Journal of Pediatric Gastroenterology & Nutrition:
Endocrine and Bone Metabolic Complications in Chronic Liver Disease and After Liver Transplantation in Children
Högler, Wolfgang*; Baumann, Ulrich‡; Kelly, Deirdre†
*Department of Endocrinology and Diabetes
†Liver Unit, Birmingham Children's Hospital, Birmingham, UK
‡Division of Paediatric Gastroenterology and Hepatology, Children's Hospital Hannover, Hannover, Germany.
Address correspondence and reprint requests to Dr Wolfgang Högler, Department of Endocrinology and Diabetes, Birmingham Children's Hospital, Steelhouse Lane, B4 6NH, Birmingham, UK (e-mail: firstname.lastname@example.org).
Received 16 December, 2010
Accepted 24 August, 2011
The authors report no conflicts of interest.
ABSTRACT: With improved survival of orthotopic liver transplantation (OLT) in children, prevention and treatment of pre- and posttransplant complications have become a major focus of care. End-stage liver failure can cause endocrine complications such as growth failure and hepatic osteodystrophy, and, like other chronic illnesses, also pubertal delay, relative adrenal insufficiency, and the sick euthyroid syndrome. Drug-induced diabetes mellitus post-OLT affects approximately 10% of children. Growth failure is found in 60% of children assessed for OLT. Despite optimisation of nutrition, rarely can further stunting of growth before OLT be prevented. Catch-up growth is usually observed after steroid weaning from 18 months post-OLT. Whether growth hormone treatment would benefit the 20% of children who fail to catch up in height requires testing in randomised controlled trials. Hepatic osteodystrophy in children comprises vitamin D deficiency rickets, low bone mass, and fractures caused by malnutrition and malabsorption. Vitamin D deficiency requires aggressive treatment with ergocalciferol (D2) or cholecalciferol (D3). The active vitamin D metabolites alphacalcidol or calcitriol increase gut calcium absorption but do not replace vitamin D stores. Prevalence of fractures is increased both before OLT (10%–28% of children) and after OLT (12%–38%). Most fractures are vertebral, are associated with low spine bone mineral density, and frequently occur asymptomatically, but they may also cause chronic pain. Fracture prediction in these children is limited. OLT in children is also associated with a greater risk of developing avascular bone necrosis (4%) and scoliosis (13%–38%). This article reviews the literature on endocrine and skeletal complications of liver disease and presents preventive screening recommendations and therapeutic strategies.
See “Liver, Hormones, and Bones” by Sturm on page 308.
Orthotopic liver transplantation (OLT) is the standard treatment for end-stage liver failure. Advances in transplantation surgery, immunosuppressive, and other medical treatment modalities have improved long-term survival rates >80% (1,2). Higher survival rates have led to a greater focus of patient care on prevention and treatment of pre- and posttransplant complications, such as cognitive and motor delay, renal impairment, and in particular several complications that require the involvement of paediatric endocrinologists. These endocrine complications include short stature; pubertal delay; hepatic osteodystrophy, including severe vitamin D deficiency, fractures, osteoporosis, and scoliosis (3–8); abnormal thyroid hormone results; adrenal insufficiency; and diabetes mellitus (Fig. 1).
End-stage liver failure affects growth plates (bone length) and bone strength, causing short stature and hepatic osteodystrophy, respectively. The multifactorial origin of these bone-related complications in children before and after OLT is still only partially understood. Pretransplant, it is the combination of malnutrition and malabsorption, impaired hepatic protein synthesis, poor mobility, and hypogonadism that causes growth failure and hepatic osteodystrophy. Posttransplant, the beneficial effects of restored liver function are counteracted by high-dose immunosuppressive medication, in particular high-dose, potent glucocorticoids (9–11). This medication causes diabetes mellitus and adrenal insufficiency.
General paediatricians and paediatric specialists care for increasing numbers of children undergoing liver transplantation and must familiarise themselves with the specific needs of this patient cohort. This article reviews the literature regarding endocrine-, growth-, and bone-related complications in paediatric OLT recipients, including recommendations for their prevention and treatment.
GROWTH FAILURE AND ENDOCRINE COMPLICATIONS
Short Stature and Failure to Thrive
Chronic liver disease inevitably causes malnutrition and malabsorption, which are particularly prevalent in the developing infant, cholestatic liver disease, and rapidly progressive liver failure. The first clinical signs of malnutrition are low fat reserves and muscle weakness followed by muscular atrophy. Severe failure to thrive (defined as weight and/or height <2 standard deviations [SD] below the mean or third centile) is observed in approximately 60% of children assessed for OLT. The associated short stature is not caused by delayed skeletal maturation, because bone age in chronic liver disease is usually not delayed (12).
The underlying causes of protein and energy malnutrition and growth failure in liver disease are diverse (8,13). First, affected children have higher resting energy expenditure, requiring higher caloric intake compared with normal children (14). They also have reduced energy intake secondary to vomiting, anorexia, ascites, and organomegaly. Second, the condition typically causes malabsorption of fat and the fat-soluble vitamins A, D, E, and K (15), as well as impaired hepatic protein synthesis and nitrogen metabolism leading to reduced plasma branched-chain amino acids (BCAAs). Even children with only mild to moderate cholestatic liver disease have significantly greater BCAA requirements (207 mg · kg−1 · day−1) compared with healthy children (147 mg · kg−1 · day−1) (16). High dietetic protein intake of 3 to 4 g · kg−1 · day−1 and BCAA supplementation has been shown to prevent protein catabolism and increases muscle bulk (15,17). Third, any coexistent renal or gut disease can independently lead to growth failure or failure to thrive.
