Low Carb in Lung Disease

Introduction

Lung disease burden

Role of inflammation in lung disease

Nutrition guidelines in lung disease

Is diet relevant in lung disease?

Benefits of carbohydrate restriction in lung disease

1. Glucose and Lung Disease
   1. Steroid-induced hyperglycemia
   1. Effect of Hyperglycemia in COPD on outcomes
   1. Diabetes and Metabolic Syndrome
   1. Hyperglycemia disrupts airway glucose homeostasis
   1. Role of carbohydrate restriction

• Nutrition and Carbon Dioxide Production
  • Macronutrient intake affects the Respiratory Quotient
  • High carbohydrate intake may be harmful in obstructive lung disease
  • Carbohydrate restriction improves ventilation in COPD

• Nutrition and Inflammation
  • Nutritional ketosis suppresses the NLRP3 Inflammasome

• Nutrient Density and the Mechanics of Breathing

Evidence – Diet and Asthma

Evidence – High fat supplemental feeding in critical care

Evidence – Use of supplements in COPD

Summary

Introduction

Modern medicine offers us a variety of pharmaceutical interventions that target specific pathophysiologic mechanisms, i.e. one drug, one target.  In the case of lung diseases such as asthma and COPD, for example, the primary (perhaps sole) target of pharmaceutical interventions is inflammation.  While inflammation is indeed a key player in COPD and asthma exacerbations, there are other relevant mechanisms of disease that are not targeted by current treatments, and perhaps many more that we have yet to discover.  

Other than smoking cessation, the treatment of COPD is strictly symptomatic, with medications such as bronchodilators and corticosteroids as the mainstays of treatment, both in maintenance phase and in the setting of acute exacerbations.  The role of nutrition, however, in managing lung disease has largely been ignored.  Yet, there are numerous anecdotal reports that a low carbohydrate diet can reduce the symptoms and severity of lung disease, and perhaps fully eradicate lung disease in some individuals.  

Simple dietary interventions offer great promise in correcting multiple pathophysiologic processes in lung disease in a simultaneous fashion.  The low carbohydrate, high/healthy fat (LCHF) diet may impart favorable benefits in the setting of lung disease by several mechanisms.  The currently available research evidence for these mechanisms will be examined.

Lung Disease – types and global burden

The two most common chronic lung diseases are Asthma and COPD.   It is estimated that 328 million people worldwide have COPD (now the 3rd leading cause of death worldwide) and 334 million people have asthma.  While smoking is the predominant cause of COPD in the United States, 24% of individuals with COPD have never smoked — in these cases, etiologies for COPD include occupational exposure and genetic conditions). 

Individuals with asthma and COPD are at risk for acute exacerbations of their chronic lung disease, often severe enough to require hospitalization.  Exacerbations of asthma and COPD, which are most commonly triggered by infection and exposure to irritants, rank among the top reasons for hospitalization. 

Role of inflammation in lung disease

Both asthma and COPD are characterized by inflammation of the airways.   Asthma is characterized by intermittent, reversible airway inflammation, whereas Chronic Obstructive Pulmonary Disease (COPD) is defined by persistent airflow obstruction, mainly emphysema and chronic bronchitis. 

Exacerbations of Asthma and COPD are characterized by inflammation, usually presenting with increased cough, (sometimes productive), shortness of breath, and wheezing.  Depending on the severity of the exacerbation, patients may require interventions such as breathing treatments (bronchodilators), antibiotics, steroids, supplemental oxygen, and hospitalization.

Nutrition guidelines in lung disease

The focus of nutritional intervention in current guidelines is focused primarily on correcting malnutrition and providing adequate energy intake to avoid weight loss.  Even in the absence of respiratory disease, malnutrition causes decreased respiratory muscle mass and function[1], a problem with more significant implications in those with chronic lung disease. 

In regards to macronutrient intake, the Academy of Nutrition and Dietetics advises that the macronutrient composition of medical supplements be directed at a patient’s preference, citing limited evidence for a particular macronutrient composition of supplements.  There is no current recommendation regarding diet composition.[2]  

Despite no formal recommendations, however, some pulmonologists (lung disease specialists) have recognized the utility of low carb, ketogenic diets in COPD.  Dr. Albert Rizzo, MD, the chief medical officer of the American Lung Association, acknowledges the potential benefit of the ketogenic diet in COPD, citing anecdotal evidence.  “Some notice they can walk faster and climb steps easier.”

