Recent developments in liver pathology.
* Context.--Hepatocellular carcinoma is the sixth most common
malignancy and the third leading cause of cancer deaths worldwide,
making pathologic identification of precursor lesions essential. Recent
molecular genetic, pathologic, and clinical data have led to the
stratification of hepatic adenomas into subgroups with unique molecular
profiles and varying potential for malignant transformation, as well as
to the reclassification of telangiectatic focal nodular hyperplasia as
telangiectatic adenoma. Clinical, morphologic, and molecular genetic
studies have also established juvenile hemochromatosis and pediatric
nonalcoholic steatohepatitis as entities distinct from their adult
Objective.--To review the recent molecular genetic characterization of telangiectatic hepatic adenomas and juvenile hemochromatosis, as well as the recent clinicopathologic characterization of pediatric nonalcoholic steatohepatitis.
Data Sources.--Literature review, personal experience, and material from the University of Chicago.
Conclusions.--Basic science and translational research have led to the classification of many pathologic entities of the liver according to molecular genetic and protein expression profiles that correspond to traditional morphologic categories. Insights into signal transduction pathways that are activated in, and protein expression patterns unique to, an individual disease may lead to the development of new therapeutic agents and novel diagnostic biomarkers.
(Arch Pathol Lab Med. 2009;133:1078-1086)
Liver cancer (Development and progression)
Liver cancer (Diagnosis)
Gene mutations (Research)
Gene mutations (Physiological aspects)
Cellular signal transduction (Research)
Cellular signal transduction (Physiological aspects)
Yan, Benjamin C.
Hart, John A.
|Publication:||Name: Archives of Pathology & Laboratory Medicine Publisher: College of American Pathologists Audience: Academic; Professional Format: Magazine/Journal Subject: Health Copyright: COPYRIGHT 2009 College of American Pathologists ISSN: 1543-2165|
|Issue:||Date: July, 2009 Source Volume: 133 Source Issue: 7|
|Topic:||Event Code: 310 Science & research|
Hepatocellular carcinoma is the sixth most common malignancy
worldwide with an incidence of 626 000 cases and 598 000 deaths
annually, making it the third most common cause of cancer deaths
globally. (1) Therefore, clinical diagnosis of predisposing conditions,
such as chronic hepatitis B and C infection, and pathologic
identification of precursor lesions, such as cirrhosis and
hepatocellular adenomas, are of paramount importance. Advances in basic
science and translational research by using diverse techniques, such as
quantitative reverse transcription polymerase chain reaction (RT-PCR),
immunohistochemistry, and mass spectrometry, have led to sophisticated
classification of diseases according to molecular profiles in addition
to traditional morphologic features. Although many of these techniques
are currently only available in research laboratories, a few may become
more widely used for diagnostic purposes in the future. In this article,
we review 3 recently described entities that confer an increased risk
for the development of hepatocellular carcinoma: telangiectatic
hepatocellular adenoma, juvenile hemochromatosis, and pediatric
TELANGIECTATIC HEPATOCELLULAR ADENOMA: MOLECULAR RECLASSIFICATION OF A PATHOLOGIC ENTITY
Telangiectatic hepatocellular adenomas, formerly termed telangiectatic focal nodular hyperplasia, are uncommon benign liver tumors that constitute 15.4% of lesions diagnosed as focal nodular hyperplasia and demonstrate a mean age at presentation of 38 years and a sex predilection with an 8:1 female to male ratio. (2) Two-thirds of cases are characterized by solitary lesions, ranging in size from 3 to 15 cm, whereas one-third of patients have multiple, typically smaller lesions (range, 0.1-10 cm). (3) Most affected patients take oral contraceptives, (3-5) although a presumably hereditary syndrome of multiple telangiectatic focal nodular hyperplasia has also been described, with additional associated lesions such as hepatic hemangioma, meningioma, astrocytoma, telangiectasias of the brain, berry aneurysms, dysplastic systemic arteries, and portal vein atresia. (6)
Telangiectatic focal nodular hyperplasia is a term describing typically unencapsulated, well-circumscribed, and lobulated tumors consisting of normal-appearing hepatocytes with interspersed portal tractlike structures containing arteries with thickened walls and lymphohistiocytic inflammatory infiltrates (Figures 1 through 5). Characteristically, there are areas of sinusoidal dilatation and peliosis, which give rise to the telangiectatic appearance and presumably increase the risk of hemorrhage. (2,3,6,7) These tumors were originally thought to represent a variant of focal nodular hyperplasia. (6) However, their radiologic and pathologic characteristics more closely resemble those of hepatocellular adenomas. (8) The pattern of inactivation of the X chromosome in focal nodular hyperplasia, hepatic adenomas, and hepatocellular carcinomas, detected by assaying the DNA methylation patterns of the X-linked human androgen receptor gene (HUMARA), revealed that focal nodular hyperplasia demonstrates a random pattern of lyonization, consistent with a polyclonal reactive proliferation. (9) In contrast, almost all hepatic adenomas and hepatocellular carcinomas contain nonrandom methylation patterns, consistent with a monoclonal origin. Similar experiments in which X chromosome inactivation was examined by methylation analysis of the HUMARA locus and genome-wide allelotyping in which loss of heterozygosity was examined by using 400 microsatellite markers showed that telangiectatic focal nodular hyperplasia represented, in fact, monoclonal lesions. (3,10) Moreover, protein profiling with surface-enhanced laser desorption/ionization with time-of-flight mass spectrometry and hierarchical clustering analysis showed that almost all cases of telangiectatic focal nodular hyperplasia clustered with hepatic adenomas rather than with typical focal nodular hyperplasia. (10) These experimental findings supported the notion that the so-called telangiectatic focal nodular hyperplasia was in fact a variant of hepatocellular adenoma, rather than typical focal nodular hyperplasia, and should henceforth be designated "telangiectatic adenomas."
