L La arrg ge

Copyright ERS Journals Ltd 1995
European Respiratory Journal
ISSN 0903 - 1936
Eur Respir J, 1995, 8, 938–947
DOI: 10.1183/09031936.95.08060938
Printed in UK - all rights reserved
Large lungs and growth hormone:
an increased alveolar number?
P.M. Donnelly, R.R. Grunstein, J.K. Peat, A.J. Woolcock, P.T.P. Bye
Large lungs and growth hormone: an increased alveolar number? P.M. Donnelly, R.R.
Grunstein, J.K. Peat, A.J. Woolcock, P.T.P. Bye. ERS Journals Ltd 1995.
ABSTRACT: Previous physiological studies suggest that increased lung growth in
patients with acromegaly is associated with either a normal or above normal pulmonary transfer factor. These findings can be interpreted to suggest either alveolar hypertrophy or hyperplasia as the mechanism for lung growth in this condition.
Since the ventilated airspaces retain normal elastic properties, we wanted to determine whether the mechanism for lung growth in acromegaly is the result of an
increased alveolar number rather than size.
Measurements of pulmonary distensibility (K) (an index of alveolar size), elastic
recoil, single-breath carbon monoxide transfer factor and carbon monoxide transfer coefficient (KCO), pulmonary capillary blood volume and alveolar membrane
diffusing capacity, together with chest width, were compared in nonsmoking, acromegalic and normal men and women, with and without an increased lung size.
Pulmonary transfer factor was normal for all groups studied, regardless of lung
size. However, KCO was inversely related to total lung capacity (% predicted) for
all subjects and KCO (% predicted) was inversely related to chest width in men.
Pulmonary capillary blood volume (% predicted) was inversely related to total lung
capacity (% predicted) for subjects with large lungs. Pulmonary distensibility (K),
membrane diffusing capacity and elastic recoil were within the normal range.
These findings suggest normal alveolar size, alveolar membrane surface area and
mechanical function in subjects with large lungs. They also suggest that KCO may
not be a reliable guide to the interpretation of the mechanism of lung growth in
individuals with disproportionately large lungs, and may be reduced because not
all the alveoli are perfused. The normal values for pulmonary distensibility found
in all our individuals with large lungs, including acromegalics, suggest that lung
growth has been achieved by an increased alveolar number rather than size. However, morphometric studies of the lungs of nonsmoking, acromegalic subjects without lung disease, are required to substantiate this finding.
Eur Respir J., 1995, 8, 938–947.
The single-breath transfer factor of the lungs for carbon monoxide (TL,CO,sb) is widely used both in clinical
and physiological laboratories as an index of gas exchange
across the alveolar capillary membrane [1]. However,
this test is not always reliable for detecting parenchymal
abnormalities, since uneven distribution of inspired gas,
as occurs in patients with airways disease, will give falsely low values. For this reason, some investigators calculate the transfer coefficient (KCO), by expressing the
observed TL,CO,sb per litre of the alveolar volume (VA)
in which the carbon monoxide is distributed. Using this
approach, any gas exchange abnormality of the lung
parenchyma can be elucidated.
In a study of the possible mechanism(s) for the increased lung growth in acromegalic subjects, BRODY et
al. [2] found increased values for total lung capacity
(TLC), normal elastic recoil and normal specific lung
compliance. Despite an increase in lung size, they found
Dept of Respiratory Medicine and Sleep
Disorders Centre, Royal Prince Alfred
Hospital, Camperdown, NSW, Australia.
Correspondence: P.M. Donnelly
Institute of Respiratory Medicine
Royal Prince Alfred Hospital (RPAH)
Missenden Road
Camperdown NSW 2050
Australia
Keywords: Acromegaly
lung growth
pulmonary capillary blood volume
pulmonary distensibility (K)
transfer factor
Received: January 6 1994
Accepted after revision January 8 1995
normal values for TL,CO,sb and a reduced KCO, which
suggested that the increased size of the lung in acromegaly
resulted from an increase in alveolar size rather than
number.
More recently, O'BRODOVICH et al. [3] studied normal
subjects aged 6–30 yrs, and showed that KCO decreased
with height in the sitting position. They suggested a
gravity dependent decrease in capillary blood volume,
relative to alveolar volume, to explain this finding.
However, increasing subject height did not entirely explain
the decrease in KCO when measured in the supine position, because, in that position, KCO still demonstrated a
small but significant decrease in their subjects. When
adult subjects over 20 yrs of age were removed from the
analysis, a stronger correlation was obtained, which suggested that lung growth per se is characterized by a
decreasing KCO. A similar conclusion can be derived
from the data of BURRI et al. [4].
ALVEOLAR HYPERPLASIA IN LARGE LUNGS ?
In view of the above findings and our own observations that KCO is reduced both in normal and acromegalic subjects with large lungs, we hypothesized that lung
size in acromegaly is achieved through a process of alveolar hyperplasia rather than hypertrophy.
In this study, we have re-examined other possible mechanisms for the increased lung size in subjects with
acromegaly, exploring both transfer factor, pulmonary
distensibility (K), pulmonary capillary blood volume and
membrane diffusing capacity. For comparison, we also
studied the lung function and physical characteristics of
healthy male and female subjects with and without an
increased lung size.
Subjects
Eight male and six female lifelong nonsmoking acromegalic subjects with large lungs were studied. They selfselected from a much larger cohort (n=55) of acromegalics,
the majority of whom were smokers. All subjects used
in the study were lifelong nonsmokers and without history of chronic cough or recurrent respiratory illness.
Ten male and six female control subjects (TLC <110%
pred) and 10 males and 11 females with increased lung
size (TLC >110% pred) of unknown cause were also
studied. They were members of either the medical, technical or student body of our institution, and were initially screened for determination of their lung size (VC,
TLC) and placed in the relevant groups based entirely
on lung size, before any other lung function test had been
performed. The difficulty of finding a sufficient number of individuals with large lungs limited our ability to
match our groups for age.
