How Can We Prevent Multisystem Complications of Cystic Fibrosis?
J. Stuart Elborn, M.D. Semin Respir Crit Care Med. 2007;28(3):303-311. ?2007 Thieme Medical Publishers
Abstract and Introduction
Cystic fibrosis (CF) is a multisystem disease. Some of this is accounted for by CF transmembrane regulator (CFTR) dysfunction in individual organs but in some cases this is compounded by the effects of systemic inflammation. The inflammation is in response to the chronic infection in the airways and is particularly important as a contributor to CF-related bone disease, CF-related diabetes mellitus, CF-related arthropathy, and vasculitis. Preventing these multisystem complications is difficult. Aggressive specific therapies to treat complications is critically important to maintain nutrition, stop the damaging effects of diabetes, and improve bone mineral density. Aggressive treatment of lung disease to reduce systemic inflammation is likely to be of benefit in preventing the development of CF- related bone disease and may be beneficial in at least delaying the onset of CF-related diabetes. Aggressive treatment of pulmonary infection and inflammation in conjunction with holistic management plans to treat specific organ diseases is an important strategy in improving morbidity and reducing mortality in people with CF.
Morbidity and mortality in cystic fibrosis (CF) are dominated by the complications and consequences of chronic infection and inflammation. Acute and chronic inflammation secondary to bacterial infection results in injury to respiratory epithelium and subsequently to alveolar tissue. Despite aggressive antibiotic therapy for acute exacerbations and disease-modifying agents to control the impact of chronic infection, inflammation continues relatively unchecked. This results not only in a local inflammatory process but also in secondary systemic complications. Chronic systemic inflammation has a significant impact on other organ systems and may contribute to the development of related conditions, such as undernutrition, CF-related bone disease, and CF-related diabetes mellitus. Systemic vasculitis and CF-related joint disease are also likely to be related to the systemic inflammatory effect driven by chronic pulmonary inflammation and infection.
CF is a disease of epithelial cells and therefore involves other organ systems apart from the lung where epithelial cells are present. Pancreatic inflammation is a major factor in the development of fat malabsorption and diabetes mellitus, whereas biliary tract disease results in several disorders affecting the liver, particularly cirrhosis and portal hypertension.
In many of these situations, CF transmembrane regulator (CFTR) dysfunction in the involved epithelium may interact with the consequences of systemic inflammation to contribute to the disease process. This article explores several of these mechanisms and suggests possible approaches to prevention or amelioration of these systemic consequences.
Nutrition and Intermediary Metabolism
The causes of undernutrition in people with CF are multifactorial ( Table 1 ). It is likely that pancreatic injury begins in utero with mucous plugging of pancreatic ducts. This causes a secondary inflammatory process with loss of exocrine pancreatic tissue, bicarbonate deficiency, and subsequently islets of Langerhans. The pancreatic disease in CF contributes to maldigestion and malabsorption by reducing the presence of pancreatic enzymes because of destruction of exocrine pancreas. However, there is also important dysregulation of neuropeptide control and bicarbonate secretion. This alters the pH in the gut and may affect the efficacy of any endogenous enzymes as well as replacement enzymes. In addition, the presence of bile salts are important for micelle formation, and these may be deficient secondary to hepatic dysfunction in CF and may further contribute to malabsorption, particularly of fats.
The pancreas is quite sensitive to the degree of CFTR dysfunction. The milder mutations, class 4 and class 5, are usually associated with pancreatic sufficiency, and pancreatic function tests in such individuals show better production of trypsin, lipases, and bicarbonate. Pancreatic enzyme deficiency associated with pancreatic insufficiency is a key factor but in the majority of cases can be corrected with the use of pancreatic enzyme replacement therapy (PERT). However, PERT usually only corrects ∼80% of the malabsorption due to enzyme deficiency and people with CF have a net loss of energy. Careful attention to enzyme replacement and energy intake should enable the majority of children with CF to attain normal growth and reach adulthood in good nutritional state and close to normal height.
