Frederick J. Suchy
The liver plays a central role in the biosynthesis and degradation of carbohydrates, lipids, and amino acids (see Chapter 418). Thus, the liver is involved primarily or secondarily in many inborn errors of metabolism. In inborn errors of metabolism such as hereditary tyrosinemia, the absence of a critical enzyme may cause an accumulation of toxic metabolites. In other disorders, progressive liver injury may occur because of failure to produce essential compounds. An example of this process is an inborn error of bile acid metabolism, which leads to progressive cholestasis because of a lack of bile acid synthesis. Severe liver injury may also result from a third mechanism, sequestration of an abnormally synthesized product within the liver, as observed in α1-antitrypsin deficiency. In this section, the focus is on those disorders that lead to acute or chronic damage to the liver. Many of these metabolic disorders are discussed further in Section 11.
Family history, including unexplained infantile deaths or the patterns of observed symptoms, may suggest metabolic liver disease. For example, liver disease occurring after the initial ingestion of fructose should suggest a diagnosis of hereditary fructose intolerance. Clinical features of metabolic liver disease may be nonspecific and can overlap with other hepatic disorders, including viral hepatitis or drug-induced liver injury. These may include jaundice, vomiting, hepatosplenomegaly, failure to thrive, developmental delay, hypotonia, seizures, and progressive neuromuscular dysfunction (Table 421-1).
Table 421-1. Clinical Features Associated with Metabolic Liver Disease
|
Coma with hyperammonemia |
|
Hypoglycemia |
|
Psychomotor retardation |
|
Acidosis |
|
Failure to thrive |
|
Muscle weakness |
|
Coagulopathy, particularly out of proportion to liver test abnormalities |
|
Dysmorphic facial features |
|
Cholestasis |
|
Cardiac disease |
Initial laboratory studies are often nonspecific and include hypoglycemia, hyperammonemia, increased aminotransferase levels, acidosis, and hypoprothrombinemia. In some disorders such as Wilson disease, hepatocyte injury and loss of hepatic mass occur largely through the process of apoptosis rather than liver cell necrosis. In this setting, liver function can be markedly deranged, but serum aminotransferase levels may be only modestly increased. Percutaneous or open liver biopsy, if possible, allows histologic examination and measurement of enzymatic pathways or substrate accumulation. A specific diagnosis is critically important in that it may allow effective therapy, including liver transplantation and genetic counseling. The natural history of several disorders such as galactosemia and tyrosinemia is changing with presymptomatic diagnosis and early treatment made possible by newborn screening.
DISORDERS OF CARBOHYDRATE METABOLISM
GALACTOSEMIA
Galactosemia is discussed in detail in Chapter 155. Early manifestations following ingestion of galactose (contained in breast milk and cow’s milk formula) include jaundice, lethargy, vomiting, acidosis, cataracts, failure to thrive, and bleeding. Indirect hyperbilirubinemia is commonly seen and can be accompanied by coagulopathy. Urinary tract infection and/or sepsis, typically with gram-negative species, are also a common presenting problem. Untreated disease causes death within the first several weeks of life in up to 75% of infants, and late recognition of disease is likely to result in severe neurologic injury.1
DIAGNOSIS AND TREATMENT
State programs screen newborns for galactosemia in most of the United States, but clinicians should not rely on these programs for diagnosis in patients with suggestive symptoms. Urine-reducing substances are detected in infants fed galactose-containing formulas, although urine glucose dipsticks are negative. Secondary galactosemia can be seen in severe liver disease because of a lack of hepatic galactose clearance, and urinary screening may be inaccurate in this circumstance. Therefore, enzymatic assays for galactose-1-phosphate uridyl transferase should ultimately be performed using red blood cells in all cases. Mutation analysis is also feasible. Treatment consists of strict elimination of galactose from the diet.2 Treated infants can lead normal lives, although speech defects, learning disabilities and behavioral problems are common.
HEREDITARY FRUCTOSE INTOLERANCE
Hereditary fructose intolerance is also discussed in detail in Chapter 155. It results from an autosomal-recessive disorder caused by a genetic deficiency in the enzyme fructose-1,6-biphosphate aldolase (aldolase B).3
PATHOPHYSIOLOGY
The accumulation of fructose-1-phosphate in affected individuals leads to the sequestration of inorganic phosphate as fructose-1-phosphate with resulting activation of adenosine monophosphate deaminase (AMP), which catalyzes the irreversible deamination of AMP to IMP (inosine monophosphate), a precursor of uric acid. Depletion of tissue ATP occurs through massive degradation to uric acid and impairment of regeneration by oxidative phosphorylation in the mitochondria because of inorganic phosphate depletion. Thus, serum uric acid may be increased and phosphate decreased with acute disease. The depletion of tissue ATP causes symptoms. Sorbitol is converted to fructose and thus can lead to a similar pathologic process in these patients.
CLINICAL FEATURES
The classical presentation occurs in infants on the initial presentation of fructose-containing foods with the acute onset of vomiting, hypoglycemia, and hypophosphatemia preceding the development of hepatomegaly with steatosis, jaundice, and ascites. The Fanconi syndrome and renal tubular acidosis may occur. Prolonged exposure to fructose may lead to death from severe liver and kidney failure.
A more chronic presentation is now recognized with presenting signs and symptoms of hepatomegaly, abnormal liver enzymes, and fatty liver. Chronic exposure to fructose causes poor feeding, failure to thrive, vomiting, irritability, and poor growth. Many affected individuals evolve an eating behavior with avoidance of fructose, thus minimizing the acute manifestations of the disease. Some individuals have not been diagnosed until challenged with fructose as adults. Therefore, this disease needs to be considered in children with unexplained hepatomegaly and steatosis.
DIAGNOSIS AND TREATMENT
Several methods are available to make the diagnosis of hereditary fructose intolerance. DNA diagnostic assays (including allele-specific oligo-nucleotide hybridization) utilizing peripheral leukocytes have identified over 15 different mutations in the aldolase gene, but 3 account for the disease in the majority of affected individuals; therefore, genetic testing is usually the initial least invasive and safest test. An intravenous fructose challenge test has been described but is associated with potentially significant complications and should be avoided given current alternative diagnostic approaches. Aldolase B activity can be readily measured from liver tissue.
Treatment involves strict avoidance of fructose, sorbitol, and sucrose. Partial adherence to this difficult diet can ameliorate many of the acute manifestations of this disease but not the chronic problems, such as growth failure. It is imperative to remember that certain intravenous solutions and oral medications can contain fructose and/or sorbitol.
