98

72-90

4



41

62-97

38



1.6

3.0

0.1



0.1

0.2

2.5



Skin Findings

Thin skinfold22

Plethora4

Hirsutism, in women4,12

Ecchymoses4,12

Red or blue striae4,12

Acne4



78

83

50-76

54-71

46-52

52



99

69

56-71

69-94

63-78

76



115.6

2.7

1.7

4.5

1.9

2.2



0.2

0.3

0.7

0.5

0.7

0.6



62-63



69-93



NS



0.4



38-57



56-83



1.8



0.7



Finding (Reference)†



Extremity Findings

Proximal muscle

­weakness4,12

Edema4,12



Present



Absent



*Diagnostic standard: For Cushing syndrome, elevated daily cortisol or corticosteroid

metabolites, or both, with loss of circadian rhythm and with abnormal dexamethasone

suppression test.

†Definition of findings: For hypertension, diastolic blood pressure >105 mm Hg; for central

obesity, central obesity index exceeds 113 or subjective appearance of central obesity sparing

the extremities4,12; for thin skinfold, skinfold thickness on back of hand <1.8 mm (women of

reproductive age only).22

‡Likelihood ratio (LR) if finding present = positive LR; LR if finding absent = negative LR.

NS, not significant.

Click here to access calculator.

CUSHING SYNDROME

Probability

Decrease

Increase

–45% –30% –15%

+15% +30% +45%

LRs



0.1



0.2



0.5



Absence of moon facies

Generalized obesity

Absence of thin skinfold

Absence of plethora

Absence of proximal muscle

weakness



1



2



5



10



Thin skinfold

Ecchymoses

Central obesity

Plethora



LRs



115.6



CHAPTER 13 — CUSHING SYNDROME   91



presenting with hirsutism and menstrual irregularity and thus applies only

to similar patients.) The findings that decrease the probability of Cushing

syndrome are generalized obesity (LR = 0.1), absence of moon facies (LR =

0.1), absence of central obesity (LR = 0.2), and normal skinfold thickness

(LR = 0.2).

In these same studies, one of the more powerful predictors of Cushing

syndrome is osteoporosis (sensitivity of 61% to 63%, specificity of 94%

to 97%, positive LR = 17.6, and negative LR = 0.4).4,12 Osteoporosis was

identified radiographically in these studies, but it is often apparent at the

bedside from vertebral fractures, kyphosis, and loss of height. Presumably,

these bedside findings also accurately identify Cushing syndrome.

B.  ETIOLOGY OF CUSHING SYNDROME AND BEDSIDE

FINDINGS

Patients who take exogenous corticosteroids have the same frequency of

central obesity, moon facies, and bruising as patients with endogenous

Cushing syndrome but a significantly lower incidence of hypertension, hirsutism, acne, striae, and buffalo humps.7

Patients with the ectopic ACTH syndrome from small cell carcinoma

are more often male, have Cushing syndrome of rapid onset (over months

instead of years), and present with prominent weight loss, myopathy, hyperpigmentation, and edema.17,31,35 The irregular hepatomegaly of metastatic

disease may suggest this diagnosis.35 In studies of patients with ACTHdependent Cushing syndrome, two findings increase the probability of

ectopic ACTH syndrome: weight loss (positive LR = 20) and symptom

duration of less than 18 months (positive LR = 15).9,35

Hirsutism and acne may occur in any woman with endogenous Cushing

syndrome, but the presence of virilization (i.e., male pattern baldness, deep

voice, male musculature, clitoromegaly) argues strongly for adrenocortical

carcinoma.36-38

The references for this chapter can be found on www.expertconsult.com.



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