Undernutrition is seen in around 20% of children and adults with CF (Fig. 1). The main reasons for not achieving good nutritional status is poor adherence to PERT and energy supplementation and poorly controlled lung disease. The challenges of dealing with nutritional adherence in childhood and early adolescence and in some adult patients are great.[10,11] Appropriate intervention should be designed for each individual to optimize both PERT and energy intake. A recent study has demonstrated that oral energy supplements in relatively well-nourished children with CF do not increase weight. Undernourished children may benefit from energy supplements but the main emphasis should be on augmenting a normal diet.
Poorly controlled lung disease can contribute to undernutrition in several important ways. Impaired lung function is associated with an increase in oxygen costs of breathing and this may increase resting energy expenditure in people with CF. Chronic inflammation is associated with increased resting energy expenditure. The combination of these two results in further energy requirements to meet this metabolic cost. Interestingly, however, total energy expenditure is not increased in people with CF, though this appears to be due to a reduction in exercise to maintain total energy expenditure similar to an age- and sex-matched control group of healthy controls. Resting energy expenditure increases at the time of pulmonary exacerbations and seems to be related to systemic markers of inflammation.[5,14] Many people with CF lose weight in the period of time coming up to pulmonary exacerbations, which they regain following treatment. It is hard to dissect out which of the multidisciplinary inputs during treatment of exacerbation makes a difference, but there is an associated reduction in energy expenditure during treatment of an exacerbation, and it is likely that the reduction in systemic inflammation is an important factor in weight gain. Anorexia is also common in severe disease and with pulmonary exacerbations. Anorexia may be mediated by inflammatory cytokines. This may significantly reduce energy intake and consequently cause weight loss. There may also be some abnormalities of intermediary metabolism during exercise, which may further add to the hypercatabolic state in people with CF.
There is a well-recognized relationship between nutritional status and lung function and this is likely to be explained by the combination of effects of oxygen costs of breathing and systemic inflammation. Careful management of CF lung disease is therefore a critically important part of nutritional management. Pulmonary exacerbations should be treated promptly and aggressively and disease-modifying therapies such as DNase, azithromycin, and nebulized antibiotics should be optimized to reduce chronic inflammation. DNase therapy and azithromycin have both, in randomized, controlled studies, resulted in small but potentially significant increases in body weight.[19,20]
Appetite-enhancing and anabolic agents have been used to manage undernutrition in CF. The abnormalities in intermediary metabolism result in a net catabolic state and anabolic agent such as insulin, insulin-like growth factor 1, and growth hormone have been shown to have a small impact on weight gain and growth hormone also on growth.[21,22] Other anabolic agents such as megestrol acetate have also been shown to improve weight gain but have significant side effects, and there are insufficient clinical trials to justify their widespread use.
Cystic Fibrosis?Related Bone Disease
CF-related bone disease (CFRBD) is an important systemic complication. CFRBD is very similar to osteoporosis with low bone mass and microarchitectural deterioration of bone tissue. This leads to an increase in bone fragility and increases the susceptibility to fracture. Several studies have now demonstrated a significant increase in risk, particularly in adults with CF, to fracture.[25,26] Most centers now undertake routine screening for CFRBD. The definition of osteoporosis with regard to bone mineral density is energy x-ray absorptiometry greater than or equal to 2.5 standard deviations (SD) below young adult means (T score). However, because this is only being validated in postmenopausal women. In CF, a Z score of less than or equal to -2 SD below the age and matched reference value is considered to indicate significant bone disease. Bone mineral density (BMD) is usually normal in children and seems to begin to fall during adolescence. There is probably reduced bone accretion during adolescence in people with CF, and in adult populations up to 30% have a Z score less than or equal to 2.
In general the prevalence of CF-related bone disease is reported as at around 30 to 35% of adults.[28?30] The prevalence is lower in children and overall the studies would suggest that children should have normal or near normal BMD if lung function and nutrition are maintained.
The pathophysiology of low BMD in people with CF has not been entirely determined but there is evidence of increased bone absorption and decreased bone formation.[32,33] Several factors have been shown to be related to the development of CFRBD. Reduced lung function and pulmonary exacerbations are important factors as are glucocorticoid usage, body mass index, CF-related diabetes mellitus, and CF-related liver disease. Indications of increased inflammation such as C-reactive protein concentrations have been consistently demonstrated as being important factors.[28,29] Osteoclasts express CFTR, and several recent studies suggest that CFTR dysfunction contributes to the development of CFRBD.[34?36] Other well-known causes of reduced BMD, such as low participation in exercise and smoking, may also be factors in some individuals.
