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54
A. R. Spector and T. J. Farrer
In summary, there is a clear association between
OSA and depression, with some studies demonstrating
a causal relationship. Clinical samples appear to have
higher reported rates of depression relative to community samples. In addition, research suggests there are
moderating variables in this association, such as the
presence of signicant comorbidities. Fatigue and daytime sleepiness are known to play a role in the degree of
4
depression in OSA patients, and clinicians must practice
caution in differentiating depression symptoms from
common OSA complaints, given the high degree of
symptom overlap.
4.7 Summary
OSA is a condition with a myriad of downstream effects,
including attention and executive dysfunction, learning
and memory impairment, visual-spatial dysfunction,
depression, and mild language impairment as well.
These effects are likely due to OSA causing any combination of the following: cyclic oxygen desaturation,
free radical formation, hypertension, dyslipidemia, insulin resistance, low testosterone, leptin resistance, and
elevations in inammatory cytokines. These changes
cause substantial real-world consequences for patients,
including job loss, major depressive disorder, or even
Alzheimer’s disease [96]. Attention must be paid to these
oft-overlooked consequences of OSA to ensure appropriate treatment is provided.
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57
Diagnostic Considerations
inMetabolic Disease Associated
withObstructive Sleep Apnea
RaymondE.Bourey
Contents
5.1 Introduction – 58
5.2 Obesity – 59
5.3 Hypertension – 60
5.4 Diabetes Mellitus – 61
5
5.5 Fatty Liver Disease – 63
5.6 Conclusions – 64
References – 65
© Springer Nature Switzerland AG 2021
K. B. Kim et al. (eds.), Management of Obstructive Sleep Apnea, https://doi.org/10.1007/978-3-030-54146-0_5
58
R. E. Bourey
Core Message
5 Recognition and diagnosis of metabolic diseases asso-
ciated with sleep apnea is important to avoid adverse
outcomes of treatment.
5 In perioperative management of OSA, associated met-
abolic diseases not only increase risk for cardiovascular
events, but also increase risk for perioperative bleeding,
infection, and slow wound healing.
5 To aid recognition and diagnosis of metabolic disease,
we recommend use of recent diagnostic criteria for rel-
5
evant metabolic diseases associated with sleep apnea,
which include obesity, hypertension, diabetes, and liver
disease.
5 Recognition and treatment of metabolic disease is
handled most efciently by a multidisciplinary sleep
disorders center that makes optimal use of diagnostic
and therapeutic protocols in the context of electronic
health records.
especially if treatment includes physiological stress of
general anesthesia and surgical procedures.
Metabolic control requires cross-talk among vari-
ous organs and signaling pathways. The relationship
between OSA and metabolic disease represents a complex interplay among organs and tissues (see .
Fig.5.1).
In this chapter, we consider current recommenda-
tions for diagnosis of major metabolic diseases associated with OSA, to include obesity, hypertension, diabetes
mellitus, and fatty liver disease. Presence and severity of
these closely related diseases will inuence decisions on
exercise and perioperative treatment through increased
risks for cardiovascular events, coagulopathy, infection,
and slow wound healing.
Given the practical nature of this book, we will not
undertake exhaustive review of diagnostic criteria generated by multiple organizations, but instead focus on
the most recent denitions of metabolic disease that
seem appropriate to practitioners of sleep medicine.
To avoid redundancy, we will not cover metabolic syn-
5.1 Introduction
drome, which is not a disease, but a syndrome that vari-
ably includes all the metabolic diseases covered in this
While accurate diagnosis of obstructive sleep apnea
(OSA) remains the core objective of this section on diagnostic considerations, one does not want to miss potentially dangerous metabolic disease associated with sleep
apnea. Recognition and diagnosis of metabolic disease
is important to avoid adverse outcomes of treatment,
chapter (v.i.).
