The Journal of Clinical Endocrinology & Metabolism Vol. 84, No. 6 2034-2036
Copyright © 1999 by The Endocrine Society
Decreased Serum Levels of Acid-Labile Subunit in Patients with Anorexia Nervosa1
Izumi Fukuda,
Mari Hotta,
Naomi Hizuka,
Kazue Takano,
Yukiko Ishikawa,
Kumiko Asakawa-Yasumoto,
Emina Tagami and
Hiroshi Demura
Department of Medicine II, Tokyo Women’s Medical University,
Tokyo, 162-8666, Japan
Address all correspondence and requests for reprints to: Dr. Naomi Hizuka, Department of Medicine II, Tokyo Women’s Medical University, 8–1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan. E-mail:
naomi-hi{at}hi-ho.ne.jp
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Abstract
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One of the observations in malnutrition is that serum insulin-like
growth factor (IGF)-I levels are decreased, and this decrease is
associated with an altered profile of IGF binding proteins (IGFBPs). In
human circulation, IGFs are mostly present as an approximately 150-kDa
ternary protein complex consisting of IGFs, IGFBP-3, and acid-labile
subunit (ALS). In the present study, to clarify the effect of nutrition
on serum ALS levels, we investigated 33 patients with anorexia nervosa.
Serum levels of ALS were measured by RIA. Furthermore, we measured
serum IGF-I, IGF-II, IGFBP-2, and IGFBP-3 levels in the patients. From
these data, we investigated which was the best predictor of body mass
index (BMI) as a nutritional status marker.
In the patients with anorexia nervosa, the serum ALS levels ranged from
0.7–16.9, with a mean of 10.6 ± 0.7 mg/L, and the levels were
significantly lower than those of normal subjects (13.8 ± 0.8
mg/L, P < 0.05). Serum ALS levels positively
correlated with BMI (r = 0.41, P < 0.05), and
the levels increased during treatment. The serum IGFBP-2 levels in the
patients were increased (871 ± 91 µg/L), and the levels
inversely correlated with BMI (r = -0.52, P
< 0.01). The serum IGF-I and IGFBP-3 levels were low (152 ± 14
µg/L and 2.56 ± 0.12 mg/L, respectively), and the levels
positively correlated with BMI (r = 0.46, P <
0.01; and r = 0.39, P < 0.05, respectively).
The serum IGFBP-2, IGF-I, and IGFBP-3 levels returned toward normal
ranges as BMI in the patients improved during treatment. Serum IGF-II
levels did not correlate with BMI (r = 0.24, P
= 0.17). Stepwise regression analysis revealed that serum IGFBP-2 was
the best marker of BMI among these variables.
The present study suggested that ALS was regulated by nutritional
status, the same as IGF-I, IGFBP-2 and IGFBP-3; but the serum IGFBP-2
was the best predictor of BMI as nutritional status marker among the
parameters in patients with anorexia nervosa.
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Introduction
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INSULIN-LIKE growth factors (IGFs) are
essential in fuel metabolism and cell growth. Serum concentration of
IGF-I is regulated by food intake and nutritional status, and the
levels are reduced in children with protein-calorie malnutrition and in
rats that have been fasted acutely and chronically nutritionally
deprived (1, 2, 3, 4, 5, 6, 7). IGFs exist in the circulation associated with a family
of high-affinity IGF binding proteins (IGFBPs). To date, six IGFBPs
(IGFBP-1 through -6) have been characterized in the circulation and
tissues (8, 9). Their functions are to modulate the bioavailability of
IGFs by prolonging the half-lives of IGFs and potentiating or
inhibiting the acute effects of free IGFs (8). In sera, IGFs are mostly
present as an approximately 150-kDa ternary protein complex consisting
of IGFs, IGFBP-3, and acid-labile subunit (ALS) (10). The RIA studies
have shown that serum levels of ALS are GH dependent (10). Recently,
several studies have demonstrated that ALS levels decreased in
catabolic conditions, such as calorie-restricted animals (11, 12) and
critically ill patients (13, 14, 15). Those findings indicate that ALS is
subject to nutritional regulation. However, to date, little is known
regarding the alternations in serum ALS levels in patients with
anorexia nervosa that could be considered as a form of chronic
malnutrition. Furthermore, it is well explored that serum IGF-I and
IGFBP-3 levels decrease and IGFBP-2 levels remarkably increase in the
patients with anorexia nervosa (16, 17, 18). The levels of those peptides
reflect the severity of malnutrition.