GLYCOGEN STORAGE DISEASES
The glycogen storage diseases include a wide range of clinical phenotypes that are the result of abnormalities in glycogen metabolism and these are discussed in detail in Chapter 154.4
CLINICAL FEATURES
The inability to utilize glycogen stores, accumulation of glycogen within the liver and/or other tissues, and the toxic effects of certain abnormal types of glycogen lead to the clinical manifestations of these disorders. Fasting hypoglycemia is the hallmark of forms of glycogen storage disease in which there is an inability to utilize glycogen stores to produce glucose including the various forms of type I glycogen storage disease and types III (debranching deficiency or Cori disease) and VI (liver phosphor-ylase deficiency or Andersen disease).
The inability to utilize glycogen normally leads to its accumulation in hepatocytes. Significant hepatomegaly is a common feature of glycogen storage disease type I but can also be seen in types III, IV (branching deficiency), and VI, where normal glycogen breakdown is impaired. Long-term glycogen deposition can increase the risk of hepatic adenomas, which are a significant risk in young adults with glycogen storage disease type I.
A very different clinical presentation can be observed in those disorders that lead to hepatic accumulation of toxic forms of glycogen. The best example of this is glycogen storage disease type IV, in which there is a deficiency of the glycogen-branching enzyme. Glycogen that accumulates in this disease has long chains of glucose in a 1 to 4 linkage and resembles plant starch or amylopectin. This form of glycogen is relatively insoluble and presumed to be toxic, leading to hepatocellular injury. Progressive liver disease thus becomes a major distinguishing feature of glycogen storage disease type IV. Portal hypertension and hepatic failure can develop in early childhood. The toxic amylopectin-like glycogen also appears to predispose to the development of hepato-cellular adenomas.
Glycogen storage disease type IX (GSD type IX) is caused by a deficiency of hepatic phosphorylase kinase activity. Clinical symptoms are characterized by hypoglycemia, hepatosplenomegaly, short stature, hepatopathy, weakness, fatigue, and motor delay. Biochemical findings include elevated lactate, urate, and lipids.
DIAGNOSIS AND TREATMENT
Diagnosis of the specific type of glycogen storage disease is critical for proper treatment and for prediction of prognosis and potential complications. Specific enzymatic assays and DNA diagnostic tests are available in specialty laboratories for each of the disorders. Diagnostic assays can be performed on a number of tissues including liver, muscle, leukocytes, and fibroblasts.
Treatment in many of these disorders is directed at maintaining normal blood sugar levels. Frequent feeding of high-carbohydrate-containing foods and nocturnal administration of slow-release glucose polymers, such as uncooked cornstarch, are utilized. This prevents the development of hypoglycemia and also limits incorporation of excess dietary glucose into glycogen. Liver transplantation has been performed for GSD-1, GSD-III, and GSD-IV. As liver pathology is not the major source of morbidity in most cases of GSD-I and GSD-III, liver transplantation should only be performed when there is hepatocellular carcinoma, complicated adenomas at high risk for cancer or evidence of substantial cirrhosis or liver dysfunction.5 Liver transplantation remains the best option for treatment of GSD-IV. It is important to remember that these are systemic diseases that have variable degrees of involvement of both skeletal and cardiac muscle.
OTHER METABOLIC DISORDERS ASSOCIATED WITH LIVER DISEASE
HEREDITARY TYROSINEMIA
Hereditary tyrosinemia type I is an autosomal-recessive disorder caused by deficiency of fumarylacetoacetate hydrolase (FAH), the last enzyme in the tyrosine degradation pathway. It is discussed in more detail in Chapter 136.6Metabolites of tyrosine that accumulate proximal to the enzymatic block, such as succinyl acetate, succinyl acetone, fumaryl acetoacetate, and maleylacetoacetate, are highly reactive electro-philic toxic compounds that bind to sulfhydryl groups, often leading to tissue injury.
CLINICAL FEATURES
Type 1 hereditary tyrosinemia occurs in acute and chronic forms that may be manifest in the same family. The acute form presents in infancy with severe liver dysfunction including jaundice, hepatosplenomegaly, failure to thrive, anorexia, ascites, coagulopathy, and rickets. The disorder may actually begin in utero as evidenced by the presence of cirrhosis and regenerative nodules at the time of presentation. The chronic form is observed later in childhood with cirrhosis, renal tubular dysfunction, rickets, and hepatocellular carcinoma. Episodes of severe peripheral neuropathy occur in patients surviving infancy, leading to morbidity from severe pain and even mortality from respiratory failure.
DIAGNOSIS AND TREATMENT
Laboratory studies usually indicate that there is more compromise of hepatic synthetic function than would be expected based upon liver biochemical tests. Hypoglycemia is common, particularly in infants. Hypoalbuminemia and a decrease in vitamin K–dependent coagulation factors is common but serum aminotransferase values are only mildly to moderately increased. Total and direct bilirubin concentrations are variably increased. Hemolytic anemia may be present. Renal tubular dysfunction producing a Fanconi syndrome may occur with hyper-phosphaturia, glucosuria, proteinuria, and aminoaciduria. Serum tyrosine and methio-nine concentrations are markedly elevated. Phenolic acid byproducts of tyrosine metabolism are detected in the urine. Succinylacetone and succinylacetoacetate in the urine are typical and diagnostic of this disorder. Serum α-fetoprotein (AFP) concentrations are often significantly elevated in affected infants and in cord blood, suggesting prenatal onset of liver disease.
Histologic examination of the liver reveals fatty infiltration, iron deposition, varying degrees of hepatocyte necrosis, and pseudoacinar formation. Significant fibrosis may be present early in life with gradual evolution to multinodular cirrhosis. Regenerative nodules mimicking neoplasms may be present in some patients. Hepatocellular carcinoma may be found in older patients with cirrhosis.
The acute form of type 1 tyrosinemia is usually fatal in the first year of life without therapy. Treatment with a diet restricted in phenylala-nine, methionine, and tyrosine does not prevent progression of the liver disease or development of hepatocellular carcinoma. Liver transplantation is the only therapy that reverses hepatic, neurologic, and most renal manifestations of the disease. Patients demonstrating cirrhotic nodules on imaging studies should undergo transplantation because of the high risk of developing carcinoma. Early liver transplantation is also indicated in patients with severe neurologic crises. In patients without these sequelae, medical therapy with 2-(nitro-4-trifluromethylbenoy1)-1,3-cyclohexanedione (NTBC) is effective in reversing the metabolic abnormalities in hereditary tyrosinemia type 1.7NTBC treatment reduces the flux through the tyrosine degradation pathway preventing the formation of metabolites that are toxic to liver and kidney. Toxic metabolites and serum α-fetoprotein levels decrease, and marked improvement in liver synthetic function occurs. NTBC usually provides protection against heptaocellular carcinoma if it is started in infancy, but cases have occurred even when NTBC was started at five months of age. AFP is a marker for both the development of liver cancer and the inadequate control of metabolic derangement of tyrosinemia type I itself. In a group of initially asymptomatic newborns identified by newborn screening in Quebec treated with NTBC within 1 month, none have developed hepatic dysfunction or liver nodules over a follow-up period of up to 9 years. However, the long-term risk of hepatocellular carcinoma even in early-treated patients is unknown.
