Children with chronic liver disease are at high risk for malnutrition, particularly when the liver disease is cholestatic and its onset is in infancy. Several recent studies have shown a significant prevalence of malnutrition among these children. Sokol and Stall (1) conducted an anthropometric evaluation of 56 children with chronic liver disease that had manifested within the first 6 months of life. Most of the children were underweight and had stunted height. Nearly 60% of the children had depleted fat stores, indicated by measurement of the triceps skinfold thickness, and 20% had evidence of more chronic malnutrition, indicated by a reduction in midarm circumference.
Malnutrition is a multifactorial process in children with chronic liver disease (Fig. 1) and alone carries an increased risk of morbidity and mortality. Maintaining optimal nutrition in children with chronic liver disease may prevent further derangement of liver function by increasing the metabolic energy available for synthetic, storage, and detoxification functions, by improving the immunologic status, and by facilitating the healing process (2). The advent of pediatric liver transplantation has placed additional emphasis on the importance of optimum nutritional management of children with chronic liver disease, because improvement of nutritional status in the pretransplantation period maximizes success of the liver transplant itself (3). Moukarzel et al. (4) have demonstrated a strict correlation between nutritional status and outcome of orthotopic liver transplantation in children. In their study, children with a pathologic height z score (a parameter of chronic malnutrition) had a higher incidence of posttransplantation infections, surgical complications, and mortality. In addition to increased morbidity and mortality both before and after transplantation, malnutrition in children with end-stage liver disease can contribute to long-term posttransplantation complications, particularly linear growth failure, mental developmental delay, and metabolic bone disease.
All these findings and the consideration that malnutrition is potentially the most important treatable pretransplantation factor underscore the importance of optimal nutritional therapy for children with chronic liver disease. In this article we review the current approach to nutritional assessment of children with chronic liver disease, discuss the nutritional support recommended for the pretransplantation and posttransplantation periods, and suggest possible interventions for preventing long-term nutritional complications, such as linear growth failure and metabolic bone disease.
ASSESSING THE NUTRITIONAL STATUS OF CHILDREN WITH CHRONIC LIVER DISEASE
Assessing the nutritional status of patients with chronic liver disease is difficult and controversial, because the conventional parameters used to make the assessment frequently are altered by other factors. Among the anthropometric measurements used to assess nutritional status, body weight fails to be a sensitive parameter because of edema, ascites, and hepatosplenomegaly. Height is a more reliable parameter than weight and can help identify children with chronic malnutrition. Skinfold thickness and midarm circumference are considered to be more accurate measurements than height, because variations in these parameters appear earlier than changes in height. However, peripheral edema may falsely increase skinfold thickness. To minimize the influence of edema in anthropometric assessment, measurements of skinfold thickness in the upper body are indicated, because excess fluid more readily accumulates in the lower body. Calipers must also be left on the fold longer to allow tissue fluid to be displaced.
To be complete, a nutrition assessment must include the patient's dietary history, a calculation of usual energy and protein intake, a record of any nutrition-related problems (i.e., nausea, vomiting, diarrhea, or anorexia), and a careful physical examination to identify any sign of vitamin or mineral deficiency (Table 1). Other conventional nutrition parameters, such as protein and immune status are unreliable tools for assessing the nutritional status of children with end-stage liver disease. Protein status is usually estimated by measuring serum levels of several proteins synthesized by the liver, such as albumin, prealbumin, and retinol-binding protein. Decreased levels of these serum proteins are better correlated with the extent of liver disease than with the patient's nutritional status. Immune status is assessed by testing for delayed skin hypersensitivity and is often used to monitor nutritional status. However, because liver disease, irrespective of nutritional status, can result in lymphopenia, abnormally delayed hypersensitivity to skin tests, and a decreased concentration of complement, immunologic studies are of limited use in patients with cirrhosis (5).
NUTRITIONAL ASSESSMENT BY USING BODY COMPOSITION METHODOLOGIES
Conventional techniques for assessing nutritional status generally are not reliable for patients with liver disease, particularly when the synthetic function of the liver is poor and fluid retention is marked. The gold standard for measuring nutritional status both in pathologic and physiologic status, is body composition analysis. The body is composed of four compartments: fat, cell mass, extra-cellular water, and fat-free extracellular solids. Because the body fat compartment is anhydrous, it is not influenced by the edematous status typical of patients with cirrhosis. Fat is the major form of stored energy, and its measurement therefore represents the ideal method to assess a nutritional status in children affected by cirrhosis.