None of the subjects were engaged in any sort of intensive athletic training, although most of the healthy male
subjects took some form of regular exercise, e.g. running, tennis, basketball, cycling. All subjects were informed
of the experimental requirements prior to attendance and
signed consent forms. All were aware that they could
discontinue testing at any time. The diagnosis of acromegaly was based on the characteristic clinical findings
and an elevation in the fasting serum growth hormone
level measured during an oral glucose tolerance test. All
subjects were out-patients at the time of the study, and
all were in a clinically stable state. None of subjects
chosen for inclusion in this study had significant kyphosis or clinical or radiological evidence of pulmonary
hypertension.
Methods
Height, weight, body composition, and pulmonary function at rest
Anthropometric measurements, including height, weight,
and chest width at TLC measured at the xyphoid process
were obtained. Relative sitting height (RSH) was derived
from an estimation of sitting height divided by standing
height in each subject. Forced vital capacity (FVC) and
939
forced expiratory volume in one second (FEV1) were
measured using a model S Vitalograph bellows spirometer, documented at body temperature and pressure saturated with water vapour (BTPS). TLC and relaxed vital
capacity (VC) were measured in a body plethysmograph
(Gould 2800). Maximal inspiratory (MIP) and maximal
expiratory (MEP) mouth pressures were recorded from
residual volume (RV) and total lung capacity, respectively using a hand held pressure gauge. All of the above
tests have been described in detail previously [5, 6].
Pulmonary distensibility
Pulmonary distensibility (K) and elastic recoil were
estimated according to the methods of COLEBATCH et al.
[7]. Static pressure-volume (P-V) data were generated
during several interrupted deflations from TLC to FRC,
with the subject seated inside an Emerson volume body
plethysmograph. Transpulmonary pressure was measured
using an oesophageal balloon catheter one metre long
(gas volume 0.5–1.0 ml) and a Hewlett Packard differential pressure transducer 267B. After measurement of
TLC and maximal elastic recoil, subjects relaxed against
the occluded mouthpiece, which allowed pressure and
volume just below TLC to be recorded with sufficient
data points to provide an entire fitted curve. Up to five
P-V curves, each with 7–10 data points, were pooled to
produce a final curve. An exponential function of the
form: V=A-Be-Kp , where V is lung volume, p is static
elastic recoil pressure, and A, B and K are constants,
was fitted to the P-V data from TLC to a lower limit not
less than 50% of TLC, and analysed by computer. The
exponential constant, K, describes the shape of the P-V
curve independent of TLC [7].
Pulmonary capillary blood volume (Vc) and membrane
diffusing capacity (Dm) at rest
This test was performed according to the method of
ROUGHTON and FORSTER [8] using a modified single-breath
technique [9], which has been shown in this laboratory
to give similar results to those obtained using the conventional method [4]. This modification consisted of a
single-breath T L,CO measured in duplicate at two different inspired oxygen concentrations supplied by demand
values from gas cylinders. These cylinders contained:
1) 0.3% CO, 10% He, 21% O2 and the balance N2 ; and
2) 0.3% CO, 10% He and 90% O2 .
A HP 47404A (Hewlett Packard) single-breath transfer system was used, which incorporated the Jones-Meade
convention for breathholding time. Between each of the
two gas mixtures, the helium and carbon monoxide analysers were recalibrated using the appropriate gas concentration. The subjects breathed room air tidally for several
breaths and then exhaled slowly to RV. At RV the subject inhaled the test gas rapidly to TLC and breathheld
for 10 s, then exhaled as fast as possible. The first 800
ml of expired gas was discarded as dead space gas, and
the next litre retained in the alveolar sample bag which
P. M . DONNELLY ET AL .
940
was fitted with a side-arm and three-way tap. A correction was made to the inspired volume to allow both
for the anatomical and instrument dead spaces (0.2 L).
After each T L,CO manoeuvre, a 20 ml aliquot of expired
gas was sampled (using several wash-outs of the syringe).
The final sample was analysed for oxygen and carbon
dioxide tensions using a blood gas analyser (Corning
175, Medical, MA, USA). These values were taken as
an estimate of alveolar oxygen and carbon dioxide tensions (PA,O2 and PA,CO2). The rate of CO uptake by the
red blood cells (1/φ) was calculated for each measurement of PA,O2, using the equation [10]:
1/φ = PA,O2 (kPa) × 0.0057 + 0.10
(1)
Because of the multiple testing, carboxyhaemoglobin levels were estimated for each TL,CO manoeuvre, following
an estimation of alveolar CO using the micro smokerlyser (Bedfont Tech. Instr., Sittingbourne, Kent, UK).
The decrease in TL,CO due to back pressure was estimated according to the equation of CARDIGAN et al. [11]
(Eq. 2), and this value was added to the observed TL,CO.
% TL,CO decrease = 0.036 ml CO·min-1·kPa-1 × COHb% (2)
Pulmonary capillary blood volume (Vc) was calculated
as follows:
1/Vc = 1/TL,CO (high P O2 ) - 1/TL,CO (low P O2 )
1/φ (high P O2 ) - 1/φ (low P O2 )
(3)
Membrane diffusing capacity was calculated as follows:
1/Dm = 1/TL,CO (low P O2 ) - (1/φ (low P O2 ) × 1/Vc)(4)
Corrections of the observed TL,CO,sb at rest and during
steady-state exercise for variation in PA,O2 were made
according to the equation of KANNER and CRAPO [12].
T L,CO varies inversely with PA,O2: TL,CO,sb corrected =
T L,CO (measured) × [1.0 + 0.0035 (PA,O2 - 120)]. When
PA,O2 was <120, this equation was rearranged accordingly.
Single-breath estimation of TL,CO and KCO during steadystate exercise
The transfer capacity of the lungs (TL,CO,sb) during
exercise was measured by the technique of NEVILLE et
al. [13]. Subjects pedalled for 3 min at 25 W without
a noseclip or mouthpiece. At the end of this period (with
noseclip on) they were attached to the TL,CO,sb apparatus mouthpiece and performed a single-breath manoeuvre, whilst still exercising. At the end of the 7–10 s
breathhold they expired forcibly, came off the mouthpiece and rested for 5 min. A 20 ml syringe of alveolar
gas was sampled, as described previously, for estimation
of PA,O2. Exercise was continued in 25–50 W increments
(each for 3 min) up to a maximum of 150 W, depending on the capacity of the subject. KCO was calculated
as TL,CO,sb/VA BTPS at each workload. VA is the alveolar volume measured by helium dilution during a 10 s
breathhold at full inspiration. T L,CO,sb at each workload
was corrected for CO backpressure and PA,O2 tension as
described earlier.