Dr. Raymond Casciari, MD, another pulmonologist, stated:  “If you eat a high carbohydrate diet and you have COPD, you will wind up more short of breath . . . The best kind of diet for a person with COPD is a high fat, high protein, low carb eating plan like the keto diet.”[3]

Is diet relevant in lung disease?  Does diet affect lung function?

There are several mechanisms by which diet is posited to play a role in lung disease, including direct impact on the underlying pathophysiology, alteration of one’s biochemistry, or even by mechanical factors.  Carbohydrate restriction may be beneficial to both acute exacerbations of lung disease as well as in management of the chronic disease states by the following mechanisms:

1. Reduced hyperglycemia
2. Reduced CO₂ production
3. Reduced inflammation
4. Improved satiety

1. Glucose and Lung Disease

Hyperglycemia is a side effect of treatment.

Hyperglycemia (elevated glucose) is common in the setting of acute exacerbations of lung disease, both as a physiologic response to stress and as a side effect of medical management.  Steroids (glucocorticoids) are a standard element of treatment in the management of a COPD exacerbation, because of their anti-inflammatory effect.  It is estimated, however, that 45% of individuals treated with steroids for COPD exacerbation develop steroid-induced diabetes.[4]

Hyperglycemia occurs in the majority of hospitalized patients receiving high-dose corticosteroids (prednisone greater than or equal to 40 mg daily), a standard intervention for acute exacerbations.  This hyperglycemia caused by steroids results from inducing insulin resistance, increasing liver gluconeogenesis, and impairing pancreatic β-cell function.[5] Furthermore, other standard medical interventions including inhaled bronchodilators and certain antibiotics are also associated with hyperglycemia.

Hyperglycemia is associated with adverse outcomes.

Just as diabetes is associated with worsened outcomes in many other medical conditions, hyperglycemia is associated with poor outcomes in patients admitted to the hospital with acute exacerbations of COPD[6].   Hyperglycemia greater than 126 mg/dL within 24 hours of admission is associated with worse outcome in patients with COPD exacerbation requiring Non-Invasive Positive Pressure Ventilation (NIPPV)[7] – more commonly known as CPAP or BiPAP.

In patients with pre-existing diabetes, the stakes are even higher, as they are already starting with a higher glucose level and they are even more sensitive to the steroid-induced hyperglycemia side effect.  Pre-existing hyperglycemia also makes them more prone to exacerbations of their lung disease.

Diabetes and Metabolic Syndrome are associated with worsened clinical course of lung disease and increased morbidity/mortality[8].

Not only is hyperglycemia relevant in the setting of exacerbations, but also longstanding hyperglycemia has significant impact on the long-term course of lung disease. 

• Type 2 Diabetes can worsen the progression of COPD and increase COPD-related mortality. 
• Pulmonary functions tests (PFT’s) are decreased in individuals with Type 2 Diabetes compared to healthy controls, suggesting that hyperglycemia may have direct negative impact on lung function. 
• For individuals with COPD, higher fasting glucoses (as seen in metabolic syndrome) are associated with increased frequency of exacerbations[9]
• Diabetics are more likely to have COPD exacerbations than non-diabetics[10].  
• When diabetic patients with COPD are hospitalized for an exacerbation, they frequently (50-80%) suffer hyperglycemia and have increased lengths of hospitalization and increased mortality compared to nondiabetic patients.  [11]

Hyperglycemia disrupts airway glucose homeostasis

High glucose levels in the blood are associated with high levels of glucose in the airways.  Thereare several mechanisms directed at regulating the amount of glucose in our airways, but these mechanisms are disrupted by hyperglycemia and airway inflammation.  Glucose in the airways serves as a nutrient source for bacteria and stimulates proliferation of many respiratory bacteria, contributing to infections and exacerbations of chronic lung disease. [12]

• COPD patients with diabetes or hyperglycemia are more likely to have bacteria grow from their sputum cultures.  
• In Cystic Fibrosis, Diabetes and hyperglycemia are associated with increased exacerbations of disease and respiratory infections. 