Many methods of measurements of fat and fat-free mass exist; however, some available techniques, such as bioelectrical impedance, are not applicable in patients with liver disease because they are too sensitive to changes in body water. Total body potassium and neutron activation methodologies are currently considered the most accurate tools for evaluating body composition; however, their clinical use is restricted by high cost and the unavailability of these facilities. Total-body electrical conductivity (TOBEC) is another method available to quantitate lean body mass and total body fat. Total body fat calculated by the TOBEC method should be accurate in patients with cirrhosis, because this parameter is not influenced by the hydration status of the subject. The method is safe, rapid, and noninvasive; its major limitation is its unavailability; TOBEC machines are only in a few specialized research centers (6–9). Dual energy x-ray absorptiometry (DEXA scan) is a noninvasive method with minimal radiation that provides accurate measurement of body composition and bone density. This method is available in many pediatric centers and not only has the advantage of assessing nutritional status through the measurement of fat mass but also monitors bone mass. As discussed later, osteopenia is a chronic problem in patients who undergo transplantation. Periodic measurement of bone mass is helpful in preventing or treating this problem. The clinical application of body composition analysis would be ideal, because these techniques permit an early and accurate diagnosis of malnutrition, allowing the institution of aggressive nutritional support before late clinical signs of malnutrition occur.
NUTRITIONAL SUPPORT OF CHILDREN WITH CHRONIC LIVER DISEASE
Careful assessment and monitoring of nutritional status and aggressive nutritional support are essential to the care of children with chronic liver disease who await transplantation. The main goals of providing nutritional support to these patients are multiple: to prevent further liver injury and promote liver regeneration, to slow the overall deterioration of the patient, to minimize the risk of infection, and to avoid vitamin and mineral deficiencies and, thereby, maximize growth potential.
Optimal nutritional therapy involves maintaining high caloric and protein intake while preventing specific nutrient deficiencies. Children with end-stage liver disease require 130% to 150% of the recommended dietary allowances of energy for their ideal body weight and 2.5 to 3.0 g/kg of protein (10). This amount of protein can blunt the catabolic state typical in these children and improve growth rate. In children, it is rarely necessary to limit protein intake because of signs of hepatic encephalopathy. Although the benefit of a diet enriched with branched-chain amino acids needs further evaluation in children, to date there are no data to justify the cost of using them routinely (11). High energy intake can be achieved by adding either glucose polymers or medium-chain triglycerides. Medium-chain triglyceride oil is well absorbed in patients with cholestasis; however, long-chain triglycerides should not be decreased to less than 10% of total energy intake, to prevent deficiencies in essential fatty acids.
The presence of advanced chronic liver disease leads to water–electrolyte imbalances clinically characterized by ascites and peripheral edema. The pathophysiology of water and sodium retention are complex, and several renal and endocrine factors may be involved, including the renin-angiotensin-aldosterone system, the sympathetic nervous system, prostaglandins, arginine vasopressin, natriuretic hormones, and nitric oxide (12,13). Sodium retention plays a key role in the pathophysiology of ascites and edema formation in children with chronic liver disease. Dietary sodium restriction, with accurate fluid monitoring, is needed to maintain homeostasis (14,15). Potassium supplementation is often required to correct the hypokalemia due to losses from diarrhea, use of diuretics, or hyperaldosteronism (16).
Nasogastric tube feedings may be required in children with advanced liver disease when significant anorexia compromises oral intake. If 24-hour nasogastric infusion becomes necessary, feeding by mouth, even in small amounts, should continue so that infants do not lose feeding skills after liver transplantation (17,18). The maintenance of oral feedings in older children is especially important for psychological reasons.
As chronic liver disease progresses, intractable diarrhea can result from severe malabsorption due to mucosal edema, inadequate bile salts, bacterial overgrowth or intercurrent intestinal infection. Parenteral nutrition may be required to maintain adequate caloric intake and restrict water and sodium. Before transplantation, parenteral nutrition can be used to optimize nutritional status, thereby reducing morbidity. Long-term parenteral nutrition, however, increases the risk of complications such as sepsis. Because the cholestatic liver can retain copper and manganese, it is recommended that they be eliminated from parenteral formulations, if serum concentrations of the minerals are normal or elevated.
