Metabolic Diseases of the Liver

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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.

Table 349-1 INBORN ERRORS OF METABOLISM THAT AFFECT THE LIVER

DISORDERS OF CARBOHYDRATE METABOLISM

Disorders of galactose metabolism

Galactosemia (galactose-1-phosphate uridylyltransferase deficiency)

Disorders of fructose metabolism

Hereditary fructose intolerance (aldolase deficiency)

Fructose-1,6 diphosphatase deficiency

Glycogen storage diseases

Type I

Von Gierke Ia (glucose-6-phosphatase deficiency)

Type Ib (glucose-6-phosphatase transport defect)

Type III Cori/Forbes (glycogen debrancher deficiency)

Type IV Andersen (glycogen branching enzyme deficiency)

Type VI Hers (liver phosphorylase deficiency)

Congenital disorders of glycosylation (multiple subtypes)

DISORDERS OF AMINO ACID AND PROTEIN METABOLISM

Disorders of tyrosine metabolism

Hereditary tyrosinemia type I (fumarylacetoacetate deficiency)

Tyrosinemia, type II (tyrosine aminotransferase deficiency)

Inherited urea cycle enzyme defects

CPS deficiency (carbamoyl phosphate synthetase I deficiency)

OTC deficiency (ornithine transcarbamoylase deficiency)

Citrullinemia type I (argininosuccinate synthetase deficiency)

Argininosuccinic aciduria (argininosuccinate deficiency)

Argininemia (arginase deficiency)

N-AGS deficiency (N-acetylglutamate synthetase deficiency)

Maple serum urine disease (multiple possible defects *)

DISORDERS OF LIPID METABOLISM

Wolman disease (lysosomal acid lipase deficiency)

Cholesteryl ester storage disease (lysosomal acid lipase deficiency)

Homozygous familial hypercholesterolemia (low density lipoprotein receptor deficiency)

Gaucher disease type I (beta-glucocerebrosidase deficiency)

Niemann-Pick type C (NPC 1 and 2 mutations)

DISORDERS OF BILE ACID METABOLISM

Isomerase deficiency

Reductase deficiency

Zellweger syndrome-cerebrohepatorenal (multiple mutations in peroxisome biogenesis genes)

DISORDERS OF METAL METABOLISM

Wilson disease (ATP7B mutations)

Hepatic copper overload

Indian childhood cirrhosis

Neonatal iron storage disease

DISORDERS OF BILIRUBIN METABOLISM

Crigler-Najjar (bilirubin-uridinediphosphoglucuronate glucuronosyltransferase mutations)

Type I

Type II

Gilbert disease (bilirubin-uridinediphosphoglucuronate glucuronosyltransferase polymorphism)

Dubin-Johnson syndrome (multiple drug-resistant protein 2 mutation)

Rotor syndrome

MISCELLANEOUS

α₁-Antitrypsin deficiency

Citrullinemia type II (citrin deficiency)

Cystic fibrosis (cystic fibrosis transmembrane conductance regulator mutations)

Erythropoietic protoporphyria (ferrochelatase deficiency)

Polycystic kidney disease

* Maple syrup urine disease can be caused by mutations in branched-chain alpha keto dehydrogenase, keto acid decarboxylase, lioamide dehydrogenase, or dihydrolipoamide dehydrogenase.

Table 349-2 CLINICAL MANIFESTATIONS THAT SUGGEST THE POSSIBILITY OF METABOLIC DISEASE

Recurrent vomiting, failure to thrive, short stature, dysmorphic features, edema/anasarca

Jaundice, hepatomegaly (± splenomegaly), fulminant hepatic failure

Hypoglycemia, organic acidemia, lactic acidemia, hyperammonemia, bleeding (coagulopathy)

Developmental delay/psychomotor retardation, hypotonia, progressive neuromuscular deterioration, seizures

Cardiac dysfunction/failure, unusual odors, rickets, cataracts

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)

Like CN type I, CN type II is an autosomal recessive disease; it is caused by homozygous missense mutations in UGT1A1, resulting in reduced (partial) enzymatic activity. More than 18 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 1st 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.

Diagnosis

Concentration of bilirubin in bile is nearly normal in CN type II. Jaundiced infants and young children with type II syndrome respond readily to 5 mg/kg/24 hr 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/24 hr. 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, induces a mild decrease in plasma bilirubin levels (~10%) in patients with CN I and II.