In this study, we investigated the serum levels of ALS in patients with
anorexia nervosa (by RIA), and we also measured serum IGF-I, IGF-II,
IGFBP-2, and IGFBP-3. From these data, we analyzed which is the best
predictor of body mass index (BMI) as a nutritional marker in the
patients with anorexia nervosa.
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Subjects and Methods
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Subjects
Thirty-three female patients, 18–29 yr old (mean ±
SD, 23 ± 4), who met the criteria of diagnosis for
anorexia nervosa outlined in the Diagnostic and Statistical Manual IV,
as well as the criteria determined by the Survey Committee for Eating
Disorders of the Japanese Ministry of Health and Welfare, were studied.
All subjects were free of other medical illness. Their BMI was
16.0 ± 0.4 (range, 11.0–21.4) kg/m2. Blood samples
were obtained from these patients to measure serum IGF-I, IGF-II,
IGFBP-2, IGFBP-3, and ALS; and the sera were frozen at -20 C until
assay. In six of 33 patients, the blood samples were obtained
repeatedly during the treatment. Therefore, a total of 39 serum samples
from the patients were studied. We also measured serum ALS and IGFBP-2
levels in 22 and 34 age-matched normal female subjects (mean ±
SD, 25 ± 1 yr; range, 24–28 yr), respectively.
Informed consent for blood sampling was obtained from all patients and
controls.
Measurements of serum ALS, IGF-I, IGF-II, IGFBP-2, and
IGFBP-3
Serum ALS was measured by RIA kit (Bioclone Australia,
Marrickville, Australia). The intra- and interassay coefficients of
variation of the RIA were less than 5.4 and 4.9%, respectively.
Serum IGF-I, IGF-II, and IGFBP-3 were measured by immunoradiometric
assay kits (Daiichi Radioisotope Laboratories, Tokyo, Japan).
The age-matched normal ranges for serum IGF-I, IGF-II, and IGFBP-3 were
determined (19).
Serum IGFBP-2 was measured by RIA kit (Diagnostic Systems Laboratories, Inc., Webster, TX).
Statistics
All data are expressed as mean ± SEM. The
Mann-Whitney U test was used to assess the differences in
serum ALS and IGFBP-2 levels between the patients with anorexia nervosa
and the normal subjects. Statistical analyses, to examine the
correlation between the levels of ALS, IGF-I, IGF-II, IGFBP-2, and
IGFBP-3 and BMI were performed with Spearman’s rank test. Significance
was established at P < 0.05. Stepwise regression
analysis was used to investigate independent predictors of BMI as a
nutritional parameter. All statistical analyses were performed using
the Stat View 4.51 (Abacus Concepts Inc. Berkeley, CA).
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Results
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The serum ALS levels in 33 patients ranged from 0.7–16.9, with a
mean of 10.6 ± 0.7 mg/L. These values were significantly lower
than those of normal subjects (13.8 ± 0.8 mg/L, P
< 0.05) (Fig. 1
). There was a positive
correlation between serum ALS levels and BMI in these patients (r
= 0.41, P < 0.05) (Fig. 2).
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Figure 1. The serum ALS and IGFBP-2 levels in the 33
patients with anorexia nervosa and in normal subjects.
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Figure 2. The relationship between serum ALS, IGF-I,
IGFBP-2, and IGFBP-3 and BMI in 33 patients with anorexia nervosa.
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The values of serum IGF-I and IGFBP-3 ranged from 19–378 (with a mean
of 152 ± 14 µg/L) and from 0.93–4.22 (with a mean of 2.56
± 0.12 mg/L), respectively (Fig. 3).
These values were lower than those of normal subjects. The serum
IGFBP-2 levels in the patients ranged from 232-2379, with a mean of
871 ± 91 µg/L, and the levels were significantly greater than
those in normal subjects (384 ± 20 µg/L, P <
0.001) (Fig. 1
). Serum IGF-II levels in the patients ranged from
224–916, with a mean of 568 ± 26 µg/L (Fig. 3). The values of
serum IGF-I and IGFBP-3 positively correlated with BMI (r = 0.46,
P < 0.01; and r = 0.39, P <
0.05, respectively) (Fig. 2). The levels of IGFBP-2 inversely
correlated with the BMI (r = -0.52, P < 0.01)
(Fig. 2). The serum IGF-II levels did not correlate with BMI (r =
0.24, P = 0.17).