Finally, several endocrine abnormalities are involved in the causation of poor somatic growth in chronic liver failure. Liver failure leads to growth hormone (GH) resistance caused by down-regulation of GH receptor expression resulting in low insulin-like growth factor 1 (IGF-1) levels (18–22), a major regulator of growth. Additional reductions (50%–68%) in IGF-binding protein 3 and acid-label subunit, as seen in adult cirrhosis (23), are likely but have not been investigated in children. Reductions in these transport proteins cause rapid clearance of IGF-1 from the circulation, leading to growth failure. Sex hormones also affect growth, so it comes as no surprise that delayed puberty, hypogonadism, and poor libido are known complications of chronic liver disease in adolescents and adults (24–28).
Optimisation of a child's nutritional status before OLT is essential because the extent of pretransplant growth failure determines overall outcome of OLT. Being small for age (29) or underweight (30,31) increases mortality in children undergoing OLT.
Growth After Transplantation
Liver transplantation generally reverses growth failure associated with chronic liver disease. Following reduction and withdrawal of steroids at around 6 to 18 months, normal growth patterns are reestablished within 2 to 3 years after OLT (12,31–36) (Table 1). Children who are shorter pre-OLT appear to have greater catch-up growth post-OLT (31,36). Beyond the initial 2 to 3 years, further catch-up growth is minimal (7) and approximately 20% to 30% of children post-OLT are reported to have persistent growth failure (19).
The determinants of post-OLT growth were recently investigated by the North American Study of Pediatric Liver Transplantation registry containing data on 1143 children. The greatest risk for growth failure in this registry was reported in children with metabolic disorders or with steroid use beyond 18 months after OLT (31). In addition, transplantation in the first 2 years of life was associated with better growth outcome than transplantation at a later stage.
Perspective on Growth-promoting Therapy
Optimal management of the underlying condition is the best therapy for growth failure in chronic liver disease. These patients are GH resistant, so treatment with GH is not indicated. When GH was given pretransplant, there was no significant increase in IGF-1 or other metabolites. A drug that could be beneficial is recombinant IGF-1 (rhIGF-1), which is licensed for severe primary IGF-1 deficiency, but has not been tested in secondary IGF-1 deficiency caused by chronic diseases such as liver failure. Presently, expeditious transplantation is considered the ultimate option to improve growth because even the best nutritional supplementation efforts may be unsuccessful (7).
To date, treatment with GH or rhIGF-1 has not been properly tested in 20% to 30% of patients failing to catch up 2 years after OLT. So far, 3 uncontrolled studies used GH off-label in a combined total of 23 patients. GH therapy led to 0.6 to 0.8 SD gain in height SD score after 1 year (37,38) and a sustained gain of 0.9 SD after 5 years (39). Patient selection in these trials, however, was heterogeneous and not randomised to aggressive nutritional therapy. Also, steroid doses decreased or tended to decrease during the GH treatment period and there was no control group in any of these studies. Therefore, randomised controlled trials are necessary before such treatment can be recommended. To date, there have been no similar studies or case series using rhIGF-1.
Sick Euthyroid Syndrome
The literature does not suggest thyroid malfunction to be a complication of liver failure. Low thyroid hormone transport protein production in liver disease leads to low total but normal free thyroxine levels; however, the sick euthyroid syndrome (nonthyroidal illness syndrome) may well be encountered. This syndrome develops in acute or chronic illnesses and is caused by malnutrition-induced central hypothyroidism, triggered by low leptin levels (40). The associated drop in free thyroid hormone concentrations is thought to be counteracted by upregulation of thyroid hormone receptors (40,41). The low T4-variant of the sick euthyroid syndrome was associated with lower long-term survival in adults with cirrhosis (42), but similar studies are lacking in children with liver failure. To date, there is no persuasive evidence for the use of thyroid hormone replacement in the sick euthyroid syndrome (43,44), but some experts recommend starting replacement in more severe cases (45).
The situation is somewhat similar in regard to adrenal insufficiency. Seventy percent of plasma cortisol is bound to corticosteroid-binding globulin and 20% to albumin. Liver disease reduces corticosteroid-binding globulin and albumin concentrations, leading to low total cortisol but normal plasma-free cortisol (PFC) concentrations (46–48). Not surprisingly, the studies that applied standard criteria for adrenocorticotropin (ACTH) stimulated peak/delta total cortisol levels to adult patients with acute or chronic liver disease found 33% to 90% of their patients to be insufficient (49). A recent Australian study (47) demonstrated that the prevalence of adrenal insufficiency was only 12% using free cortisol criteria (peak PFC 33 nmol/L) compared with 58% using standard total cortisol criteria (peak cortisol <500 nmol/L or delta cortisol <250 nmol/L). Nevertheless, there remains a small group with relative adrenal insufficiency demonstrated by a blunted PFC response to ACTH stimulation with haemodynamic instability and lower survival (49). Recent evidence suggests that this adrenal insufficiency is not of primary (adrenal) origin, but of secondary (central) origin caused by elevated bile acids (50). Associations have been made to the metabolism of patients with septic shock, and studies in both conditions suggest that steroid supplementation is beneficial (49). Based on the evidence in adults (46,47), we would recommend that total cortisol response to ACTH remain the gold standard to test adrenal function in children (51). If albumin levels are low and the total cortisol response is abnormal, however, then the ACTH test should be repeated with analysis of free cortisol in plasma (PFC) or saliva (SC). Evidence for diagnostic cutoffs for these 2 analytes is accumulating, at least in adults. Proposed peak PFC cutoffs for adrenal insufficiency were 33 nmol/L (47) and 52.4 nmol/L (46) in stable liver disease, and 85.3 nmol/L in times of critical illness (46). Proposed peak SC cutoff levels are lower and probably less well defined, ranging from 18.0 to 25.9 nmol/L (52–54), in children and adults without critical illness. Much more evidence needs to be gathered in children to test the clinical application of PFC and SC cutoff values, to guide clinicians in their decision on the necessity of corticosteroid replacement.