This chapter also avoids entry into the debate, now
fueled by thousands of publications, over effectiveness
of treatment of sleep apnea to improve in metabolic consequences of sleep apnea, other than to simply note that
improvements in associated metabolic disease reect
. Fig. 5.1 Relationships
among obstructive sleep apnea,
obesity, hypertension, diabetes
mellitus, steatohepatosis, and
dyslipidemia
Dyslipidemia
Hypertension
Sleep apnea
Elevated sympathetic nervous
system activity
Stress hormones
Hypoxemia
Vascular resistance
Inammation
Elevated venous pressure
Insulin resistance
Diabetes
mellitus
or
prediabetes
Obesity
Fatty liver
disease
Diagnostic Considerations inMetabolic Disease Associated withObstructive Sleep Apnea
59
5
sufcient effectiveness of treatment over sufcient time.
Treatment of sleep apnea is covered in parts III and IV
of this book.
This chapter underscores recommendations for a
multidisciplinary team in diagnosis and treatment of
patients with OSA. Potential consequences of associated metabolic diseases will affect development and
implementation of the treatment plan and the team
should include individuals familiar with diagnosis and
treatment of those diseases.
5.2 Obesity
Obesity, a disease of epidemic proportions in the United
States and other industrialized countries, carries a close
relationship to sleep apnea and other metabolic disease.
Obesity can cause or exacerbate sleep apnea. In a reinforcing cycle, disruption of sleep due to sleep apnea (or
any cause) can lead to weight gain and obesity [1–3]. Not
surprisingly, treatment of obesity can lead to improvement in sleep apnea [4–6] and conversely, treatment of
sleep apnea associates with early improvement in intraabdominal fat mass, if not the total amount of adipose
tissue [7, 8]. Although continuous positive airway pressure(CPAP) therapy can initially be associated with a
disconcerting increase in mass, perhaps due to vascular
relaxation and blood volume expansion, therapy seems
important to subsequent success at weight loss [9].
As with other metabolic disease associated with sleep
apnea, we should recognize not only the high prevalence
of obesity in patients with sleep apnea, but also the high
prevalence of sleep apnea in patients with obesity.
Obesity is now generally recognized as a disease [10],
although some denitions of obesity include a somewhat
circular denition that obesity must cause a second disease process, such as arthritis, diabetes mellitus, or sleep
apnea. This requirement for comorbidity often makes
the diagnosis of obesity somewhat redundant to other
metabolic disease, but we believe diagnosis of obesity is
important to care of patients with sleep apnea, as obesity and severity of obesity can be used as a marker of
risk for hypoventilation and general anesthesia. Further,
it is often used by third-party payers to justify payment
for diagnostic and therapeutic procedures.
Patients with body mass index (BMI) of 30 or more
are generally considered obese and patients with BMI
of greater than 40kg/m2 are considered morbidly obese.
Although this might be all that is needed for current
requirements by third-party payers, a more physiological denition that includes markers of central adiposity and comorbidity is needed to rene diagnosis and
therefore potential therapies.
The American Association of Clinical Endocrinology
has dedicated signicant resources to better dene obesity in patients who warrant therapy. Recently published
guidelines include both an anthropometric component
and a clinical (associated disease) component to better
identify patients who will benet from therapy [11]. In this
denition, the anthropometric component of the diagnosis of obesity is generally provided by BMI >30 kg/m
2
with evidence for obesity provided by a waist measurement of ≥102cm (40 inches) for men in the United States
or ≥88cm (35 inches) for women, or BMI >35. I note that
among untrained personnel, measurement of waist circumference can be problematic, as most patients with central obesity do not technically have a waist when dened
as a narrowing between chest and hips. In this context,
I recommend no measurement of waist circumference
except in athletes in whom a diagnosis of obesity is inappropriate and a waist or narrowing is easily identied.
Tip
Measurement of waist circumference in patients
without an identiable waist or narrowing between
chest and hips is problematic, and should be avoided.
Absence of an identiable waist should be sufcient
evidence for adiposity.
See . Table5.1 for a working denition of obesity and
staging of obesity based upon these guidelines.
