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Endocrine Care
Liver Fat Content in People with Pituitary Diseases: Influence of
Serum IGF1 Levels
Authors
Amandine Nguyen, Fréderic Ricolfi, Brivel Lemogne, Serge Aho, Stéphanie Lemaire, Benjamin Bouillet, Laurence
Duvillard, Damien Denimal, Coralie Fourmont, Romaric Loffroy, Jean Pierre Cercueil, Bruno Verges, Jean Michel Petit
Key words
steatosis, non-alcoholic fatty liver disease, IGF1, pituitary
diseases
received 06.06.2017
accepted 26.09.2017
Bibliography
DOI https://doi.org/10.1055/s-0043-120673
Published online: 2017 | Horm Metab Res
© Georg Thieme Verlag KG Stuttgart · New York
ISSN 0018-5043
Correspondence
Dr. Jean Michel Petit
Service de Diabétologie et d’Endocrinologie
CHU du Bocage
BP 77908
21079 Dijon cedex
France
Tel.: + 33/3/80 29 34 53, Fax: + 33/3/80 29 35 19
jean-michel.petit@chu-dijon.fr
Introduction
Non-alcoholic fatty liver disease (NAFLD) is commonly and bidirectionally associated with obesity, metabolic syndrome, and type 2
diabetes [1, 2]. The prevalence of non-alcoholic fatty liver disease
(NAFLD) reaches 30 % to 50 % in Western countries and is continuing to increase as an epidemic worldwide. NAFLD is due to an accumulation of lipid within hepatocytes and encompasses various
stages of liver disorders from benign hepatic steatosis, non-alcoholic steatohepatitis, and hepatic fibrosis to cirrhosis of liver and
hepatocellular carcinoma [3].
Some data suggest an association between NAFLD and pituitary
dysfunction [4]. Hormonal disorders including GH deficiency may
alter body composition causing visceral adiposity, an abnormal lipid
profile and insulin resistance [5]. GH and IGF1deficiency, also im-
Nguyen A et al. Liver Fat Content in … Horm Metab Res
Abs trac t
Non-alcoholic fatty liver disease (NAFLD) is commonly associated with obesity, metabolic syndrome, and type 2 diabetes.
NAFLD is also seen in patients with endocrinopathies. However, the relationship between endocrine diseases and the development of NAFLD is not well known. In this study, we set out
to determine whether liver fat content (LFC) was associated
with IGF1 levels in people with pituitary diseases (PD). Eightynine patients with pituitary diseases and 74 healthy controls
were included in this study. LFC was measured using MRI. Hepatic steatosis was defined as LFC > 5.5 %. Patients with PD were
older, and had a higher BMI than healthy controls. LFC was significantly higher in people with PD than in controls (6.5 % vs.
3.2 %; p < 0.001). LFC was negatively associated with the IGF1
level. The prevalence of steatosis was higher in PD patients than
in controls (36.3 % vs. 14.8 %; p = 0.002). In multivariate analysis, which included patients and controls, the predictive variables for steatosis were age, BMI and IGF1 levels, whereas the
presence of pituitary diseases and gender were not associated
with steatosis. Our data showed that LFC was strongly associated with IGF1 levels. These results suggest that steatosis associated with PD is probably a consequence of a low IGF1 level
in these patients.
pair hepatic metabolism, thus contributing to the development of
NAFLD (4). It has been shown that GH and IGF-I levels are reduced
in subjects with NAFLD [6–8]. In the same way, NAFLD is a major
late adverse effect in childhood-onset craniopharyngioma [9]. Previous studies regarding the association between GH deficiency and
liver fat content are conflicting, probably because of the discrepancies in methods to evaluate liver fat content. Moreover, patients
with pituitary diseases may have NAFLD related to the increased
frequency of obesity and metabolic syndrome in such patients. Because of the contrasting results on the role of pituitary function in
the development of NAFLD, we performed a clinical study to investigate the association between liver fat content and pituitary diseases. The main objective of our study was to determine whether
the prevalence of NAFLD was more frequent in patients with pitu-
Downloaded by: Vanderbilt University. Copyrighted material.