Whilst “relative adrenal insufficiency” remains heavily debated, there are of course recognised entities in which adrenal insufficiency is associated with liver disease, such as autoimmune polyendocrinopathy, (pan-)hypopituitarism of the neonate, or the steroid-withdrawal syndrome, for example, after liver transplantation.
New-onset Diabetes Mellitus After Liver Transplantation
Ten percent of children develop new-onset diabetes within 2 years after OLT. Development of new-onset diabetes mellitus after liver transplantation (NODAT) is related to therapy with corticosteroids and calcineurin inhibitors, and both cyclosporine and tacrolimus may be implicated. In recipients with cystic fibrosis, the prevalence of diabetes is 50% because of their preexisting pancreatic damage. Pretransplant risk factors for NODAT development in children without cystic fibrosis include ages older than 5 years at OLT, African American descent, severe acute rejection, and the pretransplant diagnoses of primary sclerosing cholangitis and/or acute hepatic necrosis (55); however, information from the large American database (54) does not include the diagnostic criteria for NODAT, whether it was transient or permanent, and how it was managed. We recommend yearly post-OLT screening for diabetes by oral glucose tolerance testing in the “at-risk” groups mentioned above.
The correct term used for the metabolic bone disease associated with chronic liver failure is hepatic osteodystrophy, which in adults involves osteoporosis, fractures, and osteomalacia (vitamin D deficiency of adult bone). In children, hepatic osteodystrophy affects not only existing bone material but also the bones’ growth plates. Therefore, hepatic osteodystrophy in children involves not only low bone mass and fractures but also rickets (vitamin D deficiency of growing bone), spine abnormalities, and growth failure.
Hepatic Osteodystrophy in Adults
As in other chronic conditions, the majority of the available information on skeletal complications of liver failure and OLT is derived from published experience in adults. In adults, hepatic osteodystrophy commonly presents as osteoporosis and fractures (9–11,26,56), sometimes aggravating preexisting osteoporosis of old age. Before OLT, low bone mineral density (areal BMD) is observed in 16% to 78% of patients (26,57–63). In the first 3 (to 6) months after OLT, rapid bone loss occurs (64–70), which is followed by slow and sometimes incomplete BMD recovery (71–75). Fractures are reported in 8% to 35% of patients pre-OLT (59,64,69,71), and in 7.5% to 65% post-OLT (56,64,69,71,72,76,77). Most fractures are vertebral compression fractures and associated with low lumbar spine BMD.
Hepatic Osteodystrophy in Children
Low Bone Mass and Fractures
BMD changes in children appear similar to adults but with greater potential for spontaneous recovery (78,79). Pretransplant areal BMD (grams per square centimeter) is often low or low-normal (78–81). In the first 3 months after OLT, BMD remains low or drops sharply before recovering to normal levels after 1 year in most studies (78,79,82,83). A more prolonged or insufficient recovery with low bone mass (BMD z score <−2) present in 7% to 15% of long-term survivors has also been reported (80,83). Some of this BMD increase could represent a size-related artefact so typical for dual-energy x-ray absorptiometry (DXA) because catch-up growth occurs during the same time period. Size-corrected volumetric BMD (bone mineral apparent density [BMAD], g/cm3) results show a similar post-OLT pattern (84,85), however. BMAD z scores <−2 at transplantation and at a mean of 6.5 years later were reported in 17% and 22% of children, respectively, in a large, mixed group of liver, kidney, and bone marrow transplant recipients (84).
Fractures occur frequently in children both before and after OLT. Pre-OLT, fracture prevalence ranges between 10% and 28% of children in most retrospective studies (80,81,84,86–88), and 40% in 1 case series (89). Post-OLT, reported fracture prevalence ranges between 12% and 38% (80,84,86) but was 50% in 1 case series (78). Most fractures were reported to be nonvertebral both pre-OLT (80,84,88) and post-OLT (86), which is in stark contrast to adult studies and likely reflects underreporting of asymptomatic vertebral fractures. More recent studies, using spine x-rays and vertebral morphometry, demonstrate a strong dominance of vertebral fractures (80,84), similar to that in adults. Eighty-nine percent of vertebral fractures were located in the thoracic spine (80). The previously mentioned mixed study of paediatric liver, kidney, and bone marrow transplant recipients (84) reported a 6-fold higher fracture rate for all of the fractures and a 160-fold higher rate for vertebral fractures. Half of the vertebral fractures were asymptomatic.
Predictors of fractures in children and adults undergoing OLT were summarised in a previous review (8). Overall, the association between low BMD and fractures is much better established in adults than in children. The published information in children is partly contradictory (80,83,84) but indicates adolescence and low lumbar spine BMD to be associated with vertebral fractures after OLT, suggesting that puberty is a particularly vulnerable phase. Much more evidence on fracture prediction needs to be established in paediatric multicentre trials. Whereas the severity of post-OLT bone disease has led to recommendations for preventive bisphosphonate treatment in the early post-OLT period irrespective of the prevailing BMD in adults (9), such preventive treatment cannot presently be recommended for children.
Low muscle force and immobility also have negative effects on bone mass. Muscle wasting (sarcopenia) is present in >80% of adults after OLT (65), which is likely caused by immobility and steroid-induced muscle catabolism (90). Muscle mass does not appear to recover after OLT in adults (90). Similar information for children is presently not available. Given children's greater ability to recover, it is assumed that muscle force improves with normalised hepatic protein synthesis, including IGF-1 production and catch-up growth after OLT (81).
