Primary Liver Diseases that Lead to Hepatic Insufficiency

End-stage liver disease is the major indication for liver transplantation in pediatrics. Progressive biliary cirrhosis, particularly that due to biliary atresia, is the most common cause of end-stage liver disease in the pediatric population. Parenchymal liver diseases, including chronic active hepatitis with cirrhosis and certain metabolic diseases, are also common (Table 112-1).

Cirrhosis is neither a specific disease entity nor a general indication for transplantation. It is an anatomic diagnosis with functional implications. Developing cirrhosis in the course of disease has grave prognostic implications with regard to the prospect of requiring transplantation. However, determining when transplantation should be performed involves estimating the functional reserve of the cirrhotic liver and its potential for supporting life of reasonable quality. Cirrhosis is an indication for immediate liver transplantation when there is evidence of functional hepatic decompensation, such as coagulopathy, ascites, frequent or massive gastrointestinal (GI) hemorrhage, malnutrition and growth failure, and frequent severe bacterial infections.

The majority of children needing orthotopic liver transplantation (OLT) reach end-stage liver disease in the first 2 years of life. Predicting the time for OLT is easier when the liver disease has a characteristic progression. Biliary atresia, for example, has a clearly defined natural history. Even though more than 80% of children with biliary atre-sia will ultimately require liver transplantation, its timing

TABLE 112-1. Classification of Diseases for which Orthotopic Liver Transplantation Has Been Performed in Infants and Children for the Indication of Hepatic Insufficiency

I Metabolic diseases a. ^-Antitrypsin deficiency b. Tyrosinemia c. Glycogen storage diseases types IV, III, and possibly I

d. Wilson's disease e. Neonatal hemochromatosis

II Acute and chronic hepatitis a. Fulminant hepatic failure: viral, toxin/drug induced b. Chronic hepatitis: HBV, HCV, autoimmune, idiopathic

III Intrahepatic cholestasis a. Idiopathic neonatal hepatitis b. Alagille syndrome (syndromic bile duct paucity)

c. Nonsyndromic bile duct paucity d. Progressive familial intrahepatic cholestasis

IV Obstructive biliary tract disease a. Extrahepatic biliary atresia b. Sclerosing cholangitis c. Traumatic/postsurgical biliary tract diseases

V Miscellaneous a. Cryptogenic cirrhosis b. Congenital hepatic fibrosis c. Caroli's disease d. Cystic fibrosis e. Cirrhosis secondary to prolonged TPN

HBV = hepatitis B virus; HCV = hepatitis C virus; TPN = total parenteral nutrition.

is determined by the success of the Kasai portoenterostomy. Patients without effective drainage will typically reach end stage and need a transplant somewhere between 9 and 18 months of age, whereas those with effective drainage have a 50% probability of living beyond 10 years without a transplant. Unfortunately, few other liver diseases in children have such a predictable course.

a 1-Antitrypsin deficiency is one of the most common liver diseases causing progressive parenchymal failure in children and the most common metabolic disease eventuating in pediatric liver transplantation. However, at the time of diagnosis, usually in infancy, the prognosis cannot be determined in most cases. Fewer than 20% of individuals with the genetic defect will have significant liver disease, and only about 15% will develop macro-nodular cirrhosis before the age of 20 years. There is a 2 to 3% incidence of hepatocellular carcinoma (HCC) in children and adults, and other organs may be involved, causing conditions such as early-onset emphysema and membranoproliferative nephritis. Liver transplantation should be considered for patients with cirrhosis and hepatic insufficiency or early HCC, whereas patients with neonatal cholestasis that resolves simply should be followed closely.

The decision to perform liver transplantation in a child with acute hepatic failure is complex. These patients have a high risk of dying without transplantation, but some may recover with medical support alone. It is not possible to predict with certainty which individual will recover without transplantation, so probabilities of recovery based on etiology and other factors are employed in the decision-making process. However, young age is one of the worst indicators of poor outcome, and all young children with fulminant liver failure should be listed for transplantation.

Growth is a sensitive measure of liver function in childhood. The integrated metabolic functions of the liver permit growth to proceed, and failure of metabolic function is often first manifested as growth failure. The infant with biliary atresia and cirrhosis may continue to grow reasonably normally, perhaps with some nutritional support, until the liver begins to decompensate. At that time, growth will cease, and no effort at nutritional support will cause it to resume. The infant cannot improve as a candidate for transplantation beyond that time even though growth arrest may precede other evidence of decompensation by several months. The point of growth arrest is, therefore, the ideal time to perform transplantation on an infant with biliary atresia and cirrhosis. Caution is required when making this assessment. If growth failure is observed in an infant with biliary atresia and otherwise normal liver function (eg, a normal bilirubin), the patient may have a correctable cause of growth failure, such as postsurgical bowel disease or bile diversion leading to malabsorption.

Symptoms of Nonprogressive Primary Liver Disease

Several disorders cause chronic intrahepatic cholestasis but infrequently lead to end-stage liver disease. In these diseases, the morbidity of the liver disease must be weighed carefully against the mortality associated with oLT.

Alagille syndrome is the most common example of such disease in children. This genetic disease produces severe symptoms, but few affected children progress to end-stage liver disease. Pruritus, growth failure, bone disease, hyper-cholesterolemia and xanthomatosis, neuropathy, and malnutrition can all be indications for transplantation. However, symptoms must be severe and have a major effect on the patient, and they must be refractory to all other treatments before considering transplant therapy.

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