Affiliation
Service de Diabétologie et d’Endocrinologie, Université de
Bourgogne-Franche Comté, INSERM - LNC UMR1231, CHU
du Bocage, BP 77908, 21079 Dijon cedex, France
Endocrine Care
Patients and Methods
Study design
This was a prospective case-control study conducted by the Endocrinology Department of Dijon University Hospital. This study was
approved by Ethics Committee. Informed consent was obtained
from all participants. We included every patient who had pituitary
disease and who needed to undergo pituitary gland MRI between
January 2016 and September 2016. We collected all of the information regarding the pituitary disease type and laboratory and
baseline characteristics (body mass index, medical history) for patients and controls.
Patients
Eighty-nine patients with a pituitary disease and 74 healthy control subjects were recruited in our study. We included 89 consecutive patients with pituitary disease who underwent pituitary MRI.
We performed MRI of the liver at the same time. For both patients
and controls, exclusion criteria included significant alcohol intake
(alcohol consumption more than 20 g/day), a history of viral, autoimmune or metabolic liver disease, or drug intake associated with
steatosis.
Liver fat content
All participants underwent MRI of the liver in a 1.5 T Siemens apparatus. For patients with pituitary disease, the pituitary MRI was
done at the same time. Liver fat quantification was based on a triple-echo gradient-echo sequence (in-phase, opposed-phase, inphase), as previously described [10]. This technique has recently
been validated with excellent correlations and accuracy compared
with proton MR spectroscopy [10]. Hepatic steatosis was defined
as LFC > 5.5 % [11, 12].
Pituitary assays
Baseline laboratory tests for pituitary function included levels of
prolactin, TSH, T4, and T3, GnrH (FSH/LH), estradiol/testosterone,
IGF-1 and GH, cortisol, and ACTH. Thyroid deficiency was defined
as low T4 associated with low or normal TSH. Patients with hypothyroidism were all treated appropriately with levothyroxine. IGF1
levels was analysed in the hospital laboratory using chemiluminescent immunometric assays using IMMULITE 2000 (Siemens Medical Solutions Diagnostics, Erlangen, Germany) according to the
manufacturer’s instructions.
Statistical analysis
Normally distributed variables were presented as means and S.D.
and non-normally distributed variables as medians and interquartile ranges. The data were analysed using chi-2 or Fisher’s exact
test. Median data were compared by one-way repeated measures
analysis of variance or the Kruskal–Wallis test. A p-value of < 0.05
was considered statistically significant. Relationships between steatosis (binary) and explanatory variables were modelled using a
logistic multiple regression model. Multicollinearity was investigated via the correlation matrix and VIF. A robust variance estimator
was used. Linearity was checked using fractional polynomials. The
adequacy of the model was checked by residuals and influence analysis. Goodness of fit of the logistic model was assessed through the
Homer–Lemeshow statistic, and ROC curves were used for classifier performance. Bootstrapping was used for internal validation of
all models. Statistical analyses were performed with Stata software
(Stata Version 14).
Results
Baseline characteristics
Eighty-nine consecutive outpatients with pituitary disease underwent both pituitary and liver MRI and were included in our study.
They were compared with 74 healthy controls. Patients with pituitary disease were older than healthy controls (p < 0.001). BMI and
fasting glycaemia was significantly higher in the group of patients
with a pituitary disease than in the control group (▶Table 1). LDL
was comparable in both groups whereas HDL and TG levels were
higher in the group of patients with pituitary disease.
Of the 89 patients with pituitary disease, 16 had a cerebral tumour (craniopharyngioma, Rathke’s cleft cysts), two had pituitary
necrosis, 67 had a pituitary adenoma, and four had another pituitary disease (▶Table 1). Of the 67 patients with a pituitary adenoma, 23 were non-functioning, 24 were prolactinoma, seven produced gonadotropin, 12 secreted GH or GH with other hormones,
and one was Cushing disease. Forty-three patients had gonadotropin deficiency: 28 men and 15 women. Among the 28 men, at the
time of pituitary MRI, 18 were treated with testosterone replacement therapy. Thirty-three patients were on long-term replacement with hydrocortisone because of corticotropin deficiency and
31 patients were on levothyroxine because of hypothyroidism.
Liver evaluation
Liver fat content was 6.54 ± 7.72 % in the group of patients with
pituitary disease and 3.27 ± 5.44 % in the control group (p < 0.001).
The prevalence of steatosis (liver fat content ≥ 5.6 %) was significantly higher in the patients group than in the control group (37.0 %
vs. 14.8 %, p = 0.001). ALT levels were significantly higher in the patients group (p = 0.004) (▶ Table 1). Liver fat content correlated
positively with age (r = 0.38, p < 0.001), BMI (r = 0.62, p < 0.001),
ALT (r = 0.42, p < 0.001) and negatively with IGF-1 (r = –0.40,
p < 0.001) (▶ Fig. 1).