Vitamin D Deficiency
One of the major causative factors for hepatic osteodystrophy is vitamin D deficiency. Vitamin D deficiency in chronic liver disease is caused by malabsorption of fat-soluble vitamins from deficient intestinal bile acids, malnutrition, lack of sunlight exposure, and, in end-stage liver failure, poor 25-hydroxylation (91). Once 25-hydroxy vitamin D (25OHD) levels fall below 50 nmol/L, parathyroid hormone (PTH) levels rise progressively to maintain normal serum calcium levels. PTH increases bone resorption and increases calcitriol (1,25(OH)2D) levels to maximise gut calcium absorption. Severe deficiency (25OHD <10 ng/mL or <25 nmol/L) causes rickets in children and osteomalacia in adults, by poor mineral supply to the bone, and excessive PTH-induced bone resorption and phosphate loss (Fig. 2). Low hepatic protein production may lead to reduced vitamin D–binding protein and albumin, major serum carriers of vitamin D metabolites, leading to falsely low total but elevated free 25OHD concentrations (92). Vitamin D binding protein saturation is low, however, and its influence on vitamin D status is considered insignificant (91). It is worth noting that vitamin K is also involved in osteocalcin production and calcium and bone matrix homeostasis, and requires adequate replacement from a bone perspective (93).
What Is the Right Vitamin D Preparation to Prevent/Treat Deficiency?
Vitamin D (25OHD) levels in children are low both pre- and post-OLT (78,79,81) but improve during the first year (81). Routine supplementation of vitamin D is recommended in children with liver failure in a high dose of 3 to 10 times the recommended daily allowance (RDA) (7). All preventive and therapeutic vitamin D should be given as ergocalciferol (vitamin D2) or cholecalciferol (vitamin D3) targeting a 25OHD level >50 nmol/L. Only these preparations replace vitamin D stores and are commonly used for the prevention and treatment of vitamin D deficiency rickets (nutritional rickets) around the world. In chronic liver failure, in particular infants with cholestatic liver disease, oral supplementation is often insufficient to overcome malabsorption and poor 25-hydroxylation. In these cases, more aggressive treatment with intramuscular injections of D2 or D3, in monthly doses of 60,000 to 150,000 U, is required (stoss therapy) which will eventually normalise 25OHD levels (91). Replacing vitamin D2 and D3 constitutes causative treatment and leads to supraphysiologic levels of active 1,25(OH)2D (94).
Alphacalcidol or calcitriol, as active vitamin D metabolites, do not replace vitamin D stores but are commonly used to increase calcium absorption in the gut or to treat coexisting renal failure. Treating vitamin D deficiency solely with alphacalcidol or calcitriol is analogous to pushing a car with an empty gas tank. Higher doses of these active vitamin D metabolites also pose a risk of overtreatment, leading to hypercalciuria and nephrocalcinosis.
Appropriate intake of the bone minerals calcium and phosphate should be ensured, in particular phosphate, which is the main culprit of all types of rickets (95). In the presence of a high PTH, phosphate is cleared rapidly from the circulation and needs to be given several times per day or per continuous infusion. Figure 3 demonstrates the successful treatment of severe vitamin D deficiency and malabsorption in a girl with cholestatic liver disease and hepatic osteodystrophy.
Avascular Necrosis and Scoliosis
Avascular necrosis (AVN) is a complication of high-dose steroid treatment and is frequently reported in adolescents treated for acute lymphoblastic leukaemia (96–99). Although steroid doses used during and after OLT are lower than for leukaemia therapy, AVN of the hip in adults is still reported in 1.4% of patients pre-OLT and 9% post-OLT (71). Helenius et al (100) reported evidence of AVN in children in 7 of 196 (3.6%) solid organ transplant recipients at an average of 9.2 years after transplantation. All of the affected patients were adolescents; 3 had undergone OLT.
Development of scoliosis is another poorly recognised complication of solid organ transplantation in children. Spine growth is most rapid during puberty, a recognised vulnerable period for vertebral fractures. In a large retrospective study of solid organ transplant recipients, 13.5% of patients after OLT had evidence of scoliosis (6), some requiring surgery (101). Another study in 40 young adults transplanted during childhood reported that 35% had at least 1 compressed or wedged vertebra, 20% had a history of vertebral fractures, 28% reported back pain at rest, but 38% had scoliosis of >10 degrees. Males appear to be more commonly affected (5). Further studies are needed to elucidate the relation among OLT, vertebral fractures, and later scoliosis development.
RECOMMENDATION FOR PREVENTION AND TREATMENT OF ENDOCRINE COMPLICATIONS AND HEPATIC OSTEODYSTROPHY
Responsible, careful medical management of progressive liver disease aims to avoid serious endocrine and bone complications. Paramount is optimal nutritional supply in energy, minerals, trace elements, and all fat-soluble vitamins but also appropriate timing of liver transplantation (Table 2).
Pretransplant growth and nutritional status is associated with mortality, and optimisation of nutrition is essential. Growth-promoting treatment is not indicated at this stage because OLT is the best available treatment of growth failure. Pubertal staging needs to be a part of routine assessment and patients with pubertal delay (no secondary sexual characteristics by the age of 13.5 years in girls and 14 years in boys) referred to the endocrinologist.
