Etienne SOKAL

e-mail: Sokal@Pedi.ucl.ac.be

Whatever its original cause, pediatric chronic liver disease will eventually lead to liver insufficiency, liver cirrhosis, and may be associated to profound cholestasis. Cholestasis may be associated to pruritus, malabsorption, malnutrition, and growth retardation. Liver cirrhosis leads to portal hypertension, ascitis, and gastrointestinal bleeding . Cholangitis and systemic bacterial infections are common in children with portoenterostomies. Rarer complications of chronic liver disease include progressive hypoxia due to hepatopulmonary shunts, or even more rarely pulmonary hypertension (Table I).

Patients presenting these complications usually become candidates to orthotopic liver transplantation. It is the task of the pediatrician to identify the right timing to decide liver transplantation and to bring these patients in the best condition to the surgical procedure, in order to enhance the success of transplantation 51° .

Chronic liver disease will soon or later affect the nutritional status of the patient. Reasons for malnutrition are listed in Table II . For these various reasons, the daily caloric intake of the patient is often lower than the daily recommended intake, while an increased basal energy expenditure ²should on the contrary be compensated by an increased caloric intake. The aim is therefore to reach a caloric intake of 130 % of recommended daily caloric intake for age. If this goal is not achieved by oral feeding, nasogastric feeding should be started, supplying sufficient amount to reach 150 Kcal/kg/day ³. These measures should be installed as soon as abnormal weight gain is observed, or even anticipated. Once malnutrition is installed , it is becoming more difficult to restore protein body mass. The diet should meet the specific requirements for these infants (Table III).

Semi-elemental diet and protein hydrolysates are not justified, since there is no evidence of protein malabsorption in these children. The poor palatibility of semi-elemental diets may further decrease the caloric intake. Experimental and clinical evidence show that an increased intake of branched chain amino acids may improve the body composition and nutritional status of cholestatic children. In an animal model of biliary atresia, a formula enriched in branched chain amino acids was able to improve weight gain, protein mass, muscle mass, nitrogen balance, body composition and mineral content of these animals. These effects were concomitant to an improvement of serum aminoacidogram, with an increased circulating concentration of valine, leucine and isoleucine ⁴. This animal experiment served as a basis to the development a special diet enriched in branched chain aminoacids designed specifically for cholestatic infants (Heparon junior, Nutricia, Bornem, Belgium). Additional clinical evidence were published showing a beneficial effect of a diet enriched in branched chain aminoacids in children with biliary atresia ⁵. Children receiving a semielemental formulation enriched in branched chain aminoacids had an increase in total body potassium , midupper arm circumference, and subscapular skinfold thickness, as compared to children receiving a standard semielemental formula. They also required fewer albumin infusions under branched chain aminoacids supplements ⁵.

In severe liver failure, the aminoacidogrma may be deeply abnormal, with very high levels of aromatic aminoacids (phenylalanine, methionine, tyrosine). This reflects the general failure of liver metabolism, and may theoritically justify to start a specific diet restricted in these aminoacids, since they may play a role in hepatic encephalopathy.

Lactase deficiency was observed in half of the cholestatic patients in our center (unpublished observation). In experimental biliary atresia, decreased activities of brush border enzymes were noticed ( -20 to – 30%), suggesting damage of the intestinal mucosae, also evidenced by protein deficiencies of the brush border membrane . Several proteins from the brush border membrane where virtually absent or markedly decreased in cholestatic animals ⁶. Although insufficient evidence exists to recommend a lactose free diet in these children, attention should be paid to any sign of lactose intolerance or malabsorption. Carbohydrate intake should equal 60% of the daily caloric intake of the child.

Although it has never been demonstrated that nutrition of these patients is improved by the use of middle chain triglycerides (MCT), theoretical evidence support their use in these children ^7,8. MCT are directly absorbed by the gastric and intestinal mucosa , without requiring emulsification by bile acids. Their short chain increase by 100 the water solubility, allowing to cross the aqueous membrane of the intestine. Absorption is direct into the portal system, so that MCT’s are directly used by the liver for energy purpose. It is to be reminded that MCT oil does not contain essential fatty acids, which may be deficient in these patients Patients may in addition present pancreatic insufficiency as an additional cause of steatorrhea.

Although any physician is supposed to be aware of the risk of fat soluble vitamin (ADEK) deficiency during cholestasis , it is unfortunately common to observe complications related to such deficiencies. In particular, death or brain damage from cranial hemorrhage are still observed in developed countries in cholestatic infants not appropriately supplemented in vitamin K . Vitamin supplementation should be given intramuscularly in these children, and effectiveness be controlled by regular determination of prothrombin time and/or levels of vitamin K dependant clotting factors. If prothrombin time is prolonged due to vitamin K deficiency, rapid correction is observed, within 12 to 24 hours following an intramuscular injection. If supplementation does not lead to correction of prothrombin time, protein synthesis defect due to liver insufficiency is probably the cause of clotting defect. In such case, factor V (vitamin K non dependant clotting factor) is decreased.