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Recent research has led to the development of a nosologic categorization of hepatic adenomas according to these molecular characteristics in addition to morphologic criteria. Biallelic loss-of-function mutations in TCF2, the gene encoding hepatocyte nuclear factor 1a (HNF1a), has been identified in some hepatic adenomas, (11) and mutations resulting in Wnt/[beta]-catenin activation had also been identified in adenomas by another group. (12-14) Zucman-Rossi and colleagues extended these observations and classified hepatic adenomas into 3 groups according to the presence or absence of mutations affecting HNF1a and [beta]-catenin. (4) Mutations in TCF1/HNF1[alpha] were detected in adenomas by direct sequencing of the gene. Glutamine synthase and GPR49, a G-protein-coupled orphan nuclear receptor, are 2 proteins whose expression is activated by [beta]-catenin in hepatocellular carcinomas and, as such, may serve as reliable markers of [beta]-catenin activation. (15,16) Activation of [beta]-catenin was detected by sequencing of the [beta]-catenin gene or by measurement, with quantitative RT-PCR, of the mRNA transcript levels of glutamine synthase and GPR49. Approximately 46% of hepatic adenomas were shown to carry mutations in TCF1/HNF1[alpha], whereas approximately 12.5% were shown to carry activating mutations in [beta]-catenin. (4) No tumors contained both mutations. The third group of adenomas, which showed no mutations in either TCF1/HNF1a or [beta]-catenin, could be further divided into 2 subgroups: tumors with inflammatory infiltrates (''inflammatory adenomas'') and those without inflammation. Inflammatory adenomas exhibited morphologic features of telangiectatic adenomas as described above. The other subgroup currently has no defining molecular or morphologic features.
The adenomas carrying mutations in TCF1/HNF1[alpha] showed marked steatosis, bland cytology, and no inflammatory infiltrates. (4) Inactivating mutations of HNF1[alpha] had previously been shown to promote lipogenesis by suppressing gluconeogenesis, activating glycolysis, and stimulating fatty acid biosynthesis in a regulatory pathway that is independent of sterol regulatory element binding protein-1 and carbohydrate response element binding protein-1. (17) [beta]-Catenin activation corresponded with cytologic atypia and pseudoglandular formation. The inflammatory subgroup with no mutations in either gene demonstrated, in addition to marked lymphohistiocytic infiltrates, cytologic atypia, reactive ductular proliferation, and dystrophic blood vessels.
The clinical importance of the subclassification of hepatic adenomas is based on the apparent difference in the risk of malignant degeneration for each type. Synchronous hepatocellular carcinomas, or borderline lesions between adenoma and hepatocellular carcinoma, were identified in 46% of the adenomas in which [beta]-catenin was aberrantly activated, in contrast to only 6.8% of adenomas carrying biallelic mutations in TCF1/HNF1a.4 Conversely, although homozygous loss of HNF1a function has been found in only 2.5% of hepatocellular carcinomas examined, (11) [beta]-catenin activation is detected in 20% to 34% of hepatocellular carcinomas. (18-21) Activated [beta]-catenin has been shown to cooperate with the Met oncoprotein in initiating hepatocellular carcinogenesis, whereas inactivation of HNF1[alpha] is more closely associated with the development of hepatic adenomas in transgenic mice. (22) [beta]-Catenin activation therefore appears to confer a significant risk of malignant transformation, whereas TCF1/HNF1 a mutation is associated with minimal risk. Because [beta]-catenin-activating mutations confer a greater risk of progression to hepatocellular carcinoma, the identification of hepatic adenomas containing these mutations and their distinction from tel-angiectatic adenomas and adenomas that do not harbor these mutations becomes clinically significant.
To more accurately discriminate between the 4 classes of hepatic adenomas, Bioulac-Sage and colleagues tested a panel of markers including L-FABP1 (liver fatty acid binding protein) and UGT2B7, targets of activation by HNF1[alpha]; glutamine synthase and GPR49, targets of activation by [beta]-catenin; and the acute phase reactants serum amyloid A2 and C-reactive protein. (23) Quantitative RT-PCR and immunohistochemistry were used to evaluate the efficacy of these surrogate markers of TCF1/HNF1[alpha] mutation and [beta]-catenin activation. Absence of L-FABP1 expression was found to be a sensitive and specific marker of TCF1/HNF1a mutation (100% sensitivity and specificity); glutamine synthase overexpression and nuclear [beta]-catenin staining correlated well with [beta]-catenin activation (85% sensitivity and 100% specificity); and serum amyloid A2 labeling of hepatocytes correlated closely with inflammatory adenomas (91% sensitivity and specificity). (23) A panel of these markers could therefore be used to construct a diagnostic immunohistochemical profile that would enable a pathologist to classify hepatic adenomas and to identify those lesions that are most at risk for malignant transformation.
JUVENILE HEMOCHROMATOSIS: SIGNAL TRANSDUCTION AND IRON METABOLISM
Hereditary hemochromatosis is a systemic metabolic disease in which aberrant and excessive iron absorption leads to pathologic accumulation in multiple organs, most commonly the liver, heart, gonads, skin, and pancreas. Iron is an essential element because its chemical properties as a transition metal--the ability to alternate between the ferrous (2+) and ferric (3+) oxidation states--allow it to participate in biologic oxidation-reduction reactions. The toxicity of this metal is also attributable to this chemical property: the Fenton reaction involves the oxidation of iron from the ferrous to the ferric state and the concomitant reduction of hydrogen peroxide to produce the hydroxyl radical, which can damage DNA, lipid membranes, and proteins. (24-28) Presumably, it is the iron-mediated generation of reactive oxygen species that leads to the tissue injury seen in hereditary hemochromatosis. The levels of reactive free iron in the body must therefore be tightly controlled to prevent this form of damage. Extracellular iron is transported in the blood by transferrin, which binds iron with high affinity, effectively sequestering it in a non-reactive form. The circulating pool of transferrin-bound iron is approximately 10% of the daily iron requirement. In this way, plasma iron is maintained at a concentration of 60 to 150 [micro]g/dL. In contrast, intracellular iron is bound to ferritin, a multimeric protein that binds iron in the less reactive ferrihydrite form. (29,30)
The daily physiologic demand for iron is 25 mg, approximately 80% of which is required for erythropoiesis. However, only 1 to 2 mg of iron is absorbed daily in the duodenum, a quantity that increases with iron deficiency, anemia, or hypoxia; approximately 20 mg of iron is supplied by macrophages that have scavenged the hemoglobin of senescent erythrocytes, accounting for most of the daily iron demand. Mammals lack efficient means of eliminating iron: only about 1 to 2 mg of iron per day is lost due to desquamation of epidermal cells, exfoliation of mucosal surfaces, and minor bleeding. Iron cannot be eliminated by the liver or the kidneys. Therefore, iron absorption is tightly regulated to meet systemic iron requirements. The inability to effectively excrete iron makes humans exquisitely susceptible to pathologic accumulation of iron if this regulation is somehow perturbed.