Inherited Conjugated Hyperbilirubinemia

Conjugated hyperbilirubinemia can be due to a small number of rare autosomal recessive conditions characterized by mild jaundice. The transfer of bilirubin and other organic anions from the liver cell to bile is defective. Chronic mild conjugated hyperbilirubinemia is usually detected during adolescence or early adulthood but can occur as early as the second year of life. The results of routine liver function tests are normal. Jaundice can be exacerbated by infection, pregnancy, oral contraceptives, alcohol consumption, and surgery. There is usually no morbidity and life expectancy is normal, but these disorders can initially present difficult problems in the differential diagnosis of more serious diseases.

Dubin-Johnson Syndrome

Dubin-Johnson syndrome is an autosomal recessive inherited defect with variable penetrance in hepatocyte secretion of bilirubin glucuronide. The defect in hepatic excretory function is not limited to conjugated bilirubin excretion but also involves several organic anions normally excreted from the liver cell into bile. Absent function of multiple drug-resistant protein 2 (MRP2), an adenosine triphosphate (ATP)-dependent canalicular transporter, is the responsible defect. More than 10 different mutations have been identified and either affect localization of MRP2 with resultant increased degradation or impair MRP2 transport activity in the canalicular membrane. Bile acid excretion and serum bile acid levels are normal. Total urinary coproporphyrin excretion is normal in quantity but coproporphrin I excretion increases to ∼80% with a concomitant decrease in coproporphyrin III excretion. Normally, coproporphyrin III is >75% of the total. Cholangiography fails to visualize the biliary tract and x-ray of the gallbladder is also abnormal. Liver histology demonstrates normal architecture, but hepatocytes contain black pigment similar to melanin.

Rotor Syndrome

Patients with Rotor syndrome have an additional deficiency in organic anion uptake; however, the genetic defect has not yet been elucidated. Unlike Dubin-Johnson syndrome, total urinary coproporphyrin excretion is elevated, with a relative increase in the amount of the coproporphyrin I isomer. The gallbladder is normal by roentgenography, and liver cells contain no black pigment. In Dubin-Johnson and Rotor syndromes, sulfobromophthalein excretion is often abnormal.

Bibliography

Bosma PJ. Inherited disorders of bilirubin metabolism. J Hepatol. 2003;38:107-117.

Hafkamp AM. Orlistat treatment of unconjugated hyperbilirubinemia in Crigler-Najjar Disease: a randomized controlled trial. Pediat Res. 2007;62:725-730.

Hsieh TY, Shiu TY, Huang SM, et al. Molecular pathogenesis of Gilbert’s syndrome: decreased TATA-binding protein binding affinity of UGT1A1 gene promoter. Pharmaco Gen. 2007;17(4):229-236.

Kadakol A, Ghosh SS, Sappal BS, et al. Genetic lesions of bilirubin uridine-diphosphoglucuronate glucuronosyltransferase (UGT1A1) causing Crigler-Najjar and Gilbert syndromes: correlation of genotype to phenotype. Hum Mutat. 2000;16:297-306.

Keitel V, Nies AT, Brom M, et al. A common Dubin-Johnson syndrome mutation impairs protein maturation and transport activity of MRP2 (ABCC2). Am J Physiol Gastrointest Liver Physiol. 2003;284:G165-G174.

Lysy PA, Najimi M, Stephenne X, et al. Liver cell transplantation for Crigler-Najjar syndrome type I: update and perspectives. World J Gastro. 2008;14(22):3463-3470.

Mor-Cohen R, Zivelin A, Rosenberg N, et al. Identification and functional analysis of two novel mutations in the multidrug resistance protein 2 gene in Israeli patients with Dubin-Johnson syndrome. J Biol Chem. 2001;276:36923-36930.

Strassburg CP. Pharmacogenetics of Gilbert’s syndrome. Pharmacogenomics. 2008;9(6):703-715.

349.2 Wilson Disease

William F. Balistreri, Rebecca G. Carey

Wilson disease (hepatolenticular degeneration) is an autosomal recessive disorder that can be associated with degenerative changes in the brain, liver disease, and Kayser-Fleischer rings in the cornea. The incidence is 1/50,00 to 1/100,000 births. It is progressive and potentially fatal if untreated; specific effective treatment is available. Rapid diagnostic investigation of the possibility of Wilson disease in a patient presenting with any form of liver disease, particularly if >5 yr of age, not only facilitates early institution of management of Wilson disease and related genetic counseling but also allows appropriate treatment of non-Wilsonian liver disease once copper toxicosis is ruled out.