CONGENITAL DISORDERS OF GLYCOSYLATION
Congenital disorders of glycosylation (CDG) are inborn errors of metabolism caused by defective N-glycosylation of proteins are discussed in detail in Chapter 163, “Congenital Disorders of Glycosylation.” Depending on the enzymatic defect, the carbohydrate side chains of glycoproteins are either completely absent from the protein core or truncated.20 CDG can affect multiple organs. Common clinical features include dysmorphic facies, mental retardation, failure to thrive, seizures, hypotonia, diarrhea, protein-losing enteropathy, recurrent infection and coagulopathy. Of the 30 known subtypes, at least twelve involve the liver. Hepatomegaly and elevated serum aminotransferases are common. The histopathology is not well defined in most subtypes, but steatosis, fibrosis and even cirrhosis have been described. In CDG-1b congenital hepatic fibrosis occurs. Thus CDG should be considered in any child with cryptogenic liver disease. Detection of abnormally glycosylated transferrin by isoelectric focusing is the commonly used diagnostic screening test, but some forms cannot be detected using this method.21 There is no specific treatment for most of these disorders. Oral mannose supplements appear to be effective for treatment of CDG-1b.
DISORDERS OF FATTY ACID OXIDATION OR METABOLISM
Normal fatty acid oxidation is shown in Figure 150-1 and discussed in Chapter 418. Disorders of fatty acid oxidation or metabolism are discussed further in Chapter 150. Abnormalities in fatty acid metabolism can lead to severe forms of acute liver injury as a result of both energy deprivation and the accumulation of highly toxic intermediary metabolites of fatty acid oxidation. At least 22 different clinical entities have been ascribed to distinct abnormalities in fatty acid oxidation.11
CLINICAL FEATURES
A range of clinical presentations has been described including sudden infant death, cardiomyopathies, skeletal myopathies, hepatopathy, and life-threatening hypoglycemia (Table 421-2). Hepatopathy has been described in two-thirds of these disorders with at least 6 involving relatively severe liver disease (long-chain fatty acid transport defect, carnitine palmitoyltransferase deficiency, long-chain hydroxyacyl-CoA-dehydrogenase deficiency, α- and β-trifunctional protein defects, and short-chain hydroxyacyl-CoA-dehydrogenase deficiency).
The typical case of severe liver disease resulting from an abnormality in fatty acid oxidation presents with acute liver disease characterized by markedly elevated serum aminotransferase levels with variable degrees of cholestasis and coagulopathy. Nonketotic hypoglycemia is a hallmark feature of these disorders. Variable degrees of myopathy (skeletal and/or cardiac) may be an accompanying feature. Some form of stressor that includes fasting typically precedes the onset of the hepatopathy. Manifestations and biochemical abnormalities may be intermittent.
DIAGNOSIS AND TREATMENT
Prompt recognition of defects in fatty acid metabolism is paramount for proper treatment. Diagnostic assays that examine intermediate metabolites of fatty acid oxidation need to be performed during illness, as many of the metabolites will clear with treatment. Testing in suspected fatty acid oxidation defects includes both nonspecific screening assays and more specific enzymatic and DNA diagnostic tests. Initial evaluation should include assays of plasma carnitine, acylcarnitines, free fatty acids, urine organic acids, and acylglycines. Microvesicular steatosis is a common although not universal feature in fatty acid oxidation defects. Analysis of acylcarnitines in bile can be informative. Typically treatment is directed at stopping ongoing fatty acid oxidation by halting fat catabolism. This often can be achieved by intravenous administration of 12 to 15 mg/kg/min of glucose. Subsequent avoidance of fasting is crucial. The benefits of carnitine administration and specific dietary fat restrictions or supplementation are controversial. In many circumstances a diagnosis cannot be made before the development of irreversible hepatic injury. Liver transplantation can be considered, but care must be taken to ensure that there is no evidence of severe systemic or neurologic disease that would not improve following hepatic replacement.
Table 421-2. Clinical Features Suggestive of an Inborn Error in Fatty Acid Oxidation
|
Infantile Reye-like illness |
|
Recurrent Reye syndrome |
|
Hepatic steatosis |
|
Unexplained hepatic failure (may be recurrent) |
|
Nonketotic hypoglycemia |
|
Skeletal or cardiac myopathy |
PRIMARY MITOCHONDRIAL HEPATOPATHIES
Hepatic disease is a common feature of primary mitochondrial disorders, which are described in more detail in Chapter 158.12
CLINICAL FEATURES
Neonatal and early childhood hepatic failure have been associated with defective activity of respiratory chain complexes and oxidative phosphorylation, but liver disease of varying severity including steatohepatitis, cholestasis, or cirrhosis with chronic liver failure at different ages has also been reported. There may be varying degrees of neuromuscular involvement in these patients, such as seizures and hypotonia. Neonatal liver failure occurs in association with deficiency of complexes I, III, or IV (cytochrome c oxidase). Evidence of liver synthetic failure is particularly prominent with hypoglycemia, hypoproteinemia, hyperbilirubinemia, hyperammonemia, and coagulopathy. Lethargy, hypotonia, vomiting, seizures, and poor feeding may be present from birth. Prenatal onset is suggested in some patients by the occurrence of fetal hydrops and congenital ascites. The spectrum of respiratory chain disorders is sufficiently broad that some patients are now being recognized with a more chronic course or onset later in infancy or childhood. Alper disease is one such disorder; it is characterized by progressive neuronal degeneration and cirrhosis of the liver in childhood.
DIAGNOSIS AND TREATMENT
A key diagnostic feature in these patients is the presence of lactic acidosis and an elevated molar ratio of plasma lactate to pyruvate (normal < 20:1). Histologic features of the liver include microvesicular and macrovesicular steatosis with abnormally increased mitochondrial density and swelling. Cholestasis, bile ductular proliferation, and fibrosis or even cirrhosis may be present. Activities of mitochondrial respiratory chain enzymes can be measured in affected tissues.
Point mutations in mitochondrial or nuclear DNA have been detected in some patients with neonatal liver failure caused by respiratory chain defects. Autosomal-recessive, maternal, and possibly X-linked modes of inheritance have been observed or proposed. Deletions and rearrangements of mtDNA have also been observed. Some patients presenting with severe liver disease have been found to have the mtDNA depletion syndrome, in which there is a generalized reduction of otherwise normal mitochondrial DNA molecules in affected organs. mtDNA depletion may be caused by mutations in several genes, including POLG that encodes a protein essential for mtDNA replication and repair and DGUOK that maintains the supply of nucleotides for mtDNA synthesis.
