See “Endocrine and Bone Metabolic Complications in Chronic Liver Disease and After Liver Transplantation in Children” by Högler et al on page 313.
As 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, Högler 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 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. Högler 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 Högler 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 protein–coupled 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 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 (18–21). In their review, Högler 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).
Högler et al (5) extensively review data on hepatic osteodystrophy. Bone-related complications are common in children with chronic liver disease and—frequently 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. Högler 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 Högler 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 long-term 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.
I thank Dr Alex Knisely, Dr Roland Schweizer, and Prof Gerhard Binder for critically reading the manuscript.
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