Pathogenesis

The abnormal gene for Wilson disease is localized to the long arm of chromosome 13 (13q14.3). The Wilson disease gene encodes a copper transporting P-type ATPase, ATP7B, which is mainly but not exclusively expressed in hepatocytes and is critical for biliary copper excretion and for copper incorporation into ceruloplasmin. Absence or malfunction of ATP7B results in decreased biliary copper excretion and diffuse accumulation of copper in the cytosol of hepatocytes. With time, liver cells become overloaded and copper is redistributed to other tissues, including the brain and kidneys, causing toxicity, primarily as a potent inhibitor of enzymatic processes. Ionic copper inhibits pyruvate oxidase in brain and ATPase in membranes, leading to decreased ATP-phosphocreatine and potassium content of tissue.

More than 250 mutations in the gene have been identified, making diagnosis by DNA mutational analysis a difficult task unless a proband mutation is known. Most patients are compound heterozygotes. Mutations that completely knock out gene function are associated with an onset of disease symptoms as early as 2-3 yr of age, when Wilson disease might not typically be considered in the differential diagnosis. Milder mutations can be associated with neurologic symptoms or liver disease as late as 70 yr of age. Cloning of the gene for Wilson disease raises the prospect of precise presymptomatic detection of Wilson disease, timely initiation of therapy, and, ultimately, gene therapy.

Clinical Manifestations

Forms of Wilsonian hepatic disease include asymptomatic hepatomegaly (with or without splenomegaly), subacute or chronic hepatitis, and acute hepatic failure (with or without hemolytic anemia). Cryptogenic cirrhosis, portal hypertension, ascites, edema, variceal bleeding, or other effects of hepatic dysfunction (delayed puberty, amenorrhea, coagulation defect) can be manifestations of Wilson disease.

Disease presentations are variable, with a tendency to familial patterns. The younger the patient, the more likely hepatic involvement will be the predominant manifestation. Girls are 3 times more likely than boys to present with acute hepatic failure. After 20 yr of age, neurologic symptoms predominate.

Neurologic disorders can develop insidiously or precipitously, with intention tremor, dysarthria, rigid dystonia, parkinsonism, choreiform movements, lack of motor coordination, deterioration in school performance, or behavioral changes. Kayser-Fleischer rings may be absent in young patients with liver disease but are always present in patients with neurologic symptoms (Fig. 349-1). Psychiatric manifestations include depression, personality changes, anxiety, or psychosis.

Figure 349-1 Kayser-Fleischer (K-F) ring. There is a brown discoloration at the outer margin of the cornea because of the deposition of copper in Descemet’s membrane. Here it is clearly seen against the light green iris. Slit lamp examination is required for secure detection.

(From Ala A, Walker AP, Ashkan K, et al: Wilson’s disease, Lancet 369:397–408, 2007.)

Coombs-negative hemolytic anemia may be an initial manifestation, possibly related to the release of large amounts of copper from damaged hepatocytes; this form of Wilson disease is usually fatal without transplantation. During hemolytic episodes, urinary copper excretion and serum copper levels (not ceruloplasmin bound) are markedly elevated. Manifestations of renal Fanconi syndrome and progressive renal failure with alterations in tubular transport of amino acids, glucose, and uric acid may be present. Unusual manifestations include arthritis, infertility or recurrent miscarriages, cardiomyopathy, and endocrinopathies (hypoparathyroidism).

Pathology

All grades of hepatic injury occur with steatosis, heptocellular ballooning and degeneration, glycogen granules, minimal inflammation, and enlarged Kupffer cells. The lesion may be indistinguishable from that of autoimmune hepatitis. With progressive parenchymal damage, fibrosis and cirrhosis develop. Ultrastructural changes primarily involve the mitochondria and include increased density of the matrix material, inclusions of lipid and granular material, and increased intracristal space with dilatation of the tips of the cristae.

Diagnosis

Wilson disease should be considered in children and teenagers with unexplained acute or chronic liver disease, neurologic symptoms of unknown cause, acute hemolysis, psychiatric illnesses, behavioral changes, Fanconi syndrome, or unexplained bone (osteoporosis, fractures) or muscle disease (myopathy, arthralgia). The clinical suspicion is confirmed by study of indices of copper metabolism.