Medications that reduce insulin resistance (and subsequently reduce hyperglycemia), such as metformin, also reduce bacterial growth in airways.  Patients with Asthma and Diabetes who are taking metformin have a 5-fold lower risk of asthma-related hospitalization and 2-3 fold lower risk of asthma exacerbation.[13]

Carbohydrate restriction reduces hyperglycemia

Carbohydrate intake is the main dietary determinant of blood glucose[14], therefore carbohydrate restriction has the greatest effect on decreasing blood glucose levels.[15]  Carbohydrate restriction is a logical intervention in the prevention of steroid-induced hyperglycemia/diabetes and improving overall glycemic control which is associated with improved outcomes in both chronic and acute lung disease.  Thus, the simple intervention of a low carb diet has the potential to dramatically alter the clinical course of lung disease.

• Nutrition and Carbon Dioxide Production

In simple terms, the lungs are responsible for bringing oxygen into the body and removing carbon dioxide from the body. 

Macronutrient intake affects the Respiratory Quotient

Carbon dioxide (CO₂) is produced as a waste product of cellular respiration – a series of chemical reactions that convert fuel sources (from fat, protein, and carbohydrates) into available energy in the form of adenosine triphosphate (ATP).

The amount of CO₂ produced varies depending on the type of fuel being consumed and can be calculated in the form of the Respiratory Quotient (RQ) – the ratio of carbon dioxide production to oxygen consumption when utilizing a particular fuel source for energy. 

For example, when 1 molecule of glucose is oxidized, 6 Oxygen (O₂) molecules are consumed and 6 molecules of CO₂ are produced.  Thus, the RQ for glucose/carbohydrate) is 6/6 = 1.0.  The RQ for fat is only 0.7, indicating that less CO₂ is produced when fat is metabolized.  Protein, as it often does, falls somewhere between those two, with an RQ of 0.8.

The Respiratory Quotient of the 3 macronutrients is as follows:  

With excess carbohydrate intake that results in fat storage (lipogenesis), the RQ is markedly elevated at 8, reflecting much greater production of CO₂ relative to O₂ consumed. 

Consider an analogy to help understand the significance of the Respiratory Quotient:

CO₂ is like smoke in a house, produced by burning fuel inside the house.  The higher the RQ, the more smoke that is produced by a particular fuel.  When carbohydrates are burned (high RQ), there is a lot of smoke production, and it will take more ventilation inside the house to remove the smoke from the air.  In contrast, burning fat (a lower RQ) is cleaner – produces less smoke – and thus does not require as much ventilation to clear the air. 

As more CO₂ is produced by the burning of fuel inside our bodies, our lungs need to work extra hard to blow off the CO₂ that accumulates.  

Why does the RQ matter?  CO₂ is a waste product and must be removed from the body by ventilation (moving air into and out of the lungs).  Healthy individuals (with healthy lungs) are easily able to compensate for the increased CO₂ production by increasing ventilation.  Those with lung disease, however, may not be able to increase ventilation appropriately and thereby develop hypercapnia (high CO₂ level in the blood).  Ventilation is a product of the amount of air being moved over a period of time.  Thus, ventilation can be increased by either increasing the amount of air moved (volume) or by increasing the rate at which the air is moved (respiratory rate).  

Further complicating the situation for COPD patients is the fact that airway obstruction causes air to become trapped in the lungs, making ventilation even more difficult. Patients report that having COPD is like breathing through a straw.

…but not that glamorous when you have COPD

Thus, it is favorable to reduce carbohydrate intake and increase fat intake to reduce production of carbon dioxide (CO­₂).  The less CO­₂ that is produced, the less effort it takes to ventilate off the CO₂.

High carbohydrate intake may be harmful in obstructive lung disease

Standard nutritional advice consistent with the US Dietary Guidelines is given to COPD patients, which is notoriously low-fat, high-carb.  Several studies have demonstrated, however, that high carbohydrate intake can be deleterious in the setting of COPD.

A high carbohydrate meal (RQ ~1) causes increased stress on the respiratory system in patients with COPD relative to a high fat (RQ ~0.7) meal[16]:

• increased CO₂ production – (V_CO2 – significantly higher compared with normal subjects)[17]
• increased CO₂ concentration in the blood (Pa_CO2)[18]
• increased RQ
• decreased exercise tolerance[19]

Carbohydrate restriction improves ventilation in COPD

Beyond the effects of a single meal, a randomized, double-blinded study in a metabolic unit compared the effects of diet over the course of 5 days.  Patients with COPD were given low, moderate, and high carbohydrate (28%, 53%, and 74% carbohydrate, respectively) diets (in randomized orders), and the effects on metabolic and ventilator parameters were measured after 5 days on each diet.  Subjects on the low carb high fat (LCHF) diet had significantly lower CO₂ production (V_CO2), lower respiratory quotient (RQ), and lower levels of CO₂ in the blood (Pa_CO2) compared to those consuming higher carbohydrate diets. 