Several proteins mediating iron uptake into cells have been identified, including the ubiquitously expressed transferrin receptor 1, which binds iron complexed to transferrin (31); transferrin receptor 2, the expression of which is restricted to hepatocytes, duodenal crypt cells, and erythroid precursors; divalent metal transporter 1, a H+/divalent metal symporter found in duodenal enterocytes, which mediates uptake of dietary iron (32,33); cubilin, a protein expressed in polarized epithelial cells in the kidney, which mediates endocytosis of iron and transferrin with its coreceptor megalin (34); and the hemoglobin scavenger receptor CD163, which is expressed on the surface of monocytes and macrophages and receives plasma hemoglobin bound to haptoglobin. (35) In contrast, ferroportin is the only iron exporter so far identified. (36-38)
By itself, iron cannot traverse lipid membranes. Intracellular iron is released into the blood through the ferroportin protein, which is expressed in hepatocytes, macrophages, and duodenal enterocytes. (39) The concentration of ferroportin in the plasma membranes of these cells is directly proportional to the amount of iron that is released into the circulation. After iron export by ferroportin, ceruloplasmin converts ferrous iron to its ferric form, after which the iron is loaded onto transferrin for transport in the blood. (40) Hepcidin is a 25-amino acid peptide hormone encoded by the HAMP gene that is synthesized predominantly in the liver. (41,42) Binding of hepcidin to ferroportin results in the internalization and degradation of ferroportin, decreasing the efflux of iron. (43) In this way, hepcidin inhibits iron efflux and therefore acts to decrease serum iron levels. Hepcidin-deficient mice have been shown to develop hemochromatosis, whereas constitutive expression of hepcidin led to the development of severe iron-deficiency anemia. (44-46) Expression of hepcidin itself is subject to careful regulation. The transcription of hepcidin mRNA is controlled by signaling pathways initiated by several proteins, including hereditary hemochromatosis protein HFE, transferrin receptor 2, and hemojuvelin. (47-49) Inflammation also influences hepcidin expression. Interleukin 6 has been shown to act via the signal transducer and activator of transcription 3 (STAT3) to induce transcription of hepcidin. (50-52) Other inflammatory cytokines besides interleukin 6 can also mediate hepcidin expression. (53) The greater number of hepcidin molecules effectively traps iron within macrophages. Hepcidin therefore appears to be a key mediator of anemia of chronic disease.
The most common form of hemochromatosis (type I) is caused by loss-of-function mutations in the HFE gene, which encodes a nonclassical major histocompatibility class I-type molecule, and is inherited in an autosomal recessive pattern. (54) The HFE protein, which associates with transferrin, transferrin receptor 1, and [[beta].sub.2]-microglobulin at the cell surface, has been shown to inhibit iron uptake. (55-57) Eighty-three percent of patients with hemochromatosis carry the C282Y mutation in the a3 domain of the HFE protein that prevents its heterodimerization with [[beta].sub.2]-microglobulin and cell surface expression. (54,58,59) The frequency of the homozygous C282Y/C282Y genotype in the general population is 0.4%, of which an estimated 40% to 70% will manifest clinical hemochromatosis (affecting 1 individual in 300); the frequency of the carrier state ranges from 0% in Asian, Indian, African, Middle Eastern, and Australasian populations to 9.2% in Europeans. (60) Two other mutations affecting HFE, namely, H63D and S65C, are also common, with the C282Y/H63D and C282Y/S65C heterozygotes at increased risk for the development of clinical disease. (61-64)
Symptomatic disease develops between 40 and 60 years of age, with a later onset in women, which may be due to loss of iron in menstruation, pregnancy, lactation, or lower iron intake. (65,66) Hepatocellular carcinoma is 219 times more common in patients with hemochromatosis who have cirrhosis than in the general population, accounting for 30% to 45% of deaths caused by hemochromatosis-related complications. (67-69) Among patients with hepatocellular carcinoma, the prevalence of hemochromatosis ranges from 1% to 15%. (70)
Forms of hemochromatosis other than the classical autosomal recessive disease had previously been described in individual patients, (71,72) including an early-onset autosomal recessive variant as well as an autosomal dominant form. However, the genes involved were unknown. Since the identification of the C282Y mutation in the HFE gene as the most common cause of hemochromatosis, mutations in the genes encoding the hepcidin, hemojuvelin, transferrin receptor 2, and ferroportin proteins have been identified as causes of hereditary hemochromatosis. (41,48,73-75)
The first form of non-HFE hemochromatosis discovered was transferrin receptor 2-associated hemochromatosis. (75) Autosomal-dominant hemochromatosis is now known to be caused by mutations in the iron exporter ferroportin. (73,74) Most recently, mutations in the hemojuvelin and hepcidin proteins were identified in patients with early-onset, or juvenile, hemochromatosis. (41,48) Collectively, these diseases are designated as "non-HFE hemochromatosis" and are classified as type 2A (hemojuvelin associated), type 2B (hepcidin associated), type 3 (transferrin receptor 2-associated), and type 4 (ferroportin associated).
Juvenile hemochromatosis presents at a younger age, often before the age of 30, with no sex predilection. (72,76) Affected patients present with a greater iron burden and a higher frequency of cardiomyopathy, diabetes mellitus, and hypogonadism than patients with HFE hemochromatosis, but with a lower frequency of hepatic involvement. The most common presenting symptom is hypogonadism, whereas the most common cause of death is cardiomyopathy. (76) The pattern of iron deposition in hepatocytes is identical in juvenile hemochromatosis and the classically described HFE form. Iron is deposited first in periportal hepatocytes and then spreads to hepatocytes in the midzonal and centrilobular areas in sequential fashion. Iron deposition in Kupffer cells, bile duct epithelium, and endothelial cells occurs only late in the disease (Figures 6 through 11).