Because heteroplasmy for mitochondrial DNA (mtDNA) mutations is not uniform in all tissues, patients may present exclusively with liver disease or with variable involvement of other organ systems. This issue is critically important because patients may undergo successful liver transplantation only to have later onset of severe neuromuscular disease. The prognosis for patients with acute liver failure secondary to a mitochondrial disorder is extremely poor. There is no proven medical therapy, although supplementation with mitochondrial cofactors such as coenzyme Q 10 and antioxidants theoretically may be beneficial. Liver transplantation has been successful in patients whose disease is restricted to the liver. In patients with acute liver failure MRI and magnetic resonance spectroscopy are useful for pretrans-plant evaluation of the central nervous system, but subsequent neurological deterioration may still occur even after an initially normal study.
REYE AND REYE-LIKE SYNDROMES
Reye syndrome is now an extremely rare disorder characterized by acute encephalopathy and liver dysfunction.13 Death occurs in about 30% to 40% of cases, primarily from cerebral edema. The disease typically is preceded by a viral infection, particularly varicella or influenza, with an intermediate disease-free interval of 3 to 5 days. There was a strong association with the use of aspirin. The reasons for the decreasing incidence of Reye syndrome are not clear but may in part be related to the avoidance of aspirin use in children with viral illnesses.
CLINICAL FEATURES
Patients develop vomiting within a few days of the antecedent illness, which is an indication of the earliest stage of encephalopathy. In the more severe cases, vomiting is followed quickly by progressive obtundation and the stages of metabolic coma. The disease reflects a generalized disturbance in mitochondrial structure and function, resulting in defective ureagenesis, ketogenesis, hyperammonemia, hypoglycemia, elevated serum free fatty acids, and lactate and dicarboxylic acids. Impairment of mitochondrial β-oxidation also occurs.
DIAGNOSIS AND TREATMENT
Laboratory findings include increased liver transaminases (AST, ALT > 3 times normal), normal bilirubin, increased blood ammonia level, variable hypoglycemia, and a prolonged INR. Cerebrospinal fluid (CSF) examination usually shows increased pressure, but normal white blood cell counts and protein levels. Microvesicular steatosis is found on liver biopsy. Electron microscopy typically shows mitochondrial pleomorphism and swelling in the liver, brain, and other tissues. Treatment is directed at maintaining metabolic homeostasis with glucose administration and minimizing intracranial hypertension with maneuvers such as hyperventilation and mannitol infusion.
There are pediatric disorders that may mimic Reye syndrome with manifestations of liver disease and encephalopathy, including systemic viral infections with multisystem involvement, toxin exposure, or inborn errors of metabolism. Fatty acid oxidation defects and urea cycle defects are most likely to be confused with Reye syndrome. There have been very few cases of Reye syndrome diseases reported during the past 10 years that could not be explained by an inborn error of metabolism or a misdiagnosis.
ALPHA-1-ANTITRYPSIN DEFICIENCY
α1-Antitrypsin deficiency can be associated with progressive liver disease in infants, children, and adults.14 α1-Antitrypsin is the principal serum inhibitor of proteolytic enzymes such as neutro-phil elastase. Patients with homozygous deficiency or the protein inhibitor ZZ phenotype (PiZZ) have low serum α1-antitrypsin activity, usually in the range of 10% to 15% of normal values.
EPIDEMIOLOGY
The incidence of the most common deficiency phenotype, PiZZ, is 1 in 2000 to 4000 live births. Only 10% to 15% of neonates with the homozygous deficiency manifest liver disease and the reason for this is unclear.
PATHOPHYSIOLOGY AND GENETICS
The PiZZ defect is caused by substitution of a lysine for a glutamate at position 342, leading to misfolding of the protein and its retention in the endoplasmic reticulum. Studies in transgenic mice expressing the abnormal human protein indicate that retained α1-antitrypsin is toxic to hepatocytes. Recent studies have shown that mutant α1-antitrypsin molecule polymerizes in the endoplasmic reticulum by a novel loop-sheet insertion mechanism. The effects of the intracellular accumulation of the mutant Z protein in the liver include the formation of protein polymers, activation of autophagy, mitochondrial injury, and caspase activation, which lead to progressive liver damage. A subpopulation of α1-antitrypsin-deficient individuals may be susceptible to liver injury because they have another trait that reduces the efficiency with which the mutant α1-antitrypsin protein is degraded in the endoplasmic reticulum.
CLINICAL FEATURES
Liver disease associated with α1-antitrypsin deficiency may present in various forms including neonatal cholestasis, juvenile cirrhosis, chronic hepatitis, and hepatocellular carcinoma. Chole-static jaundice occurs in approximately 10% to 15% of infants with the PiZZ phenotype. Hepatomegaly and acholic stools may occur. Patients rarely may present with signs of advanced liver disease such as ascites or gastrointestinal bleeding. Although asymptomatic, another 40% to 50% of homozygous infants have abnormal liver biochemical tests in the first months of life.
Giant-cell hepatitis is a typical histologic finding in the neonate.15 Bile ductular proliferation may be observed initially; occasionally, paucity of bile ducts is found later. Periodic acid–Schiff-positive, diastase-resistant inclusions within hepatocytes, especially in the periportal region, represent the abnormal α1-antitrypsin accumulation. These are a hallmark of the disorder but are not prominent before 4 months of age. Variable degrees of fibrosis may be present. Cirrhosis has been reported as early as the neonatal period, but progression to cirrhosis is quite variable. α1-Antitrypsin deficiency can present later in life with clinical features similar to autoimmune hepatitis. α1-Antitrypsin deficiency is associated with emphysema in young adulthood as discussed in Chapter 516.
DIAGNOSIS AND TREATMENT
α1-Antitrypsin concentration and phenotype should be measured in any child or adult presenting with chronic liver disease. Measurement of α1-antitrypsin concentration alone is unreliable because the protein is an acute-phase reactant and may be elevated as the result of an illness. Heterozygotes with the SZ and MZ phenotypes have a less severe reduction in serum α1-antitrypsin concentration. The role of α1-antitrypsin heterozygosity as a modifier for other liver diseases remains unsettled. There is no specific treatment for α1-antitrypsin deficiency. Liver transplantation is curative for patients progressing to end-stage liver disease; the recipient assumes the Pi type of the donor organ.
OUTCOMES
The outcome of neonatal liver disease related to α1-antitrypsin deficiency is variable. Patients presenting with cirrhosis may deteriorate within the first months of life. However, in most infants, the jaundice clears by 4 months of age. Patients may present with cirrhosis later in childhood and are at risk for hepatocellular carcinoma. Of 127 PiZZ patients identified by neonatal screening in one study of 200,000 births, 12% developed neonatal cholestasis, and another 7% had clinical evidence of liver disease in infancy. On follow-up at 18 years of age, 5 PiZZ patients had died, but the majority of remaining patients had normal liver biochemical tests and were free of clinical liver disease.
