The Impact of Liver Disease on Growth and Nutrition

Abstract

Chronic liver disease, particularly cholestatic liver disease, in infants and children is often associated with protein-calorie malnutrition, poor growth, vitamin deficiencies, and bone disease. The most common liver disease in infancy, biliary atresia, has an incidence of approximately 1 in 10,000 to 20,000. In addition, other uncommon diseases of infancy, including Alagille syndrome, progressive familial intrahepatic cholestasis (PFIC) syndromes, and neonatal hepatitis syndrome initially may compromise nutrition because of cholestasis with an attendant decrease in intraluminal bile acid content resulting in fat and fat-soluble vitamin malabsorption. With progressive liver injury secondary to chronic cholestasis and in other conditions such as α-1-antitrypsin deficiency, end-stage liver disease may develop with its concomitant effects on nutrition and growth. Pediatric patients with chronic liver failure or cirrhosis and related complications, including portal hypertension, ascites, and varices, manifest a myriad of nutritional complications that must be studied. Therapeutic options, including chronic use of medications to control these complications and surgical procedures (including transjugular intrahepatic portosystemic shunts [TIPS]), alter the nutritional status in these growing patients in ways that have not been investigated systematically. Cadaveric and living-related orthotopic liver transplantation (OLT) offer potentially viable treatment alternatives for these patients, with significant improvement in absorption and direct impact on nutrition and growth. Long-term effects of OLT on nutrition are currently unknown. Analysis of data from transplant recipients may allow determination of differences in outcome (rejection, immunosuppressive regimen, and subsequent effects on growth) based on graft type (cadaveric vs. living-related donor). Chronic cholestatic liver disease or liver failure may lead to decreased oral intake and malnutrition and to growth hormone resistance with its potential effects on linear growth. Fat-soluble vitamin deficiency states are relatively uncommon; however, the precise frequency of each deficiency state is unknown. Vitamin A deficiency may be more common than reported previously if based on the relative dose response technique. Osteopenia frequently accompanies cholestasis and, in some cases, repeated long bone fractures seriously compromises quality of life. Preliminary studies suggest that magnesium deficiency may be one of several factors, including growth hormone resistance, that contribute to osteopenia. To better define the cause and treatment of nutrition-related problems in children with chronic liver disease, research strategies should be directed at the following: Defining the mechanisms by which chronic liver disease and cholestasis cause protein-calorie malnutrition, growth failure, vitamin deficiencies, and bone disease, before and after OLT Developing evidence-based strategies for easy, reliable, and early detection of fat-soluble vitamin and mineral deficiency (e.g., zinc, calcium, magnesium, phosphorus) Exploring the mechanism underlying growth hormone resistance and the potential benefit of growth factors such as insulinlike growth factor 1 (IGF-1) in facilitating growth Determining the nutritional implications of chronic liver failure or complications of chronic liver disease with or without cirrhosis Determining the nutritional effects of medical management of complications of liver disease, including medical management of portal hypertension, ascites, and varices Assessing the effects of TIPS and other surgical alternatives for treating portal hypertension Assessing the effects of nutritional status on results of OLT, including interventions that may improve nutrition before transplantation Assessing the nutritional consequences of OLT in children, including the effect of hyperlipidemia on cardiovascular risk, the long-term effect of immunosuppressive medications on bone accretion and development of osteoporosis, and the potential adverse growth effects of immunosuppressive medications (e.g., renal or other adverse effects) AREAS OF EMPHASIS Chronic liver failure and cholestatic liver diseases in childhood affect growth and lead to nutritional deficiencies. Malnutrition leads to increased susceptibility to infection and increased morbidity and mortality. Consequences of malabsorption may compromise quality of life because of diarrhea, bleeding, bone disease, and even neurologic disease. Malnutrition may significantly affect outcomes with OLT. Post-OLT nutritional deficiencies may contribute to significant morbidity. The following research areas are suggested: Defining the Cause of Growth Failure and Nutritional Deficiencies and Their Treatment in Infants and Children With Chronic Liver