Multivariate analysis
In multivariate analysis, which included patients with a pituitary
disease and control subjects, steatosis was associated with BMI (OR
1.34; 95 % CI 1.20–1.50; p < 0.001), age (OR 1.04; 95 % CI 1.00–
1.08; p = 0.02), and IGF1 level (OR 0.98; 95 % CI 0.98–0.99;
p = 0.006), whereas pituitary disease (OR 0.75; 95 % CI 0.24–2.42;
p = 0.63) and gender (OR 0.46; 95 % CI 0.16–1.30; p = 0.14) were
not.
Nguyen A et al. Liver Fat Content in … Horm Metab Res
Downloaded by: Vanderbilt University. Copyrighted material.
itary diseases. We sought to investigate the association between
hormonal disorders, such as a low IGF1 level, and liver fat content.
To get the most reliable results, we determined liver fat content
using magnetic resonance imaging (MRI), a non-invasive but very
sensitive technique.
▶Table 1 Anthropometric and laboratory characteristics of the study groups.
Patients with pituitary disease (n = 89)
Healthy control subjects (n = 74)
Sex (M/W)
37/52
30/44
Age (years)
53.1 ± 16.0
40.8 ± 14.5
p
0.9
< 0.001
BMI (kg/m²)
29.2 ± 6.2
25.8 ± 5.0
0.005
Cholesterol (mmol/l)
5.44 ± 1.76
5.04 ± 0.95
0.33
LDL (mmol/l)
2.97 ± 0.82
3.09 ± 0.75
0.21
HDL(mmol/l)
1.51 ± 0.40
1.36 ± 0.39
0.003
Triglyceride(mmol/l)
1.60 ± 0.69
1.21 ± 0.56
0.02
IGF1 (ng/ml)
143 ± 89
Pituitary disease
209 ± 90
< 0.001
Adenoma
67
Cerebral mass/tumour
16
Vascular
2
Other
4
Hormone deficiency
N/A
ACTH deficiency
33
Hypothyrodism
31
Hypogonadism
43
Liver parameters
ASAT
21 (15; 26)
18 (16; 23)
0.08
ALAT
26 ( 20; 35)
21 (17; 25)
0.004
Liver fat content ( %)
6.53 ± 7.72
3.26 ± 5.44
< 0.001
Steatosis (LFC > 5.5 %) n ( %)
33 (37.0 %)
11 (14.8 %)
0.001
ASAT: Aspartate aminotransferase; ALAT: Alanine aminotransferase.
500
IGF1 (ng/ml)
400
300
200
100
0
0
10
20
Liver fat content (%)
30
40
▶Fig. 1 Correlation between Liver fat content and IGF 1 concentrations (r = –0.40; p < 0.001) (patients and controls groups together).
Discussion
Our study showed that the prevalence of steatosis was higher in
patients with pituitary diseases than in control subjects. However,
in multivariate analysis taking into account the IGF1 level, the presNguyen A et al. Liver Fat Content in … Horm Metab Res
ence of pituitary diseases was not associated with the presence of
steatosis or liver fat content. Only IGF1 level was associated with
liver fat content. These data suggest that GH deficiency is probably the main factor explaining the link between pituitary diseases
and steatosis. There are conflicting data regarding the association
between GH deficiency and liver fat content. A previous study
showed that IGF-I levels were reduced in subjects with NAFLD [6].
In this study, NAFLD was determined by US scan. In the Gardner
study, the prevalence of steatosis was comparable between patients with GH deficiency and controls: 50 % of controls had more
than 5.6 % of intrahepatocellular lipids [13]. In our study, only 15 %
had steatosis, which is in agreement with findings usually seen in
other publications. The difference between our two control groups
concerning the prevalence of steatosis is probably one explanation
of the discrepancy between these studies. Recently, in a cross-sectional comparison of 22 GH deficiency patients and 44 controls, no
significant difference in LFC was found [14]. However, this study
detected a low baseline liver fat content in GH deficiency patients
and in controls, which could explain the lack of difference between
the two groups. The main difference between all these studies is
that they did not use the same methods to diagnose steatosis. MRI
has been shown to be as sensitive as spectroscopy [10]. The diagnosis of steatosis based on ultrasound or biological scores is less
sensitive than MRI or spectroscopy.
