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INVITED COMMENTARY

Liver, Hormones, and Bones


Ekkehard Sturm
See Endocrine and Bone Metabolic Complications in
Chronic Liver Disease and After Liver Transplantation
in Children by Hogler et al on page 313.

s the modern era of pediatric liver transplantation (LT) moves


into its third decade, we face 2 fundamental problems. First,
many national organ procurement organizations are confronted with
numbers of terminally ill patients with liver disease that exceed by
far the numbers of available suitable donors. In consequence, the
issue of morbidity and mortality in children on the waiting list
repeatedly stimulates discussions on prioritization (1). It also shows
clearly that understanding and prevention of medical complications
in these children is crucial to improve overall outcome in this group
(2). Second, overall expectation for most pediatric liver transplant
recipients is >85% survival and preserved graft function in the long
term (3,4). Medical management is challenging for both the patient
waiting for a transplant and the organ recipient. For those patients
on the waiting list, it is essential that alterations of metabolic
homeostasis be prevented or ameliorated. In the long term after
LT, the goal is to reach a desirable if not normal state of health
for our patients. To achieve both goals, both before and after LT, it is
mandatory that endocrine functions be well monitored and complications of dysregulation with consequences for energy homeostasis,
growth, and bone development be prevented. In the present issue of
the Journal of Pediatric Gastroenterology and Nutrition, Hogler et al
(5) have summarized important data on endocrine and bone metabolic
complications associated with liver disease and LT, which are highly
relevant for those providing care to the child with chronic liver
disease or to the recipient of a transplanted organ.
The spectrum of endocrine complications in chronic liver
disease includes disorders such as pubertal delay that can occur in
children with any chronic disease. Included also are endocrine
complications that are confined to patients after LT, for example,
new-onset diabetes after liver transplantation. Although new-onset
diabetes after liver transplantation was studied in a large American
database, precise diagnostic criteria are not well defined and the
course of disease is not well known. Candidates at risk must be
identified (eg, patients with cystic fibrosis), and post-LT screening
must be established in these patients (6). Two frequently encountered
endocrine complications before and after LT are growth failure and

Received October 21, 2011; accepted October 24, 2011.


From the Hospital for Children and Adolescents, University Hospital
Tubingen, Tubingen, Germany.
Address correspondence and reprint requests to Ekkehard Sturm, MD, PhD,
Hospital for Children and Adolescents, Pediatric Gastroenterology and
Hepatology, University Hospital Tubingen, Hoppe Seyler Strasse 72076
Tubingen, Germany (e-mail: ekkehard.sturm@med.uni-tuebingen.de).
The author reports no conflicts of interest.
Copyright # 2012 by European Society for Pediatric Gastroenterology,
Hepatology, and Nutrition and North American Society for Pediatric
Gastroenterology, Hepatology, and Nutrition
DOI: 10.1097/MPG.0b013e31823e9436

hepatic osteodystrophy (7,8). Both complications are important


in patient management: growth failure can affect prognosis of LT
(9) and is, like hepatic osteodystrophy, an important determinant
of posttransplant quality of life. Hogler et al (5) focus on these
complications, which warrant particular comment.
Multiple factors contribute to failure to thrive in children
with liver disease, particularly those affected by cholestasis.
Malabsorption of fat and fat-soluble vitamins, impaired protein
and nitrogen metabolism, reduced energy intake, resistance to
growth hormone, and, in consequence, low insulin-like growth
factor (IGF)-1 and IGF-binding protein 3 levels lead to deficiency
of important substrates and disturbed regulation of pathways
controlling growth and development (5). Of importance is that
severe growth failure is predominantly observed in children with
cholestasis (7). Affected children have a higher resting energy
expenditure requiring a higher caloric intake than do normal
children (10). The background of this observation is not discussed
in detail in the review by Hogler et al; however, to comprehend the
pathophysiology of altered energy metabolism in children with liver
failure, it may be important to focus on the role of bile acids (BAs)
as endocrinological regulators (11). BAs are amphipathic molecules
that facilitate the uptake of lipids. Their levels fluctuate in the
intestine as well as in the blood circulation, depending on food
intake and on absence or presence of cholestatic liver disease.
Besides their role in dietary lipid absorption, BAs function as
signaling molecules capable of activating specific receptors. These
BA receptors not only are important in the regulation of BA
synthesis and metabolism but they also regulate glucose homeostasis, lipid metabolism, and energy expenditure (12). TGR5, for
example, is a G proteincoupled receptor expressed in brown
adipose tissue and muscle, where its activation by BAs triggers
an increase in energy expenditure (12,13). This process may play a
role in cholestatic liver disease, which is characterized by the
accumulation of BAs acting as ligands for receptors critical to
energy metabolism. Most of the data accumulated so far originate
from animal experiments (13,14); however, controversy about the
potential role of BAs in energy metabolism in humans exists.
A recent study assessed BA levels in humans with respect to energy
expenditure (15). In this study, cirrhotic patients with elevated
plasma BA levels and healthy controls were compared with respect
to energy expenditure. It was concluded that no correlations
between BA levels and energy expenditure exist; however, the
study was not controlled for many factors that may affect
metabolism in cirrhotics. This likely confounded the study
outcome. A better understanding of the effect of BA on energy
expenditure in human disease will require further studies specifically designed to address this question (12).
Growth in children following LT is an important determinant
of quality of life. Growth retardation in this group is caused by
several factors. The strongest effect probably originates from the
influence of factors before LT (7). Among those factors, metabolic
and nonbiliary atresia cholestatic disease, severe growth retardation
before LT, and older age may have a negative effect on catch-up
growth after receipt of a transplant (7,16). Interestingly, when
growth failure occurs in critical phases of development, the
phenomenon of imprinting may prevent full growth restoration
(7,17). The role of steroids in persistent growth failure after LT has