LIVER DISEASE ASSOCIATED WITH DISORDERS OF METAL METABOLISM
WILSON DISEASE
Wilson disease (hepatolenticular degeneration) is an autosomal-recessively inherited disorder of copper metabolism.16 The clinical manifestations of Wilson disease result from the excessive deposition of copper in the liver, brain, kidneys, and eyes. This excessive accumulation results from disturbed incorporation of copper into ceruloplasmin and reduced biliary copper excretion.
EPIDEMIOLOGY
A single abnormal copy of the Wilson disease gene is found in up to 1 in 100 people. The disorder occurs in between 1 and 4 per 100,000 individuals.
PATHOPHYSIOLOGY AND GENETICS
The gene for Wilson disease, mapped to the long arm of chromosome 13 and designated ATP7B, encodes a copper-transporting P-type ATPase expressed predominantly in hepatocytes. Over 400 disease-specific mutations of ATP7B have now been reported in individuals with Wilson disease. Genotype/phenotype correlations are complicated by the fact that many Wilson disease patients are compound heterozygotes. The ATP7B protein is localized predominantly in the trans-Golgi network, to a vesicular compartment, and possibly in mitochondria. The mechanism of copper toxicity likely includes the generation of free radicals, lipid peroxidation of membranes and DNA, inhibition of protein synthesis, and reduced levels of cellular antioxidants. Hepatocellular necrosis and apoptosis may be triggered by copper-induced cellular injury. When the storage capacity of the liver for copper is exceeded, or when liver-cell necrosis results in release of cellular copper into the systemic circulation, the concentration of non-ceruloplasmin-bound copper in the circulation becomes elevated with resultant extrahepatic deposition in sites such as the brain.
CLINICAL FEATURES
Wilson disease should be considered in any child with an unexplained hepatic, neurologic, or psychiatric illness. The natural history of Wilson disease begins with the asymptomatic accumulation of copper in hepatocytes. The clinical presentation is highly variable. Although patients as young as 2 have presented with liver disease, symptoms are rarely evident before 5 years of age. Younger children, identified by family screening or after evaluation of abnormal liver biochemical tests, are often asymptomatic. Patients younger than 20 years of age tend to present predominantly with hepatic manifestations. Asymptomatic hepatomegaly or an illness mimicking acute hepatitis may occur. Hepatic insufficiency associated with cirrhosis may evolve slowly or be manifest at the time of initial diagnosis with variceal hemorrhage, ascites, edema, and stigmata of chronic liver disease. A fulminant form of the disease most often occurs in the second decade of life with the abrupt onset of liver failure associated with nonimmune hemolytic anemia. The latter complication likely results from oxidative injury to red blood cells as massive amounts of copper are released from hepatocytes.
Older patients may present with predominantly neurologic and psychiatric dysfunction. Findings initially may be quite subtle and include deterioration in school performance, behavioral changes, slurred speech, and tremors. If untreated, severe dysarthria and dystonia result, sometimes leading to psychiatric hospitalization. Kayser-Fleischer rings, copper deposits on the inner surface of the Descemet membrane, are invariably found in patients with a neurologic presentation. They are often absent in younger patients when they present with only liver disease.
Abnormalities of other organ systems are sometimes present in Wilson disease. Copper toxicity in the kidney may induce nephrocalcinosis, hematuria, and aminoaciduria. Arthritis, arthralgias, and premature osteoarthritis may also occur. Cardiomyopathy and arrhythmias may result from copper accumulation in the myocardium.
DIAGNOSIS
Routine laboratory studies demonstrate variable elevation in serum aminotransferase values and in the conjugated and unconjugated serum bilirubin concentrations. Serum alkaline phosphatase levels tend to be normal or even low. The serum copper concentration is usually low but may be elevated during episodes of hemolysis. Serum ceruloplasmin, an α2-globulin involved in copper transport, is typically low, although this serum protein may also be reduced in other disorders associated with acute or chronic hepatic insufficiency. Urinary copper excretion, normally less than 40 to 60 μg per 24 hours, is usually more than 100 μg per 24 hours in Wilson disease. Urinary copper excretion may be elevated in other forms of liver disease, such as chronic hepatitis or fulminant hepatic necrosis.
Hepatic copper content remains the gold standard for the diagnosis of Wilson disease. The typical diagnostic concentration is more than 250 μg per gram dry weight of liver, commonly more than 1000 μg per gram. Histologic examination may show fatty infiltration, glycogen accumulation, glycogenated nuclei, and enlarged Kupffer cells. However, sometimes there are findings indistinguishable from those of chronic active hepatitis. Significant hepatic fibrosis or even cirrhosis may be a presenting feature. Distinctive mitochondrial changes may be found even at an early stage of the disease, including enlargement, separation of the inner and outer membranes, widening of the intercristal spaces, and increased density and granularity of the matrix or replacement by large vacuoles. Histochemical stains for copper may be useful when positive but are not reliable in excluding copper overload.
The most striking neuropathologic changes in Wilson disease are found in the lenticular nuclei, which may manifest atrophy, cystic degeneration, and discoloration. The thalamus, the subthalamus, and even the cerebral cortex may be involved.
TREATMENT
Without treatment, Wilson disease is uniformly fatal. The mainstay of treatment involves chelation therapy with copper-binding agents—D-penicillamine or trientine. D-penicillamine is administered orally in increasing doses to approximately 1 g/day in adults and 0.5 to 0.75 g/day for younger children. Chelating agents remove copper from potentially toxic sites within cells and detoxify the remaining copper. Urinary copper excretion markedly increases on initiation of therapy with D-penicillamine. Later, urinary copper excretion stabilizes, reflecting a new steady state of copper balance. A low-copper diet must also be instituted to maintain a daily intake below 1 mg per day. Foods containing high amounts of copper, such as liver, chocolate, nuts, and shellfish, should be avoided. Water sources should also be assayed for copper content. With effective chelation therapy, there is usually improvement of hepatic and neurologic function and regression of Kayser-Fleischer rings. Chelation therapy must be maintained for life. For patients who are intolerant to D-penicillamine because of hypersensitivity reactions or bone marrow suppression, therapy with an alternative chelating agent, trientine, is equally effective. Tetrathiomolybdate is another chelating agent potentially useful in patients with neurologic disease in whom D-penicillamine therapy may be associated with an initial worsening of symptoms. Several studies have indicated that zinc administration may maintain a negative copper balance in patients with Wilson disease, but zinc should be considered as a primary therapy only in patients unable to tolerate standard chelating agents. Zinc acts to prevent intestinal absorption of copper, rather than as a chelating agent.
