Background: The association between emphysema and weight loss is well known. Severe [[alpha].sub.1]-antitrypsin deficiency is an important risk factor for the development of emphysema.
Study objective: To study nutritional status and muscle strength in patients with severe [[alpha].sub.1]-antitrypsin deficiency and emphysema.
Methods: Fifteen [[alpha].sub.1]-antitrypsin-deficient patients with emphysema (7 men) and 18 healthy control subjects (9 men) were included in the study. Total body protein (TBP) was measured by in vivo neutron activation analysis of nitrogen. Lean body mass (LBM) was estimated from measurement of total body potassium. In analogy with body mass index (BMI), TBP index and LBM index were calculated as TBP/height squared and LBM/height squared, respectively. Respiratory muscle strength was studied by maximal inspiratory pressure (PImax) and maximal expiratory pressure (PEmax), and skeletal muscle strength by handgrip test. Plasma albumin, transthyretin, and retinol-binding protein concentrations were analyzed as biochemical markers of nutritional status.
Results: In the [[alpha].sub.1]-antitrypsin-deficient individuals, lung function test results were consistent with severe chronic airway obstruction, whereas the healthy control subjects had normal lung function. No significant differences were found in age, body weight, or BMI between the groups. TBP (p < 0.05), TBP index (p < 0,001), LBM index (p < 0.05), and plasma concentration of transthyretin (p < 0.01) were significantly lower in the patients than in the control subjects. There was a significant correlation between TBP and LBM (p < 0.001), and between TBP and body weight (p < 0.001). In the male subgroup, PImax (p < 0.05) and PEmax (p < 0.05) were significantly lower in the patients than in the control subjects. In the female subgroup, handgrip strength was Significantly lower in the patients than in the control subjects (p < 0.05). Body weight was significantly correlated with handgrip test (p < 0.05) in the male patients. In the female patients, body weight was significantly correlated with PImax (p < 0.05), LBM with PEmax (p < 0.05), and LBM with handgrip test (p < 0.01).
Conclusion: Reduced TBP and plasma transthyretin concentration in [[alpha].sub.1]-antitrypsin-deficient patients with emphysema may indicate early signs of malnutrition.
Key words: [[alpha].sub.1]-antitrypsin deficiency; body protein; emphysema; malnutrition; muscle strength
Abbreviations: BMI = body mass index; IVNAA = in vivo neutron activation analysis of nitrogen; LBM = lean body mass; PEmax = maximal expiratory pressure; PImax = maximal inspiratory pressure; RBP = retinol-binding protein; RV = residual volume; TBP = total body protein; TLC = total lung capacity; TLCO = transfer factor for carbon monoxide; VC = vital capacity
The association between COPD and weight loss is well known. (1) Previous studies (2,3) have shown that while body weight is poorly correlated to lung function impairment, weight loss is associated with poor prognosis. Weight loss is especially characteristic in patients with COPD with pure emphysema (characterized as "pink puffers"), while the patients with mainly chronic bronchitis ("blue bloaters") maintain essentially normal body weight in late stages of the disease. (4) Several studies (1-4) have shown malnutrition and decreased body weight in patients with COPD. Muscle wasting is an important consequence of malnutrition. (5-8) Reduced respiratory and forearm muscle strength have been described as functional correlates to muscle wasting. (5,6)
In recent years, there has been increasing interest in rehabilitation and nutritional support of patients with COPD. Such interventions have positive effects on their quality of life and disease status. (5,9) Nutritional support is recommended in patients suffering from involuntary weight loss. (10) Hepatic secretory proteins, such as albumin, prealbumin (ie, transthyretin), and retinol-binding protein (RBP) have been considered as markers of visceral protein stores. Changes in the plasma concentration of these proteins may reflect changes in nutritional status. (1,11) If malnutrition could be detected in patients with COPD while they still have normal body weight, weight loss might be prevented by nutritional support. Sensitive methods to detect early signs of malnutrition are therefore needed.