25OHD levels should be kept >20 ng/mL (50 nmol/L) and PTH <55 pg/mL (5.8 pmol/L) with whatever dose of ergocalciferol (D2) or cholecalciferol (D3) is needed. Recommended oral doses are 3 to 10 times the usual RDA (7), but monthly intramuscular application of 60,000 to 150,000 U may be required to normalise 25OHD levels if high oral doses are ineffective, especially in cholestatic conditions. As with all of the invasive procedures in this patient group, there is a small risk of causing haematomas. Alphacalcidol or calcitriol does not replace vitamin D stores. Their use in liver disease is restricted to increase gut calcium absorption to treat secondary hyperparathyroidism and hypocalcaemia, or associated renal failure. Check age-appropriate calcium/creatinine ratio from morning fasting urine (102) to avoid overtreatment. Mobility should be encouraged.
Growth improves after OLT, along with a reduction in steroid dose and better mobility. Careful monitoring of growth and pubertal development is required because approximately 20% of patients may not show catch-up growth within 2 to 3 years post-OLT. Whether this group could benefit from GH (or rhIGF-1) therapy needs to be studied in randomised controlled trials. Pubertal arrest or renal impairment needs to be detected and treated at all stages. Yearly oral glucose tolerance testing screening in “at-risk” groups for NODAT and ACTH testing after steroid withdrawal are recommended (Table 3).
Children after OLT are at increased risk of vertebral and nonvertebral fractures. Vertebral fractures (usually thoracic) often occur asymptomatically and are related to low spine BMD, but they may also cause chronic pain and later scoliosis. The growing spine of children and adolescents after OLT should be monitored for development of tenderness, scoliosis, and fractures.
Given the increased vertebral fracture risk, we believe that screening is justified, in particular in adolescents. In children older than 5 years, we recommend DXA scanning at the time of OLT and 12 and 24 months thereafter. Normative DXA data in children are widely available and require body size adjustment (103–106). In case of low size-corrected BMD/BMAD, lateral thoracic spine x-rays or, where available, instant vertebral assessment by DXA should be performed to detect vertebral fractures. In children younger than 5 years, hand x-rays and lateral thoracic spine x-rays are presently required because of the lack of normative DXA data and the need to sedate children for the scan.
The combined presence of low bone mass and ≥1 vertebral fracture, ≥1 lower extremity fracture, or ≥2 upper limb fractures allows the diagnosis of paediatric osteoporosis according to the paediatric position papers of the International Society of Clinical Densitometry (107) and justifies treatment with bisphosphonates. Such treatment (108) and all related diagnostic investigations must be initiated and supervised by a paediatric bone expert. Preventive bisphosphonate treatment for the immediate post-OLT period, as recommended in adults (9), presently cannot be justified in children.
SUMMARY AND RESEARCH AGENDA
Chronic liver disease, in particular cholestatic liver disease, has adverse effects on growth and bone metabolism, which tend to resolve slowly following OLT. Careful mineral and fat-soluble vitamin supplementation, especially vitamin D (D2, D3), is essential and should continue post-OLT until normal bone metabolism and growth are established. Post-OLT follow-up should include screening for pubertal arrest, diabetes, adrenal insufficiency after steroid withdrawal, and vertebral fractures. Bisphosphonate treatment is indicated for patients with fractures and low bone mass not caused by rickets. The role of GH for OLT in patients with persistent growth failure is not yet established. Several clinical questions need to be addressed in clinical research studies (Table 4).
1. Martin SR, Atkison P, Anand R, et al. Studies of pediatric liver transplantation 2002: patient and graft survival and rejection in pediatric recipients of a first liver transplant in the United States and Canada. Pediatr Transplant
2. Diem HV, Evrard V, Vinh HT, et al. Pediatric liver transplantation for biliary atresia: results of primary grafts in 328 recipients. Transplantation
3. Adeback P, Nemeth A, Fischler B. Cognitive and emotional outcome after pediatric liver transplantation. Pediatr Transplant
4. Campbell KM, Yazigi N, Ryckman FC, et al. High prevalence of renal dysfunction in long-term survivors after pediatric liver transplantation. J Pediatr
5. Helenius I, Remes V, Tervahartiala P, et al. Spine after solid organ transplantation in childhood: a clinical, radiographic, and magnetic resonance imaging analysis of 40 patients. Spine
6. Helenius I, Jalanko H, Remes V, et al. Scoliosis after solid organ transplantation in children and adolescents. Am J Transplant
7. Alonso EM. Growth and developmental considerations in pediatric liver transplantation. Liver Transpl
8. Högler W, Baumann U, Kelly D. Growth and bone health in chronic liver disease and following liver transplantation in children. Pediatr Endocrinol Rev
9. Ebeling PR. Approach to the patient with transplantation-related bone loss. J Clin Endocrinol Metab
10. Cohen A, Sambrook P, Shane E. Management of bone loss after organ transplantation. J Bone Miner Res
11. Cohen A, Shane E. Osteoporosis after solid organ and bone marrow transplantation. Osteoporos Int
12. Scheenstra R, Gerver WJ, Odink RJ, et al. Growth and final height after liver transplantation during childhood. J Pediatr Gastroenterol Nutr