Together, these findings suggest that a low carb high fat diet is more beneficial in individuals with COPD.  Certain patients are unable to handle increased loads of CO₂ due to limitations in their ability to increase ventilation to blow off CO₂, whether due to the severity of airway obstruction or impairment in respiratory effort.  A high-carbohydrate diet (or Standard American Diet) may simply be intolerable due to the high production of CO₂ relative to a high fat diet.  In patients with marginal ventilatory reserve, the increased load of CO₂ resulting from carbohydrate metabolism may ultimately lead to respiratory distress or respiratory failure. [20] 

Even if relatively small improvements in ventilation are seen in patients with COPD on a high fat diet, such differences may be clinically relevant in patients who are in a borderline situation and at risk for respiratory failure.  Whether carbohydrate restriction results in decreased morbidity/mortality from COPD is yet unknown. 

• Nutrition and Inflammation

Carbohydrate restriction reduces inflammation

Given that COPD and Asthma are driven by inflammation, any intervention that reduces inflammation could theoretically reduce the clinical impact of these chronic lung diseases, particularly in the setting of acute exacerbations.  Low carb diets are anti-inflammatory, resulting in reduced levels of markers of inflammation,[21] and thus may be of utility in lung disease. 

A very low carb, ketogenic diet, specifically is known to suppress an important mediator of inflammation involved in COPD.

Nutritional ketosis suppresses the NLRP3 Inflammasome

On a molecular level, a specific series of events involved in inflammation occurring in a particular cellular complex known as an inflammasome has been identified.  This so-called NLRP3 inflammasome is implicated in COPD exacerbations and has been demonstrated to be triggered by infections, cigarette smoke, and air pollutants.   It is thought to be involved with the development and progression of COPD, as well as playing a significant role in acute exacerbations.[22] 

NLRP3 Inflammasome activation in COPD­²¹

The ketone body, β-hydroxybutyrate, actually suppresses the activation of the NLRP3 inflammasome.  Thus, when conducted properly, the ketogenic diet theorectically may reduce the inflammation associated with COPD exacerbations.[23]  The clinical significance of this suppression of inflammation is unknown at this time.  Defining this precise anti-inflammatory mechanism, however, gives promise to the role of the ketogenic diet in COPD.

• Nutrient Density and the Mechanics of Breathing

In addition to the biochemical advantages, there are also mechanical benefits of carbohydrate restriction related to the work of breathing/ventilation. 

A low carb high fat diet is more satiating[24] than a high fat low carb diet, even with fewer calories consumed.[25] ­­­ Thus, a low carb high fat diet allows for smaller-volume meals with increased nutrient density, which leads to better descent of the diaphragm[26] from decreased stomach filling.  In contrast, larger meals with increased carbohydrate intake may contribute to abdominal bloating and increased difficulty with taking deep breaths.  

In the setting of an exacerbation of lung disease, breathing suddenly becomes the #1 priority.  Patients in respiratory distress often don’t feel hungry, may be too lethargic to eat, or may have mechanical barriers to eating, such as an oxygen mask or BiPAP mask in place.  Their situation may be so tenuous as to make even temporary removal of the mask a risky endeavor.  Thus, if possible, smaller meals with increased nutrient density are preferable, in order to meet the patient’s energy needs and allow sufficient rest before meals.[27] 

Evidence – Diet and Asthma

In 1930, researchers selected 15 children (ages 3-15 years) with severe, chronic asthma who did not respond to conventional treatment for a trial of a low carbohydrate ketogenic diet.[28]  The diet progressed from a ketogenic:antiketogenic ratio (roughly fat:carb ratio) of 1:1.5 in the beginning to a ratio of 3:1. 

After 2 weeks of treatment, 10 of 15 children showed moderate improvement and 3 children showed marked improvement.  At the end of the 3^rd week, 14 of 15 children showed moderate or marked improvement in their asthma.  These improvements were maintained for 2 months, and several children continued to participate with moderate to marked improvement for up to 10 months. 