Most patients with Wilson disease have decreased ceruloplasmin levels (<20 mg/dL). The failure of copper to be incorporated into ceruloplasmin leads to a plasma protein with a shorter half-life and, therefore, a reduced steady-state concentration of ceruloplasmin in the circulation. Caution should be used in interpreting serum ceruloplasmin levels, because they may be elevated in acute inflammation and in states of elevated estrogen such as pregnancy, estrogen supplementation, or oral contraceptive use. The serum copper level may be elevated in early Wilson disease, and urinary copper excretion (usually <40 µg/day) is increased to >100 µg/day and often up to 1,000 µg or more per day. In equivocal cases, the response of urinary copper output to chelation may be of diagnostic help. During the 24 hr urine collection patients are given two 500 mg oral doses of D-penicillamine 12 hr apart; affected patients excrete >1,600 µg/24 hr. Demonstration of Kayser-Fleischer rings, which might not be present in younger children, requires a slit-lamp examination by an ophthalmologist.

Liver biopsy is of value for determining the extent and severity of liver disease and for measuring the hepatic copper content (normally <10 µg/g dry weight). In Wilson disease, hepatic copper content exceeds 250 µg/g dry weight. In healthy heterozygotes, levels may be intermediate. In later stages of Wilson disease hepatic copper content can be unreliable because cirrhosis leads to variable hepatic copper distribution and sampling error.

Family members of patients with proven cases require screening for presymptomatic Wilson disease. Such screening should include determination of the serum ceruloplasmin level and urinary copper excretion. If these results are abnormal or equivocal, liver biopsy should be carried out to determine morphology and hepatic copper content. Genetic screening by either linkage analysis or direct DNA mutation analysis is possible, especially if the mutation for the proband case is known or the patient is from an area where a specific mutation is known (in central and eastern Europe, the H1069Q mutation is present in 50-80% of patients).

Treatment

A major attempt should be made to restrict dietary copper intake to <1 mg/day. Foods such as liver, shellfish, nuts, and chocolate should be avoided. If the copper content of the drinking water exceeds 0.1 mg/L, it may be necessary to demineralize the water.

The initial treatment in symptomatic patients is the administration of copper-chelating agents, which leads to rapid excretion of excess deposited copper. Chelation therapy is managed with oral administration of D-penicillamine (β,β-dimethylcysteine) in a dose of 1 g/day in 2 doses before meals for adults and 20 mg/kg/day for pediatric patients or triethylene tetramine dihydrochloride (Trien, TETA, trientine) at a dose of 0.5-2.0 g/day for adults and 20 mg/kg/day for children. In response to chelation, urinary copper excretion markedly increases, and with continued administration, urinary copper levels can become normal, with marked improvement in hepatic and neurologic function and the disappearance of Kayser-Fleischer rings.

Approximately 10-50% of patients initially treated with penicillamine for neurologic symptoms have a worsening of their condition. Toxic effects of penicillamine occur in 10-20% and consist of hypersensitivity reactions (Goodpasture syndrome, systemic lupus erythematosus, polymyositis), interaction with collagen and elastin, deficiency of other elements such as zinc, and aplastic anemia and nephrosis. Because penicillamine is an antimetabolite of vitamin B₆, additional amounts of this vitamin are necessary. For these reasons, triethylene tetramine dihydrochloride is a preferred alternative, and is considered 1st-line therapy for some patients.

Trientine has few known side effects. Ammonium tetrathiomolybdate is another alternative chelating agent under investigation for patients with neurologic disease; initial results suggest that significantly fewer patients experience neurologic deterioration with this drug compared to penicillamine. The initial dose is 120 mg/day (20 mg between meals tid and 20 mg with meals tid). Side effects include anemia, leukopenia, thrombocytopenia, and mild elevations of transaminases.

Zinc has also been used as adjuvant therapy, maintenance therapy, or primary therapy in presymptomatic patients, owing to its unique ability to impair the gastrointestinal absorption of copper. Zinc acetate is given in adults at a dose of 25-50 mg of elemental zinc 3 times a day, and 25 mg 3 times a day in children >5 yr of age. Side effects are mostly limited to gastric upset.