13. Kelly DA. Nutrition and growth in patients with chronic liver disease. Indian J Pediatr
14. Pierro A, Koletzko B, Carnielli V, et al. Resting energy expenditure is increased in infants and children with extrahepatic biliary atresia. J Pediatr Surg
15. Protheroe SM, Kelly DA. Cholestasis and end-stage liver disease. Baillieres Clin Gastroenterol
16. Mager DR, Wykes LJ, Roberts EA, et al. Branched-chain amino acid needs in children with mild-to-moderate chronic cholestatic liver disease. J Nutr
17. van Mourik ID, Beath SV, Brook GA, et al. Long-term nutritional and neurodevelopmental outcome of liver transplantation in infants aged less than 12 months. J Pediatr Gastroenterol Nutr
18. Held MA, Cosme-Blanco W, Difedele LM, et al. Alterations in growth hormone receptor abundance regulate growth hormone signaling in murine obstructive cholestasis. Am J Physiol Gastrointest Liver Physiol
19. Maes M, Sokal E, Otte JB. Growth factors in children with end-stage liver disease before and after liver transplantation: a review. Pediatr Transplant
20. Bucuvalas JC, Horn JA, Chernausek SD. Resistance to growth hormone in children with chronic liver disease. Pediatr Transplant
21. Baruch Y, Assy N, Amit T, et al. Spontaneous pulsatility and pharmacokinetics of growth hormone in liver cirrhotic patients. J Hepatol
22. Assy N, Pruzansky Y, Gaitini D, et al. Growth hormone-stimulated IGF-I generation in cirrhosis reflects hepatocellular dysfunction. J Hepatol
23. Moller S, Juul A, Becker U, et al. The acid-labile subunit of the ternary insulin-like growth factor complex in cirrhosis: relation to liver dysfunction. J Hepatol
24. Foresta C, Schipilliti M, Ciarleglio FA, et al. Male hypogonadism in cirrhosis and after liver transplantation. J Endocrinol Invest
25. Le GL. Bone involvement in patients with chronic cholestasis. Joint Bone Spine
26. Monegal A, Navasa M, Guanabens N, et al. Osteoporosis and bone mineral metabolism disorders in cirrhotic patients referred for orthotopic liver transplantation. Calcif Tissue Int
27. Floreani A, Mega A, Tizian L, et al. Bone metabolism and gonad function in male patients undergoing liver transplantation: a two-year longitudinal study. Osteoporos Int
28. Burra P, Germani G, Masier A, et al. Sexual dysfunction in chronic liver disease: is liver transplantation an effective cure? Transplantation
29. Moukarzel AA, Najm I, Vargas J, et al. Effect of nutritional status on outcome of orthotopic liver transplantation in pediatric patients. Transplant Proc
30. Chin SE, Shepherd RW, Cleghorn GJ, et al. Survival, growth and quality of life in children after orthotopic liver transplantation: a 5 year experience. J Paediatr Child Health
31. Alonso EM, Shepherd R, Martz KL, et al. Linear growth patterns in prepubertal children following liver transplantation. Am J Transplant
32. Renz JF, de Roos M, Rosenthal P, et al. Posttransplantation growth in pediatric liver recipients. Liver Transpl
33. Codoner-Franch P, Bernard O, Alvarez F. Long-term follow-up of growth in height after successful liver transplantation. J Pediatr
34. McDiarmid SV, Gornbein JA, DeSilva PJ, et al. Factors affecting growth after pediatric liver transplantation. Transplantation
35. Viner RM, Forton JT, Cole TJ, et al. Growth of long-term survivors of liver transplantation. Arch Dis Child
36. Bartosh SM, Thomas SE, Sutton MM, et al. Linear growth after pediatric liver transplantation. J Pediatr
37. Rodeck B, Kardorff R, Melter M, et al. Improvement of growth after growth hormone treatment in children who undergo liver transplantation. J Pediatr Gastroenterol Nutr
38. Sarna S, Sipila I, Ronnholm K, et al. Recombinant human growth hormone improves growth in children receiving glucocorticoid treatment after liver transplantation. J Clin Endocrinol Metab
39. Puustinen L, Jalanko H, Holmberg C, et al. Recombinant human growth hormone treatment after liver transplantation in childhood: the 5-year outcome. Transplantation
40. Warner MH, Beckett GJ. Mechanisms behind the non-thyroidal illness syndrome: an update. J Endocrinol
41. Williams GR, Franklyn JA, Neuberger JM, et al. Thyroid hormone receptor expression in the “sick euthyroid” syndrome. Lancet
42. Caregaro L, Alberino F, Amodio P, et al. Nutritional and prognostic significance of serum hypothyroxinemia in hospitalized patients with liver cirrhosis. J Hepatol
43. Adler SM, Wartofsky L. The nonthyroidal illness syndrome. Endocrinol Metab Clin North Am
44. Bello G, Ceaichisciuc I, Silva S, et al. The role of thyroid dysfunction in the critically ill: a review of the literature. Minerva Anestesiol
45. De Groot LJ. Non-thyroidal illness syndrome is a manifestation of hypothalamic-pituitary dysfunction, and in view of current evidence, should be treated with appropriate replacement therapies. Crit Care Clin
46. Hamrahian AH, Oseni TS, Arafah BM. Measurements of serum free cortisol in critically ill patients. N Engl J Med
47. Tan T, Chang L, Woodward A, et al. Characterising adrenal function using directly measured plasma free cortisol in stable severe liver disease. J Hepatol
48. Raff H. Utility of salivary cortisol measurements in Cushing's syndrome and adrenal insufficiency. J Clin Endocrinol Metab
49. O’Beirne J, Holmes M, Agarwal B, et al. Adrenal insufficiency in liver disease—what is the evidence? J Hepatol
50. McNeilly AD, Macfarlane DP, O’Flaherty E, et al. Bile acids modulate glucocorticoid metabolism and the hypothalamic-pituitary-adrenal axis in obstructive jaundice. J Hepatol