Severe [[alpha].sub.1]-antitrypsin deficiency is a hereditary risk factor for development of emphysema, especially in smokers. (12,13) Low body mass index (BMI) in patients with severe [[alpha].sub.1]-antitrypsin deficiency in dicates poor survival, (14) but to our knowledge, no studies on body composition in [[alpha].sub.1]-antitrypsin-deficient patients with emphysema have been published previously. The aim of the present study was to investigate nutritional status in patients with severe [[alpha].sub.1]-antitrypsin deficiency and emphysema by measurement of total body protein (TBP), lean body mass (LBM), muscle strength, and biochemical markers of malnutrition.
MATERIALS AND METHODS
Patients and Healthy Control Subjects
The patient group consisted of seven male and eight female patients with severe [[alpha].sub.1]-antitrypsin deficiency and emphysema. In addition to the PiZZ phenotype, the inclusion criteria were FE[V.sub.1] < 50% of the predicted value and FE[V.sub.1]/vital capacity (VC) ratio < 50%. All individuals with [[alpha].sub.1]-antitrypsin deficiency having visited the Department of Pulmonary Medicine, Malmo University Hospital, and meeting the inclusion criteria, were invited to participate in the study. One male patient was a current smoker; four men and seven women had stopped smoking 4 to 17 years prior to the study. Two men and one woman had never smoked. The exclusion criteria included the following: any disease other than COPD influencing nutritional status (eg, thyroid gland dysfunction, malignancy, connective tissue disease, diabetes mellitus), neuromuscular disease, severe left heart failure, hypoxemia with Pa[O.sub.2] < 8.0 kPa, continuous oxygen therapy, and treatment with diuretics or oral corticosteroids.
All patients were in a clinically stable condition without acute exacerbation of COPD for at least 4 weeks. All patients were treated with inhaled and/or oral bronchodilators and inhaled corticosteroids. Four male and six female patients were treated with theophylline.
The group of healthy control subjects included nine men and nine women. All were in excellent health and had normal lung function. Four healthy men and two women were ex-smokers for 15 to 24 years; five men and seven women had never smoked. One healthy control subject was married to one of the patients; the other control subjects were recruited from the hospital staff and their relatives. All study participants gave their informed consent to take part in the study, which was approved by the research ethics committee of Lund University.
Measurement of Body Weight, Height, and Biochemical Analysis
Body weight of all study participants was measured on the same scale. The subjects wore underwear only and had emptied their bladders immediately before the measurement. Body height was determined to the nearest 1.0 cm with subjects standing barefoot. BMI was calculated as body weight/height squared. Venous blood samples were analyzed by standard methods for hemoglobin, hematocrit, plasma albumin, transthyretin (prealbumin), and RBP. In the patients, serum aspartate aminotransferase, serum alanine aminotransferase, and serum alkaline phosphatase were also analyzed. The PiZZ phenotypes were identified by isoelectric focusing. (15)
Lung Function Tests
Dynamic spirometry was performed with a bellow spirometer. Static lung volumes, ie, total lung capacity (TLC) and residual volume (RV), were measured with nitrogen dilution technique. The transfer factor for carbon monoxide (TLCO) was measured with the single-breath technique. The lung function test results are expressed as a percentage of predicted values according to Berglund and coworkers, (16) Grimby and Soderholm (17) (lung volumes), and Quanjer (18) (TLCO). The FE[V.sub.1]/VC ratio was expressed as a percentage. Arterial blood was sampled anaerobically from the radial artery, and the blood was immediately analyzed for Pa[O.sub.2], PaC[O.sub.2], and pH with a blood gas analyzer.
Measurement of TBP
The total body content of protein was measured with prompt gamma in vivo neutron activation analysis of nitrogen (IVNAA), using a measuring system that has been described earlier. (19) The patient was lying on a movable couch (aluminum and wood) and was scanned with a vertically collimated neutron beam from a [sup.252]Cf source (approximately 35 [micro]g) positioned below the patient.