For patients with end-stage liver disease unresponsive to chelation therapy, and for most patients with the fulminant form of Wilson disease, liver transplantation may be life saving. Various degrees of regression of neurologic and psychiatric abnormalities have been described following liver replacement.
FAMILY SCREENING
Siblings of patients with Wilson disease should be screened carefully for the disorder. Zinc has been used successfully in asymptomatic or presymptomatic affected family members of individuals with Wilson disease. The abundance of disease-specific mutations and their locations at multiple sites have limited molecular genetic diagnosis to kindred of known patients. Thorough evaluation by well-established clinical and biochemical tests remains essential.
NEONATAL IRON STORAGE DISEASE
Neonatal iron storage disease, also known as neonatal hemocromatosis, is a form of neonatal liver failure characterized by an in utero onset of hepatic and extrahepatic hemosiderosis.18 This entity is unrelated to hereditary hemochromatosis and does not appear to be the result of a primary abnormality in fetal iron metabolism. The rate of occurrence of severe disease in subsequent newborns after the index case is 60% to 80%.
PATHOPHYSIOLOGY AND GENETICS
Although the apparent rate of occurrence of severe disease in siblings after an index is very high, the inheritance of neonatal iron storage disease had never been satisfactorily explained. This led to the hypothesis that neonatal iron storage disease results from a gestational alloimmune response. Indeed, a recent study has shown that occurrence of severe neonatal iron storage disease in at-risk pregnancies can be significantly reduced by treatment with high-dose intravenous immunoglobulin during gestation. This is a treatment that has been successfully used to reduce the severity of other gestational alloimmune diseases.18
CLINICAL FEATURES
The initial clinical presentation of neonatal iron storage disease can be subtle and can be confused with other pathologic conditions commonly seen in the newborn. The finding of cholestatic jaundice with coagulopathy and/or ascites at birth should prompt diagnostic evaluations for neonatal iron storage disease. Supporting biochemical features include hypoalbuminemia, hypoglycemia, hyperammonemia, and high iron saturation and serum ferritin levels.
DIAGNOSIS
Diagnosis is dependent on documentation of hepatic insufficiency and extrahepatic siderosis with no other apparent etiology of the liver failure. Extrahepatic siderosis can be demonstrated by either biopsy of a minor salivary gland or magnetic resonance imaging of the pancreas and/or heart. Analysis of both of these studies requires assessment by a specialist experienced in these uncommon applications of the diagnostic tests. Liver histology, when available, reveals nonspecific findings with evidence of chronic hepatic insufficiency, well-established fibrosis or cirrhosis, significant hepatocellular loss, and reactive bile ductular proliferation.
TREATMENT
Infants with neonatal hemochromatosis have an expected mortality of more than 90% unless prompt treatment and/or liver transplantation is undertaken. Early recognition of neonatal hemochromatosis is a requisite for successful treatment. Sepsis often leads to significant morbidity and mortality in these infants because they are immunocompromised on the basis of both age and decompensated cirrhotic liver disease. Immediate referral of infants with neonatal hemochromatosis to a center experienced in liver transplantation in infants is advised. Medical therapy consists of a combination of antioxidants (vitamin E in the form of tocopheryl polyethylene glycol succinate, selenium, and N-acetyl cysteine), membrane stabilizers (prostaglandin E1), and iron chelators (deferoxamine). The efficacy of medical therapy alone has been questioned, but it appears at a minimum to stabilize infants in preparation for liver transplantation. Liver transplantation has been successfully utilized in very small infants with neonatal hemochromatosis, but mortality in these acutely ill babies may still exceed 50%. Recurrence of the disease posttransplant has not been reported, although apparent iron toxicity has been observed in an infant who did not undergo chelation before transplantation. Parents of infants with neonatal hemochromatosis need to be advised about the risk of recurrence and referred for therapy to a center experienced with this disorder in subsequent pregnancies.
HEREDITARY HEMOCHROMATOSIS
Hereditary hemochromatosis is an inherited disorder of iron metabolism leading to progressive iron loading of parenchymal cells of the liver, pancreas, and heart.19
PATHOPYSIOLOGY AND GENETICS
The most common form of this disease is caused by homozygosity for the C282Y mutation in the HFE gene. Not all patients with this genetic mutation have phenotypic expression. Other mutations have been described, but their prevalence is low. Hereditary hemochromatosis is not a disorder of childhood, but iron studies may be abnormal in children, leading to early diagnosis of children with affected parents.
A genetically heterogeneous but rare disorder called juvenile hemochromatosis has been recognized for many years. Owing to the early and accelerated pace of iron overloading, these patients may have more prominent cardiac and endocrine dysfunction than severe liver disease. Mutations in two genes important in regulating iron homeostasis have been identified: (1) the HAMP gene, encoding hepcidin, which is essential for inhibiting the release of iron from enterocytes and macrophages to circulating transferring, and (2) HFE2, encoding hemojuvelin, a protein that increases hepcidin expression.
CLINICAL FEATURES
Symptoms of hemochromatosis include nonspecific findings such as weakness, fatigue, and weight loss. More specific symptoms and signs include arthralgias, diabetes, hepatomegaly, amenorrhea, and congestive heart failure.
DIAGNOSIS AND TREATMENT
Once a proband with hereditary hemochromatosis is identified, family screening is recommended for all first-degree relatives. In children of an affected parent, it is useful to perform HFE mutation analysis on the spouse to accurately predict the genotype in the children. If the spouse has either mutation, then the children will also need to undergo HFE mutation analysis, although the value of genetic testing in children is still being evaluated. In a child at risk, serum iron studies should be periodically evaluated and therapeutic phlebotomy considered if liver function tests are elevated and ferritin level is greater than 1000 ng/mL. This is unlikely until after the second decade of life.
DISORDERS OF BILIRUBIN METABOLISM AND EXCRETION
Jaundice is a common presenting feature of a wide range of pediatric disorders. In most circumstances the jaundice results from increased bilirubin load and/or toxic effects on the relatively immature bilirubin conjugation/excretory system that is found in the newborn liver. Neonatal hyperbilirubinemia is discussed in Chapters 53 and 419. Occasionally jaundice is the result of a primary abnormality in the liver’s capacity to conjugate or transport bilirubin. Normal hepatic clearance of bilirubin includes glucuronidation and carrier-mediated transport of bilirubin at the basolateral and canalicular membranes of the hepatocyte. Hyperbilirubinemia is seen in primary genetic abnormalities of these processes; Crigler-Najjar and Gilbert syndromes result from defects in glucuronidation, and Dubin-Johnson syndrome results from defects in canalicular excretion of conjugated bilirubin.