Vitamin E deficiency causes neurological disease including hyporeflexia , ataxia and cerebellar dysfunction , which necessitates intramuscular supplementation . More recently, it has been shown that vitamin E can be given orally provided that the water soluble form ( d-a-Tocopheryl polyethylene Glycol – 1000 succinate ) is used (1064,1454). Serum levels of vitamin E should be monitored ( range 600 to 1400 µg/dl), and the ratio Vitamin E (µg/dl) / Total lipids (mg/dl) should be kept above 0.6. Similarly, vitamin D should be given intramuscularly unless the 25OH D3 form is used (Calcifediol, Dedrogyl ^R ,Hoechst Marion Roussel ). Monitoring includes levels of serum vitamin D and calcium , and control of calciuria. Particular attention should be paid to risk of vitamin D intoxication during summer time and sunny periods.

Vitamin A serum levels can also be monitored, but do not reflect the true reserves: vitamin A is stored in the liver, and serum levels decrease ultimately when tissue reserves are low. To evaluate reserves, dosage should therefore be performed on the liver tissue itself, which is practically non feasible routinely ⁹. Chronic intoxication can by itself cause liver disease ( Ito cell hyperplasia, fibrosis, cirrhosis), or cause other damages such as pseudotumor cerebri. Table IV gives the appropriate schedule for fat soluble vitamin supplementation.

In addition to vitamins, mineral supplementation with calcium and zinc are advised. Calcium deficiency and bone demineralistaion are common in these patients, due to calcium malabsorption. Calcium absorption will be improved by vitamin D supplementation in deficient patients^6,10. In addition to this saturable transport system dependant of vitamin D, increased concentrations of calcium in the gut lumen may also increase non saturable, intercellular, vitamin D independant transport: it is therefore useful to increase calcium intake whenever bone demineralisation is observed.

In view of the extensive use of bile acids treatments of cholestatic patients, it should be stressed that these bile acids may interfer with calcium transport mechanisms, and hence decrease calcium absorption, by formation of complexes between bile salts and ionized calcium⁶.

Zinc deficiency is common in cholestasis. Zinc is a common cofactor of various enzymatic systems, and deficiency may affect liver metabolism such as for example ammonium metabolism and urea cycle ¹¹.

Metabolic alkalosis is regularly observed in cholestatic children: this stresses the major role played by the liver in acido-basic homeostasis: Urea synthesis is a highly bicarbonate consuming system (two molecules of bicarbonate for one ammonium), and impairment of urea synthesis due to porto systemic shunt, liver insufficiency or zinc deficiency, may lead to excessive bicarbonate levels and alkalosis. Free ammonium , not incorporated in urea in the periportal acinar zone, can be detoxified by glutamine synthase, a high affinity system located in the last few layers of hepatocytes around the central vein: this system is non bicarbonate consuming, and may enhance its activity whenever bicarbonate consumption should be reduced, such as in metabolic acidosis ^11,12. The metabolic distribution of this and other enzymatic systems – called liver metabolic zonation- along the liver plate plays a major role in liver function. The acinar metabolic zonation is replaced by a cirrho-nodular distribution of enzymatic systems in the cirrhotic liver, helping to maintain the function of the whole organ ^13,14.

Iron deficiency may be observed and is most often associated to occult or overt GI bleeding

TABLE I

JAUNDICE Abnormal appearance

Social eviction

PRURITUS Behavioral and character disturbances

Sleep deprivation

Skin lesions and infections

Impaired quality of life

BILIARY INSUFICIENCY Malabsorption, malnutrition, diarrhea, developmental delay

ASCITIS Body deformation

Impaired motility

Impaired lung capacity

Impaired digestion

Sepsis

CHOLANGITIS Fever, septicemia, shock

PORTAL HYPERTENSION Variceal or ulcer bleeding

Impaired liver perfusion - Portosystemic shunts Impaired liver perfusion, liver necrosis

LIVER INSUFFICIENCY End stage liver failure

Encepahlopathy

Hypoglycemia

HEPATOPULMONARY

SHUNTS Profound Hypoxia

PULMONARY

HYPERTENSION Hypoxia, sudden death

TABLE I I

• Delay in diagnosis Delay before nutritional support
• Abdominal distension Poor satiety
• Gastro oesophageal reflux Caloric loss
• Semielemental diet Poor palatibility
• Undue protein restriction Endogenous protein catabolism
• Water restriction Caloric restriction
• Intraluminal bile Fat malabsorption

• Zinc deficiency Diarrhea
• Calcium malabsorption Bone demineralization
• Cirrhosis Increased energy expenditure
• Porto systemic shunt Metabolic skip
• Portal hypertension Ulcers

• Ascitis Protein loss
• Liver insufficiency Impaired protein synthesis

• Sepsis Catabolism
• Repeated surgery Fasting
• Transplantation Catabolism
• Ursodeoxycholic acid Calcium chelation

Vitamin K: - 1 mg/kg, maximum 10 mg, intra-muscular, once weekly to 2 weeks

Vitamin E: - 10 mg/kg, intra-muscular, every two weeks

Vitamin A: - 25000 to 50000 IU, IM, every other month

Vitamin D - 30000 to 60000 IU, IM, every other month

Calcium: - 50 mg/kg/day, orally

Zinc: - 1 mg/kg/day, zinc sulfate, orally

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