Haemoglobin
Correction of TL,CO,sb for variation in haemoglobin
(Hb) concentration was not made either at rest or during exercise. We used the values of ROCA et al. [14] for
resting normal TL,CO,sb values derived from a regression
equation which omitted this correction. This predicted
resting values of ROCA et al. [14] were, however, similar to those of KENDRIK and LASZLO [15], who did standardize their TL,CO,sb values to a Hb level of 146 g· L-1 .
We measured Hb concentration in four of our normal
females with the largest lungs, and found a mean Hb
level of 139±4 g· L-1 . Calculations to correct for Hb in
these subjects revealed a 2.5% underestimation in TL,CO,sb
and KCO in these women, insufficient to explain the low
KCO values found in this group with large lungs.
Closing volume (CV%VC) and ventilation distribution
These indices of lung function were measured in the
acromegalic subjects using the single-breath nitrogen test,
as modified by ANTHONISEN et al. [16], and expressed as
a percentage of predicted values [17]. Delta N2 was
calculated from the single-breath nitrogen wash-out curve
as the percentage rise of nitrogen per litre of expired gas,
800–1,200 ml after the start of expiration (∆N2 %· L-1 ).
Expiratory flow rates were kept between 0.3–0.5 L· s-1 .
A 200 ml dead space containing room air separated the
patient from the 100% O2 used for the test; this was
done in order to preferentially prime the apical lung zones
with 80% N2 , so that the point of airway closure could
be more easily differentiated from the slope of phase
three (alveolar plateau).
Statistical methods
Analysis of variance was used to determine between
group differences of continuous variables shown in the
tables. Duncan's multiple range test was used for post
hoc comparisons, to determine statistical differences
between groups at the p less than 0.05 level, using the
pooled variance [18]. The degree of association between
variables shown in the figures were computed using
Pearson's correlation coefficient. Multiple regression was
used to determine the significance of gender or group in
the models, and where these were not significant, data
for males and females, or for different groups, were
included together. Repeated measures analysis of variance was used to assess between group differences in
changes in KCO and TL,CO during steady-state exercise.
Predicted values
The normal values used to predict spirometric lung function, maximal inspiratory and expiratory mouth pressures,
lung volumes, K and elastic recoil pressures [7] have
ALVEOLAR HYPERPLASIA IN LARGE LUNGS ?
been reported in detail previously [5, 6]. Regression
equations of BURRI et al. [4] (based on TLC) were used
to predict pulmonary capillary blood volume (Vc) and
membrane diffusing capacity (Dm) at rest. We predicted Vc on the basis of TLC and not body surface area
(BSA), in order to show that in large lungs the KCO is
low because not all the alveoli are perfused. Normal
values used for predicting exercise TL,CO,sb and KCO were
from KENDRICK and LASZLO [15].
Results
Table 1 shows the age, height, weight, relative sitting
height, chest width and serum growth hormone levels
for the male and female groups, respectively. In table
1, the acromegalic male subjects (Group 3) were significantly older than either the male subjects with normal
sized lungs (Group 1) or the male subjects with increased
lung size (Group 2). There was no significant difference in either standing height or relative sitting height
between the three groups studied. The acromegalic males
(Group 3) were both heavier and had wider chests than
Group 1 with a normal TLC. Chest width at TLC for
Groups 1 and 2 were not statistically different. In table
1, the acromegalic females (Group 3) were significantly older than either Group 1 (normal subjects with a normal TLC) or Group 2 (normal subjects with an increased
TLC); Group 2 with an increased TLC were older than
Group 1 with a normal TLC. There was no significant
difference in height, chest width, weight, or relative sitting height between these three groups.
Mean serum insulin-like growth factor (IGF-1) levels
were measured in the acromegalic subjects only. Serum
IGF-1 levels were approximately double the predicted
value for women and treble the predicted value for men,
but a wide standard deviation was observed (females 78
(37) nmol· L-1 , males 139 (79) nmol· L-1 ; predicted <45
nmol· L-1 ).
Lung volumes, spirometry, TL,CO,sb, Vc, Dm
Mean subdivisions of lung volume, spirometric function, TL,CO,sb, KCO, Vc and Dm are reported in table 2.
941
Because of the differences in age between the groups,
percentages of the predicted values were used in analysis. For males, VC% pred for the acromegalic males
(Group 3) was significantly larger than VC% pred for
Groups 1 and 2 (control males with and without an
increased TLC), and VC% pred for the males with an
increased TLC (Group 2) was significantly bigger than
VC% pred for the males with a normal TLC (Group 1).
Similar results were obtained when TLC% pred was compared between the three groups. There was no significant difference between FEV1/FVC% pred, Dm% pred
or T L,CO% pred for the three groups studied. Transfer
coefficient (KCO% pred) for Group 1 (males with a normal TLC) was found to be significantly greater than in
Groups 2 and 3 (males with an increased TLC and the
acromegalic males). Pulmonary capillary blood volume
(Vc% pred) for the males with a normal TLC (Group 1)
was significantly greater than for the acromegalic males
(Group 3), despite their increased lung size.
For females, VC% pred was similar for Groups 2 and
3 (normal females with increased TLC and acromegalic
females with big lungs), and both these groups had significantly bigger VC% pred than Group 1 (females with
normal TLC). Similar results were obtained for TLC %
pred. There was no significant difference for either
FEV1/FVC% pred, T L,CO% pred or Vc% pred for the
three groups studied. KCO% pred was significantly bigger in Group 1 with the normal TLC than in either the
females with increased TLC (Group 2) or the acromegalic females (Group 3), and a similar result was obtained
for Dm% pred.
Lung mechanics, pulmonary distensibility (K) and elastic recoil
Mean values expressed as % of predicted are shown
in table 3. In the male groups, there was no significant difference for either K, elastic recoil at maximal
inspiration (Pel,MI) or elastic recoil at 60% of TLC
(Pel,60), for the three groups studied. In the female groups,
similar results were obtained. The distribution of the
original pressure volume data about the derived curve
(mean residual variance) and the ratio A/TLC% (a test
of the validity of the exponential model) are reported as
Table 1. – Anthropometric characteristics of male and female subjects
Males
Age yrs
Group 1
Normal
TLC
n=10
Group 2
Increased
TLC
n=10
32 (11.3)
30 (8.9)
Females
Group 3
Sig. diff.
