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).
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