Finally, supplementation of fat-soluble vitamins, iron, zinc, magnesium, and calcium is required to prevent specific deficiencies. Water-soluble vitamins should also be supplemented. The current recommended dosages and monitoring guidelines are summarized in Table 2. It is usually possible to achieve adequate levels of fat-soluble vitamins by means of oral supplementation. However, in children with severe chronic cholestasis intraluminal bile acids can decrease below the critical micellar concentration, resulting in impaired fat-soluble vitamin absorption. Vitamin E, in the form of D-α-tocopherol polyethylene glycol-1000 succinate (TPGS), is the only fat-soluble vitamin that comes in an oral water-soluble formulation. It forms micelles in the absence of bile acids because of its amphipathic structure, allowing efficient absorption in severely cholestatic patients. It has been shown that the absorption of vitamin D can be enhanced when administered in combination with TPGS because of TPGS's micellar formation. The solubilization of vitamin D by incorporation into these micelles facilitates its delivery to the intestinal mucosal cell (19). Whether all fat-soluble oral supplements are better absorbed when administered in combination with TPGS is not yet known. Parenteral supplementation of fat-soluble vitamins is recommended in children with cholestasis when biochemical or clinical signs of vitamin deficiency persist despite adequate oral vitamin supplementation.
NUTRITIONAL SUPPORT IN CHILDREN AFTER TRANSPLANTATION
Nutritional support in the postoperative period is an essential component of the care of children who have undergone organ transplantation. In the immediate postoperative period, aggressive nutritional support can help facilitate separation from the ventilator, reduce the possibility of infection, and improve wound repair. After organ transplantation, most children require total parenteral nutrition for a period lasting from several days to several weeks. In general, total parenteral nutrition should begin on postoperative day 2 or 3 and should progress to enteral feedings as soon as the postoperative ileus resolves. Infants who have received liver transplants commonly have feeding intolerance and vomiting. The malabsorption often found in these patients may be the result of chronic malnutrition before transplantation. Temporary treatment with elemental formulas administered by continuous drip feedings may improve absorption.
Along with surgical and medical complications, iatrogenic factors may affect nutrition after liver transplantation. It is important to remember that all the immunosuppressive drugs used in the posttransplantation period carry side effects that may affect nutrition (Table 3). Decreased appetite normally occurs early in the posttransplantation period and can interfere with achieving nutritional goals. Oral defensiveness can be problematic in infants who have had prolonged tube feeding or parenteral nutrition. Chronically ill children experience developmental delays that can affect nutritional rehabilitation. The diet of pediatric liver transplant recipients should be monitored for energy and protein intakes for the first 2 to 3 years after transplantation to maximize growth. Occasionally, a cholesterol-lowering diet is necessary to counteract the hypercholesterolemia, which is a side effect of cyclosporine treatment (20).
LONG-TERM NUTRITIONAL COMPLICATIONS IN CHILDREN WITH LIVER TRANSPLANTS
With the continuous improvement of posttransplantation survival rates, it is becoming more important to focus on the quality of life after liver transplantation. Clearly, optimal nutritional support can improve the long-term quality of life in pediatric transplant recipients by reducing or avoiding linear growth failure, rickets or osteomalacia with related pathologic fractures and neurodevelopmental delay.
Linear Growth Failure
Reaching a normal height is an important aspect of quality of life after orthotopic liver transplantation because of its impact on social reintegration and self-esteem. Chronic liver disease in childhood often results in linear growth retardation, and growth in most children is stunted at the time of transplantation (21). After the first year after surgery, however, growth may improve, particularly if graft function remains stable. Nevertheless, the growth of many patients remains below normal for many years after transplantation. A recent study conducted in The Netherlands (22) concluded that the deficit in linear growth before transplantation might not be completely restored, emphasizing the need for early transplantation in children with end-stage liver disease. The cause of poor linear growth after orthotopic liver transplantation is multifactorial. Pretransplantation growth failure, poor graft function, and long-term glucocorticoid treatment are the main factors held responsible. Although low doses of corticosteroids have been associated with suppression of linear growth when administered daily, alternate-day regimens allow some growth improvement (23,24).
