Chapter 349 Metabolic Diseases of the Liver

Because the liver has a central role in synthetic, degradative, and regulatory pathways involving carbohydrate, protein, lipid, trace element, and vitamin metabolism, many metabolic abnormalities or specific enzyme deficiencies affect the liver primarily or secondarily (Table 349-1). Much has been learned in the past few years about the biochemical basis, molecular biology, and molecular genetics of metabolic liver diseases. This information has led to more precise diagnostic strategies and novel therapeutic approaches. Liver disease can arise when absence of an enzyme produces a block in a metabolic pathway, when unmetabolized substrate accumulates proximal to a block, when deficiency of an essential substance produced distal to an aberrant chemical reaction develops, or when synthesis of an abnormal metabolite occurs. The spectrum of pathologic changes includes: hepatocyte injury, with subsequent failure of other metabolic functions, often eventuating in cirrhosis, liver tumors, or both; storage of lipid, glycogen, or other products manifested as hepatomegaly, often with complications specific to deranged metabolism (hypoglycemia with glycogen storage disease); and absence of structural change despite profound metabolic effects, as with urea cycle defects. Clinical manifestations of metabolic diseases of the liver mimic infections, intoxications, and hematologic and immunologic diseases (Table 349-2). Many metabolic diseases are detected in expanded newborn metabolic screening programs (Chapter 78). Clues are provided by family history of a similar illness or by the observation that the onset of symptoms is closely associated with a change in dietary habits; for example, in patients with hereditary fructose intolerance, symptoms follow ingestion of fructose. Clinical and laboratory evidence often guides the evaluation. Liver biopsy offers morphologic study and permits enzyme assays, as well as quantitative and qualitative assays of various other constituents. Genetic/molecular diagnostic approaches are also available. Such studies require cooperation of experienced laboratories and careful attention to collection and handling of specimens. Treatment depends on the specific type of metabolic defect, and although individually rare when taken together, metabolic diseases of the liver account for up to 10% of the indications for liver transplantation in children.

349.1 Inherited Deficient Conjugation of Bilirubin (Familial Nonhemolytic Unconjugated Hyperbilirubinemia)

Rebecca G. Carey, William F. Balistreri

Bilirubin is the metabolic end product of heme. Before excretion into bile, it is first glucuronidated by the enzyme bilirubin-uridinediphosphoglucuronate glucuronosyltransferase (UDPGT). UDPGT activity is deficient or altered in 3 genetically and functionally distinct disorders (Crigler-Najjar [CN] syndromes type I and II and Gilbert syndrome), producing congenital nonobstructive, nonhemolytic, unconjugated hyperbilirubinemia. UGT1A1 is the primary UDPGT isoform needed for bilirubin glucuronidation, and complete absence of UGT1A1 activity causes CN type I. CN type II is due to decreased UGT1A1 activity. Gilbert syndrome is caused by a common polymorphism, a TA insertion in the promoter region of UGT1A1 that leads to decreased binding of the TATA binding protein and decreases normal gene activity but only to ∼30%. Unlike the Crigler-Najjar syndromes, Gilbert syndrome usually occurs after puberty; it is not associated with chronic liver disease and no treatment is required. However, it is more common, affecting up to 5-10% of the white population with total serum bilirubin concentrations that fluctuate from 1 to 6 mg/dL. Because UGT1A1 is involved in glucuronidation of multiple substrates other than bilirubin (e.g., pharmaceutical drugs, endogenous hormones, environmental toxins, and aromatic hydrocarbons) and glucuronidation leads to inactivation of these substrates, mutations in the UGT1A1 gene have been implicated in cancer risk and the disposition to drug toxicity.

Crigler-Najjar Syndrome Type I (Glucuronyl Transferase Deficiency)

CN type I is inherited as an autosomal recessive trait and is usually secondary to mutations that cause a premature stop codon or frameshift mutation and thereby abolish UGT1A1 activity. More than 35 mutations have been identified to date. Parents of affected children have partial defects in conjugation as determined by hepatic specific enzyme assay or by measurement of glucuronide formation; their serum unconjugated bilirubin concentrations are normal.

Clinical Manifestations

Severe unconjugated hyperbilirubinemia develops in homozygous affected infants in the 1st 3 days of life, and without treatment, serum unconjugated bilirubin concentrations of 25-35 mg/dL are reached in the 1st month. Kernicterus, an almost universal complication of this disorder, is usually 1st noted in the early neonatal period; some treated infants have survived childhood without clinical sequelae. Stools are pale yellow. Persistence of unconjugated hyperbilirubinemia at levels >20 mg/dL after the 1st wk of life in the absence of hemolysis should suggest the syndrome.

Diagnosis

The diagnosis of CN type I is based on the early age of onset and the extreme level of bilirubin elevation in the absence of hemolysis. In the bile, bilirubin concentration is <10 mg/dL compared with normal concentrations of 50-100 mg/dL; there is no bilirubin glucuronide. Definitive diagnosis is established by measuring hepatic glucuronyl transferase activity in a liver specimen obtained by a closed biopsy; open biopsy should be avoided because surgery and anesthesia can precipitate kernicterus. DNA diagnosis is also available and may be preferable. Identification of the heterozygous state in parents also strongly suggests the diagnosis. The differential diagnosis of unconjugated hyperbilirubinemia is discussed in Chapter 96.3.

Treatment

The serum unconjugated bilirubin concentration should be kept to <20 mg/dL for at least the 1st 2-4 wk of life; in low birthweight infants, the levels should be kept lower. This usually requires repeated exchange transfusions and phototherapy. Phenobarbital therapy should be considered to determine responsiveness and differentiation between type I and II (see later).

The risk of kernicterus persists into adult life, although the serum bilirubin levels required to produce brain injury beyond the neonatal period are considerably higher (usually >35 mg/dL). Therefore, phototherapy is generally continued through the early years of life. In older infants and children, phototherapy is used mainly during sleep so as not to interfere with normal activities. Despite the administration of increasing intensities of light for longer periods, the serum bilirubin response to phototherapy decreases with age. Adjuvant therapy using agents that bind photobilirubin products such as calcium phosphate, cholestyramine, or agar can be used to interfere with the enterohepatic recirculation of bilirubin.

Prompt treatment of intercurrent infections, febrile episodes, and other types of illness might help prevent the later development of kernicterus, which can occur at bilirubin levels of 45-55 mg/dL. All patients with CN type I have eventually experienced severe kernicterus by young adulthood.

Orthotopic liver transplantation cures the disease and has been successful in a small number of patients; isolated hepatocyte transplantation has been reported in fewer than 10 patients, but all patients eventually required orthotopic transplantation. Other therapeutic modalities have included plasmapheresis and limitation of bilirubin production. The latter option, inhibiting bilirubin generation, is possible via inhibition of heme oxygenase using metalloporphyrin therapy.

Crigler-Najjar Syndrome Type II (Partial Glucuronyl Transferase Deficiency)

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