. Table 5.1 Diagnosis of obesity with adiposity based on AACE denitions [11]
Diagnostic categories No obesity Stage 0 Stage 1 Stage 2
Risk stratication None Mild to moderate Severe
Anthropometric
diagnosis
Clinical diagnosis
(list of complications)
BMI<25kg/m
2
BMI=25–29.9kg/m2≡overweight
BMI≥30kg/m2≡obesity
Evidence for excess adiposity
No
complications
One or more mild–moderate
complications
One severe complication or requires
signicant weight loss to treat
60
R. E. Bourey
. Table 5.2 Diagnosis of obesity
Anthropometric component Clinical component
BMI≥25kg/m
or
(BMI≥23kg/m
in certain ethnicities)
AND excess adiposity
5
2
2
Obstructive sleep apnea
Gastroesophageal reux
Asthma/restrictive airway
disease
Hypoventilation
Hypertension
Prediabetes
Diabetes type 2
Fatty liver disease
Dyslipidemia
Cardiovascular disease
Polycystic ovarian syndrome
Female infertility
Male hypogonadism
Osteoarthritis
Depression/anxiety
A strong relationship between hypertension and
sleep apnea has long been recognized and formally
reported since the early 1970s [12, 13]. As with other
metabolic disease associated with sleep apnea, we need
to recognize not only the high prevalence of hypertension in patients with sleep apnea [14–16], but also the
high prevalence of sleep apnea in patients with hypertension [17, 18].
In the course of preparation of this chapter, the
American Heart Association released an updated clinical
practice guideline blood pressure [19]. Unlike the 2014
guidelines from the Joint National Commission, which
dropped mention of sleep apnea or any other sleep disorder in relation to management of hypertension, these
guidelines have reinstated recommendations for evaluation and treatment of sleep apnea, with the caveat that
current data studies have demonstrated mixed results
and that treatment of sleep apnea might not reduce cardiovascular disease risk.
As with all metabolic disease, early recognition and
treatment can prevent progression and irreversible complications. Analogous to overweight and prediabetes,
recommendations for hypertension have decreased the
blood pressure at which treatment is recommended. The
current categorization is seen in .
Table5.3.
The diagnosis is based on accurate measurement of
blood pressure in the ofce using rst and fth Korotkoff
sounds to establish systolic and diastolic blood pressure,
The clinical component needed for staging of obesity
consists of identication of an associated metabolic or
and/or use of an automated, validated, and calibrated
home device.
mechanical problem as listed in . Table5.2.
Once the diagnosis of obesity is made, it should be
graded by severity and included in the problem list to
guide decisions as regards pulmonary function tests and
tests for hypoventilation at rest or during sleep. I note
that by this denition, all patients with BMI >35kg/m2
with severe sleep apnea have stage 2 obesity, and no further evaluation is required to add this diagnosis to the
list of related problems that will need to be addressed in
Tip
It is our opinion that 24-hour blood pressure monitoring should be considered for all patients with
obstructive sleep apnea, but especially for those with
variably normal, elevated, or stage I hypertension or
those with unexplained left ventricular hypertrophy.
treatment of sleep apnea.
5.3 Hypertension
Hypertension is a consequence of multiple metabolic
and subsequent hormonal and nervous system changes
that occur with obstructive sleep apnea. Recognition of
hypertension during evaluation of the patient with sleep
apnea becomes important during therapy to reduce risks
of cardiovascular events, which can be further increased
by some medications for obesity, general anesthesia, and
perioperative stress. Accurate diagnosis and staging of
hypertension allow specic treatment plans to reduce
these risks.
For all patients with elevated blood pressure or hypertension, screening for secondary hypertension such
as obstructive sleep apnea and nonpharmacological
intervention is recommended. In addition to obstructive sleep apnea, consideration should also be given to
measurement of potassium and screening for renal vascular disease, aldosteronism, coarctation of the aorta,
or endocrine disease. If the diagnostic team does not
include an endocrinologist or other specialist in secondary hypertension, then consideration should be given to
referral.