Hemojuvelin is a protein encoded by a gene initially named HFE2 but later designated HJV because it is not a member of the HFE family but instead is related to the repulsive guidance molecule family of proteins. (77-79) This protein exists in 2 forms: a glycosylphosphatidy linositol-anchored, membrane-associated form and a soluble form. (80) Glycosylphosphatidy linositol-anchored hemojuvelin was shown to be a coreceptor for bone morphogenic proteins 2, 4, and 9, which stimulate hepcidin expression in mice in a signal transduction pathway that does not involve HFE, transferrin receptor 2, or interleukin 6. (81-84) In contrast, soluble hemojuvelin antagonizes bone morphogenic protein signaling, reducing hepcidin expression. (80) Iron deficiency in murine skeletal muscle cells and human liver cells in culture resulted in increased release of soluble hemojuvelin. (85) In contrast, increased iron concentrations inhibited its release. (80) The soluble and glycosylphosphatidylinositol-anchored forms of hemojuvelin therefore appear to reciprocally regulate hepcidin expression in response to the concentration of extracellular iron.
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Soluble hemojuvelin can be generated by phospholipase C digestion, followed by endoproteolytic cleavage by furin, which itself is upregulated by iron deficiency and hypoxia, or directly by cleavage with a proprotein convertase. (86,87) These findings are consistent with other data. Transcription of hepcidin mRNA has been shown to be suppressed by hypoxic conditions, in which the hypoxiainducible factor 1[alpha] (HIF1[alpha]) transcription factor is stabilized. (88,89) Mice containing a liver-specific disruption of the von Hippel-Lindau gene, which encodes a ubiquitin ligase that degrades HIF1[alpha], have been shown to have decreased hepcidin mRNA levels, consistent with stabilization of HIF1[alpha]. (90) Mice lacking both a functional von Hippel-Lindau protein and the aryl hydrocarbon receptor nuclear translocator component of the HIF transcriptional complex had normal hepcidin mRNA levels, confirming that suppression of hepcidin expression was specifically due to HIF. Chromatin immunoprecipitation studies showed that HIF1 bound to murine and human hepcidin promoters. However, in vitro experiments with cultured HepG2 cells (human hepatocellular carcinoma cells) found that hepcidin expression was independent of the HIF complex. (88) The solubilization of hemojuvelin has also been linked to the hemojuvelin receptor neogenin. Overexpression of neogenin leads to the release of soluble hemojuvelin, whereas suppression of neogenin expression by RNA interference leads to a decrease in the release of soluble hemojuvelin. (85)
Iron uptake is not balanced by an analogous mechanism for its excretion and is therefore a process that must be carefully controlled to prevent pathologic accumulation. Hepcidin is the central regulator of iron uptake and distribution and is itself subject to complex regulatory mechanisms by diverse proteins. Sophisticated biochemical and molecular genetic studies have elucidated many of the signaling pathways and molecular mechanisms underlying the pathogenesis of hemochromatosis. The subtypes of this disease follow different clinical courses and are inherited in various ways. Diagnostic subclassification is therefore of paramount importance. The sequencing of the genes encoding hemojuvelin and hepcidin will serve as confirmatory tests in the diagnosis of cases of suspected juvenile hemochromatosis. In addition to confirming that these different subtypes of hemochromatosis are distinct entities, the recent studies reviewed here provide a molecular basis for their classification, a distinction that was previously made on clinical grounds alone.
PEDIATRIC NONALCOHOLIC STEATOHEPATITIS
Nonalcoholic fatty liver disease (NAFLD), which includes a spectrum of liver diseases ranging from simple steatosis to nonalcoholic steatohepatitis (NASH), is the most common cause of pediatric liver pathologic disease and is becoming increasingly prevalent in association with childhood obesity. (91-95) However, because only liver biopsy is diagnostic of NAFLD and NASH, the true prevalence of these diseases remains unknown. Nonalcoholic steatohepatitisis is associated with obesity, hyperglycemia and insulin resistance, hypertriglyceridemia, low levels of high-density lipoprotein, and hypertension, the major clinical features of the metabolic syndrome. (96,97)
An autopsy study examining fatty liver disease (98) found that the prevalence of NAFLD increased with age, ranging from 0.7% in children aged 2 to 4 years and up to 17.3% in persons aged 15 to 19 years. Pediatric NAFLD demonstrates a male predilection: boys with NAFLD outnumber girls by a 2:1 ratio. (99)
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Schwimmer and colleagues classified pediatric NASH into 2 types. Morphologically, type 1 pediatric NASH resembles classical adult NASH and is characterized by macrovesicular steatosis, lobular inflammation, and ballooning degeneration with or without perisinusoidal fibrosis, whereas type 2 pediatric NASH is characterized by macrovesicular steatosis and portal inflammation without evidence of hepatocyte injury in the form of hepatocyte ballooning degeneration, Mallory body formation, or lobular inflammation. In contrast to the centrilobular perisinusoidal fibrosis typical of adult-type NASH, portal fibrosis develops in type 2 pediatric NASH (100) (Figures 12 through 14). Pediatric patients with type 2 pediatric NASH tended to present at a younger age, to be more obese, to have more advanced fibrosis, and were much likelier to be male. Type 2 disease also tended to develop in Asians, Hispanics, and Native Americans. Almost all the children in this study were obese (92%), with a median body mass index of 30.7 kg/[m.sup.2]. Most of the patients had mildly elevated serum aminotransferase levels. (100) The risk of hepatocellular carcinoma upon development of cirrhosis due to NASH at a young age has not yet been determined.
Clinical and epidemiologic analyses (99,101-105) have revealed that NAFLD is more common in boys than in girls. In addition, experimental studies (106) have found that male rats fed a methionine-choline-deficient diet, which leads to the development of steatohepatitis, have a greater degree of steatohepatitis than their female counterparts. Because of this sex predilection, sex hormones, particularly estrogen, have been suspected to play a role in the pathogenesis of steatohepatitis. Estrogen has been implicated as a regulator of hepatic lipid uptake and [beta]-oxidation. (107) Work with ultrasonography to evaluate fatty liver disease suggested that women of child-bearing age had more severe liver disease than postmenopausal women. (108) Aromatase-deficient mice have been shown to develop fatty liver disease, which is reversible upon administration of estrogen. (109,110) Cases of tamoxifen- and raloxifene-induced NASH and cirrhosis in nonobese, nondiabetic patients with breast cancer have been reported. (111-116) One case of a man with aromatase deficiency and steatohepatitis has been documented in the literature. (117) Treatment with transdermal estrogen resulted in improvement in this patient's liver disease. Moreover, in their study, Schwimmer and colleagues (100) state that the girls who presented with type 2 pediatric NASH were most likely prepubertal and, therefore, their hormonal status was similar to that of boys. Recent research (118,119) has found that genetic polymorphisms in a gene encoding a cytochrome P450c17[alpha] may determine susceptibility to tamoxifen-induced liver injury Further investigation of the molecular mechanisms governing estrogen signaling and its effects on hepatic lipid metabolism is required to explain these findings.