The neutrons were thermalized inside the body, and some were captured in the [sup.14]N(n,[gamma])[sup.15]N reaction. Prompt gamma rays, 10.8 megaelectron volts, were emitted. By moving the couch, it was possible to scan the whole body to measure total body nitrogen. The patients were measured for 40 min, giving a whole body mean equivalent dose of 0.25 millisieverts (using a radiation weighting factor of 20).
Four large NaI(Tl) detectors (diameter, 125 mm; thickness, 100 mm) were placed around the couch to detect the 10.8-megaelectron volt gamma rays. Each detector was connected to a separate analog-to-digital converter. To reduce the signal from scattered neutrons and low-energy gamma rays in the detectors, a shield of polythene/polyester and a 3-mm lead shield were used.
The sensitivity of the system was checked in conjunction with all patient measurements against a solid phantom simulating the human trunk and containing a known concentration of nitrogen. The height and weight of the patient were parameters needed to calculate the cross-sectional area of the trunk, and this area was used to correct the signals from the detectors for each patient. Four phantoms shaped as elliptical cylinders simulating the trunk were built to study how the system responded to patients of different sizes. The detector signal corrected in this way is proportional to the number of nitrogen atoms in the body. Nitrogen is mainly present in the body in the form of protein, and a measurement of nitrogen will give direct information of the protein content because of an almost-constant relation between body protein and nitrogen. (20) On an average, 1 g of nitrogen is equivalent to 6.25 g of protein. The result of the measurement was expressed as the TBP mass. In analog w with BMI, TBP index was calculated as TBP/height squared. The reproducibility of the IVNAA system by duplicate measurements in 17 healthy volunteers was 5% (1 SD). (19)
Measurement of Body Potassium and Estimation of LBM
Total body potassium was measured in the Malmo whole-body counter using two opposite NaI(Tl) detectors. Each detector was 12.7 cm in diameter and 10 cm thick. The gap between the detectors was 40 cm. The subject was placed in the supine position on a bed between the detectors. The detectors started to scan at the level of the jugular fossa and continued 156 cm in the caudal direction. The measuring time was 1,000 s, For each subject, a calibration measurement was performed on a humanlike phantom, constructed from plastic bottles, (21) containing KCl solution of known volume, and concentration. The net count rate from [sup.40]K in the energy interval 1.30 to 1.55 megaelectron volts was measured.
The sensitivity of the system was of the order of 10 counts/s/kg of potassium in the human body. A correction for the difference in body weight between patients and phantoms was applied. Assuming a potassium concentration of 65 mmol/kg LBM for male subjects and 58 mmol/kg LBM for female subjects, LBM was estimated. LBM index was defined as LBM/height squared.
Respiratory/and Skeletal Muscle Strength
Respiratory muscle strength was assessed by measurement of mouth pressures at maximal static inspiratory and expiratory efforts from RV and TLC, respectively (maximal ,inspiratory pressure [PImax] and maximal expiratory pressure [PEmax]) against an obstructed mouthpiece with a small leak to minimize oral pressure artifacts. (22) The skeletal muscle function was assessed by measurement of handgrip strength. The Martin Vigorimeter (Gebrtider Martin; Tuttlingen, Germany) was used. A rubber ball was compressed in the hand, and the pressure within the ball was recorded. The diameter of the ball was 6 cm for men and 5 cm for women. The best of three efforts for each hand was determined. The results of grip strength in the dominant hand were analyzed. All handgrip strength tests were supervised by the same technician.
The results are presented as means (SD) unless otherwise indicated. Student t test was used to compare the continuous variables between the groups. Standard least-squares linear regression analysis was used to compare two continuous variables. Values of p < 0.05 were considered significant.
Anthropometric and Lung Function Variables
Age, height, and BMI did not differ significantly between the patients and the control subjects. The mean body weight was somewhat lower in the male patients than in the control subjects, but the difference was not significant (Table 1).
In the [[alpha].sub.1]-antitrypsin-deficient individuals, lung function test results were consistent with severe chronic airway obstruction with decreased FE[V.sub.1] and FE[V.sub.1]/VC ratio, elevated RV, and low TLCO, whereas the healthy control subjects had normal lung function (Table 2). FE[V.sub.1] and TLCO were lower in the female patients than in the male patients, but the differences were not significant.