Prognosis

Untreated patients with Wilson disease can die of hepatic, neurologic, renal, or hematologic complications. The prognosis for patients receiving prompt and continuous penicillamine is variable and depends on the time of initiation of and the individual response to chelation. Liver transplantation should be considered for patients with fulminant liver disease, decompensated cirrhosis, or progressive neurologic disease; the last indication remains controversial. Liver transplantation is curative, with a survival rate of ∼85-90%. In asymptomatic siblings of affected patients, early institution of chelation or zinc therapy can prevent expression of the disease.

Bibliography

Ala A, Walker AP, Ashkan K, et al. Wilson’s disease. Lancet. 2007;369:397-408.

Brewer GJ, Hedera P, Kluin KJ, et al. Treatment of Wilson disease with ammonium tetrathiomolybdate. Arch Neurol. 2003;60:379-385.

Roberts EA, Schilsky ML. Diagnosis and treatment of Wilson disease: an update. Hepatology. 2008;47(6):2089-2111.

Schilsky ML. Wilson disease: new insights into pathogenesis, diagnosis, and future therapy. Curr Gastroenterol Rep. 2005;7:26-31.

Taly AB, Meenakshi-Sundaram S, Sinha S, et al. Wilson disease. Description of 282 patients evaluated over 3 decades. Medicine. 2007;82:112-121.

349.3 Indian Childhood Cirrhosis

William F. Balistreri, Rebecca G. Carey

Indian childhood cirrhosis (ICC) is a chronic liver disease of young children unique to the Indian subcontinent. ICC manifests with jaundice, pruritus, lethargy, and hepatosplenomegaly. Untreated ICC has a mortality of 40-50% within 4 wk. Histologically, it is characterized by hepatocyte necrosis, Mallory bodies, intralobular fibrosis, and inflammation.

The etiology has remained elusive; it was once believed that excess copper ingestion in the setting of a genetic susceptibility to copper toxicosis was the most likely cause. Epidemiological data demonstrated that the copper toxicity theory is unlikely. The increased hepatic copper content, usually >700 µg/g dry weight, seen in ICC is only seen in the late stages of disease and is accompanied by even higher levels of zinc, a nonhepatotoxic metal. The copper-contaminated utensils used to feed babies and implicated in excess copper ingestion are found in only 10-15% of all cases. The current hypothesis implicates the postnatal use of local hepatotoxic therapeutic remedies, although the exact causative agent is unknown.

Over the last few decades, as the awareness of the disease has increased, the incidence of ICC has decreased and has even been virtually eliminated in some areas of India. Variants of this syndrome have been named according to the population where it has been described, such as Tyrolean childhood cirrhosis. It has also been reported in the Middle East, West Africa, and North and Central America.

Bibliography

Sriramachari S, Nayak NC. Indian childhood cirrhosis: several dilemmas resolved. Indian J Med Res. 2008;128:93-96.

Tao TY, Gitlin JD. Hepatic copper metabolism: insights from genetic disease. Hepatology. 2003;37:1241-1247.

349.4 Neonatal Iron Storage Disease

Rebecca G. Carey, William F. Balistreri

Neonatal iron storage disease (NISD), also known as neonatal hemochromatosis, is a rare form of fulminant liver disease that manifests in the 1st few days of life. It is unrelated to the familial forms of hereditary hemochromatosis that occur later in life. NISD has a high rate of recurrence in families, with ∼80% probability that subsequent infants will be affected. NISD is postulated to be a gestational alloimmune disease and has also been classified as congenital alloimmune hepatitis. Alloimmunity develops in the pregnant mother of the affected infant when she is exposed to an unknown fetal hepatocyte cell surface antigen that she does not recognize as self. Maternal IgG to this fetal antigen then crosses the placenta and induces hepatic injury via immune system activation. Additional evidence of a gestational insult is given by the fact that affected infants may be born prematurely or with intrauterine growth restriction. Several infants with NISD also have renal dysgenesis.

NISD is a rapidly fatal, progressive illness characterized by hepatomegaly, hypoglycemia, hypoprothrombinemia, hypoalbuminemia, hyperferritinemia, and hyperbilirubinemia. The coagulopathy is refractory to therapy with vitamin K. Liver pathology demonstrates severe liver injury with acute and chronic inflammation, fibrosis, and cirrhosis. The diagnosis can be confirmed in the neonate with severe liver injury and extrahepatic siderosis (biopsy material of buccal mucosal glands is laden with iron) or MRI determination of iron storage in organs such as the pancreas.