GILBERT SYNDROME
Gilbert syndrome is the most benign of these disorders and probably represents a relatively common genetic phenotype as opposed to a distinct disease entity. Estimates indicate that 2% to 10% of individuals have Gilbert syndrome.9The most common genotype of Gilbert syndrome is the homozygous polymorphism in the promoter of the gene for UDP-glucuronosyltransferase 1A1 (UGT1A1), with one or more thymine adenine insertions in the TATA-box-like sequence, which results in a decrease in UGT1A1 activity. The altered promoter is transcriptionally less active and leads to a relative deficiency of the enzyme. Clinically this translates into a condition characterized by mild indirect hyperbilirubinemia (typically < 5 mg/dL) without associated hemolysis or hepatocellular/canalicular injury. This may manifest with jaundice during times of stress and fasting. In addition, Gilbert syndrome may explain many cases of prolonged “physiological” jaundice in the newborn period. Gilbert syndrome has not been associated with any specific morbidity or mortality, although altered metabolism of certain chemotherapeutics (eg, irinotecan) has been reported. Gilbert syndrome does not require treatment.
CRIGLER-NAJJAR SYNDROME
Crigler-Najjar syndrome exists in two forms, types I and II.9 Type I is more severe, the result of a complete absence of bilirubin UDP-GT activity. This disease presents in the newborn period with severe indirect hyperbilirubinemia, necessitating continuous phototherapy and/or exchange transfusions. Analysis of bile reveals no bilirubin conjugates. Kernicterus is a serious potential complication for children with Crigler-Najjar syndrome type I and can occur at any time in their lives. Specific DNA testing can be performed to confirm a diagnosis of Crigler-Najjar type I and can be utilized for prenatal testing. Phototherapy is the mainstay of therapy. Liver transplantation can be curative, although risk-benefit decisions for this approach are complex. Preliminary reports of hepatocyte transplantation for this disorder have been disappointing. Gene therapy may ultimately be an attractive means of curing this disease.
Crigler-Najjar syndrome type II is the result of genetic abnormalities in the bilirubin UDP-GT gene that lead to partial activity. Hyperbilirubinemia of less than10 mg/dL is usually observed, and this is typically responsive to cytochrome P450-inducing compounds such as phenobarbital. Long-term treatment with phenobarbital is generally not recommended because it results in a cosmetic improvement but is associated with potential neurodevelop-mental complications.
DUBIN-JOHNSON SYNDROME
Dubin-Johnson syndrome is the result of a genetic deficiency in the cMOAT/MRP2 gene (Abcc2), which encodes the canalicular transporter of conjugated bilirubin.10 The disease is manifest by relatively mild conjugated hyperbilirubinemia (3–8 mg/dL) with no evidence of significant hepatocellular or canalicular injury. Analysis of urinary coproporphyrins reveals a preponderance of the isoform I. Like Gilbert syndrome and Crigler-Najjar type II, this is a disease that is not associated with specific morbidity and mortality and as such does not require treatment.
BILE ACID SYNTHESIS DISORDERS
Bile acids are one of the primary driving forces for bile flow, and any impairment in bile acid biosynthesis or transport can result in cholestasis. Bile acid biosynthesis is mediated by a series of at least 14 enzymatic steps in the liver that convert cholesterol into the primary bile acids cholic and chenodeoxycholic acid (Fig. 165-1). Nine inborn errors of bile acid metabolism have been described that have different clinical phenotypes as also described in Chapter 165.8 Defects in modification of steroid ring of cholesterol are most likely to produce severe cholestasis and liver disease, whereas defects in side chain modification lead to neurological dysfunction, fat soluble vitamin malabsorption, and milder liver disease.
Primary defects in bile acid biosynthesis generally present with cholestasis, although chronic hepatitis (ie, serum aminotransferase elevations) has also been observed. The enzymatic block in bile acid synthesis results in diminished production of the primary bile acids that are essential for promoting bile flow and the concomitant accumulation of unusual bile acids and metabolites that are toxic to the hepatocyte. However, in contrast to other disorders associated with cholestasis, impaired synthesis of bile salts results in a condition that is not associated with either pruritus or elevated serum bile salt concentrations because the normal end products are not synthesized. Indeed, measurement of serum bile acids by standard methods shows low to absent primary bile acids, even in the face of severe cholestasis. A high index of suspicion for these disorders needs to be maintained because their presentations may be protean, and diagnosis requires relatively specialized testing. The possibility of a primary abnormality in bile acid biosynthesis should be entertained in any child with chronic cholestasis or hepatitis for which a clear etiology cannot be identified. Screening for these defects is done by liquid secondary ionization mass spectrometry of urine. Additional information is derived from gas chromatography-mass spectrometry of urine, serum, and bile as well as enzymatic and molecular assays for some of the defects.
Prompt diagnosis of an inborn error of bile acid metabolism is important because several of these disorders can be treated with oral bile acid replacement. Treatment with the primary bile acid, cholic acid, has been particularly successful in patients with 3 beta-hydroxy-C27-steroid oxidoreductase deficiency and D4-3-oxosteroid 5 beta-reductase deficiency. Cholic acid provides the missing end product required to generate bile flow and down-regulates the production of toxic bile acid precursors. Therapy is life long. Ursodeoxycholic acid, which is commonly used in other forms of cholestasis, is ineffective because it does not inhibit bile acid synthesis.
INHERITED DISORDERS OF BILE FORMATION
The term progressive familial intrahepatic cholestasis (PFIC) denotes a group of inherited disorders of bile formation, often presenting in infancy and associated with progression at a variable rate to end stage liver disease.22Mutations in several genes encoding transport proteins located on the liver canalicular membrane have been defined (Table 421-3).23 Benign recurrent intrahepatic cholestasis (BRIC1) is also associated with a mutation of the same gene causing one of these disorders and is therefore discussed in this section.
PROGRESSIVE FAMILIAL INTRAPHEPATIC CHOLESTASIS 1
PFIC1, also called Byler disease, is characterized by unremitting cholestasis with pruritus and jaundice that usually starts before the age of 1 year and progresses to cirrhosis and liver failure.24 Patients with PFIC1 have mutations in the gene FIC1. The gene encodes for Atp8b1, a P-type ATPase, that is localized to the liver canalicular and cholangiocyte apical membranes and functions as an aminophospholipid flippase, transferring aminophospholipids from the outer to inner hemi-leaflet of cell membranes. The FIC1 gene is also highly expressed in extrahepatic organs including the lungs, small intestine, pancreas, and kidneys. This may account for some of the clinical diversity of PFIC1.
Atp8b1 expression influences the posttranslational modification of the farnesoid x-receptor (FXR), a critical transcription factor involved in regulating bile acid homeostasis. The net effect of defective FXR signaling is enhanced reabsorption of intestinal bile acids coupled with diminished hepatic excretion of bile acids.