It is difficult to determine the relative importance of many of these risk factors, but evidence increasingly points to systemic inflammation as being one of the most important drivers of low BMD. Proinflammatory cytokines such as interleukin (IL)-1, IL-6, and tumor necrosis factor-α stimulate osteoclast numbers.[37,38] Several studies have shown increased bone turnover and increased osteoclast progenitor cells in the systemic circulation, indicating that inflammation is stimulating bone resorption. A further study demonstrated a longerterm relationship for increased IL-6 levels and change over 12 months in BMD. This was attributed to systemic inflammation's being a very important factor in the development of CFRBD.
Several interventions are likely to be very beneficial in preventing the development of CFRBD. Aggressive treatment of lung disease, as already noted, for nutritional interventions is very important. If oral and inhaled glucocorticosteroids must be used, the physician should be careful to titrate to the lowest possible dose because these can have an effect on bone metabolism. Appropriate calcium and vitamin D supplementation is also recommended, though there is no direct evidence to support a protective role in people with CF. Calcium is most effective when supplied as part of the normal diet, and in any case, CF patients should be encouraged to drink milk and other calcium drinks regularly. Vitamin K may also be an important cofactor in maintaining normal BMD. In deficient patients it may be useful to supplement this vitamin but there is no direct evidence to support this. Those with hormonal abnormalities of sex hormones such as low testosterone levels should have these appropriately investigated and treated. Regular physical activity is of benefit in CF for maintenance of general health status. In particular, weightbearing exercise should be encouraged as a useful preventative strategy for CFRBD. CFRBD is a particular problem post?lung transplantation and in some centers a low BMD is considered to be a factor contraindicating transplantation. It is very important therefore to prevent this condition because it can have an impact on transplant decision making.
Once reduced BMD has occurred, further deterioration can be attenuated by bisphosphonate treatment.[44?46] This approach has not been subject to a large randomized, controlled trial but smaller studies have demonstrated an increase in BMD following treatment. Several large controlled trials are under way to determine the exact place of bisphosphonates in the treatment of CF-related bone disease.
Systemic Vasculitis and Cystic Fibrosis Arthropathy
Systemic vasculitis and arthropathy are uncommon complications of CF but can often present considerable challenges in management. Recurrent episodes of distal purpuric vasculitic rash are well described and are probably related again to systemic infection with immune complex depredation in skin capillaries. Autoantibodies to bactericidal permeability?increasing protein (BPI) antibodies has been suggested as important in the pathophysiology of CF arthropathy. This is usually self-limiting, but if troublesome, generally responds to treatment with nonsteroidal anti-inflammatory agents or oral corticosteroids.
The cause of CF arthropathy and arthritis is not determined. They are generally thought to be either an immune complex or antibody response to connective tissue. Arthropathy occurs in a small proportion of people with CF but often has a very negative impact on quality of life, and when it develops into a full arthropathy, it is very troublesome. The main cause is likely systemic inflammation secondary to lung inflammation and infection. Again the best approach to prevention of both of these systemic conditions is to maintain good pulmonary function.
Cystic Fibrosis?Related Diabetes Mellitus
CF-related diabetes mellitus (CFRD) is an increasingly common systemic complication of CF. It is rare in children under 10 years but increases with age, occurring in up to 24% of patients aged 20 years and 74% of those over 30 years. CFRD is defined according to World Health Organization (WHO) criteria ( Table 2 ). The cause of CFRD is multifactorial. Pancreatic fibrosis due to inflammation secondary to obstruction of pancreatic ducts eventually involves pancreatic islet cells. There may also be an intrinsic functional abnormality in CF islet cells.[52,53] Insulinopenia is a key feature of CFRD and results from the destruction of islet cells. There are, however, other changes in intermediary metabolism that increase insulin resistance. Their may be some intrinsic metabolic adaptations that cause this, but systemic inflammation, again, plays a role in increasing insulin resistance (Fig. 2). This is not fully understood in CFRD but the counterregulatory mechanisms of increased sympathetic nervous system activity and cytokine release are almost certainly driven by the sustained inflammatory processes occurring in the lung.