Medications that cause hypertension are commonly
used in patients with obstructive sleep apnea; these
Diagnostic Considerations inMetabolic Disease Associated withObstructive Sleep Apnea
. Table 5.3 AHA denition of normal blood pressure, elevated blood pressure and Stages 1, 2,
and 3 hypertension (c.f. [19])
>100 Stage 2 Stage 2 Stage 2 Stage 2 Stage 2
90–99 Stage 2 Stage 2 Stage 2 Stage 2 Stage 2
80–89 Stage 1 Stage 1 Stage 1 Stage 2 Stage 2
<80 Normal Elevated Stage 1 Stage 2 Stage 2
Diastolic BP mm Hg
<120 120–129 130–139 140–159 >160
Systolic BP mm Hg
61
5
Pharmacological treatment with cardiovascular disease (CVD) or estimated 10-year risk for
CVD >10%
Pharmacological treatment with estimated 10-year risk for cardiovascular disease <10%
include not only self-medication with alcohol, caffeine,
nonsteroidal anti-inammatory medication, or nonprescription stimulants such as methamphetamine, but also
prescribed medications that include amphetamines for
treatment of attention decit disorder, pseudoephedrine
as a decongestant, and antipsychotics or antidepressants including high-dose serotonin noradrenaline reuptake inhibitor (SNRIs).
Evaluation of hypertension consists not only of
good history and physical, but also basic blood testing
to include glucose, metabolic panel, lipid prole, creatinine, electrolytes, thyroid-stimulating hormone (TSH),
urinalysis, electrocardiogram, and perhaps echocardiogram.
Pharmacological treatment of hypertension is generally considered reasonable when the patient meets a
combination of elevated mean blood pressure and a
measure of cardiovascular risk; see . Table5.3.
We note that recent guidelines for diagnosis and
treatment of hypertension include recommendation
for care by multidisciplinary team members to include
nephrologists, endocrinologists, cardiologists, pharmacists, etc. In the computer era, the sleep disorders center
can easily institute electronic health record-driven testing and treatment protocols for hypertension and metabolic disease in collaboration with these specialists. This
is important as treatment of one metabolic disease often
leads to improvement in others. For example, treatment
of hypertension improves blood ow and thereby insulin resistance, and it is generally recognized that any
therapy for blood pressure (outside of thiazide diuretics and beta-adrenergic receptor antagonists, which
decrease glucose-stimulated insulin release) will improve
insulin action and decrease progression of prediabetes
to diabetes.
5.4 Diabetes Mellitus
The relationship among insulin resistance, diabetes
mellitus, and obstructive sleep apnea is well known.
Prevalence of diabetes among patients with sleep
apnea is proportional to severity of sleep apnea and
has been most recently reported between 16% in a
European group of 6442 patients with OSA [20] and
30% in a multiethnic group of 745 consecutive patients
with OSA, at an urban medical center in the United
States [21]. Prevalence of sleep apnea in patients with
diabetes has been less well studied, and has been limited to home apnea testing, a less specic test at low
apnea–hypopnea index (AHI). Results range from 36%
in La Jolla (AHI>15) [22] to 87% in the multicenter
Sleep AHEAD trial (AHI>5) [23]. Ethnic differences
in the prevalence of sleep apnea among patients with
diabetes seem to be explained more by obesity than
diabetes [24].
62
R. E. Bourey
Obstructive sleep apnea activates a cascade of metabolic changes that can contribute to diabetes mellitus
including hypertension, sympathetic nervous system
activation, and elevated cortisol that in turn cause resistance to insulin action and accelerate gluconeogenesis.
In susceptible individuals, this causes metabolically
mediated, type 2 diabetes mellitus (T2DM).
Coordination between dedicated centers for both
sleep medicine and metabolic disease is necessary to successful care. A recent study [25] underscored not only the
5
high prevalence of undiagnosed sleep apnea in patients
with T2DM, but also the problems encountered in the
absence of specialists in sleep medicine. Although 90%
of patients with T2DM screened by questionnaire for
sleep apnea had sleep with high risk of apnea, only 29%
agreed to test after contact from a large, primary care
clinic. Of this group of 213, 91% had OSA on the basis
of predominantly home testing (AHI>5), but only twothirds agreed to trial therapy, that is, only one of every
six patients thought to have sleep apnea agreed to a trial
of treatment [25]. Discussion of results and education
of patients to risks and benets of their decisions should
always be handled by a team that is trained and experienced in sleep medicine.
Although this section deals with metabolically mediated, T2DM, I should note a potential relationship
among obesity, sleep apnea, and autoimmune-medi-
. Table 5.4 ADA criteria for diagnosis of diabetes [28]
Tests to establish the diagnosis
of diabetes
Repeat test or use a different test
to conrm
Oral glucose
tolerance test
Hemoglobin
Fasting plasma
glucose
Hyperglycemic
crisis
A1C
2-h PG
≥200mg/dL
(11mM)
≥6.5%
(48mmol
glc/mol hb).
FPG
≥126mg/dL
(7.0mM).
Random
plasma
glucose
≥200mg/dL
(11mM).
Notes
Oral glucose tolerance test
with 75g glucose in water
in the morning after a fast
with glucose measured at
0, 60, and 120minutes
The test should be
performed in a laboratory
using a method that is
NGSP-certied and
standardized to the
DCCT assay
Fasting is dened as no
caloric intake for 8hours,
though it should be noted
that sham feeding can
result in insulin release
and caffeine can cause
gluconeogenesis
Must be associated with
classic symptoms of
hyperglycemia or
hyperglycemic crisis
ated type I diabetes mellitus (T1DM). The incidence
of T1DM is increasing worldwide [26]. Whether this
increase in incidence is related to a higher incidence of
preclinical autoimmunity or faster progression to diabetes after development of autoimmunity is not clear.
Rise in T1DM has stimulated speculation that insulin
resistance and obesity might modulate autoimmunity. A
patient to be fasting, is more convenient than a 2-hour
oral glucose tolerance test, and is less dependent on the
patient’s health status at the time of testing. The following caveats should be acknowledged [30].
recent meta-analysis supports the association between
childhood obesity and subsequent T1DM [27].
The diagnosis of diabetes mellitus and related hyperglycemia is important to trigger evaluation for microvascular and macrovascular complications that can
complicate therapy. From a surgical perspective, diagnosis of diabetes mellitus should not be missed, lest
one has the diagnosis forced upon him in the postoperative period, incurring a higher risk of infection and
slow wound healing, and necessitating a scramble for
resources to immediately control glucose and train a
naïve, post-operative patient for high intensity care at
home.
Tip
5 HbA1C should not be considered the primary cri-
terion for diagnosis of diabetes. Conrmation with
another test is recommended.
5 HbA1C may be misleading in several ethnic popu-
lations (for example, African–American patients).
5 HbA1C may be misleading in the setting of vari-
ous hemoglobinopathies, iron deciency, hemolytic
anemias, thalassemias, spherocytosis, and severe
hepatic and renal disease.
Criteria used for the diagnosis of diabetes by the
American Diabetes Association [28] are relatively
straight forward (See .
often cut corners and diagnosis of diabetes is missed.
For example, over-reliance on Hb
of patients with diabetes mellitus [29, 30].
The use of A1C for the diagnosis of diabetes has
several advantages. Such testing does not require the
Table 5.4), but practitioners
, will miss 20-50%
A1C
As with other metabolic disease, once the diagnosis of
diabetes or prediabetes is established, patients should be
referred to a multidisciplinary specialty clinic to educate
the patient- and design-specic therapy. Centers accredited
by the American Diabetes Association or the American
Association of Diabetes Educators have the added advan-
()
()
..
*-
()
()
Diagnostic Considerations inMetabolic Disease Associated withObstructive Sleep Apnea
63
5
tage of payment from third-party payers such as Medicare
for these services. These centers may include nurse educators, registered dietitians, exercise physiologists, physical
therapists, pharmacists, psychologists, social workers, and
physicians. Administrators should appreciate that from an
institutional perspective, certied centers for diabetes education can be used also for comprehensive and efcient
treatment of obesity, hypertension, steatohepatitis, dyslipidemia, and other metabolic disease.