Failure or Cholestatic Liver Disease Despite timely surgical intervention in the management of biliary atresia, at least one half to two thirds of infants have unsuccessful portoenterostomy and have poor postoperative bile drainage with persistent severe cholestasis or have partially successful outcome with clearance of jaundice but ongoing hepatocellular injury. In both circumstances, and in conditions such as PFIC, relentless liver injury ultimately leads to end-stage liver disease. Cholestatic liver disease significantly affects growth and nutrition, particularly fat, fat-soluble vitamin, and mineral absorption. Unfortunately, only modest advances have been made in understanding the consequences of cholestasis in children. Although it is well recognized that fat is malabsorbed, the impact on energy requirements and essential fatty acid sufficiency has been defined poorly (1). Although pediatric patients with cholestatic liver disease have increased energy requirements secondary to both malabsorption and underlying disease, the mechanisms involved in these issues require clarification. Providing adequate calories remains problematic in many patients with chronic liver failure, portal hypertension, or cholestatic liver disease, even when supplemented with nasogastric tube feedings. The role of supplementing with branched-chain amino acid–enriched formulas for infants and children with cholestasis or chronic liver failure and its effects on accretion of lean body mass require further investigation. The potential role of growth factors and zinc in improving nutrition and growth is poorly defined (2,3). Generally, empiric treatment with vitamin and mineral supplements has been effective in preventing vitamin deficiencies but it is unclear what impact it has on mineral status. Malabsorption of vitamins E, D, and K is well documented and can lead to significant acute and chronic effects. Vitamin E deficiency may cause neurologic deficits if left untreated; however, effective water-soluble forms of vitamin E have led to improved management (4). Rickets due to vitamin D deficiency is rare in children with chronic cholestasis who are adequately treated; however, essentially all pediatric patients with significant long-term cholestasis have decreased age-matched, sex-matched bone mineral density (5). Although vitamin K deficiency may lead to catastrophic bleeding, particularly in the central nervous system, the effects of vitamin K on other processes such as bone disease are not well characterized. Vitamin A status is difficult to assess in cholestatic liver disease because plasma retinol levels are not necessarily reflective of either deficiency or excess states, and tests such as the intravenous relative dose response and conjunctival impression cytology are not readily available (6). Malabsorption of calcium, phosphorus, and magnesium and decreased plasma concentrations of essential fatty acids would be predicted because of the presence of steatorrhea. Calcium malabsorption has not been proven, and studies that examine the absorption of phosphorus and magnesium have not been performed (7). Urinary excretion of zinc is increased in chronic cholestasis; however, the cause and consequences of this abnormality in zinc homeostasis are unknown. Recent preliminary results suggest that magnesium deficiency, probably caused by chronic malabsorption, may contribute to the decreased bone density in childhood cholestasis (8). Evidence-based recommendations for either monitoring or dosing of vitamins or minerals in chronic childhood cholestasis are lacking or sparse at best (4,9). Determining the Impact of Acute and Chronic Malnutrition on OLT Outcomes Infants and children with chronic cholestatic disorders, metabolic liver disease, or hepatitis may develop end-stage liver disease and require OLT. Although extensive research has been performed on the effect of nutritional status on operative outcomes in adults, little work has been undertaken in infants and children. Specifically, the effect of nutritional status on postoperative morbidity and mortality in pediatric OLT is limited to a single study, the results of which showed that infection rates, surgical complications, and mortality were significantly increased with increasing malnutrition (10). The effect of pre-OLT nutritional status on cognitive and neurodevelopmental outcome after OLT has received little attention, yet is of great importance. Furthermore, no interventional studies have been undertaken to determine whether nutritional rehabilitation with growth factors, total parenteral nutrition, or enteral nutrition, or treatment with trophic factors (such as glutamine) decrease morbidity (including infectious complications, duration of hospitalization), mortality, and cost of post–liver transplantation care. Determining the Short- and Long-term Impact of OLT on