Acromegalic intra-groups
subjects
p<0.05
n=8
45 (14.7)
Height cm 180 (6.7)
182 (5.9)
176 (6.6)
Weight cm 80 (9.6)
83 (6.5)
94 (17.4)
RSH
0.52 (0.01) 0.51 (0.01) 0.52 (0.02)
Chest width 30.4 (2.4) 32.3 (0.5) 33.5 (3.5)
at TLC cm
Group 1
Normal
TLC
n=6
3 > 1, 2
25
(3.2)
NS
167
63
0.52
27.3
(7.5)
(12.5)
(0.01)
(1.6)
3>1
NS
3>1
Group 2
Increased
TLC
n=11
Group 3
Acromegalic
subjects
n=6
Sig. diff.
intra-groups
p<0.05
38 (8.5)
54 (4.1)
3 > 1, 2
2>1
169
65
0.53
28.6
(7.7)
(8.9)
(0.01)
(2.2)
Data are presented as mean (SD). RSH: relative sitting height (sitting height/standard height);
lung capacity.
NS:
162
74
0.53
28.3
(2.2)
(15.9)
(0.01)
(0.6)
NS
NS
NS
NS
nonsignificant; TLC: total
942
Table 2. – Lung volumes, spirometry, diffusing capacity and its subdivisions in male and female subjects
Males
Group 1
Normal
TLC
n=10
VC
5.72 (0.8)
104
(7)
7.39 (0.7)
103
(4)
81
(4)
98
(5)
12.9 (1.8)
102 (14)
1.79 (0.12)
94
(6)
89
(16)
104 (17)
38
(12)
133 (42)
6.51
117
8.56
116
78
96
13.1
100
1.58
84
83
88
42
133
Group 3
Acromegalic
subjects
n=8
(0.6)
(5)
(0.8)
(3)
(6.0)
(6)
(1.7)
(13)
(0.15)
(8)
(18)
(19)
(13)
(36)
6.58
134
9.07
135
79
97
11.5
101
1.39
77
73
74
31
96
(1.1)
(14)
(0.9)
(14)
(4)
(6)
(1.7)
(15)
(0.19)
(10)
(10)
(12)
(5)
(12)
Significant
differences
between groups
p<0.05
3 > 1, 2; 2 > 1
3 > 1, 2; 2 > 1
NS
NS
1 > 2, 3
1>3
NS
Group 1
Normal
TLC
n=6
4.22 (0.6)
104 (10)
5.53 (0.7)
104
(1)
85.0
(6)
98
(6)
9.7 (1.1)
105 (12)
1.79 (0.16)
92
(8)
60
(9)
89
(16)
33
(13)
149 (52)
Group 2
Increased
TLC
n=11
4.98
129
6.68
123
80.7
98
9.2
104
1.42
78
63
79
26
100
Group 3
Acromegalic
subjects
n=6
(0.8)
(10)
(1.1)
(12)
(6)
(8)
(1.8)
(20)
(0.18)
(10)
(12)
(12)
(6)
(22)
3.71
121
5.89
122
80.8
101
7.4
91
1.39
75
53
75
24
105
(0.4)
(7)
(0.4)
(7)
(3)
(7)
(1.2)
(15)
(0.20)
(11)
(12)
(15)
(13)
(48)
Significant
differences
between groups
p<0.05
2, 3 > 1
2, 3 > 1
NS
NS
1 > 2, 3
NS
1 > 2, 3
Data are presented as mean (SD) and as % predicted (SD). VC: vital capacity; TLC: total lung capacity; FEV1/FVC%: forced expiratory volume in one second; TL,CO,sb: singlebreath estimate of transfer factor of the lung for carbon monoxide at rest; KCO: carbon monoxide transfer coefficient (TL,CO STPD/alveolar volume (VA) BTPS); Vc: pulmonary capillary blood volume; Dm: alveolar/capillary membrane diffusing capacity; NS: nonsignificant; BTPS: body temperature and pressure saturated with water vapour; STPD: standard
temperature and pressure dry.
Table 3. – Alveolar distensibility (K) and elastic recoil in male and female subjects
Males
K kPa-1
% pred
Pel,MI kPa
% pred
Pel60 kPa
% pred
Females
Group 1
Normal
TLC
n=8
Group 2
Increased
TLC
n=9
Group 3
Acromegalic
subjects
n=6
1.20 (0.30)
94
(22)
3.91 (1.04)
101
(24)
0.71 (0.22)
109
(23)
1.29 (0.30)
103
(28)
3.84 (0.83)
99
(25)
0.77 (0.14)
117
(31)
1.21 (0.10)
86
(7)
3.03 (1.42)
85
(31)
0.65 (0.20)
116 (18)
Significant
differences
between groups
NS
NS
NS
Group 1
Normal
TLC
n=4
Group 2
Increased
TLC
n=7
Group 3
Acromegalic
subjects
n=4
1.14 (0.20)
93
(18)
3.67 (0.29)
106
(9)
0.76 (0.10)
122
(13)
1.42 (0.30)
104
(23)
2.96 (0.72)
99
(20)
0.61 (0.20)
122
(37)
1.38 (0.20)
93
(18)
2.13 (0.23)
86
(9)
0.35 (0.05)
90
(10)
Significant
differences
between groups
NS
NS
NS
Data are presented as mean (SD) and as % predicted (SD). K: pulmonary distensibility; Pel,MI: elastic recoil of the lung at maximal inspiration; Pel60: elastic recoil of the lung at
60% of maximal inspiration; NS: nonsignificant.
P. M . DONNELLY ET AL .
L
% pred
TLC L
% pred
FEV1/FVC %
% pred
T L,CO mmol·min-1·kPa-1
% pred
KCO mmol·min-1·kPa-1·L-1
% pred
Vc ml
% pred
Dm mmol·min-1·kPa-1
% pred
Group 2
Increased
TLC
n=10
Females
ALVEOLAR HYPERPLASIA IN LARGE LUNGS ?
