Malnutrition is an important and common sequela of chronic liver disease (CLD). It is associated with decreased quality of life and increased morbidity and mortality before and after liver transplantation. The etiology of malnutrition in CLD is multifactorial and related to decreased intake, malabsorption, and increased metabolic demands. A multidisciplinary approach with frequent assessment of the nutritional status early in the course of the disease is imperative to prevent long-term complications such as rickets, pathologic fractures, essential fatty acid deficiency, hemorrhagic disease, and other micronutrient deficiencies.
Effects of Liver Disease on the Nutritional State and Growth
The liver plays a vital role in metabolic homeostasis and is a key player in digestion, storage, and distribution of nutrients. As such, a compromise in hepatic function may lead to malnutrition and growth retardation, which is not uncommon in end-stage liver disease (ESLD). An estimated 60% to 80% of children awaiting a liver transplant are malnourished1,2 and as a result are at risk for complications and increased rates of morbidity and mortality both before and after liver transplantation. In fact, one of the factors used in the pediatric ESLD score for prioritizing allocation of liver grafts by the United Network for Organ Sharing is the presence of growth failure as it reflects the severity of liver disease.3 Therefore, it is crucial to assess the patient's nutritional status at every visit and address the nutritional needs promptly.
Etiology of Chronic Liver Disease in Children
The true prevalence of liver disease in children is unknown. In 2000, it was estimated that approximately 15,000 children were hospitalized for liver disease in the United States. The incidence of liver disease in infants is approximately 1 in 2,500 live births.4
Etiologies for chronic liver disease in children can be acquired or inherited. In infancy, the most common causes are biliary atresia, other biliary conditions, inherited metabolic disorders (eg, glycogen storage disease), viral hepatitis, TORCH (Toxoplasmosis, Other [syphilis, varicella-zoster, parvovirus B19], Rubella, Cytomegalovirus, and Herpes) infections, endocrine disorders, and other genetic conditions. In older children, conditions such as autoimmune hepatitis, nonalcoholic fatty liver disease, Wilson's disease, hepatoma, chronic granulomatous infection, and drug-induced liver disease play a much greater role.5–8
Mechanisms of Malnutrition in Children with Chronic Liver Disease
The liver is the main regulator of hemostasis of serum proteins, gluconeogenesis, and lipid balance. Malnutrition is a common complication in children with CLD and the causes are multifactorial. Key factors include low consumption, increased energy requirements, fat malabsorption from cholestasis, as well as abnormal nutrient metabolism.9–11 In infancy, the most significant factor leading to malnutrition is younger age at diagnosis, whereas in older children it is the degree of hepatic failure.10
Decreased Dietary Intake
Low consumption often occurs because these children experience anorexia and nausea from mucosal congestion related to hypoalbuminemia and/or portal hypertension, decreased intestinal motility, and early satiety from organomegaly and ascites.12 Additionally, many children find that the modified diets they are asked to adhere to are unpalatable. These diets are suggested when there is a need to improve fat absorption (by using medium-chain fatty acid-based fat), decrease the nitrogenous load on the body as the liver gradually loses the ability to clear ammonia, or to address the specific inherited metabolic disorder causing the liver disease (eg, tyrosinemia, galactosemia, glycogen storage disease, Wilson's disease).7 Altered taste perception can also be present in CLD, from a general inflammatory state, from zinc and magnesium deficiency, or from a drug effect, all of which further contribute to the anorexia.
Increased Dietary Needs
ESLD is a hypermetabolic state with a 30% increase in resting energy expenditure (REE) and total energy expenditure.13,14 When an additional stressor, such as an infection, is present, it places these children in catabolic stress and further worsens their baseline nutritional status. Most chronic liver diseases progress to fibrosis and some, eventually, to cirrhosis with portal hypertension and portosystemic shunting in collateral circulation or via portosystemic shunts that allow the nutrients to bypass the liver without being metabolically processed.15
Cholestasis is defined as conjugated bilirubinemia from decreased bile flow due to impaired secretion by hepatocytes or from obstruction of bile flow through intra- or extrahepatic bile ducts. Decrease in intraluminal bile acids not only leads to impaired absorption of long-chain fatty acids, but also to deficiencies in the fat-soluble vitamins. Patients with ESLD are particularly susceptible to vitamin D deficiency in addition to cholestasis, as they have decreased exposure to direct sunlight and poor 25-hydroxylation of vitamin D. In severe cases, a deficiency in essential fatty acids can also occur.16
Macro- and Micronutrient Deficiencies
Children with CLD are at a higher risk for fasting hypoglycemia from impaired gluconeogenesis and glycogenolysis secondary to impaired hepatic glycogen storage capacity. Infants are particularly at risk because of their limited glycogen reserves and increased metabolic demands from the accelerated state of their growth. Older children are also able to use fat and protein as energy sources and, therefore, are at a lower risk for hypoglycemia.
