Journal of Hepatology
Volume 46, Issue 6 , