Many patients who have obstructive lung disease, ie, chronic obstructive pulmonary disease (COPD) or asthma, also have obstructive sleep apnea (OSA), and vice versa.

The combination of COPD and OSA was first described almost 30 years ago by Flenley, who called it “overlap syndrome.”¹ At that time, he recommended that a sleep study be considered in all obese patients with COPD who snore and in those who have frequent headaches after starting oxygen therapy. In the latter group, he doubted that nocturnal oxygen was the correct treatment. He also believed that the outcomes in patients with overlap syndrome were worse than those in patients with COPD or OSA alone. These opinions remain largely valid today.

We now also recognize the combination of asthma and OSA (alternative overlap syndrome) and collectively call both combinations obstructive lung disease-obstructive sleep apnea (OLDOSA) syndrome.² Interestingly, these relationships are likely bidirectional, with one condition aggravating or predisposing to the other.

Knowing that a patient has one of these overlap syndromes, one can initiate continuous positive airway pressure (CPAP) therapy, which can improve clinical outcomes.^3–6  Therefore, when evaluating a patient with asthma or COPD, one should consider OSA using a validated questionnaire and, if the findings suggest the diagnosis, polysomnography. Conversely, it is prudent to look for comorbid obstructive lung disease in patients with OSA, as interactions between upper and lower airway dysfunction may lead to distinctly different treatment and outcomes.

Here, we briefly review asthma and COPD, explore shared risk factors for sleep-disordered breathing and obstructive lung diseases, describe potential pathophysiologic mechanisms explaining these associations, and highlight the importance of recognizing and individually treating the overlaps of OSA and COPD or asthma.

COPD AND ASTHMA ARE VERY COMMON

About 10% of the US population have COPD,⁷ a preventable and treatable disease mainly caused by smoking, and a leading cause of sickness and death worldwide.^8,9

About 10% of the US population have COPD, and 8% have asthma

About 8% of Americans have asthma,⁷ which has become one of the most common chronic conditions in the Western world, affecting about 1 in 7 children and about 1 in 12 adults. The World Health Organization estimates that 235 million people suffer from asthma worldwide, and by 2025 this number is projected to rise to 400 million.^10,11

The prevalence of these conditions in a particular population depends on the frequency of risk factors and associated morbidities, including OSA. These factors may allow asthma or COPD to arise earlier or have more severe manifestations.^8,12

Asthma and COPD: Similarities and differences

Asthma and COPD share several features. Both are inflammatory airway conditions triggered or perpetuated by allergens, viral infection, tobacco smoke, products of biomass or fossil fuel combustion, and other substances. In both diseases, airflow is “obstructed” or limited, with a low ratio of forced expiratory volume in 1 second to forced vital capacity (FEV₁/FVC). Symptoms can also be similar, with dyspnea, cough, wheezing, and chest tightness being the most frequent complaints. The similarities support the theory proposed by Orie et al¹³ (the “Dutch hypothesis”) that asthma and COPD may actually be manifestations of the same disease.

But there are also differences. COPD is strongly linked to cigarette smoking and has at least three phenotypes:

• Chronic bronchitis, defined clinically by cough and sputum production for more than 3 months per year for 2 consecutive years
• Emphysema, characterized anatomically by loss of lung parenchyma, as seen on tomographic imaging or examination of pathologic specimens
• A mixed form with bronchitic and emphysematous features, which is likely the most common.

Particularly in emphysematous COPD, smoking predisposes patients to gas-exchange abnormalities and low diffusing capacity for carbon monoxide.

In asthma, symptoms may be more episodic, the age of onset is often younger, and atopy is common, especially in allergic asthma. These episodic symptoms may correlate temporally with measurable airflow reversibility (≥ 12% and ≥ 200 mL improvement in FVC or in FEV₁ after bronchodilator challenge).

However, the current taxonomy does not unequivocally divide obstructive lung diseases into asthma and COPD, and major features such as airway hyperresponsiveness, airflow reversibility, neutrophilic or CD8 lymphocytic airway inflammation, and lower concentration of nitric oxide in the exhaled air may be present in different phenotypes of both conditions (Table 1).

AIRFLOW IN OBSTRUCTIVE LUNG DISEASES AND DURING SLEEP

Normal airflow involves a complex interplay between airway resistance and elastic recoil of the entire respiratory system, including the airways, the lung parenchyma, and the chest wall (Figure 1).

In asthma and COPD, resistance to airflow is increased, predominantly in the upper airways (nasal passages, pharynx, and larynx) and in the first three or four subdivisions of the tracheobronchial tree. The problem is worse during exhalation, when elastic recoil of the lung parenchyma and chest wall also increases airway resistance, reduces airway caliber, and possibly even constricts the bronchi. This last effect may occur either due to mass loading of the bronchial smooth muscles or to large intrathoracic transmural pressure shifts that may increase extravasation of fluid in the bronchial walls, especially with higher vascular permeability in inflammatory conditions.

Furthermore, interactions between the airway and parenchyma and between the upper and lower airways, as well as radial and axial coupling of these anatomic and functional components, contribute to complex interplay between airway resistance and parenchymal-chest wall elastic energy—stretch or recoil.

The muscles of the upper and lower airway may not work together due to the loss of normal lung parenchyma (as in emphysema) or to the acute inflammation in the small airways and adjacent parenchyma (as in severe asthma exacerbations). This loss of coordination makes the upper airway more collapsible, a feature of OSA.

Additionally, obesity, gastroesophageal reflux, disease chronic rhinitis, nasal polyposis, and acute exacerbations of chronic systemic inflammation all contribute to more complex interactions between obstructive lung diseases and OSA.⁶

Sleep affects breathing, particularly in patients with respiratory comorbidities, and sleep-disordered breathing causes daytime symptoms and worsens quality of life.^1,13–15 During sleep, respiratory centers become less sensitive to oxygen and carbon dioxide; breathing becomes more irregular, especially during rapid eye movement (REM) sleep; the chest wall moves less, so that the tidal volume and functional residual capacity are lower; sighs, yawns, and deep breaths become limited; and serum carbon dioxide concentration may rise.

OBSTRUCTIVE SLEEP APNEA

The prevalence of OSA, a form of sleep-disordered breathing characterized by limitation of inspiratory and (to a lesser degree) expiratory flow, has increased significantly in recent years, in parallel with the prevalence of its major risk factor, obesity.

OSA is generally defined as an apnea-hypopnea index of 5 or higher, ie, five or more episodes of apnea or hypopnea per hour.

Based on Ioachimescu OC, Teodorescu M. Integrating the overlap of obstructive lung disease and obstructive sleep apnoea: OLDOSA syndrome. Respirology 2013; 18:421–431; with permission from John Wiley & Sons, Inc.

OSA syndrome, ie, an apnea-hypopnea index of 5 or higher and excessive daytime sleepiness (defined by an Epworth Sleepiness Scale score > 10) was found in the initial analysis of the Wisconsin Sleep cohort in 1993 to be present in about 2% of women and 4% of men.¹⁶ A more recent longitudinal analysis showed a significant increase—for example, in people 50 to 70 years old the prevalence was up to 17.6% in men and 7.5% in women.¹⁷

Upper airway resistance syndrome, a milder form of sleep-disordered breathing, is now included under the diagnosis of OSA, as its pathophysiology is not significantly different.¹⁸

In the next section, we discuss what happens when OSA overlaps with COPD (overlap syndrome) and with asthma (“alternative overlap syndrome”)^2,8 (Figure 2).

OSA AND COPD (OVERLAP SYNDROME)

Flenley¹ hypothesized that patients with COPD in whom supplemental oxygen worsened hypercapnia may also have OSA and called this association overlap syndrome.

How common is overlap syndrome?

Since both COPD and OSA are prevalent conditions, overlap syndrome may also be common.

The reported prevalence of overlap syndrome varies widely, depending on the population studied and the methods used. In various studies, COPD was present in 9% to 56% of patients with OSA,^19–23 and OSA was found in 5% to 85% of patients with COPD.^24–27

Based on the prevalence of COPD in the general population (about 10%¹²) and that of sleep-disordered breathing (about 5% to 10%¹⁷), the expected prevalence of overlap syndrome in people over age 40 may be 0.5% to 1%.²⁸ In a more inclusive estimate with “subclinical” forms of overlap syndrome—ie, OSA defined as an apnea-hypopnea index of 5 or more (about 25% of the population¹⁷) and COPD Global initiative for Chronic Obstructive Lung Disease (GOLD) stage 1 (16.8% in the National Health and Nutrition Education Survey¹²)—the expected prevalence of overlap is around 4%. Some studies found a higher prevalence of COPD in OSA patients than in the general population,^21,29 while others did not.^22,28,30 The studies differed in how they defined sleep-disordered breathing.

Larger studies are needed to better assess the true prevalence of sleep-disordered breathing in COPD. They should use more sensitive measures of airflow and standardized definitions of sleep-disordered breathing and should include patients with more severe COPD.

Fatigue and insomnia are common in COPD

At near-maximal ventilatory capacity, even a mild increase in upper airway resistance increases the work of breathing

Fatigue is strongly correlated with declining lung function, low exercise tolerance, and impaired quality of life in COPD.³¹ Factors that contribute to fatigue include dyspnea, depression, and impaired sleep.³² Some suggest that at least half of COPD patients have sleep complaints such as insomnia, sleep disruption, or sleep fragmentation.³³ Insomnia, difficulty falling asleep, and early morning awakenings are the most common complaints (30%–70% of patients) and are associated with daytime fatigue.³⁴ Conversely, comorbid OSA can contribute to fatigue and maintenance-type insomnia (ie, difficulty staying asleep and returning to sleep).

Multiple mechanisms of hypoxemia in overlap syndrome

Oxygenation abnormalities and increased work of breathing contribute to the pathophysiology of overlap syndrome. In patients with COPD, oxygenation during wakefulness is a strong predictor of gas exchange during sleep.³⁵ Further, patients with overlap syndrome tend to have more severe hypoxia during sleep than patients with isolated COPD or OSA at rest or during exercise.³⁶

In overlap syndrome, hypoxemia is the result of several mechanisms:

• Loss of upper airway muscle tone from intermittent episodes of obstructive apnea and hypopnea leads to upper airway collapse during sleep, particularly during REM sleep, increasing the severity of OSA.³⁷
• Reductions in functional residual capacity from lying in the recumbent position and during REM sleep render patients with COPD more vulnerable, as compensatory use of accessory muscles to maintain near-normal ventilation in a hyperinflated state becomes impaired.³⁷
• Alterations in pulmonary ventilation-perfusion matching may lead to altered carbon dioxide homeostasis and impaired oxygenation in patients with emphysema.
• Circadian variation in lower airway caliber may also be observed, in parallel with the bronchoconstriction caused by increased nocturnal vagotonia.
• Hypercapnia (Paco₂ ≥ 45 mm Hg) may lead to overall reduced responsiveness of respiratory muscles and to a blunted response of respiratory centers to low oxygen and high carbon dioxide levels.³⁸ Thus, hypercapnia is a better predictor of the severity of nocturnal hypoxemia than hypoxemia developing during exercise.³⁹

In a person who is at near-maximal ventilatory capacity, even a mild increase in upper airway resistance (as seen with snoring, upper airway resistance syndrome, or OSA) increases the work of breathing. This phenomenon can lead to early arousals even before significant oxyhemoglobin desaturation occurs.

Normally, inspiratory flow limitation is counteracted by increasing inspiratory time to maintain ventilation. Patients with COPD may not be able to do this, however, as they need more time to breathe out due to narrowing of their lower airways.⁴⁰ The inability to compensate for upper airway resistance, similar to the increased work of breathing seen with exercise, may lead to early arousals and increased sleep fragmentation.

Consequences of overlap syndrome

Patients with overlap syndrome appear to have higher morbidity and mortality rates than those with COPD or sleep-disordered breathing alone.

Cor pulmonale. Nighttime hypoxia is more severe and persistent in overlap syndrome than with COPD or OSA alone. This may contribute to more significant pulmonary hypertension and to the development of cor pulmonale, in which the right ventricle is altered in structure (eg, hypertrophied, dilated) or reduced in function, or both, from severe pulmonary hypertension.

In contrast to right ventricular failure due to disorders of the left heart, cor pulmonale is a result of diseases of the vasculature (eg, idiopathic pulmonary arterial hypertension), lung parenchyma (eg, COPD), upper airway (eg, OSA), or chest wall (eg, severe kyphoscoliosis). COPD is the most common cause of cor pulmonale in the United States, accounting for up to 30% of cases of cor pulmonale.^41–45 In OSA, cor pulmonale is seen in up to 20% of cases,⁴³ while in overlap syndrome cor pulmonale is encountered even more often (ie, in up to 80%); these patients have a dismal 5-year survival rate of about 30%.⁴⁶

Obesity hypoventilation syndrome is characterized by obesity (body mass index ≥ 30 kg/m²) and daytime hypercapnia (Paco₂ ≥ 45 mm Hg) that cannot be fully attributed to an underlying cardiopulmonary or neurologic condition.¹⁸ Hypercapnia worsens during sleep (especially during REM sleep) and is often associated with severe arterial oxygen desaturation. Up to 90% of patients with obesity hypoventilation syndrome have comorbid OSA, and the rest generally have sleep-related hypoventilation, particularly during REM sleep.

Overlap syndrome with cor pulmonale typically has a poor prognosis; one study found a 5-year survival rate of 30%

In patients with obesity hypoventilation syndrome, daytime hypercapnia may improve or even normalize with adequate positive airway pressure treatment and sustained adherence to treatment.¹⁸ Many patients with obesity hypoventilation syndrome respond to CPAP or bilevel positive airway pressure (BPAP), with improvement in daytime Paco₂. However, normalization of daytime Paco₂ occurs only in a subgroup of patients. In contrast, treatment with oxygen therapy alone may worsen hypercapnia.

Oxygen therapy for pure COPD, but maybe not for overlap syndrome

Continuous oxygen therapy reduces mortality in COPD,^47,48 but the duration and severity of hypoxemia that warrant oxygen therapy are less clear. Oxygen therapy in hypoxemic patients has been shown to improve sleep quality and reduce arousals.⁴⁹

Indications for oxygen treatment of nocturnal hypoxemia are generally based on Medicare guidelines:

• At least 5 minutes of sleep with peripheral oxygen saturation ≤ 88% or Pao₂ ≤ 55 mm Hg, or
• A decrease in Pao₂ of more than 10 mm Hg or in peripheral oxygen saturation of more than 5% for at least 5 minutes of sleep and associated with signs or symptoms reasonably attributable to hypoxemia (group I criteria), or
• At least 5 minutes of sleep with peripheral oxygen saturation ≥ 89% or Pao₂ 56 to 59 mm Hg and pedal edema, pulmonary hypertension, cor pulmonale, or erythrocytosis (group II criteria).⁵⁰

Approximately 47% of COPD patients who are hypoxemic during the day spend about 30% of sleep time with an oxygen saturation less than 90%, even while on continuous oxygen therapy.⁵¹ Current recommendations for nocturnal oxygen therapy are to increase the oxygen concentration by 1 L/minute above the baseline oxygen flow rate needed to maintain an oxygen saturation higher than 90% during resting wakefulness, using a nasal cannula or face mask.⁵²

Caveat. In overlap syndrome, supplemental oxygen may prolong the duration of apnea episodes and worsen hypercapnia.

Positive airway pressure for OSA

Positive airway pressure therapy improves cardiovascular outcomes in OSA.⁵³ Several studies^54–58 compared the effectiveness of CPAP vs BPAP as initial therapy for OSA but did not provide enough evidence to favor one over the other in this setting. Similarly, the results are mixed for the use of fixed or auto-adjusting BPAP as salvage therapy in patients who cannot tolerate CPAP.^59–61

In overlap syndrome, CPAP or BPAP with or without supplemental oxygen has been investigated in several studies.^26,62–65 In general, the mortality rate of COPD patients who require oxygen therapy is quite high.^47,66 In hypoxemic COPD patients with moderate to severe sleep-disordered breathing, the 5-year survival rate was 71% in those treated with CPAP plus oxygen, vs 26% in those on oxygen alone, independent of baseline postbronchodilator FEV₁.⁶⁷

There is no specific FEV₁ cutoff for prescribing CPAP. In general, daytime hypercapnia and nocturnal hypoxemia despite supplemental oxygen therapy are indications for BPAP therapy, regardless of the presence of OSA. Whether noninvasive nocturnal ventilation for COPD patients who do not have OSA improves long-term COPD outcomes is not entirely clear.^65,68,69

Adding nocturnal BPAP in spontaneous timed mode to pulmonary rehabilitation for severe hypercapnic COPD was found to improve quality of life, mood, dyspnea, gas exchange, and decline in lung function.⁷⁰ Other studies noted that COPD patients hospitalized with respiratory failure who were randomized to noninvasive nocturnal ventilation plus oxygen therapy as opposed to oxygen alone experienced improvement in health-related quality of life and reduction in intensive-care-unit length of stay but no difference in mortality or subsequent hospitalizations.⁶⁹ In stable hypercapnic COPD patients without OSA, there is no clear evidence that nocturnal noninvasive ventilation lessens the risk of death despite improved daytime gas exchange,^71,72 but additional long-term studies are needed.

Lung volume reduction surgery, a procedure indicated for highly selected patients with severe COPD, has been shown to reduce hyperinflation, improve nocturnal hypoxemia, and improve total sleep time and sleep efficiency in patients without sleep-disordered breathing.⁷³ More studies are needed to determine if reduction in lung hyperinflation has an impact on the occurrence of OSA and on morbidity related to sleep-disordered breathing.

Benefit of CPAP in overlap syndrome

In a nonrandomized study, Marin et al⁶² found that overlap syndrome is associated with an increased risk of death and hospitalization due to COPD exacerbations. CPAP therapy was associated with improved survival rates and decreased hospitalization rates in these patients.

Stanchina et al,⁷⁴ in a post hoc analysis of an observational cohort, assessed the outcomes of 227 patients with overlap syndrome. Greater use of CPAP was found to be associated with lower mortality rates.

Jaoude et al⁷⁵ found that hypercapnic patients with overlap syndrome who were adherent to CPAP therapy had a lower mortality rate than nonadherent hypercapnic patients (P = .04). In a multivariate analysis, the comorbidity index was the only independent predictor of mortality in normocapnic patients with overlap syndrome, while CPAP adherence was associated with improved survival.

Lastly, patients with overlap syndrome tend to need more healthcare and accrue higher medical costs than patients with COPD alone. An analysis of a state Medicaid database that included COPD patients showed that beneficiaries with overlap syndrome spent at least $4,000 more in medical expenditures than beneficiaries with “lone” COPD.²⁴

In conclusion, CPAP is the first line of therapy for overlap syndrome, while daytime hypercapnia or nocturnal hypoxemia despite supplemental oxygen therapy are indications for nocturnal BPAP therapy, regardless of whether patients have OSA.

OSA AND ASTHMA (ALTERNATIVE OVERLAP SYNDROME)

Epidemiology and clinical features

The coexistence of asthma and OSA can begin in childhood and continue throughout adult life. A higher prevalence of lifetime asthma and OSA has been noted in children of racial and ethnic minorities, children of lower socioeconomic status, and those with atopy.⁷⁶

In a pediatric asthma clinic, it was noted that 12 months into structured asthma management and optimization, children with sleep-disordered breathing were nearly four times more likely to have severe asthma at follow-up, even after adjusting for obesity, race, and gender.⁷⁷

In adult patients with OSA, the prevalence of asthma is about 35%.⁷⁸ Conversely, people with asthma are at higher risk of OSA. High risk of OSA was more prevalent in a group of patients with asthma than in a general medical clinic population (39.5% vs 27.2%, P < .05).⁷⁹

Analysis of a large prospective cohort found that asthma was a risk factor for new-onset OSA. The incidence of OSA over 4 years in patients with self-reported asthma was 27%, compared with 16% without asthma. The relative risk adjusted for risk factors such as body mass index, age, and gender was 1.39 (95% confidence interval [CI] 15%–19%).⁸⁰

Patients with asthma who are at high risk of OSA are more likely to have worse daytime and nighttime asthma symptoms. Interestingly, patients who are diagnosed with OSA and treated with CPAP seem to have better asthma control.

Patients with asthma who are more likely to have OSA are women (odds ratio [OR] 2.1), have greater asthma severity (OR 1.6), have gastroesophageal reflux disease (OR 2.7), and use inhaled corticosteroids (OR 4.0).⁸¹ These associations are different than the traditional, population-wide risk factors for OSA, such as male sex, excess body weight, and nocturnal nasal congestion.⁸²

OSA also worsens asthma control. Teodorescu et al¹⁵ found that severe asthma was more frequent in older asthma patients (ages 60–75, prevalence 49%) than in younger patients (ages 18–59, 39%). Older adults with OSA were seven times as likely to have severe asthma (OR 6.6), whereas young adults with sleep apnea were only three times as likely (OR 2.6).

In a group of patients with difficult-to-treat asthma, OSA was significantly associated with frequent exacerbations (OR 3.4), an association similar in magnitude to that of psychological conditions (OR 10.8), severe sinus disease (OR 3.7), recurrent respiratory tract infections (OR 6.9), and gastroesophageal reflux disease (OR 4.9).⁸³ More than half of the patients had at least three of these comorbid conditions.

Sleep quality can greatly affect asthma control, and its importance is often underestimated. Patients with severe asthma have worse sleep quality than patients with milder asthma or nonasthmatic patients, even after excluding patients with a high risk of OSA, patients on CPAP therapy, and patients with a history of gastroesophageal reflux disease. Furthermore, regardless of asthma severity, sleep quality is a significant predictor of asthma-related quality of life, even after accounting for body mass index, daytime sleepiness, and gastroesophageal reflux disease.⁸⁴

Pathophysiology of alternative overlap syndrome

Sleep significantly affects respiratory pathophysiology in asthma. The underlying mechanisms include physical and mechanical stressors, neurohormonal changes, hypoxia, confounding medical conditions, and local and systemic inflammatory changes.

Patients with nocturnal asthma experience more pronounced obstruction when sleep-deprived, suggesting that sleep loss may contribute to worsening airflow limitation.¹⁴ Although changes in pulmonary mechanics and lung volumes may also have a role, volume-dependent airway narrowing does not appear to account for all observed nocturnal increases in airway resistance. Intrathoracic blood pooling may also contribute to nocturnal bronchoconstriction through stimulation of pulmonary C fibers and increased bronchial wall edema, a mechanism that may be similar to the “cardiac asthma” seen in left ventricular dysfunction.

Early studies of sleep-disordered breathing demonstrated that patients with asthma were breathing more irregularly (with hypopnea, apnea, and hyperpnea) in REM sleep than those without asthma.⁸⁵ Interestingly, REM-related hypoxia has also been noted in children with asthma.⁸⁶ This may be related to the increased cholinergic outflow that occurs during REM sleep, which in turn modulates the caliber and reactivity of the lower airways.

In overlap syndrome, oxygen may prolong the duration of apnea episodes and worsen hypercapnia

Physical changes such as upper airway collapse and reduced pharyngeal cross-sectional area may cause further mechanical strain.⁸⁷ This can further propagate airway inflammation, alter airway mucosal muscle fibers, and stimulate neural reflexes, thereby increasing cholinergic tone and bronchoconstriction. Furthermore, heightened negative intrathoracic pressure during obstructive episodes can increase nocturnal pulmonary blood pooling.¹⁴ Hypoxia itself can augment airway hyperresponsiveness via vagal pathways or carotid body receptors, increasing reactive oxygen species and inflammatory mediators. Local inflammation can “spill over” into systemic inflammatory changes, while alterations in airway inflammatory markers in asthma seem to follow a circadian rhythm, in parallel with the nocturnal worsening of the asthma symptoms.⁸⁸ Finally, altered sleep may be related to other comorbid conditions, such as gastroesophageal reflux disease, insomnia, and restless leg syndrome.

Management and outcomes of alternative overlap syndrome

Despite optimization of asthma management, OSA can still significantly affect asthma control and symptoms.⁸⁴

Interestingly, medications that reduce airway inflammation (eg, corticosteroids) may promote OSA. This occurrence cannot be fully explained by an increase in body mass, as more respiratory disturbances occur during sleep with continuous corticosteroid treatment even without increases in body mass index.⁸⁷ Therefore, these associations may be related to upper airway myopathy caused by the treatment, a small pharynx, facial dysmorphisms, or fat deposition.⁸⁹

Does CPAP improve asthma?

OSA is often unrecognized in patients with asthma, and treating it can have an impact on asthma symptoms.

CPAP therapy has not been shown to significantly change airway responsiveness or lung function, but it has been noted to significantly improve both OSA-related and asthma-related quality of life and reduce the use of rescue bronchodilators.^3,90 CPAP has demonstrated improvement of quality of life that positively correlated with body weight and apnea-hypopnea index at baseline, suggesting that asthmatic patients with greater obesity or worse OSA may benefit most from aggressive management.⁹⁰

However, CPAP should be used only if the patient has confirmed OSA. Empiric use of CPAP without a diagnosis of OSA was poorly tolerated and failed to improve asthma symptoms or lung function.⁹¹ More importantly, using CPAP in a patient who does not have OSA may contribute to further sleep disruption.⁹¹

Second-line treatments such as mandibular advancing devices and airway or bariatric surgery have not yet been studied in alternative overlap syndrome.

A multidimensional assessment of asthma

The Western world is experiencing an epidemic of obesity and of asthma. Obesity contributes to the pathogenesis of OSA by altering the anatomy and collapsibility of the upper airway, affecting ventilatory control and increasing respiratory workload. Another paradigm, supported by some evidence, is that OSA itself may contribute to the development of obesity. Both OSA and obesity lead to activation of inflammatory biologic cascades, which are likely the pathogenic mechanisms for their cardiovascular and metabolic consequences. As such, early recognition of OSA is important, as effective treatments are available.

In some patients, obesity may cause asthma, as obesity precedes the onset of asthma in a significant proportion of patients, and bariatric surgery for morbid obesity may resolve asthma. The obese asthma phenotype seems to include chronic rhinosinusitis, gastroesophageal reflux disease, poorer asthma control, limited responsiveness to corticosteroids, and even different sets of biomarkers (eg, neutrophilic airway inflammation). A cohort of obese patients with poor asthma control demonstrated significant improvement in asthma symptoms, quality of life, and airway reactivity after weight loss from bariatric surgery.⁹²

To improve our knowledge about airway disease phenotypes and endotypes and their response to therapy, we propose taking a multidimensional, structured assessment of all patients with asthma, using a schema we call “ABCD-3P-PQRST” (Table 2).

The purpose of using this type of system in clinics and research is to capture the multi­dimensionality of the disease and better develop future individualized therapeutic strategies by employing the latest advances in systems biology and computational methods such as cluster and principal component analysis.

Multidimensional assessments addressing airway problems such as asthma, COPD, OSA, other comorbidities and risk factors, and personalized management plans will need to be the basis of future therapeutic interventions. Increased attention to the complications of asthma and obstructive airway and lung diseases in our patients is imperative, specifically to develop effective systems of care, appropriate clinical guidelines, and research studies that lead to improved health outcomes.

Many patients who have obstructive lung disease, ie, chronic obstructive pulmonary disease (COPD) or asthma, also have obstructive sleep apnea (OSA), and vice versa.

The combination of COPD and OSA was first described almost 30 years ago by Flenley, who called it “overlap syndrome.”¹ At that time, he recommended that a sleep study be considered in all obese patients with COPD who snore and in those who have frequent headaches after starting oxygen therapy. In the latter group, he doubted that nocturnal oxygen was the correct treatment. He also believed that the outcomes in patients with overlap syndrome were worse than those in patients with COPD or OSA alone. These opinions remain largely valid today.

We now also recognize the combination of asthma and OSA (alternative overlap syndrome) and collectively call both combinations obstructive lung disease-obstructive sleep apnea (OLDOSA) syndrome.² Interestingly, these relationships are likely bidirectional, with one condition aggravating or predisposing to the other.

Knowing that a patient has one of these overlap syndromes, one can initiate continuous positive airway pressure (CPAP) therapy, which can improve clinical outcomes.^3–6  Therefore, when evaluating a patient with asthma or COPD, one should consider OSA using a validated questionnaire and, if the findings suggest the diagnosis, polysomnography. Conversely, it is prudent to look for comorbid obstructive lung disease in patients with OSA, as interactions between upper and lower airway dysfunction may lead to distinctly different treatment and outcomes.

Here, we briefly review asthma and COPD, explore shared risk factors for sleep-disordered breathing and obstructive lung diseases, describe potential pathophysiologic mechanisms explaining these associations, and highlight the importance of recognizing and individually treating the overlaps of OSA and COPD or asthma.

COPD AND ASTHMA ARE VERY COMMON

About 10% of the US population have COPD,⁷ a preventable and treatable disease mainly caused by smoking, and a leading cause of sickness and death worldwide.^8,9

About 10% of the US population have COPD, and 8% have asthma

About 8% of Americans have asthma,⁷ which has become one of the most common chronic conditions in the Western world, affecting about 1 in 7 children and about 1 in 12 adults. The World Health Organization estimates that 235 million people suffer from asthma worldwide, and by 2025 this number is projected to rise to 400 million.^10,11

The prevalence of these conditions in a particular population depends on the frequency of risk factors and associated morbidities, including OSA. These factors may allow asthma or COPD to arise earlier or have more severe manifestations.^8,12

Asthma and COPD: Similarities and differences

Asthma and COPD share several features. Both are inflammatory airway conditions triggered or perpetuated by allergens, viral infection, tobacco smoke, products of biomass or fossil fuel combustion, and other substances. In both diseases, airflow is “obstructed” or limited, with a low ratio of forced expiratory volume in 1 second to forced vital capacity (FEV₁/FVC). Symptoms can also be similar, with dyspnea, cough, wheezing, and chest tightness being the most frequent complaints. The similarities support the theory proposed by Orie et al¹³ (the “Dutch hypothesis”) that asthma and COPD may actually be manifestations of the same disease.

But there are also differences. COPD is strongly linked to cigarette smoking and has at least three phenotypes:

• Chronic bronchitis, defined clinically by cough and sputum production for more than 3 months per year for 2 consecutive years
• Emphysema, characterized anatomically by loss of lung parenchyma, as seen on tomographic imaging or examination of pathologic specimens
• A mixed form with bronchitic and emphysematous features, which is likely the most common.

Particularly in emphysematous COPD, smoking predisposes patients to gas-exchange abnormalities and low diffusing capacity for carbon monoxide.

In asthma, symptoms may be more episodic, the age of onset is often younger, and atopy is common, especially in allergic asthma. These episodic symptoms may correlate temporally with measurable airflow reversibility (≥ 12% and ≥ 200 mL improvement in FVC or in FEV₁ after bronchodilator challenge).

However, the current taxonomy does not unequivocally divide obstructive lung diseases into asthma and COPD, and major features such as airway hyperresponsiveness, airflow reversibility, neutrophilic or CD8 lymphocytic airway inflammation, and lower concentration of nitric oxide in the exhaled air may be present in different phenotypes of both conditions (Table 1).

AIRFLOW IN OBSTRUCTIVE LUNG DISEASES AND DURING SLEEP

Normal airflow involves a complex interplay between airway resistance and elastic recoil of the entire respiratory system, including the airways, the lung parenchyma, and the chest wall (Figure 1).

In asthma and COPD, resistance to airflow is increased, predominantly in the upper airways (nasal passages, pharynx, and larynx) and in the first three or four subdivisions of the tracheobronchial tree. The problem is worse during exhalation, when elastic recoil of the lung parenchyma and chest wall also increases airway resistance, reduces airway caliber, and possibly even constricts the bronchi. This last effect may occur either due to mass loading of the bronchial smooth muscles or to large intrathoracic transmural pressure shifts that may increase extravasation of fluid in the bronchial walls, especially with higher vascular permeability in inflammatory conditions.

Furthermore, interactions between the airway and parenchyma and between the upper and lower airways, as well as radial and axial coupling of these anatomic and functional components, contribute to complex interplay between airway resistance and parenchymal-chest wall elastic energy—stretch or recoil.

The muscles of the upper and lower airway may not work together due to the loss of normal lung parenchyma (as in emphysema) or to the acute inflammation in the small airways and adjacent parenchyma (as in severe asthma exacerbations). This loss of coordination makes the upper airway more collapsible, a feature of OSA.

Additionally, obesity, gastroesophageal reflux, disease chronic rhinitis, nasal polyposis, and acute exacerbations of chronic systemic inflammation all contribute to more complex interactions between obstructive lung diseases and OSA.⁶

Sleep affects breathing, particularly in patients with respiratory comorbidities, and sleep-disordered breathing causes daytime symptoms and worsens quality of life.^1,13–15 During sleep, respiratory centers become less sensitive to oxygen and carbon dioxide; breathing becomes more irregular, especially during rapid eye movement (REM) sleep; the chest wall moves less, so that the tidal volume and functional residual capacity are lower; sighs, yawns, and deep breaths become limited; and serum carbon dioxide concentration may rise.

OBSTRUCTIVE SLEEP APNEA

The prevalence of OSA, a form of sleep-disordered breathing characterized by limitation of inspiratory and (to a lesser degree) expiratory flow, has increased significantly in recent years, in parallel with the prevalence of its major risk factor, obesity.

OSA is generally defined as an apnea-hypopnea index of 5 or higher, ie, five or more episodes of apnea or hypopnea per hour.

Based on Ioachimescu OC, Teodorescu M. Integrating the overlap of obstructive lung disease and obstructive sleep apnoea: OLDOSA syndrome. Respirology 2013; 18:421–431; with permission from John Wiley &amp; Sons, Inc.

OSA syndrome, ie, an apnea-hypopnea index of 5 or higher and excessive daytime sleepiness (defined by an Epworth Sleepiness Scale score > 10) was found in the initial analysis of the Wisconsin Sleep cohort in 1993 to be present in about 2% of women and 4% of men.¹⁶ A more recent longitudinal analysis showed a significant increase—for example, in people 50 to 70 years old the prevalence was up to 17.6% in men and 7.5% in women.¹⁷

Upper airway resistance syndrome, a milder form of sleep-disordered breathing, is now included under the diagnosis of OSA, as its pathophysiology is not significantly different.¹⁸

In the next section, we discuss what happens when OSA overlaps with COPD (overlap syndrome) and with asthma (“alternative overlap syndrome”)^2,8 (Figure 2).

OSA AND COPD (OVERLAP SYNDROME)

Flenley¹ hypothesized that patients with COPD in whom supplemental oxygen worsened hypercapnia may also have OSA and called this association overlap syndrome.

How common is overlap syndrome?

Since both COPD and OSA are prevalent conditions, overlap syndrome may also be common.

The reported prevalence of overlap syndrome varies widely, depending on the population studied and the methods used. In various studies, COPD was present in 9% to 56% of patients with OSA,^19–23 and OSA was found in 5% to 85% of patients with COPD.^24–27

Based on the prevalence of COPD in the general population (about 10%¹²) and that of sleep-disordered breathing (about 5% to 10%¹⁷), the expected prevalence of overlap syndrome in people over age 40 may be 0.5% to 1%.²⁸ In a more inclusive estimate with “subclinical” forms of overlap syndrome—ie, OSA defined as an apnea-hypopnea index of 5 or more (about 25% of the population¹⁷) and COPD Global initiative for Chronic Obstructive Lung Disease (GOLD) stage 1 (16.8% in the National Health and Nutrition Education Survey¹²)—the expected prevalence of overlap is around 4%. Some studies found a higher prevalence of COPD in OSA patients than in the general population,^21,29 while others did not.^22,28,30 The studies differed in how they defined sleep-disordered breathing.

Larger studies are needed to better assess the true prevalence of sleep-disordered breathing in COPD. They should use more sensitive measures of airflow and standardized definitions of sleep-disordered breathing and should include patients with more severe COPD.

Fatigue and insomnia are common in COPD

At near-maximal ventilatory capacity, even a mild increase in upper airway resistance increases the work of breathing

Fatigue is strongly correlated with declining lung function, low exercise tolerance, and impaired quality of life in COPD.³¹ Factors that contribute to fatigue include dyspnea, depression, and impaired sleep.³² Some suggest that at least half of COPD patients have sleep complaints such as insomnia, sleep disruption, or sleep fragmentation.³³ Insomnia, difficulty falling asleep, and early morning awakenings are the most common complaints (30%–70% of patients) and are associated with daytime fatigue.³⁴ Conversely, comorbid OSA can contribute to fatigue and maintenance-type insomnia (ie, difficulty staying asleep and returning to sleep).

Multiple mechanisms of hypoxemia in overlap syndrome

Oxygenation abnormalities and increased work of breathing contribute to the pathophysiology of overlap syndrome. In patients with COPD, oxygenation during wakefulness is a strong predictor of gas exchange during sleep.³⁵ Further, patients with overlap syndrome tend to have more severe hypoxia during sleep than patients with isolated COPD or OSA at rest or during exercise.³⁶

In overlap syndrome, hypoxemia is the result of several mechanisms:

• Loss of upper airway muscle tone from intermittent episodes of obstructive apnea and hypopnea leads to upper airway collapse during sleep, particularly during REM sleep, increasing the severity of OSA.³⁷
• Reductions in functional residual capacity from lying in the recumbent position and during REM sleep render patients with COPD more vulnerable, as compensatory use of accessory muscles to maintain near-normal ventilation in a hyperinflated state becomes impaired.³⁷
• Alterations in pulmonary ventilation-perfusion matching may lead to altered carbon dioxide homeostasis and impaired oxygenation in patients with emphysema.
• Circadian variation in lower airway caliber may also be observed, in parallel with the bronchoconstriction caused by increased nocturnal vagotonia.
• Hypercapnia (Paco₂ ≥ 45 mm Hg) may lead to overall reduced responsiveness of respiratory muscles and to a blunted response of respiratory centers to low oxygen and high carbon dioxide levels.³⁸ Thus, hypercapnia is a better predictor of the severity of nocturnal hypoxemia than hypoxemia developing during exercise.³⁹

In a person who is at near-maximal ventilatory capacity, even a mild increase in upper airway resistance (as seen with snoring, upper airway resistance syndrome, or OSA) increases the work of breathing. This phenomenon can lead to early arousals even before significant oxyhemoglobin desaturation occurs.

Normally, inspiratory flow limitation is counteracted by increasing inspiratory time to maintain ventilation. Patients with COPD may not be able to do this, however, as they need more time to breathe out due to narrowing of their lower airways.⁴⁰ The inability to compensate for upper airway resistance, similar to the increased work of breathing seen with exercise, may lead to early arousals and increased sleep fragmentation.

Consequences of overlap syndrome

Patients with overlap syndrome appear to have higher morbidity and mortality rates than those with COPD or sleep-disordered breathing alone.

Cor pulmonale. Nighttime hypoxia is more severe and persistent in overlap syndrome than with COPD or OSA alone. This may contribute to more significant pulmonary hypertension and to the development of cor pulmonale, in which the right ventricle is altered in structure (eg, hypertrophied, dilated) or reduced in function, or both, from severe pulmonary hypertension.

In contrast to right ventricular failure due to disorders of the left heart, cor pulmonale is a result of diseases of the vasculature (eg, idiopathic pulmonary arterial hypertension), lung parenchyma (eg, COPD), upper airway (eg, OSA), or chest wall (eg, severe kyphoscoliosis). COPD is the most common cause of cor pulmonale in the United States, accounting for up to 30% of cases of cor pulmonale.^41–45 In OSA, cor pulmonale is seen in up to 20% of cases,⁴³ while in overlap syndrome cor pulmonale is encountered even more often (ie, in up to 80%); these patients have a dismal 5-year survival rate of about 30%.⁴⁶

Obesity hypoventilation syndrome is characterized by obesity (body mass index ≥ 30 kg/m²) and daytime hypercapnia (Paco₂ ≥ 45 mm Hg) that cannot be fully attributed to an underlying cardiopulmonary or neurologic condition.¹⁸ Hypercapnia worsens during sleep (especially during REM sleep) and is often associated with severe arterial oxygen desaturation. Up to 90% of patients with obesity hypoventilation syndrome have comorbid OSA, and the rest generally have sleep-related hypoventilation, particularly during REM sleep.

Overlap syndrome with cor pulmonale typically has a poor prognosis; one study found a 5-year survival rate of 30%

In patients with obesity hypoventilation syndrome, daytime hypercapnia may improve or even normalize with adequate positive airway pressure treatment and sustained adherence to treatment.¹⁸ Many patients with obesity hypoventilation syndrome respond to CPAP or bilevel positive airway pressure (BPAP), with improvement in daytime Paco₂. However, normalization of daytime Paco₂ occurs only in a subgroup of patients. In contrast, treatment with oxygen therapy alone may worsen hypercapnia.

Oxygen therapy for pure COPD, but maybe not for overlap syndrome

Continuous oxygen therapy reduces mortality in COPD,^47,48 but the duration and severity of hypoxemia that warrant oxygen therapy are less clear. Oxygen therapy in hypoxemic patients has been shown to improve sleep quality and reduce arousals.⁴⁹

Indications for oxygen treatment of nocturnal hypoxemia are generally based on Medicare guidelines:

• At least 5 minutes of sleep with peripheral oxygen saturation ≤ 88% or Pao₂ ≤ 55 mm Hg, or
• A decrease in Pao₂ of more than 10 mm Hg or in peripheral oxygen saturation of more than 5% for at least 5 minutes of sleep and associated with signs or symptoms reasonably attributable to hypoxemia (group I criteria), or
• At least 5 minutes of sleep with peripheral oxygen saturation ≥ 89% or Pao₂ 56 to 59 mm Hg and pedal edema, pulmonary hypertension, cor pulmonale, or erythrocytosis (group II criteria).⁵⁰

Approximately 47% of COPD patients who are hypoxemic during the day spend about 30% of sleep time with an oxygen saturation less than 90%, even while on continuous oxygen therapy.⁵¹ Current recommendations for nocturnal oxygen therapy are to increase the oxygen concentration by 1 L/minute above the baseline oxygen flow rate needed to maintain an oxygen saturation higher than 90% during resting wakefulness, using a nasal cannula or face mask.⁵²

Caveat. In overlap syndrome, supplemental oxygen may prolong the duration of apnea episodes and worsen hypercapnia.

Positive airway pressure for OSA

Positive airway pressure therapy improves cardiovascular outcomes in OSA.⁵³ Several studies^54–58 compared the effectiveness of CPAP vs BPAP as initial therapy for OSA but did not provide enough evidence to favor one over the other in this setting. Similarly, the results are mixed for the use of fixed or auto-adjusting BPAP as salvage therapy in patients who cannot tolerate CPAP.^59–61

In overlap syndrome, CPAP or BPAP with or without supplemental oxygen has been investigated in several studies.^26,62–65 In general, the mortality rate of COPD patients who require oxygen therapy is quite high.^47,66 In hypoxemic COPD patients with moderate to severe sleep-disordered breathing, the 5-year survival rate was 71% in those treated with CPAP plus oxygen, vs 26% in those on oxygen alone, independent of baseline postbronchodilator FEV₁.⁶⁷

There is no specific FEV₁ cutoff for prescribing CPAP. In general, daytime hypercapnia and nocturnal hypoxemia despite supplemental oxygen therapy are indications for BPAP therapy, regardless of the presence of OSA. Whether noninvasive nocturnal ventilation for COPD patients who do not have OSA improves long-term COPD outcomes is not entirely clear.^65,68,69

Adding nocturnal BPAP in spontaneous timed mode to pulmonary rehabilitation for severe hypercapnic COPD was found to improve quality of life, mood, dyspnea, gas exchange, and decline in lung function.⁷⁰ Other studies noted that COPD patients hospitalized with respiratory failure who were randomized to noninvasive nocturnal ventilation plus oxygen therapy as opposed to oxygen alone experienced improvement in health-related quality of life and reduction in intensive-care-unit length of stay but no difference in mortality or subsequent hospitalizations.⁶⁹ In stable hypercapnic COPD patients without OSA, there is no clear evidence that nocturnal noninvasive ventilation lessens the risk of death despite improved daytime gas exchange,^71,72 but additional long-term studies are needed.

Lung volume reduction surgery, a procedure indicated for highly selected patients with severe COPD, has been shown to reduce hyperinflation, improve nocturnal hypoxemia, and improve total sleep time and sleep efficiency in patients without sleep-disordered breathing.⁷³ More studies are needed to determine if reduction in lung hyperinflation has an impact on the occurrence of OSA and on morbidity related to sleep-disordered breathing.

Benefit of CPAP in overlap syndrome

In a nonrandomized study, Marin et al⁶² found that overlap syndrome is associated with an increased risk of death and hospitalization due to COPD exacerbations. CPAP therapy was associated with improved survival rates and decreased hospitalization rates in these patients.

Stanchina et al,⁷⁴ in a post hoc analysis of an observational cohort, assessed the outcomes of 227 patients with overlap syndrome. Greater use of CPAP was found to be associated with lower mortality rates.

Jaoude et al⁷⁵ found that hypercapnic patients with overlap syndrome who were adherent to CPAP therapy had a lower mortality rate than nonadherent hypercapnic patients (P = .04). In a multivariate analysis, the comorbidity index was the only independent predictor of mortality in normocapnic patients with overlap syndrome, while CPAP adherence was associated with improved survival.

Lastly, patients with overlap syndrome tend to need more healthcare and accrue higher medical costs than patients with COPD alone. An analysis of a state Medicaid database that included COPD patients showed that beneficiaries with overlap syndrome spent at least $4,000 more in medical expenditures than beneficiaries with “lone” COPD.²⁴

In conclusion, CPAP is the first line of therapy for overlap syndrome, while daytime hypercapnia or nocturnal hypoxemia despite supplemental oxygen therapy are indications for nocturnal BPAP therapy, regardless of whether patients have OSA.

OSA AND ASTHMA (ALTERNATIVE OVERLAP SYNDROME)

Epidemiology and clinical features

The coexistence of asthma and OSA can begin in childhood and continue throughout adult life. A higher prevalence of lifetime asthma and OSA has been noted in children of racial and ethnic minorities, children of lower socioeconomic status, and those with atopy.⁷⁶

In a pediatric asthma clinic, it was noted that 12 months into structured asthma management and optimization, children with sleep-disordered breathing were nearly four times more likely to have severe asthma at follow-up, even after adjusting for obesity, race, and gender.⁷⁷

In adult patients with OSA, the prevalence of asthma is about 35%.⁷⁸ Conversely, people with asthma are at higher risk of OSA. High risk of OSA was more prevalent in a group of patients with asthma than in a general medical clinic population (39.5% vs 27.2%, P < .05).⁷⁹

Analysis of a large prospective cohort found that asthma was a risk factor for new-onset OSA. The incidence of OSA over 4 years in patients with self-reported asthma was 27%, compared with 16% without asthma. The relative risk adjusted for risk factors such as body mass index, age, and gender was 1.39 (95% confidence interval [CI] 15%–19%).⁸⁰

Patients with asthma who are at high risk of OSA are more likely to have worse daytime and nighttime asthma symptoms. Interestingly, patients who are diagnosed with OSA and treated with CPAP seem to have better asthma control.

Patients with asthma who are more likely to have OSA are women (odds ratio [OR] 2.1), have greater asthma severity (OR 1.6), have gastroesophageal reflux disease (OR 2.7), and use inhaled corticosteroids (OR 4.0).⁸¹ These associations are different than the traditional, population-wide risk factors for OSA, such as male sex, excess body weight, and nocturnal nasal congestion.⁸²

OSA also worsens asthma control. Teodorescu et al¹⁵ found that severe asthma was more frequent in older asthma patients (ages 60–75, prevalence 49%) than in younger patients (ages 18–59, 39%). Older adults with OSA were seven times as likely to have severe asthma (OR 6.6), whereas young adults with sleep apnea were only three times as likely (OR 2.6).

In a group of patients with difficult-to-treat asthma, OSA was significantly associated with frequent exacerbations (OR 3.4), an association similar in magnitude to that of psychological conditions (OR 10.8), severe sinus disease (OR 3.7), recurrent respiratory tract infections (OR 6.9), and gastroesophageal reflux disease (OR 4.9).⁸³ More than half of the patients had at least three of these comorbid conditions.

Sleep quality can greatly affect asthma control, and its importance is often underestimated. Patients with severe asthma have worse sleep quality than patients with milder asthma or nonasthmatic patients, even after excluding patients with a high risk of OSA, patients on CPAP therapy, and patients with a history of gastroesophageal reflux disease. Furthermore, regardless of asthma severity, sleep quality is a significant predictor of asthma-related quality of life, even after accounting for body mass index, daytime sleepiness, and gastroesophageal reflux disease.⁸⁴

Pathophysiology of alternative overlap syndrome

Sleep significantly affects respiratory pathophysiology in asthma. The underlying mechanisms include physical and mechanical stressors, neurohormonal changes, hypoxia, confounding medical conditions, and local and systemic inflammatory changes.

Patients with nocturnal asthma experience more pronounced obstruction when sleep-deprived, suggesting that sleep loss may contribute to worsening airflow limitation.¹⁴ Although changes in pulmonary mechanics and lung volumes may also have a role, volume-dependent airway narrowing does not appear to account for all observed nocturnal increases in airway resistance. Intrathoracic blood pooling may also contribute to nocturnal bronchoconstriction through stimulation of pulmonary C fibers and increased bronchial wall edema, a mechanism that may be similar to the “cardiac asthma” seen in left ventricular dysfunction.

Early studies of sleep-disordered breathing demonstrated that patients with asthma were breathing more irregularly (with hypopnea, apnea, and hyperpnea) in REM sleep than those without asthma.⁸⁵ Interestingly, REM-related hypoxia has also been noted in children with asthma.⁸⁶ This may be related to the increased cholinergic outflow that occurs during REM sleep, which in turn modulates the caliber and reactivity of the lower airways.

In overlap syndrome, oxygen may prolong the duration of apnea episodes and worsen hypercapnia

Physical changes such as upper airway collapse and reduced pharyngeal cross-sectional area may cause further mechanical strain.⁸⁷ This can further propagate airway inflammation, alter airway mucosal muscle fibers, and stimulate neural reflexes, thereby increasing cholinergic tone and bronchoconstriction. Furthermore, heightened negative intrathoracic pressure during obstructive episodes can increase nocturnal pulmonary blood pooling.¹⁴ Hypoxia itself can augment airway hyperresponsiveness via vagal pathways or carotid body receptors, increasing reactive oxygen species and inflammatory mediators. Local inflammation can “spill over” into systemic inflammatory changes, while alterations in airway inflammatory markers in asthma seem to follow a circadian rhythm, in parallel with the nocturnal worsening of the asthma symptoms.⁸⁸ Finally, altered sleep may be related to other comorbid conditions, such as gastroesophageal reflux disease, insomnia, and restless leg syndrome.

Management and outcomes of alternative overlap syndrome

Despite optimization of asthma management, OSA can still significantly affect asthma control and symptoms.⁸⁴

Interestingly, medications that reduce airway inflammation (eg, corticosteroids) may promote OSA. This occurrence cannot be fully explained by an increase in body mass, as more respiratory disturbances occur during sleep with continuous corticosteroid treatment even without increases in body mass index.⁸⁷ Therefore, these associations may be related to upper airway myopathy caused by the treatment, a small pharynx, facial dysmorphisms, or fat deposition.⁸⁹

Does CPAP improve asthma?

OSA is often unrecognized in patients with asthma, and treating it can have an impact on asthma symptoms.

CPAP therapy has not been shown to significantly change airway responsiveness or lung function, but it has been noted to significantly improve both OSA-related and asthma-related quality of life and reduce the use of rescue bronchodilators.^3,90 CPAP has demonstrated improvement of quality of life that positively correlated with body weight and apnea-hypopnea index at baseline, suggesting that asthmatic patients with greater obesity or worse OSA may benefit most from aggressive management.⁹⁰

However, CPAP should be used only if the patient has confirmed OSA. Empiric use of CPAP without a diagnosis of OSA was poorly tolerated and failed to improve asthma symptoms or lung function.⁹¹ More importantly, using CPAP in a patient who does not have OSA may contribute to further sleep disruption.⁹¹

Second-line treatments such as mandibular advancing devices and airway or bariatric surgery have not yet been studied in alternative overlap syndrome.

A multidimensional assessment of asthma

The Western world is experiencing an epidemic of obesity and of asthma. Obesity contributes to the pathogenesis of OSA by altering the anatomy and collapsibility of the upper airway, affecting ventilatory control and increasing respiratory workload. Another paradigm, supported by some evidence, is that OSA itself may contribute to the development of obesity. Both OSA and obesity lead to activation of inflammatory biologic cascades, which are likely the pathogenic mechanisms for their cardiovascular and metabolic consequences. As such, early recognition of OSA is important, as effective treatments are available.

In some patients, obesity may cause asthma, as obesity precedes the onset of asthma in a significant proportion of patients, and bariatric surgery for morbid obesity may resolve asthma. The obese asthma phenotype seems to include chronic rhinosinusitis, gastroesophageal reflux disease, poorer asthma control, limited responsiveness to corticosteroids, and even different sets of biomarkers (eg, neutrophilic airway inflammation). A cohort of obese patients with poor asthma control demonstrated significant improvement in asthma symptoms, quality of life, and airway reactivity after weight loss from bariatric surgery.⁹²

To improve our knowledge about airway disease phenotypes and endotypes and their response to therapy, we propose taking a multidimensional, structured assessment of all patients with asthma, using a schema we call “ABCD-3P-PQRST” (Table 2).

The purpose of using this type of system in clinics and research is to capture the multi­dimensionality of the disease and better develop future individualized therapeutic strategies by employing the latest advances in systems biology and computational methods such as cluster and principal component analysis.

Multidimensional assessments addressing airway problems such as asthma, COPD, OSA, other comorbidities and risk factors, and personalized management plans will need to be the basis of future therapeutic interventions. Increased attention to the complications of asthma and obstructive airway and lung diseases in our patients is imperative, specifically to develop effective systems of care, appropriate clinical guidelines, and research studies that lead to improved health outcomes.

Many patients who have obstructive lung disease, ie, chronic obstructive pulmonary disease (COPD) or asthma, also have obstructive sleep apnea (OSA), and vice versa.

The combination of COPD and OSA was first described almost 30 years ago by Flenley, who called it “overlap syndrome.”¹ At that time, he recommended that a sleep study be considered in all obese patients with COPD who snore and in those who have frequent headaches after starting oxygen therapy. In the latter group, he doubted that nocturnal oxygen was the correct treatment. He also believed that the outcomes in patients with overlap syndrome were worse than those in patients with COPD or OSA alone. These opinions remain largely valid today.

We now also recognize the combination of asthma and OSA (alternative overlap syndrome) and collectively call both combinations obstructive lung disease-obstructive sleep apnea (OLDOSA) syndrome.² Interestingly, these relationships are likely bidirectional, with one condition aggravating or predisposing to the other.

Knowing that a patient has one of these overlap syndromes, one can initiate continuous positive airway pressure (CPAP) therapy, which can improve clinical outcomes.^3–6  Therefore, when evaluating a patient with asthma or COPD, one should consider OSA using a validated questionnaire and, if the findings suggest the diagnosis, polysomnography. Conversely, it is prudent to look for comorbid obstructive lung disease in patients with OSA, as interactions between upper and lower airway dysfunction may lead to distinctly different treatment and outcomes.

Here, we briefly review asthma and COPD, explore shared risk factors for sleep-disordered breathing and obstructive lung diseases, describe potential pathophysiologic mechanisms explaining these associations, and highlight the importance of recognizing and individually treating the overlaps of OSA and COPD or asthma.

COPD AND ASTHMA ARE VERY COMMON

About 10% of the US population have COPD,⁷ a preventable and treatable disease mainly caused by smoking, and a leading cause of sickness and death worldwide.^8,9

About 10% of the US population have COPD, and 8% have asthma

About 8% of Americans have asthma,⁷ which has become one of the most common chronic conditions in the Western world, affecting about 1 in 7 children and about 1 in 12 adults. The World Health Organization estimates that 235 million people suffer from asthma worldwide, and by 2025 this number is projected to rise to 400 million.^10,11

The prevalence of these conditions in a particular population depends on the frequency of risk factors and associated morbidities, including OSA. These factors may allow asthma or COPD to arise earlier or have more severe manifestations.^8,12

Asthma and COPD: Similarities and differences

Asthma and COPD share several features. Both are inflammatory airway conditions triggered or perpetuated by allergens, viral infection, tobacco smoke, products of biomass or fossil fuel combustion, and other substances. In both diseases, airflow is “obstructed” or limited, with a low ratio of forced expiratory volume in 1 second to forced vital capacity (FEV₁/FVC). Symptoms can also be similar, with dyspnea, cough, wheezing, and chest tightness being the most frequent complaints. The similarities support the theory proposed by Orie et al¹³ (the “Dutch hypothesis”) that asthma and COPD may actually be manifestations of the same disease.

But there are also differences. COPD is strongly linked to cigarette smoking and has at least three phenotypes:

• Chronic bronchitis, defined clinically by cough and sputum production for more than 3 months per year for 2 consecutive years
• Emphysema, characterized anatomically by loss of lung parenchyma, as seen on tomographic imaging or examination of pathologic specimens
• A mixed form with bronchitic and emphysematous features, which is likely the most common.

Particularly in emphysematous COPD, smoking predisposes patients to gas-exchange abnormalities and low diffusing capacity for carbon monoxide.

In asthma, symptoms may be more episodic, the age of onset is often younger, and atopy is common, especially in allergic asthma. These episodic symptoms may correlate temporally with measurable airflow reversibility (≥ 12% and ≥ 200 mL improvement in FVC or in FEV₁ after bronchodilator challenge).

However, the current taxonomy does not unequivocally divide obstructive lung diseases into asthma and COPD, and major features such as airway hyperresponsiveness, airflow reversibility, neutrophilic or CD8 lymphocytic airway inflammation, and lower concentration of nitric oxide in the exhaled air may be present in different phenotypes of both conditions (Table 1).

AIRFLOW IN OBSTRUCTIVE LUNG DISEASES AND DURING SLEEP

Normal airflow involves a complex interplay between airway resistance and elastic recoil of the entire respiratory system, including the airways, the lung parenchyma, and the chest wall (Figure 1).

In asthma and COPD, resistance to airflow is increased, predominantly in the upper airways (nasal passages, pharynx, and larynx) and in the first three or four subdivisions of the tracheobronchial tree. The problem is worse during exhalation, when elastic recoil of the lung parenchyma and chest wall also increases airway resistance, reduces airway caliber, and possibly even constricts the bronchi. This last effect may occur either due to mass loading of the bronchial smooth muscles or to large intrathoracic transmural pressure shifts that may increase extravasation of fluid in the bronchial walls, especially with higher vascular permeability in inflammatory conditions.

Furthermore, interactions between the airway and parenchyma and between the upper and lower airways, as well as radial and axial coupling of these anatomic and functional components, contribute to complex interplay between airway resistance and parenchymal-chest wall elastic energy—stretch or recoil.

The muscles of the upper and lower airway may not work together due to the loss of normal lung parenchyma (as in emphysema) or to the acute inflammation in the small airways and adjacent parenchyma (as in severe asthma exacerbations). This loss of coordination makes the upper airway more collapsible, a feature of OSA.

Additionally, obesity, gastroesophageal reflux, disease chronic rhinitis, nasal polyposis, and acute exacerbations of chronic systemic inflammation all contribute to more complex interactions between obstructive lung diseases and OSA.⁶

Sleep affects breathing, particularly in patients with respiratory comorbidities, and sleep-disordered breathing causes daytime symptoms and worsens quality of life.^1,13–15 During sleep, respiratory centers become less sensitive to oxygen and carbon dioxide; breathing becomes more irregular, especially during rapid eye movement (REM) sleep; the chest wall moves less, so that the tidal volume and functional residual capacity are lower; sighs, yawns, and deep breaths become limited; and serum carbon dioxide concentration may rise.

OBSTRUCTIVE SLEEP APNEA

The prevalence of OSA, a form of sleep-disordered breathing characterized by limitation of inspiratory and (to a lesser degree) expiratory flow, has increased significantly in recent years, in parallel with the prevalence of its major risk factor, obesity.

OSA is generally defined as an apnea-hypopnea index of 5 or higher, ie, five or more episodes of apnea or hypopnea per hour.

Based on Ioachimescu OC, Teodorescu M. Integrating the overlap of obstructive lung disease and obstructive sleep apnoea: OLDOSA syndrome. Respirology 2013; 18:421–431; with permission from John Wiley &amp; Sons, Inc.

OSA syndrome, ie, an apnea-hypopnea index of 5 or higher and excessive daytime sleepiness (defined by an Epworth Sleepiness Scale score > 10) was found in the initial analysis of the Wisconsin Sleep cohort in 1993 to be present in about 2% of women and 4% of men.¹⁶ A more recent longitudinal analysis showed a significant increase—for example, in people 50 to 70 years old the prevalence was up to 17.6% in men and 7.5% in women.¹⁷

Upper airway resistance syndrome, a milder form of sleep-disordered breathing, is now included under the diagnosis of OSA, as its pathophysiology is not significantly different.¹⁸

In the next section, we discuss what happens when OSA overlaps with COPD (overlap syndrome) and with asthma (“alternative overlap syndrome”)^2,8 (Figure 2).

OSA AND COPD (OVERLAP SYNDROME)

Flenley¹ hypothesized that patients with COPD in whom supplemental oxygen worsened hypercapnia may also have OSA and called this association overlap syndrome.

How common is overlap syndrome?

Since both COPD and OSA are prevalent conditions, overlap syndrome may also be common.

The reported prevalence of overlap syndrome varies widely, depending on the population studied and the methods used. In various studies, COPD was present in 9% to 56% of patients with OSA,^19–23 and OSA was found in 5% to 85% of patients with COPD.^24–27

Based on the prevalence of COPD in the general population (about 10%¹²) and that of sleep-disordered breathing (about 5% to 10%¹⁷), the expected prevalence of overlap syndrome in people over age 40 may be 0.5% to 1%.²⁸ In a more inclusive estimate with “subclinical” forms of overlap syndrome—ie, OSA defined as an apnea-hypopnea index of 5 or more (about 25% of the population¹⁷) and COPD Global initiative for Chronic Obstructive Lung Disease (GOLD) stage 1 (16.8% in the National Health and Nutrition Education Survey¹²)—the expected prevalence of overlap is around 4%. Some studies found a higher prevalence of COPD in OSA patients than in the general population,^21,29 while others did not.^22,28,30 The studies differed in how they defined sleep-disordered breathing.

Larger studies are needed to better assess the true prevalence of sleep-disordered breathing in COPD. They should use more sensitive measures of airflow and standardized definitions of sleep-disordered breathing and should include patients with more severe COPD.

Fatigue and insomnia are common in COPD

At near-maximal ventilatory capacity, even a mild increase in upper airway resistance increases the work of breathing

Fatigue is strongly correlated with declining lung function, low exercise tolerance, and impaired quality of life in COPD.³¹ Factors that contribute to fatigue include dyspnea, depression, and impaired sleep.³² Some suggest that at least half of COPD patients have sleep complaints such as insomnia, sleep disruption, or sleep fragmentation.³³ Insomnia, difficulty falling asleep, and early morning awakenings are the most common complaints (30%–70% of patients) and are associated with daytime fatigue.³⁴ Conversely, comorbid OSA can contribute to fatigue and maintenance-type insomnia (ie, difficulty staying asleep and returning to sleep).

Multiple mechanisms of hypoxemia in overlap syndrome

Oxygenation abnormalities and increased work of breathing contribute to the pathophysiology of overlap syndrome. In patients with COPD, oxygenation during wakefulness is a strong predictor of gas exchange during sleep.³⁵ Further, patients with overlap syndrome tend to have more severe hypoxia during sleep than patients with isolated COPD or OSA at rest or during exercise.³⁶

In overlap syndrome, hypoxemia is the result of several mechanisms:

• Loss of upper airway muscle tone from intermittent episodes of obstructive apnea and hypopnea leads to upper airway collapse during sleep, particularly during REM sleep, increasing the severity of OSA.³⁷
• Reductions in functional residual capacity from lying in the recumbent position and during REM sleep render patients with COPD more vulnerable, as compensatory use of accessory muscles to maintain near-normal ventilation in a hyperinflated state becomes impaired.³⁷
• Alterations in pulmonary ventilation-perfusion matching may lead to altered carbon dioxide homeostasis and impaired oxygenation in patients with emphysema.
• Circadian variation in lower airway caliber may also be observed, in parallel with the bronchoconstriction caused by increased nocturnal vagotonia.
• Hypercapnia (Paco₂ ≥ 45 mm Hg) may lead to overall reduced responsiveness of respiratory muscles and to a blunted response of respiratory centers to low oxygen and high carbon dioxide levels.³⁸ Thus, hypercapnia is a better predictor of the severity of nocturnal hypoxemia than hypoxemia developing during exercise.³⁹

In a person who is at near-maximal ventilatory capacity, even a mild increase in upper airway resistance (as seen with snoring, upper airway resistance syndrome, or OSA) increases the work of breathing. This phenomenon can lead to early arousals even before significant oxyhemoglobin desaturation occurs.

Normally, inspiratory flow limitation is counteracted by increasing inspiratory time to maintain ventilation. Patients with COPD may not be able to do this, however, as they need more time to breathe out due to narrowing of their lower airways.⁴⁰ The inability to compensate for upper airway resistance, similar to the increased work of breathing seen with exercise, may lead to early arousals and increased sleep fragmentation.

Consequences of overlap syndrome

Patients with overlap syndrome appear to have higher morbidity and mortality rates than those with COPD or sleep-disordered breathing alone.

Cor pulmonale. Nighttime hypoxia is more severe and persistent in overlap syndrome than with COPD or OSA alone. This may contribute to more significant pulmonary hypertension and to the development of cor pulmonale, in which the right ventricle is altered in structure (eg, hypertrophied, dilated) or reduced in function, or both, from severe pulmonary hypertension.

In contrast to right ventricular failure due to disorders of the left heart, cor pulmonale is a result of diseases of the vasculature (eg, idiopathic pulmonary arterial hypertension), lung parenchyma (eg, COPD), upper airway (eg, OSA), or chest wall (eg, severe kyphoscoliosis). COPD is the most common cause of cor pulmonale in the United States, accounting for up to 30% of cases of cor pulmonale.^41–45 In OSA, cor pulmonale is seen in up to 20% of cases,⁴³ while in overlap syndrome cor pulmonale is encountered even more often (ie, in up to 80%); these patients have a dismal 5-year survival rate of about 30%.⁴⁶

Obesity hypoventilation syndrome is characterized by obesity (body mass index ≥ 30 kg/m²) and daytime hypercapnia (Paco₂ ≥ 45 mm Hg) that cannot be fully attributed to an underlying cardiopulmonary or neurologic condition.¹⁸ Hypercapnia worsens during sleep (especially during REM sleep) and is often associated with severe arterial oxygen desaturation. Up to 90% of patients with obesity hypoventilation syndrome have comorbid OSA, and the rest generally have sleep-related hypoventilation, particularly during REM sleep.

Overlap syndrome with cor pulmonale typically has a poor prognosis; one study found a 5-year survival rate of 30%

In patients with obesity hypoventilation syndrome, daytime hypercapnia may improve or even normalize with adequate positive airway pressure treatment and sustained adherence to treatment.¹⁸ Many patients with obesity hypoventilation syndrome respond to CPAP or bilevel positive airway pressure (BPAP), with improvement in daytime Paco₂. However, normalization of daytime Paco₂ occurs only in a subgroup of patients. In contrast, treatment with oxygen therapy alone may worsen hypercapnia.

Oxygen therapy for pure COPD, but maybe not for overlap syndrome

Continuous oxygen therapy reduces mortality in COPD,^47,48 but the duration and severity of hypoxemia that warrant oxygen therapy are less clear. Oxygen therapy in hypoxemic patients has been shown to improve sleep quality and reduce arousals.⁴⁹

Indications for oxygen treatment of nocturnal hypoxemia are generally based on Medicare guidelines:

• At least 5 minutes of sleep with peripheral oxygen saturation ≤ 88% or Pao₂ ≤ 55 mm Hg, or
• A decrease in Pao₂ of more than 10 mm Hg or in peripheral oxygen saturation of more than 5% for at least 5 minutes of sleep and associated with signs or symptoms reasonably attributable to hypoxemia (group I criteria), or
• At least 5 minutes of sleep with peripheral oxygen saturation ≥ 89% or Pao₂ 56 to 59 mm Hg and pedal edema, pulmonary hypertension, cor pulmonale, or erythrocytosis (group II criteria).⁵⁰

Approximately 47% of COPD patients who are hypoxemic during the day spend about 30% of sleep time with an oxygen saturation less than 90%, even while on continuous oxygen therapy.⁵¹ Current recommendations for nocturnal oxygen therapy are to increase the oxygen concentration by 1 L/minute above the baseline oxygen flow rate needed to maintain an oxygen saturation higher than 90% during resting wakefulness, using a nasal cannula or face mask.⁵²

Caveat. In overlap syndrome, supplemental oxygen may prolong the duration of apnea episodes and worsen hypercapnia.

Positive airway pressure for OSA

Positive airway pressure therapy improves cardiovascular outcomes in OSA.⁵³ Several studies^54–58 compared the effectiveness of CPAP vs BPAP as initial therapy for OSA but did not provide enough evidence to favor one over the other in this setting. Similarly, the results are mixed for the use of fixed or auto-adjusting BPAP as salvage therapy in patients who cannot tolerate CPAP.^59–61

In overlap syndrome, CPAP or BPAP with or without supplemental oxygen has been investigated in several studies.^26,62–65 In general, the mortality rate of COPD patients who require oxygen therapy is quite high.^47,66 In hypoxemic COPD patients with moderate to severe sleep-disordered breathing, the 5-year survival rate was 71% in those treated with CPAP plus oxygen, vs 26% in those on oxygen alone, independent of baseline postbronchodilator FEV₁.⁶⁷

There is no specific FEV₁ cutoff for prescribing CPAP. In general, daytime hypercapnia and nocturnal hypoxemia despite supplemental oxygen therapy are indications for BPAP therapy, regardless of the presence of OSA. Whether noninvasive nocturnal ventilation for COPD patients who do not have OSA improves long-term COPD outcomes is not entirely clear.^65,68,69

Adding nocturnal BPAP in spontaneous timed mode to pulmonary rehabilitation for severe hypercapnic COPD was found to improve quality of life, mood, dyspnea, gas exchange, and decline in lung function.⁷⁰ Other studies noted that COPD patients hospitalized with respiratory failure who were randomized to noninvasive nocturnal ventilation plus oxygen therapy as opposed to oxygen alone experienced improvement in health-related quality of life and reduction in intensive-care-unit length of stay but no difference in mortality or subsequent hospitalizations.⁶⁹ In stable hypercapnic COPD patients without OSA, there is no clear evidence that nocturnal noninvasive ventilation lessens the risk of death despite improved daytime gas exchange,^71,72 but additional long-term studies are needed.

Lung volume reduction surgery, a procedure indicated for highly selected patients with severe COPD, has been shown to reduce hyperinflation, improve nocturnal hypoxemia, and improve total sleep time and sleep efficiency in patients without sleep-disordered breathing.⁷³ More studies are needed to determine if reduction in lung hyperinflation has an impact on the occurrence of OSA and on morbidity related to sleep-disordered breathing.

Benefit of CPAP in overlap syndrome

In a nonrandomized study, Marin et al⁶² found that overlap syndrome is associated with an increased risk of death and hospitalization due to COPD exacerbations. CPAP therapy was associated with improved survival rates and decreased hospitalization rates in these patients.

Stanchina et al,⁷⁴ in a post hoc analysis of an observational cohort, assessed the outcomes of 227 patients with overlap syndrome. Greater use of CPAP was found to be associated with lower mortality rates.

Jaoude et al⁷⁵ found that hypercapnic patients with overlap syndrome who were adherent to CPAP therapy had a lower mortality rate than nonadherent hypercapnic patients (P = .04). In a multivariate analysis, the comorbidity index was the only independent predictor of mortality in normocapnic patients with overlap syndrome, while CPAP adherence was associated with improved survival.

Lastly, patients with overlap syndrome tend to need more healthcare and accrue higher medical costs than patients with COPD alone. An analysis of a state Medicaid database that included COPD patients showed that beneficiaries with overlap syndrome spent at least $4,000 more in medical expenditures than beneficiaries with “lone” COPD.²⁴

In conclusion, CPAP is the first line of therapy for overlap syndrome, while daytime hypercapnia or nocturnal hypoxemia despite supplemental oxygen therapy are indications for nocturnal BPAP therapy, regardless of whether patients have OSA.

OSA AND ASTHMA (ALTERNATIVE OVERLAP SYNDROME)

Epidemiology and clinical features

The coexistence of asthma and OSA can begin in childhood and continue throughout adult life. A higher prevalence of lifetime asthma and OSA has been noted in children of racial and ethnic minorities, children of lower socioeconomic status, and those with atopy.⁷⁶

In a pediatric asthma clinic, it was noted that 12 months into structured asthma management and optimization, children with sleep-disordered breathing were nearly four times more likely to have severe asthma at follow-up, even after adjusting for obesity, race, and gender.⁷⁷

In adult patients with OSA, the prevalence of asthma is about 35%.⁷⁸ Conversely, people with asthma are at higher risk of OSA. High risk of OSA was more prevalent in a group of patients with asthma than in a general medical clinic population (39.5% vs 27.2%, P < .05).⁷⁹

Analysis of a large prospective cohort found that asthma was a risk factor for new-onset OSA. The incidence of OSA over 4 years in patients with self-reported asthma was 27%, compared with 16% without asthma. The relative risk adjusted for risk factors such as body mass index, age, and gender was 1.39 (95% confidence interval [CI] 15%–19%).⁸⁰

Patients with asthma who are at high risk of OSA are more likely to have worse daytime and nighttime asthma symptoms. Interestingly, patients who are diagnosed with OSA and treated with CPAP seem to have better asthma control.

Patients with asthma who are more likely to have OSA are women (odds ratio [OR] 2.1), have greater asthma severity (OR 1.6), have gastroesophageal reflux disease (OR 2.7), and use inhaled corticosteroids (OR 4.0).⁸¹ These associations are different than the traditional, population-wide risk factors for OSA, such as male sex, excess body weight, and nocturnal nasal congestion.⁸²

OSA also worsens asthma control. Teodorescu et al¹⁵ found that severe asthma was more frequent in older asthma patients (ages 60–75, prevalence 49%) than in younger patients (ages 18–59, 39%). Older adults with OSA were seven times as likely to have severe asthma (OR 6.6), whereas young adults with sleep apnea were only three times as likely (OR 2.6).

In a group of patients with difficult-to-treat asthma, OSA was significantly associated with frequent exacerbations (OR 3.4), an association similar in magnitude to that of psychological conditions (OR 10.8), severe sinus disease (OR 3.7), recurrent respiratory tract infections (OR 6.9), and gastroesophageal reflux disease (OR 4.9).⁸³ More than half of the patients had at least three of these comorbid conditions.

Sleep quality can greatly affect asthma control, and its importance is often underestimated. Patients with severe asthma have worse sleep quality than patients with milder asthma or nonasthmatic patients, even after excluding patients with a high risk of OSA, patients on CPAP therapy, and patients with a history of gastroesophageal reflux disease. Furthermore, regardless of asthma severity, sleep quality is a significant predictor of asthma-related quality of life, even after accounting for body mass index, daytime sleepiness, and gastroesophageal reflux disease.⁸⁴

Pathophysiology of alternative overlap syndrome

Sleep significantly affects respiratory pathophysiology in asthma. The underlying mechanisms include physical and mechanical stressors, neurohormonal changes, hypoxia, confounding medical conditions, and local and systemic inflammatory changes.

Patients with nocturnal asthma experience more pronounced obstruction when sleep-deprived, suggesting that sleep loss may contribute to worsening airflow limitation.¹⁴ Although changes in pulmonary mechanics and lung volumes may also have a role, volume-dependent airway narrowing does not appear to account for all observed nocturnal increases in airway resistance. Intrathoracic blood pooling may also contribute to nocturnal bronchoconstriction through stimulation of pulmonary C fibers and increased bronchial wall edema, a mechanism that may be similar to the “cardiac asthma” seen in left ventricular dysfunction.

Early studies of sleep-disordered breathing demonstrated that patients with asthma were breathing more irregularly (with hypopnea, apnea, and hyperpnea) in REM sleep than those without asthma.⁸⁵ Interestingly, REM-related hypoxia has also been noted in children with asthma.⁸⁶ This may be related to the increased cholinergic outflow that occurs during REM sleep, which in turn modulates the caliber and reactivity of the lower airways.

In overlap syndrome, oxygen may prolong the duration of apnea episodes and worsen hypercapnia

Physical changes such as upper airway collapse and reduced pharyngeal cross-sectional area may cause further mechanical strain.⁸⁷ This can further propagate airway inflammation, alter airway mucosal muscle fibers, and stimulate neural reflexes, thereby increasing cholinergic tone and bronchoconstriction. Furthermore, heightened negative intrathoracic pressure during obstructive episodes can increase nocturnal pulmonary blood pooling.¹⁴ Hypoxia itself can augment airway hyperresponsiveness via vagal pathways or carotid body receptors, increasing reactive oxygen species and inflammatory mediators. Local inflammation can “spill over” into systemic inflammatory changes, while alterations in airway inflammatory markers in asthma seem to follow a circadian rhythm, in parallel with the nocturnal worsening of the asthma symptoms.⁸⁸ Finally, altered sleep may be related to other comorbid conditions, such as gastroesophageal reflux disease, insomnia, and restless leg syndrome.

Management and outcomes of alternative overlap syndrome

Despite optimization of asthma management, OSA can still significantly affect asthma control and symptoms.⁸⁴

Interestingly, medications that reduce airway inflammation (eg, corticosteroids) may promote OSA. This occurrence cannot be fully explained by an increase in body mass, as more respiratory disturbances occur during sleep with continuous corticosteroid treatment even without increases in body mass index.⁸⁷ Therefore, these associations may be related to upper airway myopathy caused by the treatment, a small pharynx, facial dysmorphisms, or fat deposition.⁸⁹

Does CPAP improve asthma?

OSA is often unrecognized in patients with asthma, and treating it can have an impact on asthma symptoms.

CPAP therapy has not been shown to significantly change airway responsiveness or lung function, but it has been noted to significantly improve both OSA-related and asthma-related quality of life and reduce the use of rescue bronchodilators.^3,90 CPAP has demonstrated improvement of quality of life that positively correlated with body weight and apnea-hypopnea index at baseline, suggesting that asthmatic patients with greater obesity or worse OSA may benefit most from aggressive management.⁹⁰

However, CPAP should be used only if the patient has confirmed OSA. Empiric use of CPAP without a diagnosis of OSA was poorly tolerated and failed to improve asthma symptoms or lung function.⁹¹ More importantly, using CPAP in a patient who does not have OSA may contribute to further sleep disruption.⁹¹

Second-line treatments such as mandibular advancing devices and airway or bariatric surgery have not yet been studied in alternative overlap syndrome.

A multidimensional assessment of asthma

The Western world is experiencing an epidemic of obesity and of asthma. Obesity contributes to the pathogenesis of OSA by altering the anatomy and collapsibility of the upper airway, affecting ventilatory control and increasing respiratory workload. Another paradigm, supported by some evidence, is that OSA itself may contribute to the development of obesity. Both OSA and obesity lead to activation of inflammatory biologic cascades, which are likely the pathogenic mechanisms for their cardiovascular and metabolic consequences. As such, early recognition of OSA is important, as effective treatments are available.

In some patients, obesity may cause asthma, as obesity precedes the onset of asthma in a significant proportion of patients, and bariatric surgery for morbid obesity may resolve asthma. The obese asthma phenotype seems to include chronic rhinosinusitis, gastroesophageal reflux disease, poorer asthma control, limited responsiveness to corticosteroids, and even different sets of biomarkers (eg, neutrophilic airway inflammation). A cohort of obese patients with poor asthma control demonstrated significant improvement in asthma symptoms, quality of life, and airway reactivity after weight loss from bariatric surgery.⁹²

To improve our knowledge about airway disease phenotypes and endotypes and their response to therapy, we propose taking a multidimensional, structured assessment of all patients with asthma, using a schema we call “ABCD-3P-PQRST” (Table 2).

The purpose of using this type of system in clinics and research is to capture the multi­dimensionality of the disease and better develop future individualized therapeutic strategies by employing the latest advances in systems biology and computational methods such as cluster and principal component analysis.

Multidimensional assessments addressing airway problems such as asthma, COPD, OSA, other comorbidities and risk factors, and personalized management plans will need to be the basis of future therapeutic interventions. Increased attention to the complications of asthma and obstructive airway and lung diseases in our patients is imperative, specifically to develop effective systems of care, appropriate clinical guidelines, and research studies that lead to improved health outcomes.

A 25-year-old woman presents to the emergency department with a 7-day history of fatigue and nausea. On presentation she denies having abdominal pain, headache, fever, chills, night sweats, vomiting, diarrhea, melena, hematochezia, or weight loss. She recalls changes in the colors of her eyes and darkening urine over the last few days. Her medical history before this is unremarkable. She takes no prescription, over-the-counter, or herbal medications. She works as a librarian and has no occupational toxic exposures. She is single and has one sister with no prior medical history. She denies recent travel, sick contacts, smoking, recreational drug use, or pets at home.

On physical examination, her vital signs are temperature 37.3°C (99.1°F), heart rate 90 beats per minute, blood pressure 125/80 mm Hg, respiration rate 14 per minute, and oxygen saturation 97% on room air. She has icteric sclera and her skin is jaundiced. Cardiac examination is normal. Lungs are clear to auscultation and percussion bilaterally. Her abdomen is soft with no visceromegaly, masses, or tenderness. Extremities are normal with no edema. She is alert and oriented, but she has mild asterixis of the outstretched hands. The neurologic examination is otherwise unremarkable.

The patient’s basic laboratory values are listed in Table 1. Shortly after admission, she develops changes in her mental status, remaining alert but becoming agitated and oriented to person only. In view of her symptoms and laboratory findings, acute liver failure is suspected.

ACUTE LIVER FAILURE

1. The diagnostic criteria for acute liver failure include all of the following except which one?

• Acute elevation of liver biochemical tests
• Presence of preexisting liver disease
• Coagulopathy, defined by an international normalized ratio (INR) of 1.5 or greater
• Encephalopathy
• Duration of symptoms less than 26 weeks

Acute liver failure is defined by acute onset of worsening liver tests, coagulopathy (INR ≥ 1.5), and encephalopathy in patients with no preexisting liver disease and with symptom duration of less than 26 weeks.¹ With a few exceptions, a history of preexisting liver disease negates the diagnosis of acute liver failure. Our patient meets the diagnostic criteria for acute liver failure.

Immediate management

Once acute liver failure is identified or suspected, the next step is to transfer the patient to the intensive care unit for close monitoring of mental status. Serial neurologic evaluations permit early detection of cerebral edema, which is considered the most common cause of death in patients with acute liver failure. Additionally, close monitoring of electrolytes and plasma glucose is necessary since these patients are susceptible to electrolyte disturbances and hypoglycemia.

Patients with acute liver failure are at increased risk of infections and should be routinely screened by obtaining urine and blood cultures.

Gastrointestinal bleeding is not uncommon in patients with acute liver failure and is usually due to gastric stress ulceration. Prophylaxis with a histamine 2 receptor antagonist or proton pump inhibitor should be considered in order to prevent gastrointestinal bleeding.

Treatment with N-acetylcysteine is beneficial, not only in patients with acute liver failure due to acetaminophen overdose, but also in those with acute liver failure from other causes.

CASE CONTINUES:
TRANSFER TO THE INTENSIVE CARE UNIT

The patient, now diagnosed with acute liver failure, is transferred to the intensive care unit. Arterial blood gas measurement shows:

• pH 7.38 (reference range 7.35–7.45)
• Pco₂ 40 mm Hg (36–46)
• Po₂ 97 mm Hg (85–95)
• Hco₃ 22 mmol/L (22–26).

A chest radiograph is obtained and is clear. Computed tomography (CT) of the brain reveals no edema. Transcranial Doppler ultrasonography does not show any intracranial fluid collections.

Blood and urine cultures are negative. Her hemoglobin level remains stable, and she does not develop signs of bleeding. She is started on a proton pump inhibitor for stress ulcer prophylaxis and is empirically given intravenous N-acetylcysteine until the cause of acute liver failure can be determined.

CAUSES OF ACUTE LIVER FAILURE

2. Which of the following can cause acute liver failure?

• Acetaminophen overdose
• Viral hepatitis
• Autoimmune hepatitis
• Wilson disease
• Alcoholic hepatitis

Drug-induced liver injury is the most common cause of acute liver failure in the United States,^2,3 and of all drugs, acetaminophen overdose is the number-one cause. In acetaminophen-induced liver injury, serum aminotransferase levels are usually elevated to more than 1,000 U/L, while serum bilirubin remains normal in the early stages. Antimicrobial agents, antiepileptic drugs, and herbal supplements have also been implicated in acute liver failure. Our patient has denied taking herbal supplements or medications, including over-the-counter ones.

Acute viral hepatitis can explain the patient’s condition. It is a common cause of acute liver failure in the United States.² Hepatitis A and E are more common in developing countries. Other viruses such as cytomegalovirus, Epstein-Barr virus, herpes simplex virus type 1 and 2, and varicella zoster virus can also cause acute liver failure. Serum aminotransferase levels may exceed 1,000 U/L in patients with viral hepatitis.

A young woman presents with acute liver failure: What is the cause? Is her sister at risk?

Autoimmune hepatitis is a rare cause of acute liver failure, but it should be considered in the differential diagnosis, particularly in middle-aged women with autoimmune disorders such as hypothyroidism. Autoimmune hepatitis can cause marked elevation in aminotransferase levels (> 1,000 U/L).

Wilson disease is an autosomal-recessive disease in which there is excessive accumulation of copper in the liver and other organs because of an inherited defect in the biliary excretion of copper. Wilson disease can cause acute liver failure and should be excluded in any patient, particularly if under age 40 with acute onset of unexplained hepatic, neurologic, or psychiatric disease.

Alcoholic hepatitis usually occurs in patients with a long-standing history of heavy alcohol use. As a result, most patients with alcoholic hepatitis have manifestations of chronic liver disease due to alcohol use. Therefore, by definition, it is not a cause of acute liver failure. Additionally, in patients with alcoholic hepatitis, the aspartate aminotransferase (AST) level is elevated but less than 300 IU/mL, and the ratio of AST to alanine aminotransferase (ALT) is usually more than 2.

CASE CONTINUES: FURTHER TESTING

The results of our patient’s serologic tests are shown in Table 2. Other test results:

• Autoimmune markers including antinuclear antibodies, antimitochondrial antibodies, antismooth muscle antibodies, and liver and kidney microsomal antibodies are negative; her immunoglobulin G (IgG) level is normal
• Serum ceruloplasmin 25 mg/dL (normal 21–45)
• Free serum copper 120 µg/dL (normal 8–12)
• Abdominal ultrasonography is unremarkable, with normal liver parenchyma and no intrahepatic or extrahepatic biliary dilatation
• Doppler ultrasonography of the liver shows patent blood vessels.

3. Based on the new data, which of the following statements is correct?

• Hepatitis B is the cause of acute liver failure in this patient
• Herpetic hepatitis cannot be excluded on the basis of the available data
• Wilson disease is most likely the diagnosis, given her elevated free serum copper
• A normal serum ceruloplasmin level is not sufficient to rule out acute liver failure secondary to Wilson disease

Hepatitis B surface antigen and hepatitis B core antibodies were negative in our patient, excluding hepatitis B virus infection. The positive hepatitis B surface antibody indicates prior immunization.

Herpetic hepatitis is an uncommon but important cause of acute liver failure because the mortality rate is high if the patient is not treated early with acyclovir. Fever, elevated aminotransferases, and leukopenia are common with herpetic hepatitis. Fewer than 50% of patients with herpetic hepatitis have vesicular rash.^4,5 The value of antibody serologic testing is limited due to high rates of false-positive and false-negative results. The gold standard diagnostic tests are viral load (detection of viral RNA by polymerase chain reaction), viral staining on liver biopsy, or both. In our patient, herpes simplex virus polymerase chain reaction testing was negative, which makes herpetic hepatitis unlikely.

Wilson disease is a genetic condition in which the ability to excrete copper in the bile is impaired, resulting in accumulation of copper in the hepatocytes. Subsequently, copper is released into the bloodstream and eventually into the urine.

However, copper excretion into the bile is impaired in patients with acute liver failure regardless of the etiology. Therefore, elevated free serum copper and 24-hour urine copper levels are not specific for the diagnosis of acute liver failure secondary to Wilson disease. Moreover, Kayser-Fleischer rings, which represent copper deposition in the limbus of the cornea, may not be apparent in the early stages of Wilson disease.

Wilson disease involves accumulation of copper in the liver and other organs as the result of a genetic defect

Since it is challenging to diagnose Wilson disease in the context of acute liver failure, Korman et al⁶ compared patients with acute liver failure secondary to Wilson disease with patients with acute liver failure secondary to other conditions. They found that alkaline phosphatase levels are frequently decreased in patients with acute liver failure secondary to Wilson disease,⁶ and that a ratio of alkaline phosphatase to total bilirubin of less than 4 is 94% sensitive and 96% specific for the diagnosis.⁶

Hemolysis is common in acute liver failure due to Wilson disease. This leads to disproportionate elevation of AST compared with ALT, since AST is present in red blood cells. Consequently, the ratio of AST to ALT is usually greater than 2.2, which provides a sensitivity of 94% and a specificity of 86% for the diagnosis.⁶ These two ratios together provide 100% sensitivity and 100% specificity for the diagnosis of Wilson disease in the context of acute liver failure.⁶

Ceruloplasmin. Patients with Wilson disease typically have a low ceruloplasmin level. However, because it is an acute-phase reaction protein, ceruloplasmin can be normal or elevated in patients with acute liver failure from Wilson disease.⁶ Therefore, a normal ceruloplasmin level is not sufficient to rule out acute liver failure secondary to Wilson disease.

CASE CONTINUES: A DEFINITIVE DIAGNOSIS

Our patient undergoes further testing, which reveals the following:

• Her 24-hour urinary excretion of copper is 150 µg (reference value < 30)
• Slit-lamp examination is normal and shows no evidence of Kayser-Fleischer rings
• Her ratio of alkaline phosphatase to total bilirubin is 0.77 based on her initial laboratory results (Table 1)
• Her AST-ALT ratio is 3.4.

The diagnosis in our patient is acute liver failure secondary to Wilson disease.

4. What is the most appropriate next step?

• Liver biopsy
• d-penicillamine by mouth
• Trientine by mouth
• Liver transplant
• Plasmapheresis

Liver biopsy. Accumulation of copper in the liver parenchyma in patients with Wilson disease is sporadic. Therefore, qualitative copper staining on liver biopsy can be falsely negative. Quantitative copper measurement in liver tissue is the gold standard for the diagnosis of Wilson disease. However, the test is time-consuming and is not rapidly available in the context of acute liver failure.

Chelating agents such as d-pencillamine and trientine are used to treat the chronic manifestations of Wilson disease but are not useful for acute liver failure secondary to Wilson disease.

Acute liver failure secondary to Wilson disease is life-threatening, and liver transplant is considered the only definitive life-saving therapy.

Therapeutic plasmapheresis has been reported to be a successful adjunctive therapy to bridge patients with acute liver failure secondary to Wilson disease to transplant.⁷ However, liver transplant is still the only definitive treatment.

CASE CONTINUES: THE PATIENT’S SISTER SEEKS CARE

The patient undergoes liver transplantation, with no perioperative or postoperative complications.

The patient’s 18-year-old sister is now seeking medical attention in the outpatient clinic, concerned that she may have Wilson disease. She is otherwise healthy and denies any symptoms or complaints.

5. What is the next step for the patient’s sister?

• Reassurance
• Prophylaxis with trientine
• Check liver enzyme levels, serum ceruloplasmin level, and urine copper, and order a slit-lamp examination
• Genetic testing

Wilson disease can be asymptomatic in its early stages and may be diagnosed incidentally during routine blood tests that reveal abnormal liver enzyme levels. All patients with a confirmed family history of Wilson disease should be screened even if they are asymptomatic. The diagnosis of Wilson disease should be established in first-degree relatives before specific treatment for the relatives is prescribed.

Based on information in Roberts EA, Schilsky ML; American Association for Study of Liver Diseases (AASLD). Diagnosis and treatment of Wilson disease: an update. Hepatology 2008; 7:2089–2111.

The first step in screening a first-degree relative for Wilson disease is to check liver enzyme levels (specifically aminotransferases, alkaline phosphatase, and bilirubin), serum ceruloplasmin level, and 24-hour urine copper, and order an ophthalmologic slit-lamp examination. If any of these tests is abnormal, liver biopsy should be performed for histopathologic evaluation and quantitative copper measurement. Kayser-Fleischer  rings are seen in only 50% of patients with Wilson disease and hepatic involvement, but they are pathognomic. Guidelines⁸ for screening first-degree relatives of Wilson disease patients are shown in Figure 1.

Genetic analysis. ATP7B, the Wilson disease gene, is located on chromosome 13. At least 300 mutations of the gene have been described,² and the most common mutation is present in only 15% to 30% of the Wilson disease population.^8–10 Routine molecular testing of the ATP7B

CASE CONTINUES: WORKUP OF THE PATIENT’S SISTER

The patient’s sister has no symptoms and her physical examination is normal. Slit-lamp examination reveals no evidence of Kayser-Fleischer rings. Her laboratory values, including complete blood counts, complete metabolic panel, and INR, are within normal ranges. Other test results, however, are abnormal:

• Free serum copper level 27 µg/dL (normal 8–12)
• Serum ceruloplasmin 9.0 mg/dL (normal 20–50)
• 24-hour urinary copper excretion 135 µg (normal < 30).

She undergoes liver biopsy for quantitative copper measurement, and the result is very high at 1,118 µg/g dry weight (reference range 10–35). The diagnosis of Wilson disease is established.

TREATING CHRONIC WILSON DISEASE

6. Which of the following is not an appropriate next step for the patient’s sister?

• Tetrathiomolybdate
• d-penicillamine
• Trientine
• Zinc salts
• Prednisone

The goal of medical treatment of chronic Wilson disease is to improve symptoms and prevent progression of the disease.

Chelating agents and zinc salts are the most commonly used medicines in the management of Wilson disease. Chelating agents remove copper from tissue, whereas zinc blocks the intestinal absorption of copper and stimulates the synthesis of endogenous chelators such as metallothioneins. Tetrathiomolybdate is an alternative agent developed to interfere with the distribution of excess body copper to susceptible target sites by reducing free serum copper (Table 3). There are no data to support the use of prednisone in the treatment of Wilson disease.

During treatment with chelating agents, 24-hour urinary excretion of copper is routinely monitored to determine the efficacy of therapy and adherence to treatment. Once de-coppering is achieved, as evidenced by a normalization of 24-hour urine copper excretion, the chelating agent can be switched to zinc salts to prevent intestinal absorption of copper.

Clinical and biochemical stabilization is achieved typically within 2 to 6 months of the initial treatment with chelating agents.⁸ Organ meats, nuts, shellfish, and chocolate are rich in copper and should be avoided.

The patient’s sister is started on trientine 250 mg orally three times daily on an empty stomach at least 1 hour before meals. Treatment is monitored by following 24-hour urine copper measurement. A 24-hour urine copper measurement at 3 months after starting treatment has increased from 54 at baseline to 350 µg, which indicates that the copper is being removed from tissues. The plan is for early substitution of zinc for long-term maintenance once de-coppering is completed.

KEY POINTS

• Acute liver failure is severe acute liver injury characterized by coagulopathy (INR ≥ 1.5) and encephalopathy in a patient with no preexisting liver disease and with duration of symptoms less than 26 weeks.
• Acute liver failure secondary to Wilson disease is uncommon but should be excluded, particularly in young patients.
• The diagnosis of Wilson disease in the setting of acute liver failure is challenging because the serum ceruloplasmin level may be normal in acute liver failure secondary to Wilson disease, and free serum copper and 24-hour urine copper are usually elevated in all acute liver failure patients regardless of the etiology.
• A ratio of alkaline phosphatase to total bilirubin of less than 4 plus an AST-ALT ratio greater than 2.2 in a patient with acute liver failure should be regarded as Wilson disease until proven otherwise (Figure 2).
• Acute liver failure secondary to Wilson disease is usually fatal, and emergency liver transplant is a life-saving procedure.
• Screening of first-degree relatives of Wilson disease patients should include a history and physical examination, liver enzyme tests, complete blood cell count, serum ceruloplasmin level, serum free copper level, slit-lamp examination of the eyes, and 24-hour urinary copper measurement. Genetic tests are supplementary for screening but are not routinely available.

A 25-year-old woman presents to the emergency department with a 7-day history of fatigue and nausea. On presentation she denies having abdominal pain, headache, fever, chills, night sweats, vomiting, diarrhea, melena, hematochezia, or weight loss. She recalls changes in the colors of her eyes and darkening urine over the last few days. Her medical history before this is unremarkable. She takes no prescription, over-the-counter, or herbal medications. She works as a librarian and has no occupational toxic exposures. She is single and has one sister with no prior medical history. She denies recent travel, sick contacts, smoking, recreational drug use, or pets at home.

On physical examination, her vital signs are temperature 37.3°C (99.1°F), heart rate 90 beats per minute, blood pressure 125/80 mm Hg, respiration rate 14 per minute, and oxygen saturation 97% on room air. She has icteric sclera and her skin is jaundiced. Cardiac examination is normal. Lungs are clear to auscultation and percussion bilaterally. Her abdomen is soft with no visceromegaly, masses, or tenderness. Extremities are normal with no edema. She is alert and oriented, but she has mild asterixis of the outstretched hands. The neurologic examination is otherwise unremarkable.

The patient’s basic laboratory values are listed in Table 1. Shortly after admission, she develops changes in her mental status, remaining alert but becoming agitated and oriented to person only. In view of her symptoms and laboratory findings, acute liver failure is suspected.

ACUTE LIVER FAILURE

1. The diagnostic criteria for acute liver failure include all of the following except which one?

• Acute elevation of liver biochemical tests
• Presence of preexisting liver disease
• Coagulopathy, defined by an international normalized ratio (INR) of 1.5 or greater
• Encephalopathy
• Duration of symptoms less than 26 weeks

Acute liver failure is defined by acute onset of worsening liver tests, coagulopathy (INR ≥ 1.5), and encephalopathy in patients with no preexisting liver disease and with symptom duration of less than 26 weeks.¹ With a few exceptions, a history of preexisting liver disease negates the diagnosis of acute liver failure. Our patient meets the diagnostic criteria for acute liver failure.

Immediate management

Once acute liver failure is identified or suspected, the next step is to transfer the patient to the intensive care unit for close monitoring of mental status. Serial neurologic evaluations permit early detection of cerebral edema, which is considered the most common cause of death in patients with acute liver failure. Additionally, close monitoring of electrolytes and plasma glucose is necessary since these patients are susceptible to electrolyte disturbances and hypoglycemia.

Patients with acute liver failure are at increased risk of infections and should be routinely screened by obtaining urine and blood cultures.

Gastrointestinal bleeding is not uncommon in patients with acute liver failure and is usually due to gastric stress ulceration. Prophylaxis with a histamine 2 receptor antagonist or proton pump inhibitor should be considered in order to prevent gastrointestinal bleeding.

Treatment with N-acetylcysteine is beneficial, not only in patients with acute liver failure due to acetaminophen overdose, but also in those with acute liver failure from other causes.

CASE CONTINUES:
TRANSFER TO THE INTENSIVE CARE UNIT

The patient, now diagnosed with acute liver failure, is transferred to the intensive care unit. Arterial blood gas measurement shows:

• pH 7.38 (reference range 7.35–7.45)
• Pco₂ 40 mm Hg (36–46)
• Po₂ 97 mm Hg (85–95)
• Hco₃ 22 mmol/L (22–26).

A chest radiograph is obtained and is clear. Computed tomography (CT) of the brain reveals no edema. Transcranial Doppler ultrasonography does not show any intracranial fluid collections.

Blood and urine cultures are negative. Her hemoglobin level remains stable, and she does not develop signs of bleeding. She is started on a proton pump inhibitor for stress ulcer prophylaxis and is empirically given intravenous N-acetylcysteine until the cause of acute liver failure can be determined.

CAUSES OF ACUTE LIVER FAILURE

2. Which of the following can cause acute liver failure?

• Acetaminophen overdose
• Viral hepatitis
• Autoimmune hepatitis
• Wilson disease
• Alcoholic hepatitis

Drug-induced liver injury is the most common cause of acute liver failure in the United States,^2,3 and of all drugs, acetaminophen overdose is the number-one cause. In acetaminophen-induced liver injury, serum aminotransferase levels are usually elevated to more than 1,000 U/L, while serum bilirubin remains normal in the early stages. Antimicrobial agents, antiepileptic drugs, and herbal supplements have also been implicated in acute liver failure. Our patient has denied taking herbal supplements or medications, including over-the-counter ones.

Acute viral hepatitis can explain the patient’s condition. It is a common cause of acute liver failure in the United States.² Hepatitis A and E are more common in developing countries. Other viruses such as cytomegalovirus, Epstein-Barr virus, herpes simplex virus type 1 and 2, and varicella zoster virus can also cause acute liver failure. Serum aminotransferase levels may exceed 1,000 U/L in patients with viral hepatitis.

A young woman presents with acute liver failure: What is the cause? Is her sister at risk?

Autoimmune hepatitis is a rare cause of acute liver failure, but it should be considered in the differential diagnosis, particularly in middle-aged women with autoimmune disorders such as hypothyroidism. Autoimmune hepatitis can cause marked elevation in aminotransferase levels (> 1,000 U/L).

Wilson disease is an autosomal-recessive disease in which there is excessive accumulation of copper in the liver and other organs because of an inherited defect in the biliary excretion of copper. Wilson disease can cause acute liver failure and should be excluded in any patient, particularly if under age 40 with acute onset of unexplained hepatic, neurologic, or psychiatric disease.

Alcoholic hepatitis usually occurs in patients with a long-standing history of heavy alcohol use. As a result, most patients with alcoholic hepatitis have manifestations of chronic liver disease due to alcohol use. Therefore, by definition, it is not a cause of acute liver failure. Additionally, in patients with alcoholic hepatitis, the aspartate aminotransferase (AST) level is elevated but less than 300 IU/mL, and the ratio of AST to alanine aminotransferase (ALT) is usually more than 2.

CASE CONTINUES: FURTHER TESTING

The results of our patient’s serologic tests are shown in Table 2. Other test results:

• Autoimmune markers including antinuclear antibodies, antimitochondrial antibodies, antismooth muscle antibodies, and liver and kidney microsomal antibodies are negative; her immunoglobulin G (IgG) level is normal
• Serum ceruloplasmin 25 mg/dL (normal 21–45)
• Free serum copper 120 µg/dL (normal 8–12)
• Abdominal ultrasonography is unremarkable, with normal liver parenchyma and no intrahepatic or extrahepatic biliary dilatation
• Doppler ultrasonography of the liver shows patent blood vessels.

3. Based on the new data, which of the following statements is correct?

• Hepatitis B is the cause of acute liver failure in this patient
• Herpetic hepatitis cannot be excluded on the basis of the available data
• Wilson disease is most likely the diagnosis, given her elevated free serum copper
• A normal serum ceruloplasmin level is not sufficient to rule out acute liver failure secondary to Wilson disease

Hepatitis B surface antigen and hepatitis B core antibodies were negative in our patient, excluding hepatitis B virus infection. The positive hepatitis B surface antibody indicates prior immunization.

Herpetic hepatitis is an uncommon but important cause of acute liver failure because the mortality rate is high if the patient is not treated early with acyclovir. Fever, elevated aminotransferases, and leukopenia are common with herpetic hepatitis. Fewer than 50% of patients with herpetic hepatitis have vesicular rash.^4,5 The value of antibody serologic testing is limited due to high rates of false-positive and false-negative results. The gold standard diagnostic tests are viral load (detection of viral RNA by polymerase chain reaction), viral staining on liver biopsy, or both. In our patient, herpes simplex virus polymerase chain reaction testing was negative, which makes herpetic hepatitis unlikely.

Wilson disease is a genetic condition in which the ability to excrete copper in the bile is impaired, resulting in accumulation of copper in the hepatocytes. Subsequently, copper is released into the bloodstream and eventually into the urine.

However, copper excretion into the bile is impaired in patients with acute liver failure regardless of the etiology. Therefore, elevated free serum copper and 24-hour urine copper levels are not specific for the diagnosis of acute liver failure secondary to Wilson disease. Moreover, Kayser-Fleischer rings, which represent copper deposition in the limbus of the cornea, may not be apparent in the early stages of Wilson disease.

Wilson disease involves accumulation of copper in the liver and other organs as the result of a genetic defect

Since it is challenging to diagnose Wilson disease in the context of acute liver failure, Korman et al⁶ compared patients with acute liver failure secondary to Wilson disease with patients with acute liver failure secondary to other conditions. They found that alkaline phosphatase levels are frequently decreased in patients with acute liver failure secondary to Wilson disease,⁶ and that a ratio of alkaline phosphatase to total bilirubin of less than 4 is 94% sensitive and 96% specific for the diagnosis.⁶

Hemolysis is common in acute liver failure due to Wilson disease. This leads to disproportionate elevation of AST compared with ALT, since AST is present in red blood cells. Consequently, the ratio of AST to ALT is usually greater than 2.2, which provides a sensitivity of 94% and a specificity of 86% for the diagnosis.⁶ These two ratios together provide 100% sensitivity and 100% specificity for the diagnosis of Wilson disease in the context of acute liver failure.⁶

Ceruloplasmin. Patients with Wilson disease typically have a low ceruloplasmin level. However, because it is an acute-phase reaction protein, ceruloplasmin can be normal or elevated in patients with acute liver failure from Wilson disease.⁶ Therefore, a normal ceruloplasmin level is not sufficient to rule out acute liver failure secondary to Wilson disease.

CASE CONTINUES: A DEFINITIVE DIAGNOSIS

Our patient undergoes further testing, which reveals the following:

• Her 24-hour urinary excretion of copper is 150 µg (reference value < 30)
• Slit-lamp examination is normal and shows no evidence of Kayser-Fleischer rings
• Her ratio of alkaline phosphatase to total bilirubin is 0.77 based on her initial laboratory results (Table 1)
• Her AST-ALT ratio is 3.4.

The diagnosis in our patient is acute liver failure secondary to Wilson disease.

4. What is the most appropriate next step?

• Liver biopsy
• d-penicillamine by mouth
• Trientine by mouth
• Liver transplant
• Plasmapheresis

Liver biopsy. Accumulation of copper in the liver parenchyma in patients with Wilson disease is sporadic. Therefore, qualitative copper staining on liver biopsy can be falsely negative. Quantitative copper measurement in liver tissue is the gold standard for the diagnosis of Wilson disease. However, the test is time-consuming and is not rapidly available in the context of acute liver failure.

Chelating agents such as d-pencillamine and trientine are used to treat the chronic manifestations of Wilson disease but are not useful for acute liver failure secondary to Wilson disease.

Acute liver failure secondary to Wilson disease is life-threatening, and liver transplant is considered the only definitive life-saving therapy.

Therapeutic plasmapheresis has been reported to be a successful adjunctive therapy to bridge patients with acute liver failure secondary to Wilson disease to transplant.⁷ However, liver transplant is still the only definitive treatment.

CASE CONTINUES: THE PATIENT’S SISTER SEEKS CARE

The patient undergoes liver transplantation, with no perioperative or postoperative complications.

The patient’s 18-year-old sister is now seeking medical attention in the outpatient clinic, concerned that she may have Wilson disease. She is otherwise healthy and denies any symptoms or complaints.

5. What is the next step for the patient’s sister?

• Reassurance
• Prophylaxis with trientine
• Check liver enzyme levels, serum ceruloplasmin level, and urine copper, and order a slit-lamp examination
• Genetic testing

Wilson disease can be asymptomatic in its early stages and may be diagnosed incidentally during routine blood tests that reveal abnormal liver enzyme levels. All patients with a confirmed family history of Wilson disease should be screened even if they are asymptomatic. The diagnosis of Wilson disease should be established in first-degree relatives before specific treatment for the relatives is prescribed.

Based on information in Roberts EA, Schilsky ML; American Association for Study of Liver Diseases (AASLD). Diagnosis and treatment of Wilson disease: an update. Hepatology 2008; 7:2089–2111.

The first step in screening a first-degree relative for Wilson disease is to check liver enzyme levels (specifically aminotransferases, alkaline phosphatase, and bilirubin), serum ceruloplasmin level, and 24-hour urine copper, and order an ophthalmologic slit-lamp examination. If any of these tests is abnormal, liver biopsy should be performed for histopathologic evaluation and quantitative copper measurement. Kayser-Fleischer  rings are seen in only 50% of patients with Wilson disease and hepatic involvement, but they are pathognomic. Guidelines⁸ for screening first-degree relatives of Wilson disease patients are shown in Figure 1.

Genetic analysis. ATP7B, the Wilson disease gene, is located on chromosome 13. At least 300 mutations of the gene have been described,² and the most common mutation is present in only 15% to 30% of the Wilson disease population.^8–10 Routine molecular testing of the ATP7B

CASE CONTINUES: WORKUP OF THE PATIENT’S SISTER

The patient’s sister has no symptoms and her physical examination is normal. Slit-lamp examination reveals no evidence of Kayser-Fleischer rings. Her laboratory values, including complete blood counts, complete metabolic panel, and INR, are within normal ranges. Other test results, however, are abnormal:

• Free serum copper level 27 µg/dL (normal 8–12)
• Serum ceruloplasmin 9.0 mg/dL (normal 20–50)
• 24-hour urinary copper excretion 135 µg (normal < 30).

She undergoes liver biopsy for quantitative copper measurement, and the result is very high at 1,118 µg/g dry weight (reference range 10–35). The diagnosis of Wilson disease is established.

TREATING CHRONIC WILSON DISEASE

6. Which of the following is not an appropriate next step for the patient’s sister?

• Tetrathiomolybdate
• d-penicillamine
• Trientine
• Zinc salts
• Prednisone

The goal of medical treatment of chronic Wilson disease is to improve symptoms and prevent progression of the disease.

Chelating agents and zinc salts are the most commonly used medicines in the management of Wilson disease. Chelating agents remove copper from tissue, whereas zinc blocks the intestinal absorption of copper and stimulates the synthesis of endogenous chelators such as metallothioneins. Tetrathiomolybdate is an alternative agent developed to interfere with the distribution of excess body copper to susceptible target sites by reducing free serum copper (Table 3). There are no data to support the use of prednisone in the treatment of Wilson disease.

During treatment with chelating agents, 24-hour urinary excretion of copper is routinely monitored to determine the efficacy of therapy and adherence to treatment. Once de-coppering is achieved, as evidenced by a normalization of 24-hour urine copper excretion, the chelating agent can be switched to zinc salts to prevent intestinal absorption of copper.

Clinical and biochemical stabilization is achieved typically within 2 to 6 months of the initial treatment with chelating agents.⁸ Organ meats, nuts, shellfish, and chocolate are rich in copper and should be avoided.

The patient’s sister is started on trientine 250 mg orally three times daily on an empty stomach at least 1 hour before meals. Treatment is monitored by following 24-hour urine copper measurement. A 24-hour urine copper measurement at 3 months after starting treatment has increased from 54 at baseline to 350 µg, which indicates that the copper is being removed from tissues. The plan is for early substitution of zinc for long-term maintenance once de-coppering is completed.

KEY POINTS

• Acute liver failure is severe acute liver injury characterized by coagulopathy (INR ≥ 1.5) and encephalopathy in a patient with no preexisting liver disease and with duration of symptoms less than 26 weeks.
• Acute liver failure secondary to Wilson disease is uncommon but should be excluded, particularly in young patients.
• The diagnosis of Wilson disease in the setting of acute liver failure is challenging because the serum ceruloplasmin level may be normal in acute liver failure secondary to Wilson disease, and free serum copper and 24-hour urine copper are usually elevated in all acute liver failure patients regardless of the etiology.
• A ratio of alkaline phosphatase to total bilirubin of less than 4 plus an AST-ALT ratio greater than 2.2 in a patient with acute liver failure should be regarded as Wilson disease until proven otherwise (Figure 2).
• Acute liver failure secondary to Wilson disease is usually fatal, and emergency liver transplant is a life-saving procedure.
• Screening of first-degree relatives of Wilson disease patients should include a history and physical examination, liver enzyme tests, complete blood cell count, serum ceruloplasmin level, serum free copper level, slit-lamp examination of the eyes, and 24-hour urinary copper measurement. Genetic tests are supplementary for screening but are not routinely available.

A 25-year-old woman presents to the emergency department with a 7-day history of fatigue and nausea. On presentation she denies having abdominal pain, headache, fever, chills, night sweats, vomiting, diarrhea, melena, hematochezia, or weight loss. She recalls changes in the colors of her eyes and darkening urine over the last few days. Her medical history before this is unremarkable. She takes no prescription, over-the-counter, or herbal medications. She works as a librarian and has no occupational toxic exposures. She is single and has one sister with no prior medical history. She denies recent travel, sick contacts, smoking, recreational drug use, or pets at home.

On physical examination, her vital signs are temperature 37.3°C (99.1°F), heart rate 90 beats per minute, blood pressure 125/80 mm Hg, respiration rate 14 per minute, and oxygen saturation 97% on room air. She has icteric sclera and her skin is jaundiced. Cardiac examination is normal. Lungs are clear to auscultation and percussion bilaterally. Her abdomen is soft with no visceromegaly, masses, or tenderness. Extremities are normal with no edema. She is alert and oriented, but she has mild asterixis of the outstretched hands. The neurologic examination is otherwise unremarkable.

The patient’s basic laboratory values are listed in Table 1. Shortly after admission, she develops changes in her mental status, remaining alert but becoming agitated and oriented to person only. In view of her symptoms and laboratory findings, acute liver failure is suspected.

ACUTE LIVER FAILURE

1. The diagnostic criteria for acute liver failure include all of the following except which one?

• Acute elevation of liver biochemical tests
• Presence of preexisting liver disease
• Coagulopathy, defined by an international normalized ratio (INR) of 1.5 or greater
• Encephalopathy
• Duration of symptoms less than 26 weeks

Acute liver failure is defined by acute onset of worsening liver tests, coagulopathy (INR ≥ 1.5), and encephalopathy in patients with no preexisting liver disease and with symptom duration of less than 26 weeks.¹ With a few exceptions, a history of preexisting liver disease negates the diagnosis of acute liver failure. Our patient meets the diagnostic criteria for acute liver failure.

Immediate management

Once acute liver failure is identified or suspected, the next step is to transfer the patient to the intensive care unit for close monitoring of mental status. Serial neurologic evaluations permit early detection of cerebral edema, which is considered the most common cause of death in patients with acute liver failure. Additionally, close monitoring of electrolytes and plasma glucose is necessary since these patients are susceptible to electrolyte disturbances and hypoglycemia.

Patients with acute liver failure are at increased risk of infections and should be routinely screened by obtaining urine and blood cultures.

Gastrointestinal bleeding is not uncommon in patients with acute liver failure and is usually due to gastric stress ulceration. Prophylaxis with a histamine 2 receptor antagonist or proton pump inhibitor should be considered in order to prevent gastrointestinal bleeding.

Treatment with N-acetylcysteine is beneficial, not only in patients with acute liver failure due to acetaminophen overdose, but also in those with acute liver failure from other causes.

CASE CONTINUES:
TRANSFER TO THE INTENSIVE CARE UNIT

The patient, now diagnosed with acute liver failure, is transferred to the intensive care unit. Arterial blood gas measurement shows:

• pH 7.38 (reference range 7.35–7.45)
• Pco₂ 40 mm Hg (36–46)
• Po₂ 97 mm Hg (85–95)
• Hco₃ 22 mmol/L (22–26).

A chest radiograph is obtained and is clear. Computed tomography (CT) of the brain reveals no edema. Transcranial Doppler ultrasonography does not show any intracranial fluid collections.

Blood and urine cultures are negative. Her hemoglobin level remains stable, and she does not develop signs of bleeding. She is started on a proton pump inhibitor for stress ulcer prophylaxis and is empirically given intravenous N-acetylcysteine until the cause of acute liver failure can be determined.

CAUSES OF ACUTE LIVER FAILURE

2. Which of the following can cause acute liver failure?

• Acetaminophen overdose
• Viral hepatitis
• Autoimmune hepatitis
• Wilson disease
• Alcoholic hepatitis

Drug-induced liver injury is the most common cause of acute liver failure in the United States,^2,3 and of all drugs, acetaminophen overdose is the number-one cause. In acetaminophen-induced liver injury, serum aminotransferase levels are usually elevated to more than 1,000 U/L, while serum bilirubin remains normal in the early stages. Antimicrobial agents, antiepileptic drugs, and herbal supplements have also been implicated in acute liver failure. Our patient has denied taking herbal supplements or medications, including over-the-counter ones.

Acute viral hepatitis can explain the patient’s condition. It is a common cause of acute liver failure in the United States.² Hepatitis A and E are more common in developing countries. Other viruses such as cytomegalovirus, Epstein-Barr virus, herpes simplex virus type 1 and 2, and varicella zoster virus can also cause acute liver failure. Serum aminotransferase levels may exceed 1,000 U/L in patients with viral hepatitis.

A young woman presents with acute liver failure: What is the cause? Is her sister at risk?

Autoimmune hepatitis is a rare cause of acute liver failure, but it should be considered in the differential diagnosis, particularly in middle-aged women with autoimmune disorders such as hypothyroidism. Autoimmune hepatitis can cause marked elevation in aminotransferase levels (> 1,000 U/L).

Wilson disease is an autosomal-recessive disease in which there is excessive accumulation of copper in the liver and other organs because of an inherited defect in the biliary excretion of copper. Wilson disease can cause acute liver failure and should be excluded in any patient, particularly if under age 40 with acute onset of unexplained hepatic, neurologic, or psychiatric disease.

Alcoholic hepatitis usually occurs in patients with a long-standing history of heavy alcohol use. As a result, most patients with alcoholic hepatitis have manifestations of chronic liver disease due to alcohol use. Therefore, by definition, it is not a cause of acute liver failure. Additionally, in patients with alcoholic hepatitis, the aspartate aminotransferase (AST) level is elevated but less than 300 IU/mL, and the ratio of AST to alanine aminotransferase (ALT) is usually more than 2.

CASE CONTINUES: FURTHER TESTING

The results of our patient’s serologic tests are shown in Table 2. Other test results:

• Autoimmune markers including antinuclear antibodies, antimitochondrial antibodies, antismooth muscle antibodies, and liver and kidney microsomal antibodies are negative; her immunoglobulin G (IgG) level is normal
• Serum ceruloplasmin 25 mg/dL (normal 21–45)
• Free serum copper 120 µg/dL (normal 8–12)
• Abdominal ultrasonography is unremarkable, with normal liver parenchyma and no intrahepatic or extrahepatic biliary dilatation
• Doppler ultrasonography of the liver shows patent blood vessels.

3. Based on the new data, which of the following statements is correct?

• Hepatitis B is the cause of acute liver failure in this patient
• Herpetic hepatitis cannot be excluded on the basis of the available data
• Wilson disease is most likely the diagnosis, given her elevated free serum copper
• A normal serum ceruloplasmin level is not sufficient to rule out acute liver failure secondary to Wilson disease

Hepatitis B surface antigen and hepatitis B core antibodies were negative in our patient, excluding hepatitis B virus infection. The positive hepatitis B surface antibody indicates prior immunization.

Herpetic hepatitis is an uncommon but important cause of acute liver failure because the mortality rate is high if the patient is not treated early with acyclovir. Fever, elevated aminotransferases, and leukopenia are common with herpetic hepatitis. Fewer than 50% of patients with herpetic hepatitis have vesicular rash.^4,5 The value of antibody serologic testing is limited due to high rates of false-positive and false-negative results. The gold standard diagnostic tests are viral load (detection of viral RNA by polymerase chain reaction), viral staining on liver biopsy, or both. In our patient, herpes simplex virus polymerase chain reaction testing was negative, which makes herpetic hepatitis unlikely.

Wilson disease is a genetic condition in which the ability to excrete copper in the bile is impaired, resulting in accumulation of copper in the hepatocytes. Subsequently, copper is released into the bloodstream and eventually into the urine.

However, copper excretion into the bile is impaired in patients with acute liver failure regardless of the etiology. Therefore, elevated free serum copper and 24-hour urine copper levels are not specific for the diagnosis of acute liver failure secondary to Wilson disease. Moreover, Kayser-Fleischer rings, which represent copper deposition in the limbus of the cornea, may not be apparent in the early stages of Wilson disease.

Wilson disease involves accumulation of copper in the liver and other organs as the result of a genetic defect

Since it is challenging to diagnose Wilson disease in the context of acute liver failure, Korman et al⁶ compared patients with acute liver failure secondary to Wilson disease with patients with acute liver failure secondary to other conditions. They found that alkaline phosphatase levels are frequently decreased in patients with acute liver failure secondary to Wilson disease,⁶ and that a ratio of alkaline phosphatase to total bilirubin of less than 4 is 94% sensitive and 96% specific for the diagnosis.⁶

Hemolysis is common in acute liver failure due to Wilson disease. This leads to disproportionate elevation of AST compared with ALT, since AST is present in red blood cells. Consequently, the ratio of AST to ALT is usually greater than 2.2, which provides a sensitivity of 94% and a specificity of 86% for the diagnosis.⁶ These two ratios together provide 100% sensitivity and 100% specificity for the diagnosis of Wilson disease in the context of acute liver failure.⁶

Ceruloplasmin. Patients with Wilson disease typically have a low ceruloplasmin level. However, because it is an acute-phase reaction protein, ceruloplasmin can be normal or elevated in patients with acute liver failure from Wilson disease.⁶ Therefore, a normal ceruloplasmin level is not sufficient to rule out acute liver failure secondary to Wilson disease.

CASE CONTINUES: A DEFINITIVE DIAGNOSIS

Our patient undergoes further testing, which reveals the following:

• Her 24-hour urinary excretion of copper is 150 µg (reference value < 30)
• Slit-lamp examination is normal and shows no evidence of Kayser-Fleischer rings
• Her ratio of alkaline phosphatase to total bilirubin is 0.77 based on her initial laboratory results (Table 1)
• Her AST-ALT ratio is 3.4.

The diagnosis in our patient is acute liver failure secondary to Wilson disease.

4. What is the most appropriate next step?

• Liver biopsy
• d-penicillamine by mouth
• Trientine by mouth
• Liver transplant
• Plasmapheresis

Liver biopsy. Accumulation of copper in the liver parenchyma in patients with Wilson disease is sporadic. Therefore, qualitative copper staining on liver biopsy can be falsely negative. Quantitative copper measurement in liver tissue is the gold standard for the diagnosis of Wilson disease. However, the test is time-consuming and is not rapidly available in the context of acute liver failure.

Chelating agents such as d-pencillamine and trientine are used to treat the chronic manifestations of Wilson disease but are not useful for acute liver failure secondary to Wilson disease.

Acute liver failure secondary to Wilson disease is life-threatening, and liver transplant is considered the only definitive life-saving therapy.

Therapeutic plasmapheresis has been reported to be a successful adjunctive therapy to bridge patients with acute liver failure secondary to Wilson disease to transplant.⁷ However, liver transplant is still the only definitive treatment.

CASE CONTINUES: THE PATIENT’S SISTER SEEKS CARE

The patient undergoes liver transplantation, with no perioperative or postoperative complications.

The patient’s 18-year-old sister is now seeking medical attention in the outpatient clinic, concerned that she may have Wilson disease. She is otherwise healthy and denies any symptoms or complaints.

5. What is the next step for the patient’s sister?

• Reassurance
• Prophylaxis with trientine
• Check liver enzyme levels, serum ceruloplasmin level, and urine copper, and order a slit-lamp examination
• Genetic testing

Wilson disease can be asymptomatic in its early stages and may be diagnosed incidentally during routine blood tests that reveal abnormal liver enzyme levels. All patients with a confirmed family history of Wilson disease should be screened even if they are asymptomatic. The diagnosis of Wilson disease should be established in first-degree relatives before specific treatment for the relatives is prescribed.

Based on information in Roberts EA, Schilsky ML; American Association for Study of Liver Diseases (AASLD). Diagnosis and treatment of Wilson disease: an update. Hepatology 2008; 7:2089–2111.