Interestingly, diabetes mellitus (DM) is common and present in almost one-third of patients with CLD. In these patients, DM is thought to be partially a result of insulin resistance related to cirrhosis, referred to as “hepatogenous diabetes.” Thus, there is not only dampened insulin secretion by the pancreatic islet beta cells to elevated blood glucose, but also hepatic insulin resistance, leading to decreased uptake of blood glucose into the liver.17
Reduced intake is the main reason for protein malnutrition. The functions of the liver include plasma protein synthesis such as clotting factors and albumin. In children with CLD, hepatic protein synthesis is impaired, which leads to hypoalbuminemia and exacerbates ascites. Insulin-like growth factor (IGF-1) and its binding protein IGF-BP3 are also produced by the liver. A reduction of their synthesis results in growth hormone resistance and may contribute to growth failure.18,19
Fats are rich in calories and constitute an important source of energy for children. In addition, fats are important for the developing brain, and essential fatty acids are key building blocks for cellular membranes and hormones in our bodies. Liver disorders that lead to cholestasis create a deficiency of bile salts in the intestinal lumen. Dietary fats, specifically, long-chain triglycerides, are dependent on bile acids for their absorption; therefore, children with cholestasis have impaired fat and fat-soluble vitamin absorption. Medium-chain triglycerides are not as affected because they do not require emulsification and micelle formation for absorption; therefore, they can enter the portal vein without the help of bile acids.
Trace elements are minerals and metals (eg, iron, zinc, magnesium, selenium, calcium) required for the proper function of many key enzymes in the body. Healthy children consuming an average, varied Western diet are typically protected from these deficiencies, but they are prevalent in children with CLD. Elevated levels of serum manganese, which is excreted through the biliary system, low serum calcium and magnesium, and low levels of copper and selenium are not uncommon in CLD.20
Nutritional assessment should be performed regularly in all children and particularly in children with CLD. It is important to identify children who are at high-risk for the development of malnutrition and provide them with the appropriate nutritional support in a timely manner during the crucial time of growth and development. There is no one specific tool that can provide all the needed information about a child's nutritional status; however, the different components used provide complementary evidence that should be interpreted collectively. The aspects of nutrition screening include obtaining a dietary history, anthropometry, physical examination with specific assessment of signs of nutrient deficiencies, and biochemical testing.
The patient history should include detailed questions about the patient's diet, including both the types of food and amounts consumed. It is best if the parents keep a dietary diary. For infants and older children consuming formula, ask about specific volumes taken per feed, the type of formula, its concentration, and its preparation. Regardless of the chief complaint, an inquiry about specific clinical manifestations should be made at every visit, such as reduced appetite, vomiting, diarrhea, steatorrhea, acholic stools, and any change in the feeding or stooling pattern.
Children with liver disease should be weighed and measured carefully at every clinic visit. Changes in the anthropometrics should be followed by reevaluation of the patient's nutritional status (Table 1). It is important to remember that standard measures of weight, height, and body mass index may not reflect the severity of malnutrition in these children, especially in those with hepatosplenomegaly and ascites.6,7 Height-for-age plots may be less accurate in certain genetic conditions of the liver, such as Alagille syndrome, in which short stature is a feature. Triceps and subscapular skinfold thickness and estimation of body protein using mid upper arm circumference are more accurate for assessment in these cases.21 However, the medical record is unlikely set up to compare these values to age-matched children, so another resource for interpretation of results needs to be used. Additionally, there will need to be a caliper available in the office/clinic as well as appropriately trained providers.