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JPGN  Volume 54, Number 3, March 2012
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JPGN

Volume 54, Number 3, March 2012

been discussed, with some controversy. Alonso et al (16) showed in


an investigation of the SPLIT database that prolonged steroid
exposure was associated with less catch-up growth. In contrast, a
study in 100 children who underwent LT showed no difference in
catch-up growth between the 2 groups treated with different steroid
doses (7). Nor does steroid withdrawal uniformly lead to better
linear growth (1821). In their review, Hogler et al (5) conclude
that steroid reduction and increased mobility are beneficial for
improving growth after LT.
What are the perspectives for growth-promoting therapy?
Children with cirrhosis could, at least in theory, benefit from IGF-1
supplementation. So far, however, only 1 pilot study in adults
showed improvement in albumin concentration and energy metabolism (22). Interestingly, expeditious organ replacement is still
considered the most effective way to promote growth in
children who fail to thrive on aggressive nutritional support
(5,23). Regarding the use of growth hormone in children who lack
catch-up growth after LT, published studies are not well controlled,
so randomized controlled trials are needed before recommendations
can be made (5).
Hogler et al (5) extensively review data on hepatic
osteodystrophy. Bone-related complications are common in
children with chronic liver disease andfrequently underrated
after LT. Fractures in this group may occur as nonvertebral or
vertebral fractures. Because the latter often occur asymptomatically
and are associated with low spine bone mineral density, screening
seems justified (5). The recommended screening method is dual
x-ray absorptiometry (DXA). This is reliable in adults, but its use in
children has limitations. DXA delivers an areal measurement of
density; smaller bones thus appear to have lower BMD than larger
bones (24,25). The wide variation of height and, therefore, bone size
in children complicates the interpretation of BMD results, especially in short children, which applies to a number of patients before
and after LT. In addition, longitudinal evaluation of a given patient
over time is complicated by the changing size of the growing
skeleton. Therefore, guidelines should be used for the interpretation
of DXA results in children older than 5 years (26). In children
younger than 5 years, DXA is impossible because of a lack of a
normative dataset, and standard x-ray methods should be applied for
screening. Hogler et al (5) propose the evaluation of new methods
such as vertebral morphometry to study vertebral fractures.
They also give detailed recommendations on the use of
vitamin D and state that dose-finding studies for prevention and
treatment of hepatic osteodystrophy are needed. The authors stress
the point that use of biphosphonates is restricted to selective patients
with severe osteoporosis-associated complications.
Endocrine complications can influence morbidity and
mortality in children with chronic liver disease on the waiting list
and can severely affect quality of life after LT. Understanding the
pathophysiology, applying diagnostic tests correctly, and treating
these complications need to be prioritized for all of the pediatricians
and multidisciplinary teams caring for these patients. The review by
Hogler et al (5) summarizes important aspects of how to approach
endocrine and bone complications in these patients. The development of children after LT will be increasingly in our focus as longterm survival improves, with the transition of many patients to adult
care. Part of our role as guides for the individual approaching,
entering, and moving through this transition period is to keep on
looking after the liver, the hormones, and the bones.

Acknowledgments: I thank Dr Alex Knisely, Dr Roland


Schweizer, and Prof Gerhard Binder for critically reading the
manuscript.

www.jpgn.org

Liver, Hormones, and Bones

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