The first step in screening a first-degree relative for Wilson disease is to check liver enzyme levels (specifically aminotransferases, alkaline phosphatase, and bilirubin), serum ceruloplasmin level, and 24-hour urine copper, and order an ophthalmologic slit-lamp examination. If any of these tests is abnormal, liver biopsy should be performed for histopathologic evaluation and quantitative copper measurement. Kayser-Fleischer  rings are seen in only 50% of patients with Wilson disease and hepatic involvement, but they are pathognomic. Guidelines⁸ for screening first-degree relatives of Wilson disease patients are shown in Figure 1.

Genetic analysis. ATP7B, the Wilson disease gene, is located on chromosome 13. At least 300 mutations of the gene have been described,² and the most common mutation is present in only 15% to 30% of the Wilson disease population.^8–10 Routine molecular testing of the ATP7B

CASE CONTINUES: WORKUP OF THE PATIENT’S SISTER

The patient’s sister has no symptoms and her physical examination is normal. Slit-lamp examination reveals no evidence of Kayser-Fleischer rings. Her laboratory values, including complete blood counts, complete metabolic panel, and INR, are within normal ranges. Other test results, however, are abnormal:

• Free serum copper level 27 µg/dL (normal 8–12)
• Serum ceruloplasmin 9.0 mg/dL (normal 20–50)
• 24-hour urinary copper excretion 135 µg (normal < 30).

She undergoes liver biopsy for quantitative copper measurement, and the result is very high at 1,118 µg/g dry weight (reference range 10–35). The diagnosis of Wilson disease is established.

TREATING CHRONIC WILSON DISEASE

6. Which of the following is not an appropriate next step for the patient’s sister?

• Tetrathiomolybdate
• d-penicillamine
• Trientine
• Zinc salts
• Prednisone

The goal of medical treatment of chronic Wilson disease is to improve symptoms and prevent progression of the disease.

Chelating agents and zinc salts are the most commonly used medicines in the management of Wilson disease. Chelating agents remove copper from tissue, whereas zinc blocks the intestinal absorption of copper and stimulates the synthesis of endogenous chelators such as metallothioneins. Tetrathiomolybdate is an alternative agent developed to interfere with the distribution of excess body copper to susceptible target sites by reducing free serum copper (Table 3). There are no data to support the use of prednisone in the treatment of Wilson disease.

During treatment with chelating agents, 24-hour urinary excretion of copper is routinely monitored to determine the efficacy of therapy and adherence to treatment. Once de-coppering is achieved, as evidenced by a normalization of 24-hour urine copper excretion, the chelating agent can be switched to zinc salts to prevent intestinal absorption of copper.

Clinical and biochemical stabilization is achieved typically within 2 to 6 months of the initial treatment with chelating agents.⁸ Organ meats, nuts, shellfish, and chocolate are rich in copper and should be avoided.

The patient’s sister is started on trientine 250 mg orally three times daily on an empty stomach at least 1 hour before meals. Treatment is monitored by following 24-hour urine copper measurement. A 24-hour urine copper measurement at 3 months after starting treatment has increased from 54 at baseline to 350 µg, which indicates that the copper is being removed from tissues. The plan is for early substitution of zinc for long-term maintenance once de-coppering is completed.

KEY POINTS

• Acute liver failure is severe acute liver injury characterized by coagulopathy (INR ≥ 1.5) and encephalopathy in a patient with no preexisting liver disease and with duration of symptoms less than 26 weeks.
• Acute liver failure secondary to Wilson disease is uncommon but should be excluded, particularly in young patients.
• The diagnosis of Wilson disease in the setting of acute liver failure is challenging because the serum ceruloplasmin level may be normal in acute liver failure secondary to Wilson disease, and free serum copper and 24-hour urine copper are usually elevated in all acute liver failure patients regardless of the etiology.
• A ratio of alkaline phosphatase to total bilirubin of less than 4 plus an AST-ALT ratio greater than 2.2 in a patient with acute liver failure should be regarded as Wilson disease until proven otherwise (Figure 2).
• Acute liver failure secondary to Wilson disease is usually fatal, and emergency liver transplant is a life-saving procedure.
• Screening of first-degree relatives of Wilson disease patients should include a history and physical examination, liver enzyme tests, complete blood cell count, serum ceruloplasmin level, serum free copper level, slit-lamp examination of the eyes, and 24-hour urinary copper measurement. Genetic tests are supplementary for screening but are not routinely available.

A 54-year-old man presented with a 2-year history of unusual skin folds on the scalp with deep furrows in an anteroposterior direction, located in parieto-occipital regions (Figure 1). A clinical diagnosis of cutis verticis gyrata was made.

CUTIS VERTICIS GYRATA: THE DIFFERENTIAL DIAGNOSIS

Cutis verticis gyrata (“bulldog scalp”) is a rare condition, with a prevalence of 0.026 to 0.1 per 100,000,¹ primary and secondary forms, and a male preponderance.² It is characterized by excessive soft-tissue proliferation with the formation of ridges on the scalp similar in appearance to cerebral cortex gyri.

Primary essential cutis verticis gyrata is extremely rare with no associated abnormalities. Primary nonessential cutis verticis gyrata is associated with neurologic manifestations (microcephaly, seizure, cerebral palsy, mental retardation) and ophthalmologic changes (cataract, strabismus, retinitis pigmentosa, blindness).

Cutis verticis gyrata can also be secondary to conditions such as pachydermoperiostosis, Rosenthal-Kloepfer syndrome, tuberous sclerosis, and insulin resistance syndrome.³ It may occur in fragile X syndrome, Noonan syndrome, Turner syndrome, Beare-Stevenson syndrome, and Ehlers-Danlos syndrome.

When cutis verticis gyrata presents at age 50 or later, acromegaly, amyloidosis, myxedema, paraneoplastic syndromes, and drug-related lipodystrophy from antiretroviral drugs or tyrosine kinase inhibitors should be excluded. Other conditions included in the differential diagnosis are inflammatory diseases of the scalp (psoriasis, pemphigus) and nevoid abnormalities (nevus sebaceous, nevus of Ota, cerebriform nevus).⁴ The male preponderance suggests a genetic determination and an endocrine cause, but the pathophysiology remains unknown.

MANAGEMENT IN OUR PATIENT

Further evaluation in our patient showed bossing of the frontal bone, coarse facial features, and acral enlargement suggestive of acromegaly. The diagnosis was confirmed by elevated levels of growth hormone and insulin-like growth factor 1.

Magnetic resonance imaging of the pituitary gland revealed a pituitary adenoma 11 × 6 × 8 mm. After treatment of the adenoma with stereotactic radiosurgery, the scalp soft-tissue thickness decreased but persisted.

Overgrowth of the scalp manifesting as cutis verticis gyrata in acromegaly is not uncommon.^2,4 The severity or duration of acromegaly is not correlated with the presence and severity of cutis verticis gyrata.⁴

Besides treatment of acromegaly, good scalp hygiene is necessary to avoid the accumulation of secretions in the furrows. Surgery for scalp reduction is only required for cosmetic reasons.⁵

A 54-year-old man presented with a 2-year history of unusual skin folds on the scalp with deep furrows in an anteroposterior direction, located in parieto-occipital regions (Figure 1). A clinical diagnosis of cutis verticis gyrata was made.

CUTIS VERTICIS GYRATA: THE DIFFERENTIAL DIAGNOSIS

Cutis verticis gyrata (“bulldog scalp”) is a rare condition, with a prevalence of 0.026 to 0.1 per 100,000,¹ primary and secondary forms, and a male preponderance.² It is characterized by excessive soft-tissue proliferation with the formation of ridges on the scalp similar in appearance to cerebral cortex gyri.

Primary essential cutis verticis gyrata is extremely rare with no associated abnormalities. Primary nonessential cutis verticis gyrata is associated with neurologic manifestations (microcephaly, seizure, cerebral palsy, mental retardation) and ophthalmologic changes (cataract, strabismus, retinitis pigmentosa, blindness).

Cutis verticis gyrata can also be secondary to conditions such as pachydermoperiostosis, Rosenthal-Kloepfer syndrome, tuberous sclerosis, and insulin resistance syndrome.³ It may occur in fragile X syndrome, Noonan syndrome, Turner syndrome, Beare-Stevenson syndrome, and Ehlers-Danlos syndrome.

When cutis verticis gyrata presents at age 50 or later, acromegaly, amyloidosis, myxedema, paraneoplastic syndromes, and drug-related lipodystrophy from antiretroviral drugs or tyrosine kinase inhibitors should be excluded. Other conditions included in the differential diagnosis are inflammatory diseases of the scalp (psoriasis, pemphigus) and nevoid abnormalities (nevus sebaceous, nevus of Ota, cerebriform nevus).⁴ The male preponderance suggests a genetic determination and an endocrine cause, but the pathophysiology remains unknown.

MANAGEMENT IN OUR PATIENT

Further evaluation in our patient showed bossing of the frontal bone, coarse facial features, and acral enlargement suggestive of acromegaly. The diagnosis was confirmed by elevated levels of growth hormone and insulin-like growth factor 1.

Magnetic resonance imaging of the pituitary gland revealed a pituitary adenoma 11 × 6 × 8 mm. After treatment of the adenoma with stereotactic radiosurgery, the scalp soft-tissue thickness decreased but persisted.

Overgrowth of the scalp manifesting as cutis verticis gyrata in acromegaly is not uncommon.^2,4 The severity or duration of acromegaly is not correlated with the presence and severity of cutis verticis gyrata.⁴

Besides treatment of acromegaly, good scalp hygiene is necessary to avoid the accumulation of secretions in the furrows. Surgery for scalp reduction is only required for cosmetic reasons.⁵

A 54-year-old man presented with a 2-year history of unusual skin folds on the scalp with deep furrows in an anteroposterior direction, located in parieto-occipital regions (Figure 1). A clinical diagnosis of cutis verticis gyrata was made.

CUTIS VERTICIS GYRATA: THE DIFFERENTIAL DIAGNOSIS

Cutis verticis gyrata (“bulldog scalp”) is a rare condition, with a prevalence of 0.026 to 0.1 per 100,000,¹ primary and secondary forms, and a male preponderance.² It is characterized by excessive soft-tissue proliferation with the formation of ridges on the scalp similar in appearance to cerebral cortex gyri.

Primary essential cutis verticis gyrata is extremely rare with no associated abnormalities. Primary nonessential cutis verticis gyrata is associated with neurologic manifestations (microcephaly, seizure, cerebral palsy, mental retardation) and ophthalmologic changes (cataract, strabismus, retinitis pigmentosa, blindness).

Cutis verticis gyrata can also be secondary to conditions such as pachydermoperiostosis, Rosenthal-Kloepfer syndrome, tuberous sclerosis, and insulin resistance syndrome.³ It may occur in fragile X syndrome, Noonan syndrome, Turner syndrome, Beare-Stevenson syndrome, and Ehlers-Danlos syndrome.

When cutis verticis gyrata presents at age 50 or later, acromegaly, amyloidosis, myxedema, paraneoplastic syndromes, and drug-related lipodystrophy from antiretroviral drugs or tyrosine kinase inhibitors should be excluded. Other conditions included in the differential diagnosis are inflammatory diseases of the scalp (psoriasis, pemphigus) and nevoid abnormalities (nevus sebaceous, nevus of Ota, cerebriform nevus).⁴ The male preponderance suggests a genetic determination and an endocrine cause, but the pathophysiology remains unknown.

MANAGEMENT IN OUR PATIENT

Further evaluation in our patient showed bossing of the frontal bone, coarse facial features, and acral enlargement suggestive of acromegaly. The diagnosis was confirmed by elevated levels of growth hormone and insulin-like growth factor 1.

Magnetic resonance imaging of the pituitary gland revealed a pituitary adenoma 11 × 6 × 8 mm. After treatment of the adenoma with stereotactic radiosurgery, the scalp soft-tissue thickness decreased but persisted.

Overgrowth of the scalp manifesting as cutis verticis gyrata in acromegaly is not uncommon.^2,4 The severity or duration of acromegaly is not correlated with the presence and severity of cutis verticis gyrata.⁴

Besides treatment of acromegaly, good scalp hygiene is necessary to avoid the accumulation of secretions in the furrows. Surgery for scalp reduction is only required for cosmetic reasons.⁵

A 60-year-old man presented to our emergency department with a 4-day history of frontal headaches he described as “stinging.” He had also had a large swollen area on his forehead for the past 8 weeks.

He denied fevers, chills, nausea, vomiting, blurry vision, tinnitus, and neck pain, as well as any recent sinus infection, intransanal cocaine use, rhinorrhea, or head trauma. A month ago, he had presented to our emergency department with forehead swelling but no headaches. At that time, the swelling was thought to be an allergic reaction to lisinopril or metformin, medications he takes for hypertension and type 2 diabetes. He had been discharged home with a prescription for a course of prednisone in tapering doses, but that had failed to resolve the swelling.

Physical examination revealed a well-circumscribed area of swelling, 3 by 4 cm, in the central forehead (Figure 1). The area was warm, erythematous, fluctuant, and tender to palpation. The nasal septum was intact and the nasal mucosa appeared pink and healthy. The remainder of the examination was unremarkable.

He was afebrile and hemodynamically stable. His peripheral white blood cell count was mildly elevated at 11.1 × 109. Computed tomography of the brain and sinuses revealed a fluid collection in the frontal scalp associated with erosion of the anterior frontal sinus with posterior extension and enhancement of the adjacent meninges. Magnetic resonance imaging (Figure 2) revealed similar findings. A diagnosis of Pott puffy tumor was made based on the imaging findings.

The name of this condition is misleading, as it is not a neoplasm but an infection. It requires urgent antibiotic therapy and surgical management because of the high risk of the infection spreading to the brain. Our patient was started on a broad-spectrum antibiotic regimen of intravenous vancomycin, ceftriaxone, and metronidazole pending tissue culture to identify the causative organism.

POTT PUFFY TUMOR: A BRIEF OVERVIEW

First described in 1760 by Sir Percivall Pott,¹ the same English surgeon who first described tuberculosis of the spine, Pott puffy tumor is a well-demarcated area of swelling that occurs when a frontal sinus infection breaks through the anterior portion of the frontal sinus and forms an abscess between the frontal bone and periosteum with associated osteomyelitis.² Though rare in adults (it is more common in children and adolescents),³ Pott puffy tumor is caused by conditions often encountered in internal medicine practice, such as bacterial sinusitis, head trauma, and intranasal cocaine use.

The infection can spread to the brain either directly by destruction of the posterior frontal sinus (as in our patient) or by way of the veins that drain the frontal sinus. Meningitis, epidural empyema, frontal lobe abscess, and cavernous sinus thrombosis² have all been described. Intracranial complications are seen in nearly 100% of children and adolescents with Pott puffy tumor. The rate in adults is 30%,^4,5 which is much lower but is nevertheless worrisome because patients can be initially misdiagnosed with scalp abscess,³ cellulitis, or epidermoid cyst,⁴ and then sent home from the emergency department or physician’s office. In a case series of 32 adult patients with Pott puffy tumor, nearly 45% were initially misdiagnosed, most often by an internist, dermatologist, ophthalmologist, or emergency room physician.⁴

The most common infective organisms are streptococci, staphylococci, and anaerobes,⁴ but Haemophilus, Aspergillus species, and invasive mucormycosis have also been described.

MANAGEMENT OPTIONS

Because of the risk of spread of the infection to the brain, rapid initiation of a broad-spectrum antibiotic is warranted in all patients with Pott puffy tumor pending results of tissue culture. Antibiotics may be necessary for at least 4 to 6 weeks to resolve osteomyelitis of the frontal bone and to decrease inflammation before surgery.⁶

Endoscopic sinus surgery is routinely done to drain the infected sinus and to remove or debride infected bone. Patients with intracranial extension of infection may require a combined endoscopic and neurosurgical approach.

OUTCOME

Our patient’s puffy tumor spontaneously ruptured externally on hospital day 3, and the purulent fluid was sent for culture that grew Streptococcus anginosus. His headaches improved almost immediately after this occurred. The antibiotic regimen was narrowed to ceftriaxone and metronidazole, and 1 week later he was discharged home with instructions to complete a 6-week course of antibiotics. Three weeks after he was discharged, he returned for outpatient endoscopic sinus surgery. At a follow-up visit 2 weeks after surgery, the forehead swelling had resolved, and he was well.

A 60-year-old man presented to our emergency department with a 4-day history of frontal headaches he described as “stinging.” He had also had a large swollen area on his forehead for the past 8 weeks.

He denied fevers, chills, nausea, vomiting, blurry vision, tinnitus, and neck pain, as well as any recent sinus infection, intransanal cocaine use, rhinorrhea, or head trauma. A month ago, he had presented to our emergency department with forehead swelling but no headaches. At that time, the swelling was thought to be an allergic reaction to lisinopril or metformin, medications he takes for hypertension and type 2 diabetes. He had been discharged home with a prescription for a course of prednisone in tapering doses, but that had failed to resolve the swelling.

Physical examination revealed a well-circumscribed area of swelling, 3 by 4 cm, in the central forehead (Figure 1). The area was warm, erythematous, fluctuant, and tender to palpation. The nasal septum was intact and the nasal mucosa appeared pink and healthy. The remainder of the examination was unremarkable.

He was afebrile and hemodynamically stable. His peripheral white blood cell count was mildly elevated at 11.1 × 109. Computed tomography of the brain and sinuses revealed a fluid collection in the frontal scalp associated with erosion of the anterior frontal sinus with posterior extension and enhancement of the adjacent meninges. Magnetic resonance imaging (Figure 2) revealed similar findings. A diagnosis of Pott puffy tumor was made based on the imaging findings.

The name of this condition is misleading, as it is not a neoplasm but an infection. It requires urgent antibiotic therapy and surgical management because of the high risk of the infection spreading to the brain. Our patient was started on a broad-spectrum antibiotic regimen of intravenous vancomycin, ceftriaxone, and metronidazole pending tissue culture to identify the causative organism.

POTT PUFFY TUMOR: A BRIEF OVERVIEW

First described in 1760 by Sir Percivall Pott,¹ the same English surgeon who first described tuberculosis of the spine, Pott puffy tumor is a well-demarcated area of swelling that occurs when a frontal sinus infection breaks through the anterior portion of the frontal sinus and forms an abscess between the frontal bone and periosteum with associated osteomyelitis.² Though rare in adults (it is more common in children and adolescents),³ Pott puffy tumor is caused by conditions often encountered in internal medicine practice, such as bacterial sinusitis, head trauma, and intranasal cocaine use.

The infection can spread to the brain either directly by destruction of the posterior frontal sinus (as in our patient) or by way of the veins that drain the frontal sinus. Meningitis, epidural empyema, frontal lobe abscess, and cavernous sinus thrombosis² have all been described. Intracranial complications are seen in nearly 100% of children and adolescents with Pott puffy tumor. The rate in adults is 30%,^4,5 which is much lower but is nevertheless worrisome because patients can be initially misdiagnosed with scalp abscess,³ cellulitis, or epidermoid cyst,⁴ and then sent home from the emergency department or physician’s office. In a case series of 32 adult patients with Pott puffy tumor, nearly 45% were initially misdiagnosed, most often by an internist, dermatologist, ophthalmologist, or emergency room physician.⁴

The most common infective organisms are streptococci, staphylococci, and anaerobes,⁴ but Haemophilus, Aspergillus species, and invasive mucormycosis have also been described.

MANAGEMENT OPTIONS

Because of the risk of spread of the infection to the brain, rapid initiation of a broad-spectrum antibiotic is warranted in all patients with Pott puffy tumor pending results of tissue culture. Antibiotics may be necessary for at least 4 to 6 weeks to resolve osteomyelitis of the frontal bone and to decrease inflammation before surgery.⁶

Endoscopic sinus surgery is routinely done to drain the infected sinus and to remove or debride infected bone. Patients with intracranial extension of infection may require a combined endoscopic and neurosurgical approach.

OUTCOME

Our patient’s puffy tumor spontaneously ruptured externally on hospital day 3, and the purulent fluid was sent for culture that grew Streptococcus anginosus. His headaches improved almost immediately after this occurred. The antibiotic regimen was narrowed to ceftriaxone and metronidazole, and 1 week later he was discharged home with instructions to complete a 6-week course of antibiotics. Three weeks after he was discharged, he returned for outpatient endoscopic sinus surgery. At a follow-up visit 2 weeks after surgery, the forehead swelling had resolved, and he was well.

A 60-year-old man presented to our emergency department with a 4-day history of frontal headaches he described as “stinging.” He had also had a large swollen area on his forehead for the past 8 weeks.

He denied fevers, chills, nausea, vomiting, blurry vision, tinnitus, and neck pain, as well as any recent sinus infection, intransanal cocaine use, rhinorrhea, or head trauma. A month ago, he had presented to our emergency department with forehead swelling but no headaches. At that time, the swelling was thought to be an allergic reaction to lisinopril or metformin, medications he takes for hypertension and type 2 diabetes. He had been discharged home with a prescription for a course of prednisone in tapering doses, but that had failed to resolve the swelling.

Physical examination revealed a well-circumscribed area of swelling, 3 by 4 cm, in the central forehead (Figure 1). The area was warm, erythematous, fluctuant, and tender to palpation. The nasal septum was intact and the nasal mucosa appeared pink and healthy. The remainder of the examination was unremarkable.