51. Marik PE, Pastores SM, Annane D, et al. Recommendations for the diagnosis and management of corticosteroid insufficiency in critically ill adult patients: consensus statements from an international task force by the American College of Critical Care Medicine. Crit Care Med
52. Cetinkaya S, Ozon A, Yordam N. Diagnostic value of salivary cortisol in children with abnormal adrenal cortex functions. Horm Res
53. Marcus-Perlman Y, Tordjman K, Greenman Y, et al. Low-dose ACTH (1 microg) salivary test: a potential alternative to the classical blood test. Clin Endocrinol (Oxf)
54. Deutschbein T, Unger N, Mann K, et al. Diagnosis of secondary adrenal insufficiency in patients with hypothalamic-pituitary disease: comparison between serum and salivary cortisol during the high-dose short synacthen test. Eur J Endocrinol
55. Kuo HT, Lau C, Sampaio MS, et al. Pretransplant risk factors for new-onset diabetes mellitus after transplant in pediatric liver transplant recipients. Liver Transpl
56. Porayko MK, Wiesner RH, Hay JE, et al. Bone disease in liver transplant recipients: incidence, timing, and risk factors. Transplant Proc
57. Ninkovic M, Love SA, Tom B, et al. High prevalence of osteoporosis in patients with chronic liver disease prior to liver transplantation. Calcif Tissue Int
58. Sokhi RP, Anantharaju A, Kondaveeti R, et al. Bone mineral density among cirrhotic patients awaiting liver transplantation. Liver Transpl
59. Millonig G, Graziadei IW, Eichler D, et al. Alendronate in combination with calcium and vitamin D prevents bone loss after orthotopic liver transplantation: a prospective single-center study. Liver Transpl
60. Pereira SP, Bray GP, Pitt PI, et al. Non-invasive assessment of bone density in primary biliary cirrhosis. Eur J Gastroenterol Hepatol
61. Bagur A, Mautalen C, Findor J, et al. Risk factors for the development of vertebral and total skeleton osteoporosis in patients with primary biliary cirrhosis. Calcif Tissue Int
62. Mobarhan SA, Russell RM, Recker RR, et al. Metabolic bone disease in alcoholic cirrhosis: a comparison of the effect of vitamin D2, 25-hydroxyvitamin D, or supportive treatment. Hepatology
63. Gallego-Rojo FJ, Gonzalez-Calvin JL, Munoz-Torres M, et al. Bone mineral density, serum insulin-like growth factor I, and bone turnover markers in viral cirrhosis. Hepatology
64. Ninkovic M, Skingle SJ, Bearcroft PW, et al. Incidence of vertebral fractures in the first three months after orthotopic liver transplantation. Eur J Gastroenterol Hepatol
65. Guichelaar MM, Kendall R, Malinchoc M, et al. Bone mineral density before and after OLT: long-term follow-up and predictive factors. Liver Transpl
66. Floreani A, Fries W, Luisetto G, et al. Bone metabolism in orthotopic liver transplantation: a prospective study. Liver Transpl Surg
67. Crosbie OM, Freaney R, McKenna MJ, et al. Predicting bone loss following orthotopic liver transplantation. Gut
68. Arnold JC, Hauser D, Ziegler R, et al. Bone disease after liver transplantation. Transplant Proc
69. Meys E, Fontanges E, Fourcade N, et al. Bone loss after orthotopic liver transplantation. Am J Med
70. Monegal A, Navasa M, Guanabens N, et al. Bone disease after liver transplantation: a long-term prospective study of bone mass changes, hormonal status and histomorphometric characteristics. Osteoporos Int
71. Guichelaar MM, Schmoll J, Malinchoc M, et al. Fractures and avascular necrosis before and after orthotopic liver transplantation: long-term follow-up and predictive factors. Hepatology
72. Eastell R, Dickson ER, Hodgson SF, et al. Rates of vertebral bone loss before and after liver transplantation in women with primary biliary cirrhosis. Hepatology
73. Giannini S, Nobile M, Dalle CL, et al. Vertebral morphometry by X-ray absorptiometry before and after liver transplant: a cross-sectional study. Eur J Gastroenterol Hepatol
74. Hamburg SM, Piers DA, van den Berg AP, et al. Bone mineral density in the long term after liver transplantation. Osteoporos Int
75. Feller RB, McDonald JA, Sherbon KJ, et al. Evidence of continuing bone recovery at a mean of 7 years after liver transplantation. Liver Transpl Surg
76. Leidig-Bruckner G, Hosch S, Dodidou P, et al. Frequency and predictors of osteoporotic fractures after cardiac or liver transplantation: a follow-up study. Lancet
77. Hardinger KL, Ho B, Schnitzler MA, et al. Serial measurements of bone density at the lumbar spine do not predict fracture risk after liver transplantation. Liver Transpl
78. D’Antiga L, Moniz C, Buxton-Thomas M, et al. Bone mineral density and height gain in children with chronic cholestatic liver disease undergoing transplantation. Transplantation
79. Argao EA, Balistreri WF, Hollis BW, et al. Effect of orthotopic liver transplantation on bone mineral content and serum vitamin D metabolites in infants and children with chronic cholestasis. Hepatology
80. Valta H, Jalanko H, Holmberg C, et al. Impaired bone health in adolescents after liver transplantation. Am J Transplant
81. Okajima H, Shigeno C, Inomata Y, et al. Long-term effects of liver transplantation on bone mineral density in children with end-stage liver disease: a 2-year prospective study. Liver Transpl
82. Ulivieri FM, Lisciandrano D, Gridelli B, et al. Bone mass and body composition in children with chronic cholestasis before and after liver transplantation. Transplant Proc
83. Guthery SL, Pohl JF, Bucuvalas JC, et al. Bone mineral density in long-term survivors following pediatric liver transplantation. Liver Transpl
84. Helenius I, Remes V, Salminen S, et al. Incidence and predictors of fractures in children after solid organ transplantation: a 5-year prospective, population-based study. J Bone Miner Res
