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Metabolic Diseases of the Liver
Metabolic liver diseases in children, although individually rare, altogether represent a significant cause of morbidity and mortality. This is because the liver has a central role in synthetic, degradative, and regulatory pathways involving carbohydrate, protein, lipid, trace element, and vitamin metabolism. Therefore, inborn errors of metabolism will result in metabolic abnormalities, specific enzyme deficiencies or defects, and disorders of protein transport that can have primary or secondary effects on the liver ( Table 384.1 ). 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 resulting in cirrhosis and/or liver cancer; abnormal 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 seen in patients with urea cycle defects. Clinical manifestations of metabolic diseases of the liver mimic infections, intoxications, and hematologic and immunologic diseases ( Table 384.2 ).
Table 384.1
Inborn Errors of Metabolism That Affect the Liver
| DISORDERS OF CARBOHYDRATE METABOLISM |
|
| DISORDERS OF AMINO ACID AND PROTEIN METABOLISM |
|
| DISORDERS OF LIPID METABOLISM |
|
| DISORDERS OF BILE ACID METABOLISM |
|
| DISORDERS OF METAL METABOLISM |
|
| DISORDERS OF BILIRUBIN METABOLISM |
|
| MISCELLANEOUS |
|
* Maple syrup urine disease can be caused by mutations in branched-chain α-keto dehydrogenase, keto acid decarboxylase, lipoamide dehydrogenase, or dihydrolipoamide dehydrogenase.
Table 384.2
Clinical Manifestations That Suggest the Possibility of Metabolic Disease
|
Many metabolic diseases are detected in expanded newborn metabolic screening programs (see Chapter 102 ). 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; in patients with hereditary fructose intolerance, symptoms follow ingestion of fructose (sucrose). 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 (e.g., hepatic copper content in Wilson disease). 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 defect and although relatively uncommon, altogether metabolic diseases of the liver account for up to 10% of the indications for liver transplantation in children, a number that may be underestimated given the acute nature of some of these conditions, precluding complete diagnostic investigation prior to transplantation.
Inherited Deficient Conjugation of Bilirubin (Familial Nonhemolytic Unconjugated Hyperbilirubinemia)
Bilirubin is the metabolic end product of heme. Before excretion into bile, it is first glucuronidated and made water-soluble by the enzyme bilirubin-uridine diphosphoglucuronate 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. Complete absence of UGT1A1 activity causes CN type I, while CN type II is caused by decreased UGT1A1 activity to ~10% of normal.
Gilbert syndrome, the most common hereditary hyperbilirubinemia syndrome, occurs in 5–10% of the white population. Common polymorphisms resulting in a TA insertion in the promoter region of UGT1A1 lead to decreased binding of the TATA binding protein and decrease normal gene activity by ~30%. Snapback primer genotyping can distinguish all UGT1A1 promoter genotypes and can provide a definitive diagnosis. Unlike the CN syndromes, Gilbert syndrome usually occurs after puberty, is not associated with chronic liver disease, and no treatment is required. Disease manifestations include fluctuating mild elevations in total serum bilirubin concentration from 1 to 6 mg/dL with no evidence of liver injury or hemolysis. Because UGT1A1 catalyzes water-soluble glucuronidation and detoxification of multiple substrates other than bilirubin (i.e., drugs, hormones, environmental toxins, and aromatic hydrocarbons), mutations in the UGT1A1 gene are implicated in cancer risk and predispose to drug toxicity and episodic jaundice specifically in cancer chemotherapy.
Crigler-Najjar Syndrome Type I (Glucuronyl Transferase Deficiency)
CN type I is a rare, autosomal recessive disease caused by homozygous or compound heterozygous mutations in the UGT1A1 gene which result in a premature stop codon or frameshift mutation and complete absence of UGT1A1 activity. At least 59 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 but have normal serum unconjugated bilirubin levels.
Clinical Manifestations
Severe unconjugated hyperbilirubinemia develops in homozygous affected infants in the first 3 days of life. Without treatment, serum unconjugated bilirubin concentrations reach 25-35 mg/dL in the 1st mo, which can cause kernicterus . Stools are pale yellow. Persistent unconjugated hyperbilirubinemia at levels >20 mg/dL without hemolysis after the 1st wk of life 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 affected infants, bile contains no bilirubin glucuronide and bilirubin concentration in bile is <10 mg/dL compared with normal concentrations of 50-100 mg/dL. The diagnosis is established by measuring hepatic glucuronyl transferase activity in a liver specimen obtained by percutaneous liver biopsy; open liver 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 123.3 .
Treatment
The serum unconjugated bilirubin concentration should be maintained at <20 mg/dL for the first few weeks of life, and even lower in low birthweight infants. This usually requires repeated exchange transfusions and phototherapy in the immediate neonatal period. Oral calcium phosphate supplementation renders phototherapy more effective as it forms complexes with bilirubin in the gut. Phenobarbital therapy, through CYP450 enzyme induction, should be considered to determine responsiveness and differentiation between CN types I and II. In patients with CN type I there is no response to phenobarbital treatment.
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. Additional adjuvant therapy using agents that bind photobilirubin products such as cholestyramine or agar can also 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 reported 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 as bridge therapy to liver transplantation, with most but not all patients eventually requiring 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)
CN type II is an autosomal recessive disease caused by homozygous missense mutations in UGT1A1 resulting in reduced (partial) enzymatic activity. More than 45 mutations have been identified to date. Type II disease can be distinguished from type I by the marked decline in serum bilirubin level that occurs in type II disease after treatment with phenobarbital secondary to an inducible phenobarbital response element on the UGT1A1 promoter.
Clinical Manifestations
When this disorder appears in the neonatal period, unconjugated hyperbilirubinemia usually occurs in the first 3 days of life; serum bilirubin concentrations can be in a range compatible with physiologic jaundice or can be at pathologic levels. The concentrations characteristically remain elevated into and after the 3rd wk of life, persisting in a range of 1.5-22 mg/dL; concentrations in the lower part of this range can create uncertainty about whether chronic hyperbilirubinemia is present. Development of kernicterus is unusual. Stool color is normal, and the infants are without clinical signs or symptoms of disease. There is no evidence of hemolysis. Liver enzymes, albumin, and PT/INR are typically normal.
Diagnosis
Concentration of bilirubin in bile is nearly normal in patients with CN type II. Jaundiced infants and young children with CN type II syndrome respond readily to 5 mg/kg/day of oral phenobarbital, with a decrease in serum bilirubin concentration to 2-3 mg/dL in 7-10 days.
Treatment
Long-term reduction in serum bilirubin levels can be achieved with continued administration of phenobarbital at 5 mg/kg/day. Therapy must be lifelong. The cosmetic and psychosocial benefit should be weighed against the risks of an effective dose of the drug because there is a small long-term risk of kernicterus even in the absence of hemolytic disease. Orlistat, an irreversible inhibitor of intestinal lipase, increases fecal fat excretion and may decrease plasma unconjugated bilirubin concentrations (~10%) in patients with CN types I and II.
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