Clinical Signs of Malnutrition in Specific Body Systems
Micronutrient deficiencies are diagnosed based on decreased plasma levels, which may be falsely reduced at times when there is a systemic inflammatory response (SIR) present. Decreased plasma levels of micronutrients with SIR are likely mediated by proinflammatory cytokines that suppress hepatic production of many carrier proteins, increase capillary permeability, and promote sequestration of some micronutrients into the liver and other organs. Therefore, it is recommended that a clinical interpretation of plasma micronutrients should be made when the C-reactive protein level is known or after clinical exclusion of SIR.23
Fat-soluble vitamins should be assessed regularly in children with cholestatic liver disease, and response to replacement therapy should be confirmed (Table 2). Retinol (vitamin A) plays a key role in maintaining healthy vision, immunity, red blood cell production, and reproductive and pulmonary systems.22 Retinol is primarily stored in the liver, which also synthesizes its carrier protein, retinol-binding protein (RBP). Measurements of both serum retinol and RBP are used for assessment of vitamin A status; however, these levels may not accurately estimate vitamin A status in children with liver disease.
Signs for Fat-Soluble Vitamin Deficiency
These children should be screened for “hepatic osteodystrophy,” which is multifactorial and occurs as a result of immobility, low calcium intake, therapy of the liver disease with corticosteroids, hypogonadism, and low muscle force. Vitamin D status, parathyroid hormone level, alkaline phosphatase level, and calcium, magnesium, and phosphorus levels should all be assessed. For patients at high risk for low bone mineral density, further assessment with dual-energy X-ray absorptiometry study or X-rays of the hand should be requested. Determination of vitamin D status is best assessed by measurement of serum 25-hydroxyvitamin D because 1,25-(OH)2D tends to fluctuate in response to calcium and phosphorus levels through the effect of parathyroid hormone secretion. Cholestatic liver disease not only leads to malabsorption, but also, with reduced hepatic function, there is impaired hepatic hydroxylation; therefore, supplementation with cholecalciferol (D3), which is more hydrophilic, may be helpful.
Vitamin E is a collective name for a group of four tocopherol compounds with antioxidant properties. The most biologically active one is alpha-tocopherol and that is what is sent to assess serum vitamin E levels; however, its blood circulation is dependent on low-density beta-lipoproteins. As such, to accurately assess vitamin E levels in patients with cholestasis, the vitamin E to total serum lipids ratio should be measured.
Vitamin K is a necessary cofactor in the clotting cascade, and assessment of the prothrombin time is typically performed as a surrogate marker of vitamin K status. However, prothrombin time is affected by liver synthetic function and, therefore, is inaccurate at measuring vitamin K status in patients with ESLD. The response to intravenous vitamin K supplementation helps differentiate vitamin K deficiency and liver failure (Table 3).
Fat-Soluble Vitamin Levels and Supplementation
Deficiencies of the trace elements zinc, selenium, and iron should be assessed regularly, especially if portal hypertension is present. Albumin and prealbumin, which are both markers of nutritional status, are less useful for assessment of nutrition in CLD because they are influenced by inflammatory state and hepatic function.
REE represents the energy, measured in calories, required by the body for a 24-hour period during a nonactive state. It can be predicted using formulas such as the Harris-Benedict equations, calculated by direct calorimetry (in which the amount of heat produced by the body is measured), by indirect calorimetry, or by measuring gas exchange.