The natural history of the pediatric form of NASH is not yet understood. It is likely that this morphologic pattern of disease can also occur in adult patients, but its significance in this population has not yet been explored.
(1.) Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin. 2005;55:74-108.
(2.) Nguyen BN, Flejou JF, Terris B, Belghiti J, Degott C. Focal nodular hyperplasia of the liver: a comprehensive pathologic study of 305 lesions and recognition of new histologic forms. Am J Surg Pathol. 1999;23:1441-1454.
(3.) Bioulac-Sage P, Rebouissou S, Sa Cunha A, et al. Clinical, morphologic, and molecular features defining so-called telangiectatic focal nodular hyperplasias of the liver. Gastroenterology. 2005;128:1211-1218.
(4.) Zucman-Rossi J, Jeannot E, Nhieu JT, et al. Genotype-phenotype correlation in hepatocellular adenoma: new classification and relationship with HCC. Hepatology. 2006;43:515-524.
(5.) Zucman-Rossi J. Genetic alterations in hepatocellular adenomas: recent findings and new challenges. J Hepatol. 2004;40:1036-1039.
(6.) Wanless IR, Albrecht S, Bilbao J, et al. Multiple focal nodular hyperplasia of the liver associated with vascular malformations of various organs and neoplasia of the brain: a new syndrome. Mod Pathol. 1989;2:456-462.
(7.) Lepreux S, Laurent C, Le Bail B, Saric J, Balabaud C, Bioulac-Sage P. Multiple telangiectatic focal nodular hyperplasia: vascular abnormalities. Virchows Arch. 2003;442:226-230.
(8.) Attal P, Vilgrain V, Brancatelli G, et al. Telangiectatic focal nodular hyperplasia: US, CT, and MR imaging findings with histopathologic correlation in 13 cases. Radiology. 2003;228:465-472.
(9.) Paradis V, Laurent A, Flejou JF, Vidaud M, Bedossa P. Evidence for the polyclonal nature of focal nodular hyperplasia of the liver by the study of X-chromosome inactivation. Hepatology. 1997;26:891-895.
(10.) Paradis V, Benzekri A, Dargere D, et al. Telangiectatic focal nodular hyperplasia: a variant of hepatocellular adenoma. Gastroenterology. 2004;126: 1323-1329.
(11.) Bluteau O, Jeannot E, Bioulac-Sage P, et al. Bi-allelic inactivation of TCF1 in hepatic adenomas. Nat Genet. 2002;32:312-315.
(12.) Chen YW, Jeng YM, Yeh SH, Chen PJ. P53 gene and Wnt signaling in benign neoplasms: beta-catenin mutations in hepatic adenoma but not in focal nodular hyperplasia. Hepatology. 2002;36:927-935.
(13.) Takayasu H, Motoi T, Kanamori Y, et al. Two case reports of childhood liver cell adenomas harboring beta-catenin abnormalities. Hum Pathol. 2002;33:852-855.
(14.) Torbenson M, Lee JH, Choti M, et al. Hepatic adenomas: analysis of sex steroid receptor status and the Wnt signaling pathway. Mod Pathol. 2002;15:189-196.
(15.) Yamamoto Y, Sakamoto M, Fujii G, et al. Overexpression of orphan G-protein-coupled receptor, Gpr49, in human hepatocellular carcinomas with betacatenin mutations. Hepatology. 2003;37:528-533.
(16.) Cadoret A, Ovejero C, Terris B, et al. New targets of beta-catenin signaling in the liver are involved in the glutamine metabolism. Oncogene. 2002;21:8293-8301.
(17.) Rebouissou S, Imbeaud S, Balabaud C, etal. HNF1alpha inactivation promotes lipogenesis in human hepatocellular adenoma independently of SREBP-1 and carbohydrate-response element-binding protein (ChREBP) activation. J Biol Chem. 2007;282:14437-14446.
(18.) Laurent-Puig P, Legoix P, Bluteau O, et al. Genetic alterations associated with hepatocellular carcinomas define distinct pathways of hepatocarcinogenesis. Gastroenterology. 2001;120:1763-1773.
(19.) Nhieu JT, Renard CA, Wei Y, Cherqui D, Zafrani ES, Buendia MA. Nuclear accumulation of mutated beta-catenin in hepatocellular carcinoma is associated with increased cell proliferation. Am J Pathol. 1999;155:703-710.
(20.) de La Coste A, Romagnolo B, Billuart P, et al. Somatic mutations of the beta-catenin gene are frequent in mouse and human hepatocellular carcinomas. Proc Natl Acad Sci USA. 1998;95:8847-8851.
(21.) Miyoshi Y, Iwao K, Nagasawa Y, et al. Activation of the beta-catenin gene in primary hepatocellular carcinomas by somatic alterations involving exon 3. Cancer Res 1998;58:2524-2527.
(22.) Tward AD, Jones KD, Yant S, et al. Distinct pathways of genomic progression to benign and malignant tumors of the liver. Proc Natl Acad Sci USA. 2007; 104:14771-14776.
(23.) Bioulac-Sage P, Rebouissou S, Thomas C, et al. Hepatocellular adenoma subtype classification using molecular markers and immunohistochemistry. Hepatology. 2007;46:740-748.
(24.) Goldstein S, Meyerstein D, Czapski G. The fenton reagents. Free Radic Biol Med. 1993;15:435-445.
(25.) Halliwell B, Gutteridge JM. Free Radicals in Biology and Medicine. 2nd ed. Oxford, United Kingdom: Oxford University Press; 1 989.
(26.) Aruoma OI, Halliwell B, Dizdaroglu M. Iron ion-dependent modification of bases in DNA by the superoxide radical-generating system hypoxanthine/xanthine oxidase. J Biol Chem. 1989;264:13024-13028.
(27.) Aruoma OI, Halliwell B, Gajewski E, Dizdaroglu M. Damage to the bases in DNA induced by hydrogen peroxide and ferric ion chelates. J Biol Chem. 1989; 264:20509-20512.
(28.) Haber F, Weiss J. The catalytic decomposition of hydrogen peroxide by iron salts. Proc R Soc Lond A Math Phys Sci. 1934;147:332-351.