150
130
V c % pred
follows. For the acromegalic men, mean residual variance values were 1.78±1.7%, and A/TLC% values 104.5±
2.9%. For the acromegalic women these same values
were 3.15±1.4% and 102.3±1.4%, respectively. For the
males and females with TLC <110% of predicted, these
values were 2.53±1.3% and 101.4±2.6%, and 1.57±1.2%
and 101.0±1.8%, respectively. For the males and females
with TLC >110% of predicted, 2.29±1.5% and 99.0±
5.3%, and 1.1±0.6% and 102.7±3.1%, respectively. Mean
maximal inspiratory mouth pressures from residual volume (MIP from RV%) and mean maximal expiratory
mouth pressures from TLC (MEP from TLC%) both for
the male (MIP 112±31%, MEP 113±41%) and female
(MIP 92±20%, MEP 106±21%) acromegalic subjects
were normal. Values for both ventilation distribution
(∆N2 %· L-1 ) and closing volume (CV%VC) for male and
female acromegalic subjects were within the normal limits (males ∆N2 %· L-1 72±29%, CV%VC 121±24%, and
females ∆N2 %· L-1 87±31% and CV%VC 130±18%).
Not all subjects were either willing or able to swallow
the oesophageal balloon catheter. In table 3, the number of subjects in each group tested for pulmonary distensibility (K) are indicated.
n=49
r=-0.57
p<0.0001
110
90
70
50
0
0 80
0
120
V c ml
KCO mmol·min-1·kPa-1·L-1
140
6
7
TLC L
8
9
11
10
TLC <110%
n=16
r=0.69
p=<0.001
TLC >110%
n=31
r=0.59
p=<0.0001
TLC <110%
TLC
>110%
80
60
0
40
0
Fig. 1. – Lung size expressed as total lung capacity percentage of
predicted (TLC % pred) plotted against transfer coefficient (KCO) for
all subjects studied. Multiple analysis of variance showed no statistical difference between males and females. ▲ : females with increased TLC; ❍ : acromegalic females; ● : females with normal
TLC;
: acromegalic males; ■ : males with normal TLC; ∆ :
males with increased TLC.
5
100
1.33
100 110 120 130 140 150 160 170
TLC % pred
0 4
Fig. 3. – Lung size expressed as total lung capacity (TLC) plotted
against % predicted membrane diffusion capacity (Dm) for all subjects studied. Multiple analysis of variance showed no statistical difference between males and females. Only 6 of the acromegalic males
and 5 acromegalic females had measurements of Dm ❍ : acromegalic females (n=6); : acromegalic males (n=8); ▼ : other subjects.
n=49
r=-0.50
p=<0.0002
0
n=44
r=0.45
p<0.003
100
160
1.67
180
160
50
2.34
2.00
120
140
TLC % pred
200
Dm %pred
The relationship between KCO, Vc% pred Dm and lung
size are shown in figures 1–3. There was an inverse
relationship between lung volume (TLC% pred) and KCO
(fig. 1) (r=-0.50; p<0.0002). A similar correlation was
obtained when Vc% pred was plotted against TLC% pred
(r=-0.57; p<0.0001), Vc% pred diminishing as lung size
(TLC% pred) increased above 100% (fig. 2). Figure 3
shows the relationship between lung size (TLC) and
membrane diffusing capacity (Dm). As TLC increased,
membrane diffusion capacity increased (r=0.45; p<0.003).
However, in nine out of 11 acromegalic subjects, Dm
fell below regression. When sex was included as a variable in the regression shown in figures 1 and 3, it was
100
Fig. 2. – Lung size expressed as total lung capacity percentage of
predicted (TLC % pred) plotted against pulmonary capillary blood
volume percentage predicted (Vc % pred). ❍ : acromegalic females
(n=6); : acromegalic males (n=7); ▼ : other subjects.
150
Relationship between lung function and physical characteristics for all groups combined
943
0 4
5
6
8
7
TLC L
9
10
11
Fig. 4. – Relationship between pulmonary capillary blood volume
(Vc) and lung size expressed as total lung capacity (TLC) for subjects with normal sized lungs <110% predicted (broken line) and for
subjects with large lungs >110% predicted (solid line). ▲ : females
with increased TLC; ❍ : acromegalic females (n=6); ● : females
with normal TLC;
: acromegalic males (n=7); ■ : males with
normal TLC; ∆ : males with increased TLC.
P. M . DONNELLY ET AL .
944
Males
TL,CO,sb mmol·min-1·kPa-1
18
16
14
12
10
8
6
0
2.5
2.0
1.5
0
slope of the regression line for 16 subjects with a TLC
<110% pred was the same as that found by BURRI et al.
[4] in their study of 34 normal subjects using the conventional method for estimation of Vc and Dm. The regression line for subjects with lungs larger than 110%
pred was of a similar slope, but was displaced to the right.
KCO mmol·min-1·kPa-1·L-1
KCO mmol·min-1·kPa-1·L-1
TL,CO,sb mmol·min-1·kPa-1
not a significant factor, therefore, data for both sexes
have been pooled.
Figure 4 shows the relationship between absolute pulmonary capillary blood volume (Vc) and lung size (TLC)
for subjects with a TLC <110% pred (broken line) and
for subjects with a TLC >110% pred (solid line). The
0
20
40
60 80 100 120 140
Workload W
Females
18
16
14
12
10
8
6
0
2.5
2.0
1.5
0
0
20
40
60
Workload W
80
100
Males
TL,CO,sb mmol·min-1·kPa-1
18
16
14
12
10
8
6
0
2.5
KCO mmol·min-1·kPa-1·L-1
KCO mmol·min-1·kPa-1·L-1
TL,CO,sb mmol·min-1·kPa-1
Fig. 5. – Relationship between single-breath transfer factor (T L,CO,sb), diffusion coefficient (KCO) and work (W) for healthy males and females
with and without an increase in lung size, expressed as total lung capacity (TLC). Each bar represents±SD; n: numbers of subjects exercised.
Isobars have been removed from the predicted slopes (dotted lines). - - -: predicted; —■—: males with normal TLC (n=8); —∆—: males with
increased TLC (n=8); —●—: females with normal TLC (n=5); —▲—: females with increased TLC (n=10).