Growth and Nutrition Although liver transplantation may reverse or alter nutritional problems in children with chronic liver disease, organ availability (for the foreseeable future) will continue to limit its timely use. Orthotopic liver transplantation leads to short-term reversal of malabsorption, growth failure, and bone disease in children (11–14). Complications of OLT may compromise nutrition, requiring enteral or parenteral supplementation. Immunosuppressive agents, such as cyclosporine, tacrolimus, and corticosteroids, may have specific effects on mineral metabolism, including renal wasting of magnesium and direct effects on bone formation and zinc homeostasis. Few data are currently available about the long-term effects (>5 to 10 years) of OLT and immunosuppressive medications on growth, cardiovascular risk, and bone disease in children (15). Although early reversal of bone disease has been observed, the long-term effects of chronic immunosuppressive medications on accretion of peak bone mass are unknown. Similarly, growth is improved in the first years after OLT; however, the long-term impact of renal compromise, its attendant acidosis, and decreased glomerular filtration rate is currently unknown. The short- and long-term effects of hyperlipidemia associated with the use of immunosuppressive drugs also has not been clearly defined for children and must be examined. RESEARCH GOALS Specific goals for research should include examination of the following: Nutritional requirements and potential interventions to improve growth and nutrition in infants and children with chronic liver failure, including its associated complications, and in children with chronic cholestatic liver disease The effects of malnutrition on OLT outcomes The nutritional effects and consequences of chronic immunosuppressive therapy and other complications after OLT RESEARCH STRATEGIES Origin and Treatment of Growth Failure in Pediatric Patients With Chronic Cholestatic Liver Disease Fat and fat-soluble vitamin malabsorption and accompanying mineral malabsorption contribute to growth failure in children with cholestasis. Growth hormone resistance may also compromise linear growth. The quality and quantity of optimal energy and protein requirements and the biologic requirements for fat-soluble vitamins and minerals, including calcium, potassium, magnesium, and zinc, in these conditions are poorly characterized. Clarifying these requirements for energy, protein, amino acids, vitamins, and minerals and defining optimal monitoring strategies would improve treatment. This area of investigation should include measuring total energy expenditure and nitrogen metabolism using stable isotopes and identifying facile monitoring methods, particularly for vitamins such as vitamin A and K for which no easy, effective methods are available currently. Well-designed studies of bone disease with adequate sample size should be undertaken to address the roles of growth factors, cytokines, minerals (e.g., calcium, magnesium) and vitamins (e.g., vitamins D and K) on bone accretion using technology such as dual-energy x-ray absorptiometry, quantitative computer tomography, and bone histomorphometry. Understanding the mechanism and natural history of growth hormone resistance and the roles of growth factors in facilitating growth is central to understanding growth failure in these patients. Interaction of Nutrition and Outcomes in Chronic Liver Failure Few studies have investigated the degree of nutritional depletion and the effectiveness of nutritional rehabilitation in chronic liver failure. The effects of complications of chronic liver failure in pediatric patients, including ascites and portal hypertension, on nutritional status, growth, and bone mineralization remain to be clarified. Finally, the treatment of pediatric patients with chronic liver failure will influence the nutritional status and growth of these patients, although the overall effects of these therapies have not been investigated systematically. In addition, few follow-up data regarding the implementation of nutritional therapies are available for these situations. Surgical treatments of complications of chronic liver disease or cholestasis (e.g., TIPS, surgical shunts, partial splenic embolization, biliary diversion procedures, hepatoportoenterostomy) often are used, and the nutritional interactions of these therapies are largely unknown. Impact of Acute and Chronic Malnutrition on OLT Outcome In adults, a clear association has been shown between preoperative nutritional state and surgical outcome, including costs, length of stay, and infectious complications. Little work has been undertaken in children for either medical or surgical outcomes in relation to nutritional status. Minimal information is available on preoperative nutritional status (including nutritional assessment) and