According to the inclusion criteria, arterial blood gas analysis showed a Pa[O.sub.2] > 8.0 kPa in all study participants. However, both Pa[O.sub.2] and PaC[O.sub.2] were significantly lower in the patients than in the control subjects (Table 2).
TBP and LBM
In the whole study group, the mean TBP was 11.0 kg (SD, 2.4 kg) in the patients and 12.7 kg (SD, 2.1 kg) in the control subjects (p < 0.05; Fig 1, top). The mean TBP index was 3.7 kg/[m.sup.2] (SD, 0.5 kg/[m.sup.2]) in the patients and 4.3 kg/[m.sup.2] (SD, 0.4 kg/[m.sup.2] in the control group (p < 0.001; Fig 1, bottom). The differences Were also significant in both gender subgroups (Table 1). The mean LBM was also lower in the patients than in the control group, but the difference was not significant: 45.6 kg (SD, 11.5 kg) vs 51.0 kg (SD, 9.9 kg), respectively. The mean LBM index was 15.3 kg/[m.sup.2] (SD 2.4 kg/[m.sup.2]) in the patients and 17.1 kg/[m.sup.2] (SD, 1.8 kg/[m.sup.2]) in the control group (p < 0.05). The difference was significant also in the male subgroup (p < 0.05; Table 1). TBP was significantly correlated both with LBM (p < 0.001) [Fig 2, top] and with body weight (p < 0.001) [Fig 2, bottom]).
[FIGURES 1-2 OMITTED]
The mean PImax was 91 cm [H.sub.2]O (SD, 33 cm [H.sub.2]O) in the patients and 111 cm [H.sub.2]O (SD, 29 cm [H.sub.2]O) in the control group (p = 0.07). The mean PEmax was 123 cm [H.sub.2]O (SD, 30 cm [H.sub.2]O) in the patients and 148 cm [H.sub.2]O (SD, 44 cm [H.sub.2]O) in the control subjects (p = 0.08). In the male subgroup, the mean PImax (p < 0.05) and PEmax (p < 0.05) were significantly lower in the patients than in the control group, while the differences in the female subgroup were not significant (Table 1).
In the series as a whole, no difference was found in the mean handgrip strength between the patients and the control subjects. In the female subgroup, the mean handgrip strength was significantly lower in the patients than in the control group (p < 0.05; Table 1).
Correlation of Body Composition to Muscle Strength and Lung Function
Correlations of body weight, BMI, TBP, and LBM to PImax, PEmax, and handgrip strength were analyzed separately in men and women. In the male patient group, a significant correlation was found between body weight and handgrip test (r = 0.81, p < 0.05), while no significant correlations were found in the male control group. In the female patient group, body weight was significantly correlated with handgrip test (r = 0.73, p < 0.05), TBP was significantly correlated with PImax (r = 0.79, p < 0.05), and LBM was significantly correlated with PEmax (r = 0.77, p < 0.05), and with handgrip test (r = 0.89, p < 0.01). In the female control group, body weight was negatively correlated with PEmax (r = - 0.80, p < 0.05).
In the female patients, there was a significant correlation between LBM and TLCO (r = 0.73, p < 0.05). No significant relationships were found between other lung function test results and TBP or LBM.
According to the inclusion criteria, all the patients had the PiZZ phenotype, while the control subjects had the PiMM phenotype. Serum aspartate amino-transferase, serum alanine aminotransferase, and serum alkaline phosphatase were within the normal range in all [[alpha].sub.1]-antitrypsin-deficient individuals. The mean hemoglobin concentration was 152 g/L (SD, 14 g/L) in the patients and 140 g/L (SD, 10 g/L) in the control subjects (p < 0.01). The mean hematocrit level was 43% (SD, 3%) in the patients and 40% (SD, 2%) in the control subjects (p < 0.01). The mean plasma albumin and RBP concentrations were similar in the patients and in the control group. The mean transthyretin concentration was 0.28 g/L (SD, 0.08 g/L) in the patients and 0.37 g/L (SD, 0.06 g/L) in the control subjects (p < 0.01). The difference was also significant in the male (p < 0.01) and female (p < 0.05) subgroups (Table 1). No significant correlations were found between transthyretin concentration and respiratory or skeletal muscle strength.