(29.) Torti FM, Torti SV. Regulation of ferritin genes and protein. Blood. 2002; 99:3505-3516.
(30.) Harrison PM. Ferritin: an iron-storage molecule. Semin Hematol. 1977;14: 55-70.
(31.) Cheng Y, Zak O, Aisen P, Harrison SC, Walz T. Structure of the human transferrin receptor-transferrin complex. Cell. 2004;116:565-576.
(32.) Fleming MD, Trenor CC III, Su MA, et al. Microcytic anaemia mice have a mutation in Nramp2, a candidate iron transporter gene. Nat Genet. 1997;16: 383-386.
(33.) Gunshin H, Mackenzie B, Berger UV, et al. Cloning and characterization of a mammalian proton-coupled metal-ion transporter. Nature. 1997;388:482-488.
(34.) Kozyraki R, Fyfe J, Verroust PJ, et al. Megalin-dependent cubilin-mediated endocytosis is a major pathway for the apical uptake of transferrin in polarized epithelia. Proc Natl Acad Sci USA. 2001;98:12491-12496.
(35.) Kristiansen M, Graversen JH, Jacobsen C, et al. Identification of the haemoglobin scavenger receptor. Nature. 2001;409:198-201.
(36.) Abboud S, Haile DJ. A novel mammalian iron-regulated protein involved in intracellular iron metabolism. J Biol Chem. 2000;275:19906-19912.
(37.) Donovan A, Brownlie A, Zhou Y, et al. Positional cloning of zebrafish ferroportin1 identifies a conserved vertebrate iron exporter. Nature. 2000;403: 776-781.
(38.) McKie AT, Marciani P, Rolfs A, et al. A novel duodenal iron-regulated transporter, IREG1, implicated in the basolateral transfer of iron to the circulation. Mol Cell. 2000;5:299-309.
(39.) Donovan A, Lima CA, Pinkus JL, et al. The iron exporter ferroportin/ Slc40a1 is essential for iron homeostasis. Cell Metab. 2005;1:191-200.
(40.) Harris ZL, Durley AP, Man TK, Gitlin JD. Targeted gene disruption reveals an essential role for ceruloplasmin in cellular iron efflux. Proc Natl Acad Sci USA. 1999;96:10812-10817.
(41.) Roetto A, Papanikolaou G, Politou M, et al. Mutant antimicrobial peptide hepcidin is associated with severe juvenile hemochromatosis. Nat Genet. 2003; 33:21-22.
(42.) Park CH, Valore EV, Waring AJ, Ganz T. Hepcidin, a urinary antimicrobial peptide synthesized in the liver. J Biol Chem. 2001;276:7806-7810.
(43.) Nemeth E, Tuttle MS, Powelson J, et al. Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science. 2004; 306:2090-2093.
(44.) Nicolas G, Viatte L, Lou DQ, et al. Constitutive hepcidin expression prevents iron overload in a mouse model of hemochromatosis. Nat Genet. 2003;34: 97-101.
(45.) Nicolas G, Bennoun M, Porteu A, et al. Severe iron deficiency anemia in transgenic mice expressing liver hepcidin. Proc Natl Acad Sci USA. 2002;99: 4596-4601.
(46.) Nicolas G, Bennoun M, Devaux I, et al. Lack of hepcidin gene expression and severe tissue iron overload in upstream stimulatory factor 2 (USF2) knockout mice. Proc Natl AcadSci USA. 2001;98:8780-8785.
(47.) Nemeth E, Roetto A, Garozzo G, Ganz T, Camaschella C. Hepcidin is decreased in TFR2 hemochromatosis. Blood. 2005;105:1803-1806.
(48.) Papanikolaou G, Samuels ME, Ludwig EH, et al. Mutations in HFE2 cause iron overload in chromosome 1q-linked juvenile hemochromatosis. Nat Genet. 2004;36:77-82.
(49.) Bridle KR, Frazer DM, Wilkins SJ, et al. Disrupted hepcidin regulation in HFE-associated haemochromatosis and the liver as a regulator of body iron homoeostasis. Lancet. 2003;361:669-673.
(50.) Pietrangelo A, Dierssen U, Valli L, et al. STAT3 is required for IL-6-gp 130-dependent activation of hepcidin in vivo. Gastroenterology. 2007;132:294-300.
(51.) Verga Falzacappa MV, Vujic Spasic M, Kessler R, Stolte J, Hentze MW, Muckenthaler MU. STAT3 mediates hepatic hepcidin expression and its inflammatory stimulation. Blood. 2007;109:353-358.
(52.) Wrighting DM, Andrews NC. Interleukin-6 induces hepcidin expression through STAT3. Blood. 2006;108:3204-3209.
(53.) Rivera S, Gabayan V, Ganz T. In chronic inflammation, there exists an IL-6 independent pathway for the induction of hepcidin [abstract]. Blood. 2004; 104:875a.
(54.) Feder JN, Gnirke A, Thomas W, et al. A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis. Nat Genet. 1996;13:399-408.
(55.) Bennett MJ, Lebron JA, Bjorkman PJ. Crystal structure of the hereditary haemochromatosis protein HFE complexed with transferrin receptor. Nature. 2000;403:46-53.
(56.) Ikuta K, Fujimoto Y, Suzuki Y, et al. Overexpression of hemochromatosis protein, HFE, alters transferrin recycling process in human hepatoma cells. Bio chim Biophys Acta. 2000;1496:221-231.
(57.) Lebron JA, Bennett MJ, Vaughn DE, et al. Crystal structure of the hemochromatosis protein HFE and characterization of its interaction with transferrin receptor. Cell. 1998;93:111-123.
(58.) Feder JN, Tsuchihashi Z, Irrinki A, et al. The hemochromatosis founder mutation in HLA-H disrupts beta2-microglobulin interaction and cell surface expression. JBiol Chem. 1997;272:14025-14028.
(59.) Waheed A, ParkkilaS, Zhou XY, et al. Hereditary hemochromatosis: effects of C282Y and H63D mutations on association with beta2-microglobulin, intracellular processing, and cell surface expression of the HFE protein in COS-7 cells. Proc Natl Acad Sci USA. 1997;94:12384-12389.
(60.) Hanson EH, Imperatore G, Burke W. HFE gene and hereditary hemochromatosis: a HuGE review-Human Genome Epidemiology. Am J Epidemiol. 2001;
(61.) Asberg A, Thorstensen K, Hveem K, Bjerve KS. Hereditary hemochromatosis: the clinical significance of the S65C mutation. Genet Test. 2002;6:59-62.