The efficacy and safety of recombinant human growth hormone (rhGH) as a treatment of linear growth failure is under investigation. Administered directly or indirectly by means of insulin-like growth factor-I, rhGH is known to counteract the catabolic actions of glucocorticoids, increase the synthesis of whole-body protein and type-I collagen, and improve growth rates in children receiving glucocorticoid therapy. It has previously been used successfully to treat children with growth stunted after renal transplantation. Although rhGH can stimulate growth, the response usually varies from patient to patient. It would be useful to identify factors that predict a good response to rhGH therapy, to treat only those patients who can benefit significantly from this costly treatment. Unfortunately, no pretreatment factors, including serum levels of growth hormone, have been identified in patients with liver transplants that can predict the growth response to rhGH (25,26). RhGH also has immunostimulatory properties that have induced acute graft rejection in some patients with renal allografts. This potential risk necessitates close monitoring of liver function and immunosuppression. To date, it is not clear whether the final height of children who are treated with rhGH after liver transplantation is affected by the hormone treatment. Although promising, the efficacy of posttransplantation rhGH therapy still needs full evaluation.
Other factors that could improve the linear growth rate of pediatric liver transplant recipients are adequate pre-and postoperative nutritional therapy and minimal corticosteroid use. When a child with end-stage liver disease does not thrive despite aggressive nutritional support, liver transplantation should be performed as soon as possible.
Metabolic Bone Disease
Several studies of adult recipients of liver transplants (27–30) showed that spontaneous fractures resulting from osteopenia are a significant cause of morbidity during the first postoperative year. There are many potential causative factors for osteopenia in patients with chronic liver disease awaiting transplantation including immobility, malnutrition, poor muscle mass, poor renal function, and chronic cholestasis. In the posttransplantation period, high-dose corticosteroid therapy has long been suspected to be the main cause of early posttransplantation bone loss.
Children are also at risk for metabolic bone disease. In a retrospective study (31) of 117 children with end-stage liver disease who underwent orthotopic liver transplantation, 19 (16.2%) had bone fractures in the preoperative or postoperative phase. In 14 of these 19 children, there was no documented trauma. Metabolic bone disease, as assessed by skeletal radiography, was diagnosed in 17 of the 19 children. Twelve of the 17 children had osteopenia, 2 had rickets, and 2 had osteosclerosis.
Irrespective of the preoperative bone density, most liver transplant recipients, as well as recipients of other solid organs, lose bone mass for 3 to 6 months after transplantation. By 6 months, this bone loss typically ceases in patients with a normally functioning allograft, and bone mass then stabilizes or increases. A longitudinal study of nine children with chronic cholestasis who underwent transplantation at less than 2 years of age showed that all had decreased bone mineral content before liver transplantation that normalized between 6.5 and 19.0 months after surgery (32).
It is useful to identify patients who have low bone mass by using bone densitometry before they undergo transplantation. Adequate treatment with calcium and vitamin D in both the pre-and posttransplantation phases, the promotion of physical activity, and the minimal use of osteopenia-producing medications are essential steps to reduce the risk of clinical complications from bone loss that occurs in the early posttransplantation phase. The high prevalence of metabolic bone disease in children with cholestatic liver disease and in children who have had liver transplantation underscores the need for awareness among clinicians of the fracture risk, particularly in the peritransplantation period when this risk appears to be higher.
Chronic malnutrition in children with chronic liver disease can contribute to gradual hepatic deterioration and eventual death from liver failure. Children with chronic liver disease who are candidates for orthotopic liver transplantation have a better postoperative survival rate and a better long-term prognosis if their nutritional status is improved. Malnutrition is a pretransplantation risk factor that is potentially reversible, making nutritional support a cornerstone of therapeutic management of these children. It is important to prevent protein–energy malnutrition and specific nutritional deficiencies in children with chronic liver disease before they undergo transplantation. Growth and bone mineralization should be carefully monitored and nutritional support optimized. Attempts should be made to minimize corticosteroid use after liver transplantation. Better methods for assessing nutritional status in children with chronic liver disease are needed to identify those patients who need aggressive nutritional management and to assure the greatest benefits from nutritional support.
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