Serum ALS, IGFs, IGFBP-2, and IGFBP-3 levels were measured repeatedly
during the recovery of body weight in six patients. In five of six
patients, the serum ALS levels increased after weight recovery (Fig. 4). In one patient, serum ALS level
decreased during the therapy. In this patient, decreases of serum IGF-I
and IGFBP-3 levels and an increase of IGFBP-2 level were observed as
BMI improved.
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Figure 4. The changes in serum ALS, IGF-I, IGFBP-2,
and IGFBP-3 levels from six patients with anorexia nervosa during the
treatment.
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Stepwise regression analysis was constructed to investigate independent
predictors of BMI as a nutritional parameter considering the variables
of IGF-I, IGF-II, IGFBP-2, IGFBP-3, and ALS levels in 33 patient
serum samples. The BMI was best predicted by serum IGFBP-2 levels
(r2 = 0.32, P < 0.001).
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Discussion
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The serum levels of ALS are GH dependent (10); however, the
nutritional status also play an important role in the regulation of
serum ALS levels. Serum ALS levels decrease after fasting or calorie
restriction in animal studies (11, 12). Critically ill patients have
markedly decreased serum ALS levels, and the levels correlate with the
values of prealbumin (which is a nutritional indicator) more strongly
than IGFBP-3 and IGF-I (14). In this study, we investigated the levels
of serum ALS in patients with anorexia nervosa to evaluate the ALS
levels under the condition in which malnutrition-induced alternations
in GH-IGF axis might have reached a steady state. We found that serum
ALS levels, as assessed by RIA, were significantly reduced in the
patients, although the patients group showed a wide range of ALS values
that overlapped the normal range. Serum ALS levels positively
correlated with BMI. The ALS levels increased after treatment,
suggesting that ALS might be useful in monitoring the response to
nutritional therapy. Thus, nutritional state is an important regulator
of circulating ALS levels in patients with anorexia nervosa.
A number of investigators have shown that serum IGFBP-2 levels
increased and IGF-I and IGFBP-3 levels decreased in a chronic
calorie-deprived state, and considered IGF-I, IGFBP-2, and IGFBP-3 as
good indicators of nutritional state (1, 16, 17, 18, 20, 21, 22, 23). We confirmed
those findings in this study. BMI correlated positively with serum
IGF-I and IGFBP-3 and inversely with serum IGFBP-2. The levels of
IGF-I, IGFBP-2, and IGFBP-3 returned toward normal ranges when the
nutritional state improved. The levels of IGF-II did not correlate with
BMI in the anorexic patients.
To evaluate the predictor of BMI as a nutritional marker, a stepwise
regression analysis was constructed, considering the variables of
IGF-I, IGF-II, IGFBP-2, IGFBP-3, and ALS levels. The analysis revealed
that serum IGFBP-2 was the best predictor of BMI.
In summary, the present study showed that serum ALS levels decreased in
patients with anorexia nervosa and the levels positively correlated
with BMI. The ALS levels increased during treatment. These data suggest
that ALS is regulated by nutritional status, the same as IGF-I,
IGFBP-2, and IGFBP-3; but the serum IGFBP-2 is the best predictor of
BMI as nutritional status marker among the parameters in patients with
anorexia nervosa.
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Acknowledgments
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We are grateful to Cosmic Corporation (Tokyo, Japan) for the ALS
kits; and to Daiichi Radioisotope Laboratories for IGF-I,
IGF-II, and IGFBP-3 kits.
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Footnotes
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1 This work was supported, in part, by Grants-in-Aid for General
Scientific Research 08671184 and 10671043 and by Grant-in Aid for
Encouragement of Young Scientists 08770833 from The Ministry of
Education, Science and Culture; The Yayoi Yoshioka Scholarship Fund;
The Novo Nordisk Growth Award; and a research grant from the Foundation
for the Growth Science, Japan. 
Received September 1, 1998.
Revised February 17, 1999.
Accepted February 26, 1999.
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Abstract
Introduction
BMI < 16 kg/m2 (n = 9); open circles, 16