85. D’Antiga L, Ballan D, Luisetto G, et al. Long-term outcome of bone mineral density in children who underwent a successful liver transplantation. Transplantation
86. Hill SA, Kelly DA, John PR. Bone fractures in children undergoing orthotopic liver transplantation. Pediatr Radiol
87. Shneider BL, Neimark E, Frankenberg T, et al. Critical analysis of the pediatric end-stage liver disease scoring system: a single center experience. Liver Transpl
88. Bales CB, Kamath BM, Munoz PS, et al. Pathologic lower extremity fractures in children with Alagille syndrome. J Pediatr Gastroenterol Nutr
89. Klein GL, Soriano H, Shulman RJ, et al. Hepatic osteodystrophy in chronic cholestasis: evidence for a multifactorial etiology. Pediatr Transplant
90. Hussaini SH, Soo S, Stewart SP, et al. Risk factors for loss of lean body mass after liver transplantation. Appl Radiat Isot
91. Compston JE. Hepatic osteodystrophy: vitamin D metabolism in patients with liver disease. Gut
92. Bikle DD, Halloran BP, Gee E, et al. Free 25-hydroxyvitamin D levels are normal in subjects with liver disease and reduced total 25-hydroxyvitamin D levels. J Clin Invest
93. Kidd PM. Vitamins D and K as pleiotropic nutrients: clinical importance to the skeletal and cardiovascular systems and preliminary evidence for synergy. Altern Med Rev
94. Papapoulos SE, Clemens TL, Fraher LJ, et al. Metabolites of vitamin D in human vitamin-D deficiency: effect of vitamin D3 or 1,25-dihydroxycholecalciferol. Lancet
95. Tiosano D, Hochberg Z. Hypophosphatemia: the common denominator of all rickets. J Bone Miner Metab
96. Arico M, Boccalatte MF, Silvestri D, et al. Osteonecrosis: an emerging complication of intensive chemotherapy for childhood acute lymphoblastic leukemia. Haematologica
97. Burger B, Beier R, Zimmermann M, et al. Osteonecrosis: a treatment related toxicity in childhood acute lymphoblastic leukemia (ALL)-experiences from trial ALL-BFM 95. Pediatr Blood Cancer
98. Högler W, Wehl G, van Staa T, et al. Incidence of skeletal complications during treatment of childhood acute lymphoblastic leukemia: comparison of fracture risk with the General Practice Research Database. Pediatr Blood Cancer
99. Mattano LA Jr, Sather HN, Trigg ME, et al. Osteonecrosis as a complication of treating acute lymphoblastic leukemia in children: a report from the Children's Cancer Group. J Clin Oncol
100. Helenius I, Jalanko H, Remes V, et al. Avascular bone necrosis of the hip joint after solid organ transplantation in childhood: a clinical and MRI analysis. Transplantation
101. Peltonen J, Remes V, Holmberg C, et al. Surgical correction of spinal deformities after solid organ transplantation in childhood. Eur Spine J
102. Kruse K. Vitamin D and parathyroid. In: Ranke MB, ed. Diagnostics of Endocrine Function in Children and Adolescents
. Basel: Karger; 2003:240–258.
103. Crabtree NJ, Kibirige MS, Fordham JN, et al. The relationship between lean body mass and bone mineral content in paediatric health and disease. Bone
104. Zemel BS, Leonard MB, Kelly A, et al. Height adjustment in assessing dual energy x-ray absorptiometry measurements of bone mass and density in children. J Clin Endocrinol Metab
105. Högler W, Briody J, Woodhead HJ, et al. Importance of lean mass in the interpretation of total body densitometry in children and adolescents. J Pediatr
106. Gordon CM, Bachrach LK, Carpenter TO, et al. Dual energy x-ray absorptiometry interpretation and reporting in children and adolescents: the 2007 ISCD Pediatric Official Positions. J Clin Densitom
107. Baim S, Binkley N, Bilezikian JP, et al. Official Positions of the International Society for Clinical Densitometry and executive summary of the 2007 ISCD Position Development Conference. J Clin Densitom
108. Bachrach LK, Ward LM. Clinical review 1: bisphosphonate use in childhood osteoporosis. J Clin Endocrinol Metab
This article has been cited 6 time(s).
Nature Reviews RheumatologyCauses, mechanisms and management of paediatric osteoporosisNature Reviews Rheumatology
Tissue Engineering Part B-ReviewsAmniotic Fluid-Derived Stem Cells for Cardiovascular Tissue Engineering ApplicationsTissue Engineering Part B-Reviews
Nutrition in Clinical PracticeNutrition Assessment and Support in Children With End-Stage Liver DiseaseNutrition in Clinical Practice
Liver TransplantationLong-term medical management of the pediatric patient after liver transplantation: 2013 practice guideline by the American Association for the Study of Liver Diseases and the American Society of TransplantationLiver Transplantation
Pediatric TransplantationPediatric post-transplant metabolic syndrome: New clouds on the horizonPediatric Transplantation
Journal of Pediatric Gastroenterology and NutritionLiver, Hormones, and BonesJournal of Pediatric Gastroenterology and Nutrition
adrenal; chronic liver failure; fractures; growth hormone; liver transplantation; rickets; short stature; sick euthyroid syndrome; vitamin D
Copyright 2012 by ESPGHAN and NASPGHAN
What does "Remember me" mean?
By checking this box, you'll stay logged in until you logout. You'll get easier access to your articles, collections,
media, and all your other content, even if you close your browser or shut down your
To protect your most sensitive data and activities (like changing your password),
we'll ask you to re-enter your password when you access these services.
What if I'm on a computer that I share with others?
If you're using a public computer or you share this computer with others, we recommend
that you uncheck the "Remember me" box.
Highlight selected keywords in the article text.
Data is temporarily unavailable. Please try again soon.
Readers Of this Article Also Read