outcome for OLT in children. Either well-designed retrospective studies using existing data should be completed or well-designed prospective studies should be undertaken to determine the impact of preoperative nutritional status on surgical complications, infectious complications, length of stay, total cost, and mortality. If the assumption is that preoperative nutritional status correlates with outcome, well-designed studies that examine the potential role of either intensive nutritional support or the use of specific growth factors or nutrients in patients awaiting transplantation should be considered. Short- and Long-Term Impact of OLT on Nutrition Recent work has suggested that growth failure and bone disease reverse during the first years after transplantation. Overall quality of life is significantly improved after OLT. The potent immunosuppressive agents tacrolimus and cyclosporine are associated with significant side effects that lead to infectious complications, hypertension, hyperlipidemia, and renal dysfunction. Outcomes after OLT should be considered for much longer terms in children than in adults. In addition, because most children grow substantially after OLT, the impacts of immunosuppressive medications are likely to be more pronounced in children. Long-term follow-up (10+ years) studies should be organized to evaluate the impact of OLT on plasma lipids, renal function, growth and maturation (i.e., puberty), and bone disease. As a direct consequence of this descriptive work, specific attention should be aimed at addressing the effects of immunosuppressive medications on cholesterol homeostasis and bile acid metabolism, their effects on renal blood flow and glomerular filtration rates with potential impact on growth, and their effects on bone accretion and resorption, using such techniques as dual-energy x-ray absorptiometry, serum-based bone markers, and bone histomorphometry. The effects of pretransplant nutritional status and posttransplantation nutritional rehabilitation on neurocognitive development and outcome must be defined clearly, particularly in children with onset of liver disease in infancy. PROJECTED TIMETABLE AND FUNDING REQUIREMENTS To study the areas of emphasis, multicenter collaborative studies are essential. For each of the emphasis areas, carefully designed studies involving at least 5 to 10 centers will be required to provide meaningful results in a short time frame. Thus, a network should be developed of pediatric liver centers that care for sufficient numbers of patients before and after liver transplantation, and that would receive sufficient funding from federal sources, industry, and private foundations to establish the necessary research infrastructure for collecting and analyzing data and for performing clinical trials. Each emphasis area relates to patient-oriented research, so each participating center will need a program coordinator; each center should have a National Institutes of Health–funded pediatric clinical research center or a general clinic research center with extensive experience in conducting research in children. The funding necessary to establish the research infrastructure and accomplish these research goals would be approximately $1 million to $2 million per year. HEALTH AND ECONOMIC OUTCOMES Improved understanding of these nutritional issues would have direct health (including quality of life) and economic benefits to children with chronic liver disorders and their families. Savings related to improved clinical outcomes of therapy for chronic liver disease and its complications or after OLT could substantially decrease associated direct and indirect costs. Recognition of undernutrition and understanding its causes and treatment in children with cholestatic liver disease or chronic liver failure could improve growth, decrease morbidity, delay OLT, and improve the quality of life of affected children. Identifying the importance of and methods to decrease pre-OLT malnutrition may lead to decreased operative morbidity, including delayed wound healing and infectious complications, and to decreased OLT-related costs. Determining the long-term effects of medical and surgical therapies for chronic liver disease and liver failure, and of immunosuppressive agents, on growth, development (mental and physical), and nutrition should prompt elaboration of strategies to prevent or reverse the consequences. CONCLUSION Chronic liver disease in children can have significant impact on nutritional status, growth, and development. Acute and chronic malnutrition may increase the morbidity and mortality associated with chronic liver disease and liver transplantation. Research should be directed at identifying factors that contribute to malnutrition and at developing evidence-based interventions to prevent or treat malnutrition using simple, safe, and effective methods.