Weight loss is an indicator of malnutrition in patients with COPD. In this study, we found significantly lower TBP in patients with emphysema and severe [[alpha].sub.1]-antitrypsin deficiency as compared with healthy control subjects, while no significant differences were found in body weight and BMI. The results may indicate early signs of malnutrition in [[alpha].sub.1]-antitrypsin-deficient patients with emphysema.
We are not aware that any studies of body composition and muscle strength in [[alpha].sub.1]-antitrypsin--deficient patients have been published previously. Seersholm (14) reported increased mortality in [[alpha].sub.1]-antitrypsin--deficient individuals with low BMI (BMI < 20) in an analysis of data from the Danish [[alpha].sub.1]-antitrypsin-deficiency registry, but body composition or muscle strength were not studied.
While treatment with bronchodilators has only limited effect on chronic airway obstruction, rehabilitation has become a standard in care of patients with COPD. Intervention against malnutrition is recommended in patients with involuntary weight loss. (10) Identification of early signs of malnutrition could make it possible, at an early stage of the disease, to select patients who may benefit by nutritional support and other rehabilitation. Thereby it could be possible to prevent advanced malnutrition.
Weight loss is especially characteristic of COPD patients with pure emphysema (pink-puffer type). (4) The obstructive lung disease in [[alpha].sub.1]-antitrypsin--deficient individuals is characteristically and predominantly pure emphysema rather than chronic bronchitis, which explains the well-preserved blood gas tensions despite severe chronic airflow obstruction in our patients (Table 2). However, we did not take body weight into consideration at inclusion, and the patients had essentially normal body weight and BMI (Table 1). The only inclusion criteria were severe chronic airflow obstruction and the PiZZ phenotype. Only 2 of 15 patients had a BMI < 20. We tested whether these two patients influenced the results, and excluded them from the statistical analyses. TBP (p < 0.05) and TBP index (p < 0.01) were still significantly lower in the patient group than in the control group (data not shown), indicating that protein stores were decreased even in patients with emphysema and normal body weight, which implies malnutrition. To avoid confounding factors influencing body weight, we excluded patients who were treated with diuretics or oral corticosteroids, while inhaled corticosteroids were allowed.
In assessment of body composition, we used two different methods: measurement of TBP and measurement of total body potassium, which allows an assessment of LBM. IVNAA has proven to be a sensitive and accurate method to measure TBP. (23) In IVNAA, no patient preparation is needed, and the measurement can be performed ambulatory. The only requirement is that the patient be able to lie in a supine position for 40 min, which is generally possible for patients with emphysema who are asymptomatic at rest. In contrast to measurement of 24-h urinary excretion of creatinine, which has been used to estimate body muscle mass in patients with emphysema, (1,24) the results are not influenced by dietary intake or other external factors.
No significant differences were found in body weight or BMI between the patients and the control subjects, while TBP was significantly decreased in the patients (Fig 1, top; Table 1). Our results indicate that IVNAA is a sensitive method to assess nutritional status in patients with emphysema. TBP was also significantly correlated to LBM (Fig 2, top) and to body weight (Fig 2, bottom).
Because there is a gender difference in body weight and muscle mass, our results were analyzed separately in men and women. In both gender subgroups, TBP and TBP index were significantly lower in the patients than in the control subjects (Table 1), while no significant differences were found in body weight and BMI.
Respiratory muscle dysfunction is considered a sign of malnutrition in underweight patients with COPD. (5) We found decreased PImax and PEmax in our patients, although the differences were statistically significant only in the male subgroup (Table 1). These findings support our other results indicating the presence of malnutrition and muscle wasting. We can, however, not exclude that hyperinflation per se contributed to respiratory muscle dysfunction.