There are currently no strategies known to prevent the development of CFRD. Reducing lung inflammation will decrease insulin resistance and could be a useful intervention to delay the onset of CFRD. It is important to screen for this condition in all adults with CF. There has been considerable debate as to the best method for such screening; annual glucose tolerance testing seems to be the most sensitive and specific.[54,56] Fasting blood glucose and HbA1c have too many false-negatives to be sufficiently reliable. There are some data to suggest that pulmonary function may decline in the few years prior to the development of CFRD. Any patient whose lung function becomes unstable, even in the absence of any symptoms of diabetes mellitus, should also have a glucose tolerance test. Diabetes has been associated with poorer outcome in people with CF, but it is not clear if correction of the insulinopenia and the successful achievement of good diabetes control alter prognosis. Females with CF seem to be particularly vulnerable to the impact of diabetes, with an even greater impact on prognosis. Home monitoring has been reported to be valuable in the diagnosis of diabetes and glucose intolerance in non-CF and CF diabetes. These studies indicate that glucose intolerance is more common than suspected in CF (Fig. 3).
Treatment of CFRD in general should aim to maintain nutrition with a high-energy diet and matching the insulin required to sustain normal blood glucose control. This is usually best achieved using a combination of long- and short-acting insulin analogs. It is very important that high energy is not restricted but that the insulin dose is matched to energy requirements. It is important that the management of diabetes is considered in people with CF who are having large energy intakes. This particularly applies to those who are feeding using a percutaneous gastrostomy tube. In this situation, blood glucose should be monitored closely when tube feeding is initiated and checked regularly subsequently.
Cystic Fibrosis?Related Liver Disease
CF-related liver disease (CFLD) occurs in up to 30% of people with CF.[61,62] However, it is only a significant clinical problem in a minority of individuals. For most there is an abnormality of liver function tests and in some of these, some fatty changes in the liver. In a minority of patients, cirrhosis develops with secondary pulmonary portal hypertension. The pathophysiology of the condition is related to obstruction of small biliary calculi and it is likely that modifier genes in addition to CFTR dysfunction play an important part in this process.[6,63,64] Screening for liver disease is taken in most CF centers with annual assessment of liver transaminases, gamma glutamyl transferase (γ GT), and alkaline phosphatase. Many centers also undertake regular ultrasound scanning, though there is no evidence that this allows for early detection or intervention with an effective therapy to prevent liver disease.
There are some studies that have investigated ursodeoxycholic acid as treatment for CF liver disease and some advocate its use to prevent the development of significant cirrhosis.[63,65?67] Ursodeoxycholic acid has been demonstrated to be beneficial in primary biliary cirrhosis; however, similar benefits have not been demonstrated in CF-related liver disease. Studies have demonstrated some improvement in liver function tests and one study suggests a reduction in hepatic fibrosis using liver biopsy. However, no studies have demonstrated any significant clinical benefit from the use of ursodeoxycholic acid.
For those people who develop liver cirrhosis and portal hypertension, regular endoscopy is indicated to prevent bleeding from esophageal varices. Depending on the extent of the varices, endoscopy is undertaken every 6 months, annually, or every 2 years.[65,69] Any varices identified are banded. In some cases a decompressing shunt may be indicated. People with CF who develop hepatic decompensation should be considered for liver transplantation. However, the development of liver failure can be rapidly fatal and it is possible that earlier intervention, for example, when there is severe portal hypertension, might be a better time to consider liver transplantation. A few individuals have combined liver and lung transplantation, though this is technically challenging and in general is not associated with as good an outcome as either procedure performed alone.
Patients with CF and pancreatic sufficiency have an increased risk of developing acute pancreatitis, and it is increasingly appreciated that it can be a presenting problem. This is predominantly a problem in individuals with milder CFTR mutations and there has been a suggestion that there may be modifier genes associated with the development of CF-related pancreatitis.[71?73] This is usually mild and not associated with systemic inflammatory response syndrome (SIRS). Cases of pancreatitis in the F508 homozygote have been described, but these are usually not severe and imply the preservation of some normal pancreatic tissue. No interventions have been shown to prevent pancreatitis. Idiopathic pancreatitis is associated with CFTR mutations and all such patients should be screened for CF.