CLINICAL FEATURES
Diarrhea, malabsorption and failure to thrive are common in the first months of life. Fat-soluble vitamin deficiencies may be severe, resulting in rickets and coagulopathy. Hepatosplenomegaly eventually develops. Pancreatitis has been reported. Pruritus is the dominant feature of cholestasis in the majority of patients, and is often out of proportion to the level of jaundice. Serum γ-glutamyl transpeptidase activity and cholesterol concentration are paradoxically normal. The serum bile acid concentration is elevated. Serum aminotransferase levels are usually no higher than twice normal values. The disorder can progress to end-stage liver disease during early childhood or evolve gradually to cirrhosis in the second decade of life.
Table 421-3. Progressive Familial Intrahepatic Cholestasis (PFIC)
A bland hepatocellular and canalicular cholestasis with some pseudoacinar transformation and fibrosis are found on liver biopsy early in the course of the disease. Cirrhosis eventually occurs. Electron microscopy shows distended bile canaliculi with microvilli that are reduced in number and length. Bile canaliculi contain unusually coarse and granular bile (so-called Byler bile).
TREATMENT
Biliary diversion or ileal bypass are used often to deplete hydrophobic bile acids, which may decrease pruritus and slow the progression of liver damage, if this surgical procedure is performed before cirrhosis has developed. Liver transplantation may be required in many patients. Owing to the extrahepatic expression of FIC1, patients may still suffer from growth failure, malabsorption, and panceratitis after an otherwise successful liver transplant.
BENIGN RECURRENT INTRAHEPATIC CHOLESTASIS (BRIC1)
Benign recurrent intrahepatic cholestasis (BRIC1) is also associated with FIC1 mutations. It is characterized by attacks of jaundice and pruritus separated by symptom-free intervals. The age of presentation of the first attack of jaundice ranges from 1 to 50 years, usually before the age of 20 years. Attacks usually are preceded by a minor illness and consist of a preicteric phase of 2 to 4 weeks (characterized by malaise, anorexia, and pruritus) and an icteric phase that may last from 1 to 18 months. Patients may also experience fatigue, anorexia, steatorrhea, dark colored urine and weight loss. Progression to cirrhosis and long-term complications of chronic liver disease do not occur.
Patients fitting the phenotype of BRIC have recently been described with mutations in the gene encoding for the bile salt export pump (BSEP) which causes PFIC 2 (see below). These patients have recurrent episodes of cholestasis and are clinically healthy and biochemically normal between attacks. The age of onset and total number of recurrent episodes were highly variable. Cholelithiasis occurs frequently. Several patients developed permanent cholestasis as adults after initial periods of recurrent attacks as children.
PROGRESSIVE FAMILIAL INTRAHEPATIC CHOLESTASIS 2 (PFIC2)
Patients with PFIC2 usually present in the neonatal period with progressive cholestasis.23 The disease is caused by mutations in ABCB11, which encodes for the bile salt export pump (BSEP), the predominant transporter for bile acids on the liver canalicular membrane. Owing to bile secretory failure, bile salts and other biliary constituents are retained in the hepatocyte and lead to progressive liver damage.
CLINICAL FEATURES
Irritability and bleeding related to vitamin K deficiency are commonly seen. Failure to thrive related to fat malabsorption and poor intake occur. The majority of patients have hepatosplenomegaly. Pruritus is the dominant feature of the disorder in the majority of patients. A rapid progression to cirrhosis is seen without therapy. Patients with PFIC2 are at risk for developing hepatocellular carcinoma and cholangiocarcinoma, even in the first year of life.
DIAGNOSIS
Patients with PFIC2 have low serum γ-glutamyl transpeptidase, and normal or near normal serum cholesterol levels. In contrast to patients with PFIC-1, serum aminotransferase levels are usually elevated to at least five times normal values. Liver morphology in PFIC2 shows a neonatal hepatitis with giant cell transformation of hepatocytes and lobular cholestasis that may persist beyond infancy. Electron microscopy demonstrates effaced microvilli and dilated bile canaliculi that contain finely granular or filamentous bile. Most patients lack BSEP expression on the canalicular membrane by immunohistochemical staining.
TREATMENT
As with PFIC1, biliary diversion and ileal exclusion have been done to treat intractable pruritus and progression of liver disease. A risk for liver cancer may still exist even with clinical improvement. Patients often require liver transplantation, but are free of extrahepatic complication seen in PFIC1 patients post transplant.
PROGRESSIVE FAMILIAL INTRAHEPATIC CHOLESTASIS 3 (PFIC3)
Another group of children have been identified with inherited intrahepatic cholestasis but an elevated serum γ-glutamyltranspeptidase level.25 The disorder is due to mutations in the MDR3 gene (ABCB4), which encodes a transporter required for biliary phosphatidylcholine secretion. The formation of mixed micelles with phosphatidylcholine, cholesterol and bile salts is needed to protect the canalicular and cholangiocyte membranes from bile acid–induced cell injury.
CLINICAL FEATURES
The age of onset of PFIC3 with jaundice, hepatomegaly, and acholic stools is extremely broad, ranging from age 1 month to over 20 years (mean age ∼ 3.5 years). Pruritus occurs less frequently than in the other types of PFIC and is usually mild. Growth failure may occur as the disease progresses. Liver disease tends to evolve slowly to biliary cirrhosis with or without overt cholestatic jaundice. Splenomegaly and esophageal varices reflecting portal hypertension may occur early in childhood. Asymptomatic disease leading to cirrhosis, portal hypertension, and variceal bleeding in adolescent and young adults has also been reported.
DIAGNOSIS
The serum concentration of γ-glutamyltranspeptidase is elevated in PFIC3, often over ten times the normal value. This distinguishes the disorder from the other forms of PFIC, but not other cholestatic liver diseases in which the serum γ-GT is usually elevated. Other liver tests are variably elevated including serum aminotransferases, conjugated bilirubin, and alkaline phosphatase. Serum cholesterol concentration is usually normal. The cardinal feature of PFIC3 is markedly reduced concentrations of biliary phospholipids. The histopathology of PFIC3 shows bile ductular proliferation and mixed inflammatory infiltrates. Periductal sclerosis affecting the interlobular bile ducts eventually occurs. Extensive portal fibrosis evolves into biliary cirrhosis in older children.
TREATMENT
Oral administration of ursodeoxycholic acid (UCDA) appears to be of value in some patients, particularly those with MDR3 missense mutations and residual biliary phospholipid secretion. The rational underlying this therapy is that enrichment of bile with this hydrophilic bile acid reduces cytotoxic injury to hepatocytes and bile ducts and stimulates bile flow. Other patients progress to biliary cirrhosis and liver failure at a variable rate and ultimately require liver transplantation.