Skeletal muscle dysfunction may be regarded as another sign of malnutrition, which has been found in underweight patients with emphysema. (10) We measured skeletal muscle function by handgrip strength test, which is easy to carry out. We found significantly decreased handgrip strength test only in the female patients (Table 1). It is possible that skeletal muscle dysfunction appears in a later stage of malnutrition than respiratory muscle dysfunction. Skeletal muscle dysfunction may also occur earlier in the lower extremities (quadriceps function) than in the upper extremities. (10)
Lack of statistically significant difference in skeletal muscle strength in the female subgroup, and in respiratory muscle strength in the male subgroup, may also be caused by the limited number of study participants in our study. The power of the statistical analyses may therefore be low, and false-negative results cannot be excluded. Therefore, larger studies are needed for confirmation of our results.
As biochemical markers of malnutrition, we analyzed plasma albumin, transthyretin, and RBP. Plasma transthyretin concentration was significantly decreased in the patients, whereas plasma albumin and RBP concentrations were similar in both groups (Table 1). Plasma transthyretin concentration is considered a more sensitive marker of malnutrition than plasma albumin concentration. (1) Therefore, decreased transthyretin concentration in the [[alpha].sub.1]-antitrypsin-deficient patients with emphysema is in agreement with our other findings and may be an indicator of malnutrition. The advantage of analyzing plasma proteins in assessment of nutritional status is that their concentrations are not influenced by body weight. The disadvantage is that the concentration of plasma proteins may be influenced by other clinical conditions than malnutrition. (11) Thus, the plasma proteins mentioned above are synthesized in the liver, and their concentration may be influenced by concomitant liver disease. Liver cirrhosis is a well-known complication in elderly individuals with [[alpha].sub.1]-antitrypsin deficiency. (25) None of the patients in our study had clinical or laboratory signs of liver disease, but liver biopsies had hot been performed.
Decreased plasma transthyretin concentration has previously been reported in individuals with [[alpha].sub.1]-antitrypsin deficiency. In 1979, Premachandra and Yu (26) reported prealbumin (transthyretin) deficiency in two individuals with [[alpha].sub.1]-antitrypsin deficiency. In 1980, Felding and coworkers (27) compared prealbumin and RBP concentrations in 19 PiZZ phenotype, 20 PiMZ phenotype, and 26 healthy (PiMM phenotype) individuals. The mean prealbumin concentration was slightly lower in the [[alpha].sub.1]-antitrypsin-deficient individuals than in the other groups. One individual with [[alpha].sub.1]-antitrypsin deficiency and emphysema showed very low concentrations Of prealbumin and RBP. (27) In our study, none of the individuals with [[alpha].sub.1]-antitrypsin deficiency had an extremely low plasma transthyretin concentration (range, 0.16 to 0.48 mg/L). It remains unclear whether our findings of decreased transthyretin concentration indicate malnutrition in [[alpha].sub.1]-antitrypsin-deficient patients with emphysema. Further studies are needed to elucidate if our findings are specific for severe [[alpha].sub.1]-antitrypsin deficiency.
The patients with [[alpha].sub.1]-antitrypsin deficiency and emphysema in this study had essentially normal body weight. Therefore, our results of reduced TBP and plasma transthyretin concentration may indicate early signs of malnutrition.
ACKNOWLEDGMENT: We are grateful to Mrs. Karin Evby for technical assistance.
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* From the Departments of Lung Medicine (Dr. Piitulainen), Radiation Physics (Drs. Areberg, Linden, and Prof. Mattsson), Medicine (Prof. Eriksson), and Clinical Physiology (Prof. Wollmer), Malmo University Hospital, Malmo, Sweden. This work was supported by grants from Swedish Medical Research Council grant No. 10841, Swedish National Heart-Lung Foundation, Pahlsson's Foundation, and `Forenade Liv' Mutual Group Life Insurance Company, Stockholm, Sweden.
Manuscript received July 16, 2001; revision accepted April 11, 2002.
Correspondence to: Eeva Piitulainen, MD, PhD, Department of Pulmonary Medicine, Malmo University Hospital, SE-205 02 Malmo. Sweden; e-mail: firstname.lastname@example.org
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