He was afebrile and hemodynamically stable. His peripheral white blood cell count was mildly elevated at 11.1 × 109. Computed tomography of the brain and sinuses revealed a fluid collection in the frontal scalp associated with erosion of the anterior frontal sinus with posterior extension and enhancement of the adjacent meninges. Magnetic resonance imaging (Figure 2) revealed similar findings. A diagnosis of Pott puffy tumor was made based on the imaging findings.

The name of this condition is misleading, as it is not a neoplasm but an infection. It requires urgent antibiotic therapy and surgical management because of the high risk of the infection spreading to the brain. Our patient was started on a broad-spectrum antibiotic regimen of intravenous vancomycin, ceftriaxone, and metronidazole pending tissue culture to identify the causative organism.

POTT PUFFY TUMOR: A BRIEF OVERVIEW

First described in 1760 by Sir Percivall Pott,¹ the same English surgeon who first described tuberculosis of the spine, Pott puffy tumor is a well-demarcated area of swelling that occurs when a frontal sinus infection breaks through the anterior portion of the frontal sinus and forms an abscess between the frontal bone and periosteum with associated osteomyelitis.² Though rare in adults (it is more common in children and adolescents),³ Pott puffy tumor is caused by conditions often encountered in internal medicine practice, such as bacterial sinusitis, head trauma, and intranasal cocaine use.

The infection can spread to the brain either directly by destruction of the posterior frontal sinus (as in our patient) or by way of the veins that drain the frontal sinus. Meningitis, epidural empyema, frontal lobe abscess, and cavernous sinus thrombosis² have all been described. Intracranial complications are seen in nearly 100% of children and adolescents with Pott puffy tumor. The rate in adults is 30%,^4,5 which is much lower but is nevertheless worrisome because patients can be initially misdiagnosed with scalp abscess,³ cellulitis, or epidermoid cyst,⁴ and then sent home from the emergency department or physician’s office. In a case series of 32 adult patients with Pott puffy tumor, nearly 45% were initially misdiagnosed, most often by an internist, dermatologist, ophthalmologist, or emergency room physician.⁴

The most common infective organisms are streptococci, staphylococci, and anaerobes,⁴ but Haemophilus, Aspergillus species, and invasive mucormycosis have also been described.

MANAGEMENT OPTIONS

Because of the risk of spread of the infection to the brain, rapid initiation of a broad-spectrum antibiotic is warranted in all patients with Pott puffy tumor pending results of tissue culture. Antibiotics may be necessary for at least 4 to 6 weeks to resolve osteomyelitis of the frontal bone and to decrease inflammation before surgery.⁶

Endoscopic sinus surgery is routinely done to drain the infected sinus and to remove or debride infected bone. Patients with intracranial extension of infection may require a combined endoscopic and neurosurgical approach.

OUTCOME

Our patient’s puffy tumor spontaneously ruptured externally on hospital day 3, and the purulent fluid was sent for culture that grew Streptococcus anginosus. His headaches improved almost immediately after this occurred. The antibiotic regimen was narrowed to ceftriaxone and metronidazole, and 1 week later he was discharged home with instructions to complete a 6-week course of antibiotics. Three weeks after he was discharged, he returned for outpatient endoscopic sinus surgery. At a follow-up visit 2 weeks after surgery, the forehead swelling had resolved, and he was well.

Obesity means having a body mass index (BMI) of 30 or higher. Being obese increases your risk of health problems including high blood pressure, diabetes, cholesterol, arthritis, cancer, and cardiovascular diseases such as stroke and heart attack. You can reduce these risks by losing weight.

The healthy way to lose weight is to eat fewer calories, eat less processed food and more whole foods, and exercise regularly. A dietitian can help you create a flexible and balanced eating plan to help you meet your goals.

When beginning an exercise plan, start slowly with a combination of aerobic, resistance, flexibility, and balance exercises. A combined aerobic and resistance exercise program will likely result in more weight loss than either alone.

Aerobic exercises should be the foundation of your program. Choose exercises that involve large muscle groups, such as walking. Walking is the easiest way for most people to start exercising, but you can also consider other exercises such as stationary bicycling, slow jogging, and water aerobics.

Resistance training involves lifting weights using either weight machines or free weights (dumbbells).

Flexibility exercises are a type of stretching that improves the movements of your muscles, joints, and ligaments.

Balance exercises improve your stability and reduce the chance of falling or other injuries. These exercises can be done without any equipment. For example, with single-leg balance, you balance on one foot for 15 seconds. A stand-sit involves standing up and sitting down without using your hands.

Your provider will design an exercise program for you that includes the frequency, intensity, time, and types of exercise. Typically, you’ll want to lose about 10% of your weight over a 6-month period. Be sure to set SMART goals (Specific, Measurable, Attainable, Realistic, Timely) to sustain the self-discipline required for long-term success. Also consider tracking your physical activity using a wearable device (eg, Fitbit) or a smartphone app. It lets you see your progress over time, helps you set new goals, and helps keep you motivated.

This information is provided by your physician and the Cleveland Clinic Journal of Medicine. It is not designed to replace a physician’s medical assessment and judgment.

This page may be reproduced noncommercially to share with patients. Any other reproduction is subject to Cleveland Clinic Journal of Medicine approval. Bulk color reprints available by calling 216-444-2661.

For patient information on hundreds of health topics, visit the Center for Consumer Health Information website, www.clevelandclinic.org/health.

Obesity means having a body mass index (BMI) of 30 or higher. Being obese increases your risk of health problems including high blood pressure, diabetes, cholesterol, arthritis, cancer, and cardiovascular diseases such as stroke and heart attack. You can reduce these risks by losing weight.

The healthy way to lose weight is to eat fewer calories, eat less processed food and more whole foods, and exercise regularly. A dietitian can help you create a flexible and balanced eating plan to help you meet your goals.

When beginning an exercise plan, start slowly with a combination of aerobic, resistance, flexibility, and balance exercises. A combined aerobic and resistance exercise program will likely result in more weight loss than either alone.

Aerobic exercises should be the foundation of your program. Choose exercises that involve large muscle groups, such as walking. Walking is the easiest way for most people to start exercising, but you can also consider other exercises such as stationary bicycling, slow jogging, and water aerobics.

Resistance training involves lifting weights using either weight machines or free weights (dumbbells).

Flexibility exercises are a type of stretching that improves the movements of your muscles, joints, and ligaments.

Balance exercises improve your stability and reduce the chance of falling or other injuries. These exercises can be done without any equipment. For example, with single-leg balance, you balance on one foot for 15 seconds. A stand-sit involves standing up and sitting down without using your hands.

Your provider will design an exercise program for you that includes the frequency, intensity, time, and types of exercise. Typically, you’ll want to lose about 10% of your weight over a 6-month period. Be sure to set SMART goals (Specific, Measurable, Attainable, Realistic, Timely) to sustain the self-discipline required for long-term success. Also consider tracking your physical activity using a wearable device (eg, Fitbit) or a smartphone app. It lets you see your progress over time, helps you set new goals, and helps keep you motivated.

This information is provided by your physician and the Cleveland Clinic Journal of Medicine. It is not designed to replace a physician’s medical assessment and judgment.

This page may be reproduced noncommercially to share with patients. Any other reproduction is subject to Cleveland Clinic Journal of Medicine approval. Bulk color reprints available by calling 216-444-2661.

For patient information on hundreds of health topics, visit the Center for Consumer Health Information website, www.clevelandclinic.org/health.

Obesity means having a body mass index (BMI) of 30 or higher. Being obese increases your risk of health problems including high blood pressure, diabetes, cholesterol, arthritis, cancer, and cardiovascular diseases such as stroke and heart attack. You can reduce these risks by losing weight.

The healthy way to lose weight is to eat fewer calories, eat less processed food and more whole foods, and exercise regularly. A dietitian can help you create a flexible and balanced eating plan to help you meet your goals.

When beginning an exercise plan, start slowly with a combination of aerobic, resistance, flexibility, and balance exercises. A combined aerobic and resistance exercise program will likely result in more weight loss than either alone.

Aerobic exercises should be the foundation of your program. Choose exercises that involve large muscle groups, such as walking. Walking is the easiest way for most people to start exercising, but you can also consider other exercises such as stationary bicycling, slow jogging, and water aerobics.

Resistance training involves lifting weights using either weight machines or free weights (dumbbells).

Flexibility exercises are a type of stretching that improves the movements of your muscles, joints, and ligaments.

Balance exercises improve your stability and reduce the chance of falling or other injuries. These exercises can be done without any equipment. For example, with single-leg balance, you balance on one foot for 15 seconds. A stand-sit involves standing up and sitting down without using your hands.

Your provider will design an exercise program for you that includes the frequency, intensity, time, and types of exercise. Typically, you’ll want to lose about 10% of your weight over a 6-month period. Be sure to set SMART goals (Specific, Measurable, Attainable, Realistic, Timely) to sustain the self-discipline required for long-term success. Also consider tracking your physical activity using a wearable device (eg, Fitbit) or a smartphone app. It lets you see your progress over time, helps you set new goals, and helps keep you motivated.

This information is provided by your physician and the Cleveland Clinic Journal of Medicine. It is not designed to replace a physician’s medical assessment and judgment.

This page may be reproduced noncommercially to share with patients. Any other reproduction is subject to Cleveland Clinic Journal of Medicine approval. Bulk color reprints available by calling 216-444-2661.

For patient information on hundreds of health topics, visit the Center for Consumer Health Information website, www.clevelandclinic.org/health.

Table of Contents

• A Prescription for Music Lessons
• A New View for the VA
• Management of Diabetic Foot Ulcers: A Review
• Monitoring Heat Injuries in a Hazmat Environment
• Hyponatremia Secondary to Lisinopril in a Veteran Patient
• Clinical Video Telehealth for Gait and Balance
• Asymptomatic but Time for a Hip Revision
• Impact of Interprofessional Care Teams on Metabolic Parameters in Patients

Table of Contents

• A Prescription for Music Lessons
• A New View for the VA
• Management of Diabetic Foot Ulcers: A Review
• Monitoring Heat Injuries in a Hazmat Environment
• Hyponatremia Secondary to Lisinopril in a Veteran Patient
• Clinical Video Telehealth for Gait and Balance
• Asymptomatic but Time for a Hip Revision
• Impact of Interprofessional Care Teams on Metabolic Parameters in Patients

Table of Contents

• A Prescription for Music Lessons
• A New View for the VA
• Management of Diabetic Foot Ulcers: A Review
• Monitoring Heat Injuries in a Hazmat Environment
• Hyponatremia Secondary to Lisinopril in a Veteran Patient
• Clinical Video Telehealth for Gait and Balance
• Asymptomatic but Time for a Hip Revision
• Impact of Interprofessional Care Teams on Metabolic Parameters in Patients

Clinical question: Have the Choosing Wisely campaign recommendations led to changes in practice?

Background: The Choosing Wisely campaign aims to reduce the incidence of low-value care by providing evidence-based recommendations for common clinical situations. The rate of adoption of these recommendations is unknown.

Study design: Retrospective review.

Setting: Anthem insurance members.

Synopsis: The study examined the claims data from 25 million Anthem insurance members to compare the rate of services that were targeted by seven Choosing Wisely campaign recommendations before and after the recommendations were published in 2012.

Investigators found the incidence of two of the services declined after the Choosing Wisely recommendations were published; the other five services remained stable or increased slightly. Furthermore, the declines were statistically significant but not a marked absolute difference, with the incidence of head imaging in patients with uncomplicated headaches going down to 13.4% from 14.9% and the use of cardiac imaging in the absence of cardiac disease declining to 9.7% from 10.8%.

The main limitations are the narrow population of Anthem insurance members and the lack of specific data that could help answer why clinical practice has not changed, but that could be the aim of future studies.

Bottom line: Choosing Wisely recommendations have not been adopted on a population level; widespread implementation likely will require financial incentives, provider-level data feedback, and systems interventions.

Citation: Rosenberg A, Agiro A, Gottlieb M, et al. Early trends among seven recommendations from the Choosing Wisely campaign. JAMA Intern Med. 2015;175(12):1913-1920. doi:10.1001/jamainternmed.2015.5441.

Clinical question: Have the Choosing Wisely campaign recommendations led to changes in practice?

Background: The Choosing Wisely campaign aims to reduce the incidence of low-value care by providing evidence-based recommendations for common clinical situations. The rate of adoption of these recommendations is unknown.

Study design: Retrospective review.

Setting: Anthem insurance members.

Synopsis: The study examined the claims data from 25 million Anthem insurance members to compare the rate of services that were targeted by seven Choosing Wisely campaign recommendations before and after the recommendations were published in 2012.

Investigators found the incidence of two of the services declined after the Choosing Wisely recommendations were published; the other five services remained stable or increased slightly. Furthermore, the declines were statistically significant but not a marked absolute difference, with the incidence of head imaging in patients with uncomplicated headaches going down to 13.4% from 14.9% and the use of cardiac imaging in the absence of cardiac disease declining to 9.7% from 10.8%.

The main limitations are the narrow population of Anthem insurance members and the lack of specific data that could help answer why clinical practice has not changed, but that could be the aim of future studies.

Bottom line: Choosing Wisely recommendations have not been adopted on a population level; widespread implementation likely will require financial incentives, provider-level data feedback, and systems interventions.

Citation: Rosenberg A, Agiro A, Gottlieb M, et al. Early trends among seven recommendations from the Choosing Wisely campaign. JAMA Intern Med. 2015;175(12):1913-1920. doi:10.1001/jamainternmed.2015.5441.

Clinical question: Have the Choosing Wisely campaign recommendations led to changes in practice?

Background: The Choosing Wisely campaign aims to reduce the incidence of low-value care by providing evidence-based recommendations for common clinical situations. The rate of adoption of these recommendations is unknown.

Study design: Retrospective review.

Setting: Anthem insurance members.

Synopsis: The study examined the claims data from 25 million Anthem insurance members to compare the rate of services that were targeted by seven Choosing Wisely campaign recommendations before and after the recommendations were published in 2012.

Investigators found the incidence of two of the services declined after the Choosing Wisely recommendations were published; the other five services remained stable or increased slightly. Furthermore, the declines were statistically significant but not a marked absolute difference, with the incidence of head imaging in patients with uncomplicated headaches going down to 13.4% from 14.9% and the use of cardiac imaging in the absence of cardiac disease declining to 9.7% from 10.8%.

The main limitations are the narrow population of Anthem insurance members and the lack of specific data that could help answer why clinical practice has not changed, but that could be the aim of future studies.

Bottom line: Choosing Wisely recommendations have not been adopted on a population level; widespread implementation likely will require financial incentives, provider-level data feedback, and systems interventions.

Citation: Rosenberg A, Agiro A, Gottlieb M, et al. Early trends among seven recommendations from the Choosing Wisely campaign. JAMA Intern Med. 2015;175(12):1913-1920. doi:10.1001/jamainternmed.2015.5441.

ALL patient

Photo by Bill Branson

New research suggests that body mass index (BMI) is an inadequate method for estimating changes in body fat and obesity in children with acute lymphoblastic leukemia (ALL).

Investigators found a discrepancy between BMI and body composition in this population, and the cause of this appeared to be increases in body fat with simultaneous loss of lean muscle mass during treatment.

The team reported these findings in Leukemia & Lymphoma.

With previous work, the investigators found that obese children diagnosed with high-risk ALL had a 50% greater risk of their disease recurring compared with children who were not obese.

“In my lab, we’ve seen a direct interaction between fat cells and leukemia cells that may help explain this increased risk of disease relapse,” said study author Steven Mittelman, MD, PhD, of Children’s Hospital Los Angeles in California.

“It appears that the fat cells ‘protect’ leukemia cells, making them less susceptible to chemotherapy and making an accurate measure of body fat essential.”

To determine if BMI accurately reflects body fat in ALL, the investigators analyzed 50 patients. They were predominantly Hispanic, between the ages of 10 to 21, and had newly diagnosed high-risk B-precursor ALL or T-cell ALL.

The team measured the percentage of total body fat and lean muscle mass at the time of diagnosis, at the end of induction, and at the end of delayed intensification. They also calculated BMI Z-score—a measure of how a given child’s BMI deviates from a population of children of the same age and sex—at these time points.

The investigators said sarcopenic obesity—gain in body fat percentage with loss of lean muscle mass—was “surprisingly common” during ALL treatment.

And sarcopenic obesity resulted in poor correlation between changes in BMI Z-score and body fat percentage overall (r=-0.05), within the time points (r=0.02), and within patients (r=-0.09, all not significant). BMI Z-score and body fat percentage changed in opposite directions in more than 50% of interval assessments.

“We found that change in BMI did not reflect changes in body fat or obesity,” said Etan Orgel, MD, of Children’s Hospital Los Angeles.

“In some patients, reaching a ‘healthy’ BMI was due solely to loss of muscle even while body fat continued to rise. Based on these results, we believe that evaluation of obesity in patients with leukemia should include direct measures of body composition.”

ALL patient

Photo by Bill Branson

New research suggests that body mass index (BMI) is an inadequate method for estimating changes in body fat and obesity in children with acute lymphoblastic leukemia (ALL).

Investigators found a discrepancy between BMI and body composition in this population, and the cause of this appeared to be increases in body fat with simultaneous loss of lean muscle mass during treatment.

The team reported these findings in Leukemia & Lymphoma.

With previous work, the investigators found that obese children diagnosed with high-risk ALL had a 50% greater risk of their disease recurring compared with children who were not obese.

“In my lab, we’ve seen a direct interaction between fat cells and leukemia cells that may help explain this increased risk of disease relapse,” said study author Steven Mittelman, MD, PhD, of Children’s Hospital Los Angeles in California.

“It appears that the fat cells ‘protect’ leukemia cells, making them less susceptible to chemotherapy and making an accurate measure of body fat essential.”

To determine if BMI accurately reflects body fat in ALL, the investigators analyzed 50 patients. They were predominantly Hispanic, between the ages of 10 to 21, and had newly diagnosed high-risk B-precursor ALL or T-cell ALL.

The team measured the percentage of total body fat and lean muscle mass at the time of diagnosis, at the end of induction, and at the end of delayed intensification. They also calculated BMI Z-score—a measure of how a given child’s BMI deviates from a population of children of the same age and sex—at these time points.

The investigators said sarcopenic obesity—gain in body fat percentage with loss of lean muscle mass—was “surprisingly common” during ALL treatment.

And sarcopenic obesity resulted in poor correlation between changes in BMI Z-score and body fat percentage overall (r=-0.05), within the time points (r=0.02), and within patients (r=-0.09, all not significant). BMI Z-score and body fat percentage changed in opposite directions in more than 50% of interval assessments.

“We found that change in BMI did not reflect changes in body fat or obesity,” said Etan Orgel, MD, of Children’s Hospital Los Angeles.

“In some patients, reaching a ‘healthy’ BMI was due solely to loss of muscle even while body fat continued to rise. Based on these results, we believe that evaluation of obesity in patients with leukemia should include direct measures of body composition.”

ALL patient

Photo by Bill Branson

New research suggests that body mass index (BMI) is an inadequate method for estimating changes in body fat and obesity in children with acute lymphoblastic leukemia (ALL).

Investigators found a discrepancy between BMI and body composition in this population, and the cause of this appeared to be increases in body fat with simultaneous loss of lean muscle mass during treatment.

The team reported these findings in Leukemia & Lymphoma.

With previous work, the investigators found that obese children diagnosed with high-risk ALL had a 50% greater risk of their disease recurring compared with children who were not obese.

“In my lab, we’ve seen a direct interaction between fat cells and leukemia cells that may help explain this increased risk of disease relapse,” said study author Steven Mittelman, MD, PhD, of Children’s Hospital Los Angeles in California.

“It appears that the fat cells ‘protect’ leukemia cells, making them less susceptible to chemotherapy and making an accurate measure of body fat essential.”

To determine if BMI accurately reflects body fat in ALL, the investigators analyzed 50 patients. They were predominantly Hispanic, between the ages of 10 to 21, and had newly diagnosed high-risk B-precursor ALL or T-cell ALL.

The team measured the percentage of total body fat and lean muscle mass at the time of diagnosis, at the end of induction, and at the end of delayed intensification. They also calculated BMI Z-score—a measure of how a given child’s BMI deviates from a population of children of the same age and sex—at these time points.

The investigators said sarcopenic obesity—gain in body fat percentage with loss of lean muscle mass—was “surprisingly common” during ALL treatment.

And sarcopenic obesity resulted in poor correlation between changes in BMI Z-score and body fat percentage overall (r=-0.05), within the time points (r=0.02), and within patients (r=-0.09, all not significant). BMI Z-score and body fat percentage changed in opposite directions in more than 50% of interval assessments.

“We found that change in BMI did not reflect changes in body fat or obesity,” said Etan Orgel, MD, of Children’s Hospital Los Angeles.

“In some patients, reaching a ‘healthy’ BMI was due solely to loss of muscle even while body fat continued to rise. Based on these results, we believe that evaluation of obesity in patients with leukemia should include direct measures of body composition.”