Downloaded by: Vanderbilt University. Copyrighted material.
N/A
A strong argument to suggest a link between GH and LFC will
be the results of human trials evaluating the influence of GH or IGF1
levels on LFC. However, the results of the different studies are controversial [15–18]. Two retrospective observational studies in patients with hypopituitarism showed a significant reduction in serum
liver enzyme levels and liver fibrotic markers in patients receiving
GH treatment for 6 to 24 months [18, 19]. In a cross-sectional study
in seven patients with acromegaly, liver fat content was up to three
times higher after successful treatment [16]. In the same way, a recent study showed that liver fat content had increased 1 year after
surgical treatment for acromegaly [15]. In their study, Reyes-Vidal
and coll. suggested that liver fat content in patients with active acromegaly was low and rose when acromegaly was treated, thus
leading to a decrease in GH and IGF1 levels [15]. These studies are
in accordance with our work and strongly suggest a link between
IGF1 and LFC. In active acromegaly, an excess of IGF1 is associated
with a decrease in LFC, and in other pituitary diseases, GH deficiency leads to an increase in LFC. In contrast to the foregoing, two studies found no significant effect of GH treatment on LFC in patient
with GH deficiency [13]. In a 6-month clinical trial in patients with
GH deficiency, GH replacement did not reduce liver fat [13]. However, this study included only 12 patients. Similarly, intrahepatocellular lipids were decreased in GH patients treated with GH replacement and increased in GH patients untreated in the Meieinberg study. However, with only nine patients per group, this
difference was not significant [14]. It is essential to evaluate the impact of GH treatment in LFC and liver fibrosis in a large cohort of
patients with GH deficiency and steatosis in order to draw definite
conclusions on whether this treatment could be a new approach
for NAFLD in patients with hypopituitarism.
The mechanism responsible for the link between GH deficiency
and NAFLD could involve the lack of GH and/or IGF1. It has been
shown that NAFLD is a frequent complication in subjects with Laron
Syndrome, who are affected by a mutation inactivating mutations
in the GH receptor [20]. In Laron syndrome, IGF-1 treatment did
not seem able to decrease the prevalence of NAFLD, suggesting
that GH is also directly involved in hepatic lipid processing [21–21].
De novo lipogenesis contributes significantly to the pathogenesis
of non-alcoholic fatty liver disease. Recently, it has been demonstrated that GH directly regulates hepatic triglyceride content by
keeping de novo lipogenesis under control [21]. Indeed, hepatic
de novo lipogenesis was increased in a mouse model of hepatic GH
resistance [21]. These results suggest that that the reduction in the
hepatic action of GH may directly contribute to inappropriate DNL
in patients with NAFLD [21]. Moreover, our results could be explained by the modification in visceral fat after GH deficiency. The
IGF-1/GH axis plays an important role in body composition: GH is
insulin antagonistic, anabolic and lipolytic. In acromegaly, the excess of GH causes insulin resistance and a reduction in fat mass [15].
Reyes-Vidal et al. showed that body composition changes with acromegaly, and that this change is related to excesses of GH and
IGF-1 [15].
Our study has several limits. This is a prospective work and includes a very heterogeneous population. In our study, the history
of viral, autoimmune or metabolic liver disease or steatosis-related drug ingestion was only investigated when transaminase levels
were high or when risk factors were detected during the interview.
We cannot rule out the possibility that some patients included in
our study may suffer from these diseases. We cannot exclude the
influence of other hormonal defects on LFC in these patients. For
instance, several older men were not treated for their hypogonadism, which could have interfered with our results. Moreover,
despite the fact that we showed a high correlation between IGF-1
levels and liver fat content, we did not evaluate all patients with a
GH stimulation test for the diagnosis of adult GH deficiency. With
the lack of GH stimulation test for the diagnosis of adult GH deficiency we do not have the possibility to compare LFC in patients
with and without the diagnosis of GH Deficiency.
In conclusion, our data showed that IGF-1 correlated strongly
with liver fat content and steatosis. The prevalence of steatosis is
high in patients with pituitary disease. These results lead us to suggest particular precautions to diagnose hepatic disorders in patients with low IGF1 level. Surveillance and GH replacement therapy could be an option for patients with GH deficiency suffering
from NAFLD and must be validated in RCT including patients with
GH deficiency and NAFLD.
Conflict of Interest
The authors declare that they have no conflict of interest.
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