2.0
1.5
0
0
20
40
60 80 100 120 140
Workload W
Females
18
16
14
12
10
8
6
0
2.5
2.0
1.5
0
0
20
40
Workload W
60
80
Fig. 6. – Relationship between single-breath transfer factor (T L,CO,sb), transfer coefficient (KCO) and workload (W) for male and female acromegalic subjects. Each bar represents±SD. Isobars have been removed from the predicted slopes (dotted lines). Statistical comparisons were not
appropriate. n: number of subjects exercised. - - -: predicted; — —: acromegalic males (n=3); —❍—: acromegalic females (n=4).
ALVEOLAR HYPERPLASIA IN LARGE LUNGS ?
Single-breath transfer factor (TL,CO,sb) and transfer coefficient (KCO) during steady-state exercise
The relationships between incremental steady-state exercise and TL,CO,sb and KCO, respectively, are shown for
all groups in figures 5 and 6. In figure 5a, TL,CO,sb for
the healthy male subjects with and without an increased
TLC (groups 2 and 1) was similar at rest, and during
exercise increased by the same amount for all workloads
attempted. KCO for the male subjects with a normal TLC
was not significantly different from KCO found for the
male subjects with an increased TLC. Similar results
were obtained for the normal females (fig. 5b) with and
without an increased TLC. In the male and female
acromegalic subjects with big lungs (fig. 6a and b), both
sexes during exercise recruited reserves of T L,CO at the
predicted rate, whilst KCO was recruited at a normal rate,
albeit at a lower level (80% pred), similar to the differences between observed and predicted KCO at rest (tables 2).
Discussion
In this study, the increased lung volumes in our patients
with acromegaly and controls with large lungs appeared
not to be due to a growth in the size of existing alveoli,
as suggested previously [2], or to an overdistension of
alveoli due to increased values for maximal inspiratory
mouth pressure (MIP), but may have resulted from an
increased alveolar number in association with increased
growth hormone (GH) secretion and with the growth of
physically larger chests. We measured pulmonary distensibility K, (an index of alveolar size [19]). This test
was part of a detailed analysis of mechanical lung function and gas exchange at rest and during exercise, which,
importantly, included for comparison groups of normal
subjects with and without an increase in lung size. Pulmonary distensibility and elastic recoil were normal for
all subjects studied.
The technique of determining alveolar distensibility by
applying an exponential function to a static compliance
curve has been described previously [7]. The relationship of the exponent K to Lm [19] (a morphometric estimate of the mean size of alveolar airspaces at TLC), the
relationship between chest size, alveolar distensibility
and alveolar size and number have also been fully discussed previously [5, 6]. Total lung capacity is determined by the number and size of airspaces in the lungs.
Alveolar distensibility is not related to alveolar number
[19], or to height [20], and is independent of lung size
and sex [20]. In intact human subjects, K is an independent determinant of TLC [21], a fact that is difficult
to explain unless K reflects airspace size.
In the present study, there was no significant difference in either K or elastic recoil between acromegalic or
normal subjects, with or without an increase in TLC,
suggesting either: 1) alveolar multiplication and not hypertrophy as the growth mechanism to account for the individuals with large lungs; or 2) alveolar hypertrophy not
detectable through the measurement of pulmonary distensibility in the present study. The finding of normal
945
values for elastic recoil in both studies (a simpler procedure to the estimation of K) strongly supports the first
hypothesis, that alveolar multiplication was the growth
mechanism in the individuals with large lungs. In support of this, HOPPIN and HILDEBRANDT [22] in their general analysis of surface forces and size of airspaces,
showed that the surface component of recoil pressure
was inversely related to Lm and directly related to the
alveolar surface to volume ratio. The strong relationship between K and Lm [r2 =0.86 [19]) is, therefore,
consistent with surface forces having the predominant
influence on lung distensibility. In this study, the normal values for elastic recoil found for all the groups studied suggest that alveolar surface area to volume ratio was
similar and, therefore, the alveoli were of similar size.
In support of the second hypothesis, it could be argued
that there was alveolar enlargement, and this was accommodated by some structural remodelling of connective
tissue or surfactant metabolism, such that K was preserved. However, it has been shown that pulmonary distensibility predominantly reflects surface forces. In the
excised lungs of rats, cats and dogs tissue, elastic properties (as assessed in saline-filled lungs) had no discernible effect on the distensibility of air-inflated lungs
[19]. The composition of surfactant is similar in various species, and the total amount of surfactant correlates
well with alveolar surface area, and there is a substantial reserve of surface active material [22].
It could also be argued that if growth hormone excess
had resulted in the formation of new alveoli (with a resultant increase in the surface area for gas exchange), TL,CO,sb
should have increased in the acromegalic and normal
subjects with large lungs. Pulmonary diffusing capacity
is the product of its components Dm and Vc. Whilst we
showed a direct relationship between TLC and Dm for
all subjects (fig. 3), the values for Dm tended to be normal for the male and female acromegalic subjects and
the Group 2 female subjects despite their increased lung
size. In their study, BRODY et al. [2] found lung tissue
volume to be twice the normal value in five out of six
male acromegalics with increased lung size, and suggested that an increase in interstitial tissue might have
impeded diffusion. This may explain the normal Dm
that we observed for the acromegalic subjects despite
evidence for an increased alveolar number (table 2).
However, another reason seems plausible: measurement
of Dm is dependent on some blood flow to the alveolus; in those subjects with big lungs, where perfusion
distances are excessive, peripheral alveoli may be so
poorly perfused as to affect Dm.
In the present study, pulmonary capillary blood volume percentage predicted (Vc% pred) and KCO were
shown to be inversely related to TLC % pred for all
subjects (figs 2 and 1). In addition, TLC% pred was
related to chest width in acromegalic men but not women
(table 1), due to differences in their thoracic indices [5].
BRODY et al. [2] found chest depth and circumference to
be increased in acromegaly, and this was also the case
in the present study. Since pulmonary capillary blood
volume (Vc) has been shown to relate to stroke volume,
these findings suggest that in sedentary individuals, with
946
P. M . DONNELLY ET AL .
large lungs, a decrease in KCO may result from an increase
in the unperfused capillary bed, and the wider or deeper their lungs the lower would be the KCO for a given
stroke volume. During exercise, these individuals recruited reserves of KCO at a normal slope but, in most instances,
at a reduced absolute level compared to those subjects
with normal sized lungs (figs 5 and 6). There is anatomical evidence in the literature to support these findings.