5.5 Fatty Liver Disease
Fatty liver disease occurs when pathological deposition of fat in the liver leads to metabolic dysfunction,
inammation, brosis, and cirrhosis. It has emerged as
the major cause of cryptogenic cirrhosis and is currently
the second most common indication for addition to the
transplant wait-list in the United States [31]. It is the
leading cause of chronic liver disease and occurs in at
least two-thirds of patients with obesity [32]. Like other
metabolic disease, prevalence and severity worsen with
sleep apnea [33–35]. We note that severity of sleep apnea
associates with severity of non-alcoholic fatty liver disease (NAFLD) even in patients without obesity [36] or
metabolic syndrome [36].
Fatty liver disease, also referred to as non-alcoholic
fatty liver disease (NAFLD), constitutes a spectrum
of disease from benign, reversible hepatosteatosis to
chronic non-alcoholic steatohepatitis (NASH) and cirrhosis. Fat deposition contributes to inammation of
the liver (steatohepatitis) and subsequent brosis or cirrhosis. The process is accelerated by liver insulin resistance [37].
Although much of the literature focuses on the relationship of OSA to non-alcoholic fatty liver disease, it is
our impression that much of the fatty liver seen in our
sleep disorders center has a contribution from alcohol
consumption, past or present. We must remember, alcohol consumption can exacerbate NAFLD at even low
levels of consumption [38]. Many patients with obstructive sleep apnea have concurrent insomnia, which they
self-treat with alcohol. Historical screening for alcohol
consumption is an important step in diagnostic and
therapeutic considerations for fatty liver.
Alcohol consumption is an important diagnostic
consideration, especially when one considers its effect
on perioperative metabolism of anesthetics as well as
risk of bleeding associated with decreased synthesis of
coagulation factors, thrombocytopenia, and effects of
alcoholic disease on platelet function. In our clinic, all
patients with sleep apnea are instructed on the relationships among alcohol, sleep apnea, and metabolic disease, and are reminded not to drink alcohol until these
problems are fully addressed.
Tip
Fatty liver disease in sleep apnea often associates with
a history of alcohol consumption. Patients should be
instructed to avoid alcohol until metabolic problems
and sleep apnea are fully addressed.
Development of diagnostic tools for both early development of NAFLD and NASH with brosis and cirrhosis are rapidly evolving. MR proton density fat fraction
(PDFF) has become the gold standard for liver fat quantication and liver biopsy remains the gold standard for
brosis. We have, however, fairly good tests to screen for
likelihood of fatty liver or brosis based on commonly
measured anthropometric and serological variables
including aspartate amino transferase (AST), gammaglutamyl transferase (GGT), alanine amino transferase
(ALT), and platelet content (PLT). (See . Table5.5).
As PDFF and liver biopsy cannot be performed universally, we have selected some screening tests that can
be easily programmed into an electronic health record
(EHR) using simple eld codes, to calculate risk for
NAFLD or NASH, and thereby add these diagnoses
to the list of problems to address in therapy. Although
the emphasis has drifted away from quantifying liver fat
because the amount of the fat in the liver is not related
to liver-related outcomes, in the context of sleep apnea
and related metabolic disease, we continue to recommend screening for risk of hepatosteatosis or NAFLD,
as this is a potentially reversible problem and treatment can lead to prevention of irreversible brosis and
cirrhosis.
For assessment of risk for fatty liver, we recommend
either Fatty liver index (FLI) or the NAFLD liver fat
score (NAFLD-LFS). FLI is given by the following calculation:
loge triglycerides BMIloge GGT
*
0 953 0 139 0 718 0....
e
FLI
=
1
+
loge triglyceride
.
0 953
*
e
+*+*
ssBMI loge ggt waist circumference
()
+*+*
+
waistcircumference
053 15 745
+* -0 139 0 718 0 053 1.. . 55 745
()
100
*
.