Madden and Morgan25 compared REE values between healthy adults and patients with cirrhosis and found that the REE was higher for the patients with cirrhosis. They also compared REE values estimated from different formulas and REE values obtained with indirect calorimetry in patients with cirrhosis and found that the formulas either underestimated or overestimated the metabolic requirements. Because of the limitation in applying these formulas to patients with cirrhosis, they recommended measuring the REE in these patients.25 Similar findings were present when estimating the REE of children with ESLD in a study by Greer et al.14 They also found that children with ESLD have a hypermetabolic state, with evidence of increased metabolic activity within the body cell mass, and higher lipid oxidation during fasting and at rest. The standard equations used to estimate energy requirements of infants and young children with ESLD significantly underestimated the energy requirements and, therefore, were advised against in this patient population.14
The goal of nutritional support is to allow normal growth, prevent and address trace elements and vitamin deficiency, and improve liver transplant readiness and postoperative outcomes. Each child should have a personalized nutrition plan based on their nutritional status, age, activity level, and the specific liver disease and its severity. An experienced pediatric dietician is an integral part of the multidisciplinary team. The follow-up should include a comprehensive review of the dietary intake, weight and height measurements to detect stunting, and a thorough physical examination including skinfold thickness and mid upper arm circumference. If malnutrition is present, an increase in the energy intake is encouraged. A CLD is a hypermetabolic state that requires an approximately 130% increase of normal energy intake,14 which can be achieved by increasing the amount of fats and carbohydrates in the diet or the infant's formula.13
An oral diet is always preferred, but when it is not sufficient then enteral supplementation through tube feeding is appropriate. Some children may need overnight nasogastric feeds, which are usually well tolerated and do not increase the risk of variceal bleeds when varices are present.11
Supplementation of Specific Nutrients
Carbohydrates typically provide the majority of calories in the diet, and given the increased energy demands of children with CLD, the intake of carbohydrates will likely need to be increased. A high carbohydrate load may lead to osmotic diarrhea and thus malabsorption. This may be addressed with the use of a glucose polymer-based formula for caloric supplementation.11
During an acute illness, when a child's intake may be suboptimal, they are at an even higher risk for fasting hypoglycemia, which may lead to neurological damage. Therefore, patients with ESLD typically require dextrose-containing intravenous fluids when admitted to the hospital. Their blood glucose levels should be monitored, and they should eat more frequently during times of acute illnesses.
In adults with cirrhosis it is common to limit the protein intake to prevent hyperammonemia-induced encephalopathy; however, this is not the case for children because they are still growing. In infants with cholestatic liver disease, 3 to 4 g/kg per day of protein is recommended. In cases where encephalopathy develops, ammonia levels may be reduced using lactulose or sodium benzoate.
Increasing total fat intake can help increase the overall calorie density of the diet, although it may cause steatorrhea. Fat intake should be enriched with medium-chain triglycerides, which do not require micelle formation and are readily absorbed in the portal circulation. In infants with significant malnutrition, medium-chain and long-chain triglyceride formulas should be used (if tolerated), but they should not contain more than 80% medium-chain triglycerides because it can lead to essential fatty acid deficiency. In older children, medium-chain triglyceride oil can be added to meals, but it must be balanced by other fat sources with high contents of polyunsaturated fatty acids.26
CLD often leads to malnutrition with significant sequelae that can sometimes be irreversible and have long-term effects. Physicians caring for children with CLD should be diligent at assessing for nutritional deficiencies and address them promptly. The etiology of malnutrition in CLD is multifactorial and is related to decreased intake and malabsorption, as well as increased metabolic demands. This leads to inadequacies in both macronutrients as well as micronutrients. A particular challenge in patients with cholestatic liver disease is the absorption of fats and fat-soluble vitamins. Children with CLD are best served by having a multidisciplinary approach to assess, prevent, and address these complications. Each child should have a personalized nutrition plan with a goal of normal growth, prevention and correction of nutritional deficiencies, and improvement of liver transplant readiness and postoperative outcomes.
- Protheroe SM, Kelly DA. 10 Cholestasis and end-stage liver disease. Baillières Clin Gastroenterol. 1998;12(4):823–841. doi:. doi:10.1016/S0950-3528(98)90010-0 [CrossRef]
- Yu R, Wang Y, Xiao Y, et al. Prevalence of malnutrition and risk of undernutrition in hospitalised children with liver disease. J Nutr Sci. 2017;6:e55. doi:. doi:10.1017/jns.2017.56 [CrossRef]
- McDiarmid SV, Anand R, Lindblad AS. Development of a pediatric end-stage liver disease score to predict poor outcome in children awaiting liver transplantation. Transplantation. 2002;74(2):173–181. doi:. doi:10.1097/00007890-200207270-00006 [CrossRef]
- Arya G, Balistreri WF. Pediatric liver disease in the United States: epidemiology and impact. J Gastroenterol Hepatol. 2002;17(5):521–525. doi:10.1046/j.1440-1746.2002.02678.x [CrossRef]
- Tahir A, Malik FR, Ahmad I, Krishin J, Akhtar P. Aetiological factors of chronic liver disease in children. J Ayub Med Coll Abbottabad. 2011;23(2):12–14.