In a study of the effects of growth on the KCO at rest
in children and young adults, O'BRODOVICH et al. [3] have
shown that KCO decreases with increasing height. Placing
their subjects in the supine position resulted in an increase
in KCO of up to 27%, more so in the taller subjects; thus,
confirming the apex to base vertical gradient in pulmonary blood flow and explaining the lower KCO in taller
individuals to be due to a decrease in the ratio of the
perfused alveolar surface area to alveolar volume during
growth. In this study, however, increasing subject height
could only partly explain the decrease in KCO with age
[3].
Whilst the gravitationally-induced (top-bottom) distribution of pulmonary blood flow is widely known and
understood, the central-peripheral three dimensional distribution of pulmonary blood flow is less so. Using a
high resolution single photon emission computerized
tomography technique (SPECT), HAKIM et al. [23] have
demonstrated a gravity independent inequality in pulmonary blood flow in humans and in dogs. The authors
argued that regional differences in vascular conductance,
independent of gravity and present in individual lobes in
man and in dogs in the supine position, may explain this
finding; and suggest that flow to a site is inversely related to the distance the blood must travel to reach that
specific site. In a more recent manuscript dealing with
capillary perfusion patterns in single alveolar walls, it
has been observed using in vivo video-microscopy that
blood flowing through peripheral alveolar capillary networks in dogs sought a unique and repeatable pattern of
vascular segments when the pulmonary arterial pressure
was altered in a repeated fashion [24]. The authors interpreted this as demonstrating that pulmonary capillary
blood flow sought the pathway of least total resistance,
and that the resistance of each segment differed from the
resistance of other segments. They observed that alveolar capillary segments perfused during these changes in
driving pressure were shorter than the segments that
were never perfused. These studies indicate that, during the resting condition, gas exchange is accomplished
primarily by the central region of the lungs, and that,
during exercise, the perfused and ventilated regions can
expand peripherally in a three dimensional fashion, thus
allowing considerable reserves for enhancing gas exchange [25].
These studies are consistent with our finding of a normal T L,CO and a reduced KCO in untrained individuals
with large lungs at rest. Conversely, trained swimmers
have been shown to have a normal KCO at rest, perhaps
reflecting their increased stroke volume resulting from
training [6]. During exercise, however, trained swimmers can utilize their considerable reserves of gas exchange
units before saturation of alveolar capillary reserves would
occur. Perhaps, the large lungs of swimmers [26–28],
in contrast to the normal lungs of runners [6, 29], really are "built for exercise". In contrast, we have recently described a case of an active young man (with an
increased stroke volume, with small thoracic cage, and
subsequent restriction of all subdivisions of lung volumes) reaching a plateau of TL,CO,sb recruitment during
exercise [30]. His resting KCO was 140 % pred and
remained unchanged during exercise. The small lung
capacity (TLC 59% pred) with normal distensibility, and
the increased stroke volume have combined to produce
full recruitment of his limited number of alveoli at rest.
The response to exercise in our subjects with large
lungs (figs 5 and 6) showed that these subjects recruited reserves of T L,CO and KCO at the same rate as those
with normal lungs, indicating that there were anatomical reserves of pulmonary capillaries available for recruitment, the exact amount probably being limited by the
stroke volume (Vc). This implies that the reduced KCO
at rest was not a result of abnormal pulmonary capillary
density or a reduction in surface area:volume ratio, but
rather that there were areas (probably peripheral), where
perfusion was either reduced or absent. The authors
believe that the normal T L,CO and the low KCO at rest
were a reflection of a normal stroke volume emptying
into a lung containing an increased number of alveoli.
Whilst it is easier to explain our findings of a low KCO
for the normal subjects with an increased lung size on
the basis of increased perfusion distances, acromegaly
is, however, a disease, and abnormalities in lung perfusion scans [31], and in cardiac size and function [32] in
untreated cases have been reported. Most patients have
some degree of hypoxaemia, usually subclinical, probably due to ventilation/perfusion mismatching [31]. On
the basis of their large lung volumes, some of our acromegalic subjects undoubtedly had this disease for a long
time. However, since none had gone untreated, abnormalities in cardiac size and function are unlikely to have
contributed to their low KCO.
When there are significant differences in age between
study groups, it is sometimes difficult to choose representative predicted values for TL,CO,sb and KCO, because
different normal predictions can give different age effects.
In our laboratory, we have found the regression equations of ROCA et al. [14] for TL,CO,sb and KCO appropriate for the testing methodology and patient population
encompassed in this study (25–54 yrs). In addition, the
mean value for TL,CO,sb obtained by BRODY et al. [2]
(98% pred) for their acromegalic males (mean age 50
yrs) was very similar to the mean value (101% pred)
obtained for the acromegalic males in the present study
(mean age 45 yrs). Thus, the predicted values that we
used for TL,CO,sb [14] showed similar age effects to those
used by BRODY et al. [2] in their study.
In conclusion, the similarities in results between all
our subjects with large lungs indicate that, mechanically, acromegalic lungs are essentially normal. The normal values for pulmonary distensibility, FEV1/FVC
ratio, T L,CO % pred, Dm% pred, ventilation distribution,
and closing volume suggest that physiological estimates of the mechanism of lung growth in acromegaly are
ALVEOLAR HYPERPLASIA IN LARGE LUNGS ?
indistinguishable from those observed in other individuals with large lungs. We believe that the KCO was low
because not all the alveoli were perfused. The similar
values for T L,CO% pred between subject groups of similar height and weight, suggest that resting T L,CO, at least
for the untrained, is more a function of BSA and not
lung size. We conclude that lung growth in the adult
with acromegaly may result from an increase in alveolar number rather than size. This information may have
relevance for growth hormone treatment of patients with
lung disease, for lung size post-pneumonectomy, and may
also be of assistance in the interpretation of lung function data of patients with large lungs. However, morphometric studies of the lungs of nonsmoking acromegalic
subjects without lung disease are required to substantiate the interpretation of our findings.
12.
13.
14.
15.
16.
17.
18.
Acknowledgements: The authors thank H.J.H. Colebatch,
S.D. Anderson and I.H. Young for their helpful comments, M.