(62.) Gochee PA, Powell LW, Cullen DJ, Du Sart D, Rossi E, Olynyk JK. A population-based study of the biochemical and clinical expression of the H63D hemochromatosis mutation. Gastroenterology. 2002;122:646-651.
(63.) Holmstrom P, Marmur J, Eggertsen G, Gafvels M, Stal P. Mild iron overload in patients carrying the HFE S65C gene mutation: a retrospective study in patients with suspected iron overload and healthy controls. Gut. 2002;51:723-730.
(64.) Mura C, Raguenes O, Ferec C. HFE mutations analysis in 711 hemochromatosis probands: evidence for S65C implication in mild form of hemochroma tosis. Blood. 1999;93:2502-2505.
(65.) Yip R. Iron deficiency. Bull World Health Organ. 1998;76(suppl 2):121-123.
(66.) Finch SC, Finch CA. Idiopathic hemochromatosis, an iron storage disease: A, iron metabolism in hemochromatosis. Medicine (Baltimore). 1955;34:381-430.
(67.) Niederau C, Fischer R, Purschel A, Stremmel W, Haussinger D, Strohmeyer G. Long-term survival in patients with hereditary hemochromatosis. Gastroenterology. 1996;110:1107-1119.
(68.) Fargion S, Mandelli C, Piperno A, et al. Survival and prognostic factors in 212 Italian patients with genetic hemochromatosis. Hepatology. 1992;15:655-659.
(69.) Niederau C, Fischer R, Sonnenberg A, Stremmel W, Trampisch HJ, Strohmeyer G. Survival and causes of death in cirrhotic and in noncirrhotic patients with primary hemochromatosis. N Engl J Med. 1985;313:1256-1262.
(70.) Cogswell ME, McDonnell SM, Khoury MJ, Franks AL, Burke W, Brittenham G. Iron overload, public health, and genetics: evaluating the evidence for hemochromatosis screening. Ann Intern Med. 1998;129:971-979.
(71.) Eason RJ, Adams PC, Aston CE, Searle J. Familial iron overload with possible autosomal dominant inheritance. Aust N Z J Med. 1990;20:226-230.
(72.) Lamon JM, Marynick SP, Roseblatt R, Donnelly S. Idiopathic hemochromatosis in a young female: a case study and review of the syndrome in young people. Gastroenterology. 1979;76:178-183.
(73.) Montosi G, Donovan A, Totaro A, et al. Autosomal-dominant hemochromatosis is associated with a mutation in the ferroportin (SLC11A3) gene. J Clin Invest. 2001;108:619-623.
(74.) Njajou OT, Vaessen N, Joosse M, et al. A mutation in SLC11A3 is associated with autosomal dominant hemochromatosis. Nat Genet. 2001;28:213-214.
(75.) Camaschella C, Roetto A, Cali A, et al. The gene TFR2 is mutated in anew type of haemochromatosis mapping to 7q22. Nat Genet. 2000;25:14-15.
(76.) De Gobbi M, Roetto A, Piperno A, et al. Natural history of juvenile haemochromatosis. Br J Haematol. 2002;117:973-979.
(77.) Kuninger D, Kuns-Hashimoto R, Kuzmickas R, Rotwein P. Complex biosynthesis of the muscle-enriched iron regulator RGMc. J Cell Sci. 2006;119: 3273-3283.
(78.) Lee PL, Beutler E, Rao SV, Barton JC. Genetic abnormalities and juvenile hemochromatosis: mutations of the HJV gene encoding hemojuvelin. Blood. 2004;103:4669-4671.
(79.) Schmidtmer J, Engelkamp D. Isolation and expression pattern of three mouse homologues of chick Rgm. Gene Expr Patterns. 2004;4:105-110.
(80.) Lin L, Goldberg YP, Ganz T. Competitive regulation of hepcidin mRNA by soluble and cell-associated hemojuvelin. Blood. 2005;106:2884-2889.
(81.) Xia Y, Babitt JL, Sidis Y, Chung RT, Lin HY. Hemojuvelin regulates hepcidin expression via a selective subset of BMP ligands and receptors independently of neogenin. Blood. 2008;111:5195-5204.
(82.) Babitt JL, Huang FW, Xia Y, Sidis Y, Andrews NC, Lin HY. Modulation of bone morphogenetic protein signaling in vivo regulates systemic iron balance. J Clin Invest. 2007;117:1933-1939.
(83.) Truksa J, Peng H, Lee P, Beutler E. Bone morphogenetic proteins 2, 4, and 9 stimulate murine hepcidin 1 expression independently of Hfe, transferrin receptor 2 (Tfr2), and IL-6. Proc Natl AcadSci USA. 2006;103:10289-10293.
(84.) Babitt JL, Huang FW, Wrighting DM, et al. Bone morphogenetic protein signaling by hemojuvelin regulates hepcidin expression. Nat Genet. 2006;38: 531-539.
(85.) Zhang AS, Anderson SA, Meyers KR, Hernandez C, Eisenstein RS, Enns CA. Evidence that inhibition of hemojuvelin shedding in response to iron is mediated through neogenin. JBiol Chem. 2007;282:12547-12556.
(86.) Kuninger D, Kuns-Hashimoto R, Nili M, Rotwein P. Pro-protein convertases control the maturation and processing of the iron-regulatory protein, RGMc/he mojuvelin. BMC Biochem. 2008;9:9.
(87.) Silvestri L, Pagani A, Camaschella C. Furin-mediated release of soluble hemojuvelin: a new link between hypoxia and iron homeostasis. Blood. 2008; 111:924-931.
(88.) Choi SO, Cho YS, Kim HL, Park JW. ROS mediate the hypoxic repression of the hepcidin gene by inhibiting C/EBPalpha and STAT-3. Biochem Biophys Res Commun. 2007;356:312-317.
(89.) Nicolas G, Chauvet C, Viatte L, et al. The gene encoding the iron regulatory peptide hepcidin is regulated by anemia, hypoxia, and inflammation. J Clin Invest. 2002;110:1037-1044.
(90.) Peyssonnaux C, Zinkernagel AS, Schuepbach RA, et al. Regulation of iron homeostasis by the hypoxia-inducible transcription factors (HIFs). J Clin Invest. 2007;117:1926-1932.