Vitamins and Trace Elements
Fat-soluble vitamin deficiency is common in people with CF. However, it must be noted that low circulating levels, particularly of vitamin A, do not necessarily indicate tissue deficiency. Most CF centers measure at least vitamins A, D, and E annually and supplement appropriately with oral replacement. Vitamin deficiency rarely causes clinical deficiency syndromes though eye problems with night blindness and conjunctival keratinization have been demonstrated in individuals with low vitamin A concentrations.[6,76] Neurological complications with peripheral neuropathy have also been demonstrated in vitamin E?deficient patients. Both vitamin A and E have significant antioxidant functions and may be important in the inflammatory response to infection.[78,79] Vitamin D deficiency is common, particularly in northwestern Europe during the winter months, and may contribute to the development of CF-related bone disease.
Vitamin K metabolism is also abnormal in CF and may have several significant consequences if there is a deficiency. Vitamin K is important in maintaining the normal blood clotting cascade. This is particularly important in patients with significant liver disease and in those who develop hemoptysis. Many CF centers annually check prothrombin time to assess clotting status. However, this is an insensitive measurement of clotting. A better way to assess vitamin K deficiency is the measurement of protein induced by vitamin K absence or antagonist II (PIVKA-II). However, this assay is not widely available and is also very expensive. Before supplementation with vitamin K up to 80% of people with CF have abnormally elevated PIVKA-II levels; this number can be halved with supplementation. Even in patients with CFLD, PIVKA levels could be reduced by 50%. Vitamin K may also have an important role in maintaining normal bone health and it is prudent to consider supplementation in all people with CF.
Although there are no convincing studies relating to outcomes, there is a suggestion that vitamin-deficient patients have more frequent pulmonary exacerbations and lower lung function. Vitamins A, C, and E are important in antioxidant pathways, and deficiency may impair cellular responses to oxidative stress and contribute to cell damage. This may not be a direct cause and effect but it is logical to maintain normal-range vitamin levels in people with CF.
Possible Role of Systemic Antiinflammatory Treatments
Systemic anti-inflammatory therapy with monoclonal antibodies to TNF is now of proven value in rheumatoid arthritis, psoriatic arthritis, and inflammatory bowel disease. These may also be of benefit in refractory asthma. Monoclonal antibodies to tumor necrosis factor- α improve local inflammatory disease and also effectively modulate systemic inflammation. It is possible that anti?tumor necrosis factor treatments or other systemic antiinflammatories will be beneficial in people with CF. It is possible they may improve lung inflammation and so reduce lung injury. They may also be beneficial in stopping the development of CF-related undernutrition and bone disease and in reducing insulin resistance. A recent study in early rheumatoid arthritis demonstrated significant improvement in fat free mass. It is possible that inflammatory fibrosis in the liver and pancreas could be modulated by anti-inflammatory or antifibrotic agents. Better understanding of the inflammatory pathophysiology in CF and its systemic consequences will be important to help identify appropriate drug targets.
Multisystem complications of CF are common. Most of these can be explained on the basis of epithelial cell dysfunction of CFTR or the effect of chronic inflammation or both. Prevention of multisystem complications requires attention to the details of treatment specific to the organ disease and the aggressive treatment of lung disease to ensure that pulmonary and consequently systemic inflammation are kept to a minimum.
Table 1. Causes of the Malnutrition in Cystic Fibrosis
Table 2. Comparison of 1999 World Health Organization and 2003 American Diabetic Association Diagnostic Criteria
Pediatric Pulmonology; Guest Editors, Bruce K. Rubin, M.D., Andrew Bush, M.D.
J Stuart Elborn, M.D., Respiratory Medicine Group, QUB and Northern Ireland Adult Cystic Fibrosis Centre, City Hospital, Lisburn Rd., Belfast, BT9 7AB, Ireland (e-mail: firstname.lastname@example.org ).
J. Stuart Elborn, M.D.1,2
1Respiratory Medicine Group, QUB
2Northern Ireland Adult Cystic Fibrosis Centre, BCH.