Potts for typing the manuscript, J. Reynolds for preparing the
figures, and K. Ho for referring the acromegalic patients.
References
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
Ogilvie CM, Forster RE, Blakemore WS, Morton JW.
A standardised breathholding technique for the clinical
measurement of the diffusing capacity of the lungs for
carbon monoxide. J Clin Invest 1957; 36: 1–17.
Brody JS, Fisher AB, Gocmen A, Dubois AB. Acromegalic
pneumonomegaly: lung growth in the adult. J Clin Invest
1970; 49: 1051–1060.
O'Brodovich HM, Mellins RB, Mansell AL. Effects of
growth on the diffusion constant for carbon monoxide.
Am Rev Respir Dis 1982; 125: 670–673.
Burri G, Cook CD, Barrie H. Studies of respiratory physiology in children: total lung diffusion, diffusing capacity of pulmonary membrane and pulmonary capillary
blood volume in normal subjects from 7 to 40 years of
age. J Pediatr 1961; 58(6): 820–828.
Donnelly PM, Yang TS, Peat JK, Woolcock AJ. What
factors explain racial differences in lung volumes? Eur
Respir J 1991; 4: 829–838.
Armour J, Donnelly PM, Bye PTP. The large lungs of
elite swimmers: an increased alveolar number? Eur
Respir J 1993; 6: 237–247.
Colebatch HJH, Ng CKY, Nikov N. Use of an exponential function for elastic recoil. J Appl Physiol: Respirat
Environ Exercise Physiol 1979; 46: 387–393.
Roughton FJW, Forster RE. Relative importance of diffusion and chemical reaction rates in determining the rate
of exchange of gases in the human lung, with special
reference to true diffusing capacity of pulmonary membrane and volume of blood in the lung capillaries. J
Appl Physiol 1957; 11: 290–302.
Theobald-Johnson GE. Pulmonary capillary blood volume. Volume 1984; 4(4): 5–8.
Forster RE, Roughton FJW, Kreuzer F, Briscoe WA.
Photocolorimetric determination of rate of uptake of CO
and O2 by reduced human red cell suspensions at 37°C.
J Appl Physiol 1957; 11(2): 260–265.
Cardigan JB, Marks A, Elliott MF, Jones RH, Gaensler
EA. An analysis of factors affecting the measurment of
pulmonary diffusing capacity by the single-breath method.
J Clin Invest 1961; 40(2): 1495–1514.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
947
Kanner RE, Crapo RO. The relationship between alveolar oxygen tension and the single-breath carbon monoxide diffusing capacity. Am Rev Respir Dis 1986; 133:
676–678.
Neville E, Kendrik AH, Gibson GJ. A standard method
of estimating Kco on exercise. Thorax 1984; 39: 823–827.
Roca J, Rodriguez-Roisin R, Cobo E, Burgos F, Perez
J, Clausen J. Single-breath carbon monoxide diffusing
capacity prediction equations from a Mediterranean population. Am Rev Respir Dis 1990; 141: 1026–1032.
Kendrik AH, Laszlo G. CO transfer on exercise: age
and sex differences. Eur Resir J 1990; 3: 323–328.
Anthonison NR, Danson J, Robertson PC, Ross WRD.
Airway closure as a function of age. Respir Physiol
1970; 8: 58–65.
Buist AS, Ross BB. Predicted values for closing volumes using a single-breath nitrogen test. Am Rev Respir
Dis 1973; 107: 744–752.
Cody RP, Smith JK. Applied statistics and the SAS programming language. 3rd edn. N. Holland, Chapter 7,
pp. 136–161.
Haber PS, Colebatch HJH, Ng CKY, Greaves IA. Alveolar
size as a determinant of pulmonary distensibility in mammalian lungs. J Appl Physiol: Respirat Environ Exercise
Physiol 1983; 54: 837–845.
Colebatch HJH, Greaves IA, Ng CYK. Exponential
analysis of elastic recoil and ageing in healthy males and
females. J Appl Physiol: Respirat Environ Exercise
Physiol 1979; 47: 683–691.
Colebatch HJH, Greaves IA, Ng CKY. Pulmonary distensibility and ventilatory function in smokers. Bull Eur
Physiopathol Respir 1985; 21: 439–447.
Hoppin G, Hildebrandt J. Mechanical properties of the
lung. In: West JB, ed. Bioengineering Aspects of the
Lung. Basel, Switzerland, Dekker, 1977; Vol. 3: pp.
83–162. (Lung Biol Health Dis Ser).
Hakim TS, Lisbona R, Dean GW. Gravity independent
inequality in pulmonary blood flow in humans. J Appl
Physiol 1987; 63(3): 1114–1121.
Okada O, Presson RG, Kirk KR, Godbey PS, Capen RL,
Wagner WW. Capillary perfusion patterns in single alveolar walls. J Appl Physiol 1992; 72(5): 1838–1844.
Hakim TS, Lisbona R, Dean GW. Effect of cardiac output on gravity dependent and nondependent inequality
in pulmonary blood flow. J Appl Physiol 1989; 66(4):
1570–1578.
Yost LJ, Zauner CW, Jaeger MJ. Pulmonary diffusing
capacity and physical working capacity in swimmers and
non-swimmers during growth. Respiration 1981; 42:
8–14.
Vaccaro P, Clarke DH, Morris AF. Physiological characteristics of young well trained swimmers. Eur J Appl
Physiol 1980; 44: 61–66.
Andersen KL, Magel JR. Physiological adaptation to a
high level of habitual physical activity during adolescence. Int Z Agnew Physiol 1970; 28: 209–227.
Dempsey JA. Is the lung built for exercise? Med Sci
Sports Ex 1985; 18(2): 143–155.
Donnelly PM, Daxini BV, Bye PTP. The upper limit of
alveolar capillary recruitment in a young man with lung
growth impairment. Eur Respir J 1994; 7(7): 1371–1375.
Luboshitzky R, Barzilai D. Hypoxaemia and pulmonary
function in acromegaly. Am Rev Respir Dis 1980; 121:
471–475.
Martins JB, Kerber RE, Sherman BM, Marcus ML,
Ehrhardt JC. Cardiac size and function in acromegaly.
Circulation 1977; 56(5): 863–869.