- Hsu EK, Murray KF. Cirrhosis and chronic liver failure. In: Suchy F, Sokol R, Balistreri W, eds. Liver Disease in Children. 4th ed. New York, NY: Cambridge University Press; 2014:52–58.
- Feranchak AP, Sokol RJ. Medical and nutritional management of cholestasis in infants and children. In: Suchy F, Sokol R, Balistreri W, eds. Liver Disease in Children. 4th ed. New York, NY: Cambridge University Press; 2014:115.
- Rosenthal P. Neonatal hepatitis and congenital infections. In: Suchy F, Sokol R, Balistreri W, eds. Liver Disease in Children. 4th ed. New York, NY: Cambridge University Press; 2014:144.
- Young S, Kwarta E, Azzam R, Sentongo T. Nutrition assessment and support in children with end-stage liver disease. Nutr Clin Pract.2013;28(3):317–329. doi:. doi:10.1177/0884533612474043 [CrossRef]
- Roggero P, Cataliotti E, Ulla L, et al. Factors influencing malnutrition in children waiting for liver transplants. Am J Clin Nutr. 1997;65(6):1852–1857. doi:. doi:10.1093/ajcn/65.6.1852 [CrossRef]
- Nel ED, Terblanche AJ. Nutritional support of children with chronic liver disease. S Afr Med J. 2015;105(7):607. doi:10.7196/SAMJnew.7783 [CrossRef]
- Aqel BA, Scolapio JS, Dickson RC, Burton DD, Bouras EP. Contribution of ascites to impaired gastric function and nutritional intake in patients with cirrhosis and ascites. Clin Gastroenterol Hepatol. 2005;3(11):1095–1100. doi:10.1016/S1542-3565(05)00531-8 [CrossRef]
- Nightingale S, Ng VL. Optimizing nutritional management in children with chronic liver disease. Pediatr Clin North Am. 2009;56(5):1161–1183. doi:. doi:10.1016/j.pcl.2009.06.005 [CrossRef]
- Greer R, Lehnert M, Lewindon P, Cleghorn GJ, Shepherd RW. Body composition and components of energy expenditure in children with end-stage liver disease. J Pediatr Gastroenterol Nutr. 2003;36(3):358–363. doi:. doi:10.1097/00005176-200303000-00010 [CrossRef]
- Cheung K, Lee SS, Raman M. Prevalence and mechanisms of malnutrition in patients with advanced liver disease, and nutrition management strategies. Clin Gastroenterol Hepatol. 2012;10(2):117–125. doi:. doi:10.1016/j.cgh.2011.08.016 [CrossRef]
- Francavilla R, Miniello VL, Brunetti L, Lionetti ME, Armenio L. Hepatitis and cholestasis in infancy: clinical and nutritional aspects. Acta Paediatr Suppl. 2003;91(441):101–104.
- Nielsen MF, Caumo A, Aagaard NK, et al. Contribution of defects in glucose uptake to carbohydrate intolerance in liver cirrhosis: assessment during physiological glucose and insulin concentrations. Am J Physiol Gastrointest Liver Physiol. 2005;288(6):G1135–G1143. doi:. doi:10.1152/ajpgi.00278.2004 [CrossRef]
- Holt RI, Jones JS, Stone NM, Baker AJ, Miell JP. Sequential changes in insulin-like growth factor I (IGF-I) and IGF-binding proteins in children with end-stage liver disease before and after successful orthotopic liver transplantation. J Clin Endocrinol Metab. 1996;81(1):160–168. doi:10.1210/jc.81.1.160 [CrossRef].