The prognosis for affected infants is generally poor, but some patients with NISD have been successfully treated with iron-chelating agents (deferoxamine) combined with aggressive antioxidant therapy. Combining this therapy with double volume exchange transfusion followed by administration of intravenous immunoglobulin (IVIG) has also been shown to remove the injury-causing maternal IgG. Liver transplantation should also be an early consideration. Recurrences of NISD may be modified with IVIG administered to the mother once a week from the 18th week of gestation until delivery. The largest experience reports 48 women with previous infants with NISD who successfully delivered 52 babies after IVIG treatment. The majority of infants had biochemical evidence of liver disease with elevated serum α-fetoprotein and ferritin. All infants survived with medical therapy or no therapy.

Bibliography

Rand EB, Karpen SJ, Kelly S, et al. Treatment of neonatal hemochromatosis with exchange transfusion and intravenous immunoglobulin. J Pediatr. 2009;155:566-571.

Whitington PF, Kelly S. Outcome of pregnancies at risk for neonatal hemochromatosis is improved by treatment with high-dose intravenous immunoglobulin. Pediatrics. 2008;121(6):e1615-e1621.

349.5 Miscellaneous Metabolic Diseases of the Liver

William F. Balistreri, Rebecca G. Carey

α₁-Antitrypsin Deficiency

A small percentage of patients homozygous for deficiency of the major serum protease inhibitor α₁-antitrypsin manifest neonatal cholestasis or later-onset childhood cirrhosis. α₁-Antitrypsin, a protease inhibitor synthesized by the liver, protects lung alveolar tissues from destruction by neutrophil elastase (Chapter 385). α₁-Antitrypsin is present in >20 different co-dominant alleles, only a few of which are associated with defective protease inhibitors. The most common allele of the protease inhibitor (Pi) system is M, and the normal phenotype is PiMM. The Z allele predisposes to clinical deficiency; patients with liver disease are usually PiZZ homozygotes and have serum α₁-antitrypsin levels <2 mg/mL (∼10-20% of normal). The incidence of the PiZZ genotype in the white population is estimated at 1/2,000-4,000. Compound heterozygotes PiZ-, PiSZ, PiZI are not a cause of liver disease alone but can act as modifier genes, increasing the risk of progression in other liver disease such as nonalcoholic fatty liver disease and hepatitis C. The null phenotype due to stop codons in the coding exon of the α₁-antitrypsin gene or complete deletion of α₁-antitrypsin coding exons leads to the complete absence of any protein and causes only lung disease.

Newly formed α₁-antitrypsin peptide normally enters the endoplasmic reticulum (ER), where it undergoes enzymatic modification and folding before transport to the plasma membrane, where it is excreted as a 55 kDa glycoprotein. In affected patients with PiZZ, the rate at which the α₁-antitrypsin peptide folds is decreased, and this delay allows the formation of polymers that are retained in the ER. How the polymers cause liver damage has not been completely elucidated, but research indicates that accumulation of abnormally folded protein leads to activation of stress and proinflammatory pathways in the ER and hepatocyte programmed cell death. In liver biopsies from patients, polymerized α₁-antitrypsin peptides can be seen by electron microscopy and histochemically as periodic acid–Schiff (PAS)-positive diastase-resistant globules primarily in periportal hepatocytes but also in Kupffer cells and biliary epithelial cells. The pattern of neonatal liver injury can be highly variable, and liver biopsies might demonstrate heptocellular necrosis, inflammatory cell infiltration, bile duct proliferation, periportal fibrosis, or cirrhosis.

In affected patients, the course of liver disease is also highly variable. Prospective studies in Sweden have shown that only 10% of patients develop clinically significant liver disease by their 4th decade. Genetic traits or environmental factors must influence the development of disease in α₁-antitrypsin–deficient patients. Infants with liver disease are indistinguishable from other infants with “idiopathic” neonatal hepatitis, of whom they constitute ∼5-10%. Jaundice, acholic stools, and hepatomegaly are present in the 1st wk of life, but the jaundice usually clears in the 2nd-4th mo. Complete resolution, persistent liver disease, or the development of cirrhosis can follow. Older children can present with asymptomatic hepatomegaly or manifestations of chronic liver disease or cirrhosis, with evidence of portal hypertension. Long-term patients are at risk for hepatocellular carcinoma.

Therapy is supportive; liver transplantation has been curative.

Bibliography

Fairbanks KD, Tavill AS. Liver disease in α₁-antitrypsin deficiency: a review. Am J Gastro. 2008;103:2136-2141.

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