(91.) Mokdad AH, Ford ES, Bowman BA, et al. Prevalence of obesity, diabetes, and obesity-related health risk factors, 2001. JAMA. 2003;289:76-79.
(92.) Daniels SR. Regulation of body mass and management of childhood overweight. Pediatr Blood Cancer. 2005;44:589-594.
(93.) Dietz WH. Overweight in childhood and adolescence. N Engl J Med. 2004;350:855-857.
(94.) Wang G, Dietz WH. Economic burden of obesity in youths aged 6 to 17 years: 1979-1999. Pediatrics. 2002;109:e81. doi:10.1542/peds.109.5.e81.
(95.) Patton HM, Sirlin C, Behling C, Middleton M, Schwimmer JB, Lavine JE. Pediatric nonalcoholic fatty liver disease: a critical appraisal of current data and implications for future research. J Pediatr Gastroenterol Nutr. 2006;43:413-427.
(96.) International Diabetes Federation. http://www.idf.org. Accessed June 6, 2008.
(97.) Alberti KG. Impaired glucose tolerance: what are the clinical implications? Diabetes Res Clin Pract. 1998;40(suppl):3S-8S.
(98.) Schwimmer JB, Deutsch R, Kahen T, Lavine JE, Stanley C, Behling C. Prevalence of fatty liver in children and adolescents. Pediatrics. 2006;118:1388-1393.
(99.) Schwimmer JB, McGreal N, Deutsch R, Finegold MJ, LavineJE. Influence of gender, race, and ethnicity on suspected fatty liver in obese adolescents. Pediatrics. 2005;115:e561-e565. doi:10.1542/peds.2004-1832.
(100.) Schwimmer JB, Behling C, Newbury R, et al. Histopathology of pediatric nonalcoholic fatty liver disease. Hepatology. 2005;42:641-649.
(101.) Schwimmer JB, Deutsch R, Rauch JB, Behling C, Newbury R, Lavine JE. Obesity, insulin resistance, and other clinicopathological correlates of pediatric nonalcoholic fatty liver disease. J Pediatr. 2003;143:500-505.
(102.) Manton ND, Lipsett J, Moore DJ, Davidson GP, Bourne AJ, Couper RT. Non-alcoholic steatohepatitis in children and adolescents. Med J Aust. 2000;173: 476-479.
(103.) Rashid M, Roberts EA. Nonalcoholic steatohepatitis in children. J Pediatr Gastroenterol Nutr. 2000;30:48-53.
(104.) Baldridge AD, Perez-Atayde AR, Graeme-Cook F, Higgins L, Lavine JE. Idiopathic steatohepatitis in childhood: a multicenter retrospective study. J Pediatr. 1995;127:700-704.
(105.) Moran JR, Ghishan FK, Halter SA, Greene HL. Steatohepatitis in obese children: a cause of chronic liver dysfunction. Am J Gastroenterol. 1983;78:374 377.
(106.) Kirsch R, Clarkson V, Shephard EG, et al. Rodent nutritional model of non-alcoholic steatohepatitis: species, strain and sex difference studies. J Gastroenterol Hepatol. 2003;18:1272-1282.
(107.) Djouadi F, Weinheimer CJ, Saffitz JE, et al. A gender-related defect in lipid metabolism and glucose homeostasis in peroxisome proliferator-activated receptor alpha-deficient mice. J Clin Invest. 1998;102:1083-1091.
(108.) Kotoh K, Nakamuta M, Fukushima M, Morizono S, Enjoji M, Nawata H. Fertile females with nonalcoholic fatty liver disease (NAFLD) have higher levels of ALT than postmenopausal females: implications for the influence of fertility on NAFLD. Hepatogastroenterology. 2007;54:224-228.
(109.) Hewitt KN, Pratis K, Jones ME, Simpson ER. Estrogen replacement reverses the hepatic steatosis phenotype in the male aromatase knockout mouse. Endocrinology. 2004;145:1842-1848.
(110.) Nemoto Y, Toda K, Ono M, et al. Altered expression of fatty acid-metabolizing enzymes in aromatase-deficient mice. J Clin Invest. 2000;105:1 819-1825.
(111.) TakamuraT, Shimizu A, Komura T, et al. Selective estrogen receptor modulator raloxifene-associated aggravation of nonalcoholic steatohepatitis. Intern Med. 2007;46:579-581.
(112.) Oien KA, Moffat D, Curry GW, et al. Cirrhosis with steatohepatitis after adjuvant tamoxifen. Lancet. 1999;353:36-37.
(113.) Ogawa Y, Murata Y, Nishioka A, Inomata T, Yoshida S. Tamoxifen-induced fatty liver in patients with breast cancer. Lancet. 1998;351:725.
(114.) Van Hoof M, Rahier J, Horsmans Y. Tamoxifen-induced steatohepatitis.
Ann Intern Med. 1996;124:855-856.
(115.) Pinto HC, Baptista A, Camilo ME, de Costa EB, Valente A, de Moura MC. Tamoxifen-associated steatohepatitis-report of three cases. J Hepatol. 1995;23: 95-97.
(116.) Pratt DS, Knox TA, Erban J. Tamoxifen-induced steatohepatitis. Ann Intern Med. 1995;123:236.
(117.) Maffei L, Murata Y, Rochira V, et al. Dysmetabolic syndrome in a man with a novel mutation of the aromatase gene: effects of testosterone, alendronate, and estradiol treatment. J Clin Endocrinol Metab. 2004;89:61-70.
(118.) Ohnishi T, Ogawa Y, Saibara T, et al. CYP17 polymorphism and tamoxifen-induced hepatic steatosis. Hepatol Res. 2005;33:178-180.
(119.) Ohnishi T, Ogawa Y, Saibara T, et al. CYP17 polymorphism asarisk factor of tamoxifen-induced hepatic steatosis in breast cancer patients. Oncol Rep. 2005;13:485-489.
Benjamin C. Yan, MD, PhD; John A. Hart, MD
Accepted for publication February 5, 2009.
From the Department of Pathology, University of Chicago Hospitals, Chicago, Illinois.
The authors have no relevant financial interest in the products or companies described in this article.
Reprints: John A. Hart, MD, Department of Pathology, University of Chicago Hospitals, 5841 S Maryland Ave, Chicago, IL 60637 (e-mail: firstname.lastname@example.org).
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