- Petersen KF, Krssak M, Navarro V, et al. Contributions of net hepatic glycogenolysis and gluconeogenesis to glucose production in cirrhosis. Am J Physiol Endocrinol Metab. 1999;276(3 Pt 1):E529–E535. doi:10.1152/ajpendo.1999.276.3.E529 [CrossRef]
- Guerra TS, Hoehr NF, Boin Ide F, Stucchi RS. Trace elements in plasma and nutritional assessment in patients with compensated cirrhosis on a liver transplant list. Arq Gastroenterol.2016;53(2):84–88. doi:. doi:10.1590/S0004-28032016000200006 [CrossRef]
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Clinical Signs of Malnutrition in Specific Body Systems
||Bruising, petechiae, purpura, ecchymosis, epistaxis, and gingival bleeding can indicate coagulopathy or thrombocytopenia
Signs of cholestasis including scleral icterus and jaundice1
Zinc deficiency may cause periorificial desquamating rash
Conjunctival and palmar crease pallor suggest anemia; nail changes (koilonychia) suggest iron deficiency16
Xanthomas: due to impairment of bile flow in cholestasis, which leads to increased plasma concentration of circulating lipoproteins and lipids1
Dry and scaly dermatitis and poor wound healing may be signs of essential fatty acids deficiency
||Dull or even alopecia with severe protein energy malnutrition and zinc or essential fatty acid deficiency10,16
||Ascites from hypoalbuminemia and portal hypertension
||Tachycardia as a sign for anemia1
|Mouth and oropharynx14
||Stomatitis or cheilitis suggest iron, folate, or riboflavin deficiency
Glossitis suggests vitamin B12, folate, riboflavin, or niacin deficiency
Dental status to look for vitamin D or calcium deficiency
||The clinician should assess the muscle bulk, especially the gluteal, temporalis, and interosseous muscles and fat deposits such as thigh creases, cheeks, and chest and abdominal wall because it can provide a gross impression of protein and fat status16
||In adolescents, delayed puberty and hypogonadism
Signs for Fat-Soluble Vitamin Deficiency
||Night blindness, Bitot's spots (small, triangular, foamy white patches on the sclera), xerophthalmia (excessive dryness)
Less common findings include xerosis (corneal drying), keratomalacia (softening of the cornea), hyperkeratosis22
||Bowed lower limbs, rachitic rosary, persistently open anterior fontanelle, tetany, enamel hypoplasia, hypotonia11,13
||Peripheral neuropathy with altered reflexes, strabismus, muscle weakness, visual field defects to complete blindness, cardiac arrhythmias22
||Easy bruising, epistaxis, bleeding with brushing of teeth, heavy menstrual periods1
Fat-Soluble Vitamin Levels and Supplementation
||Serum retinol, RBP, retinol:RBP ratio
||0–6 mo: retinol
6 mo: 30–80 mcg/dL
||Retinol: <20 mcg/dL
Retinol: RBP ratio <0.8 mg/g
0–6 y: RBP <1 mg/dL
6 y: RBP <2 mg/dL
||Liver, milk, cheese, eggs, orange-yellow fruits, and vegetables (eg, carrots and ripe mangos)
||Form: water-miscible formulation
Dose: 5,000–20,000 IU/da
||Desirable level: 30–40 ng/mL
||Deficiency: <12 ng/mL
Potential deficiency: <20 ng/mL
Potential Insufficiency: <30 ng/mL
||Fish liver oils, fatty fish, fortified foods
||Form: cholecalciferol (D3 because more water-soluble)
Dose: depends on severity of liver disease; for children with cholestasis the recommended dose is 80–160 IU/kg per day
Goal: 25-OH-D level should be >50 nmol/L and PTH <55 pg/mL
||Alpha-tocopherol: >0.7 mg/dL
||Alpha-tocopherol: <0.7 mg/dL
||Vegetable oils, cereals, dairy products, eggs
||Form: d-alpha-tocopheryl polyethylene glycol succinate
Dose: 20–25 IU/kg per day as a single morning dose
|Serum alpha-tocopherol to total serum lipids ratio
||Serum alpha-tocopherol: lipid ratio <0.6 mg/g in high-risk group(lipid adjustment is recommended in cholestasis)
||11–15 seconds in childhood
||Prolonged prothrombin time
||Leafy vegetables, soybean oil, fruits, seeds, cow's milk
||Dose: 2.5–5 mg/d orallyb