While this study showed great promise, there has not been subsequent published research on the role of low carbohydrate diets in Asthma, instead focusing mostly on specific foods or nutrients. 

• Increased consumption of fast food and sugar-containing beverages is associated with increased asthma symptoms
• Increased consumption of fruits (especially apples and oranges) and vegetables is associated with a decrease in symptoms
• A Mediterranean diet was associated with improvement in asthma for children, but not adults
• A Western diet is associated with poor asthma control in adults[29] 
• Populations with a higher intake of omega-6 fatty acids have a higher prevalence of asthma compared to populations with a higher intake of omega-3 fatty acids[30] 

Given that these findings are associations only, there is no good evidence at this time to recommend for/against a particular eating pattern in Asthma. 

There is, however, a Randomized Controlled Trial (RCT) that compared a Mediterranean diet that included fatty fish consumed twice weekly (intervention) with the usual diet (control) in children with mild asthma.  Children in the intervention group demonstrated decreased bronchial inflammation and decreased medication use.[31]

The role of diet in asthma remains unclear, warranting further research. 

Evidence – High fat supplemental feeding in critical care

Individuals who suffer severe or complex lung disease may require mechanical ventilation in a critical care setting, such as the Intensive Care Unit (ICU).  Since these patients are intubated (tube inserted in airway) and usually sedated, they are not able to eat and thus are given total parenteral nutrition (TPN) through an IV. 

The content of standard TPN formulas is high carbohydrate, with dextrose (glucose produced from corn[32]) representing the predominant non-protein energy source

The large load of glucose provided in TPN can precipitate respiratory failure in patients with underlying lung disease in a similar manner as described above, secondary to the high respiratory quotient of carbohydrates and the resulting hypercapnia.[33]  High carbohydrate administration results in significant increases in CO₂ production and minute ventilation (reflecting increased respiratory effort to remove the CO₂).[34]  The CO₂ production is significantly higher in patients receiving glucose compared to those receiving a large percentage of fat.[35] 

In critically ill patients, tube feeding with a low carb, high fat solution was superior to standard, high carbohydrate formulas, as measured by lower PaCO₂ and significantly shorter durations of mechanical ventilation, with the high fat group spending an average of 62 hours less time on the ventilator in 2 separate studies.^.[36],[37]

Evidence – Use of supplements in COPD

Nutrition supplements are a standard intervention utilized by dietitians to correct malnutrition in patients, as supplements are calorie-dense and easy to consume.  Use of high fat supplements in COPD is associated with significant reductions in RQ, CO₂ production, and concentration of CO₂ in the blood.[38]  In addition, supplementation with other nutrients is associated with improvements in COPD patients[39]:

• omega-3 fatty acids associated with decreased inflammatory markers,
• essential amino acids associated with increased lean body mass, strength, and cognitive function,
• vitamin D associated with a reduced risk of COPD exacerbations
• antioxidant vitamins, selenium, calcium, chloride, and iron independently associated with higher FEV₁ values

It is impossible to draw conclusions from such correlational studies, with a large confounding variable being the baseline diet, which could vary drastically.  

Perhaps the most important takeaway regarding supplements is that high fat supplements are an option to correct malnutrition without causing negative respiratory side effects from standard, high carbohydrate supplements.

Summary

A low carb high fat dietary intervention may be an important, under-utilized tool in treating Asthma and COPD, by virtue of its glycemic control properties, favorable metabolic byproducts, anti-inflammatory effect, and favorable nutrient density. 

Numerous studies have documented the effect of low carb high fat dietary intervention at reducing the production of CO₂ in patients with lung disease, both in acute and chronic disease states.  It is now important to understand whether this biochemical advantage translates into improvement in clinical status and/or reductions in morbidity/mortality.  For patients with limited ventilatory reserve, even a small reduction in the burden of blowing off CO₂ may be clinically relevant in patients who are in a borderline situation and at risk for respiratory failure.  Furthermore, the anti-inflammatory and glucose-lowering effects of eating low carb have been well-documented and make it a valuable and powerful adjunct to current treatment. 

These advantages over the standard approach to managing lung disease make the low carb diet an ideal solution for individuals with lung disease.

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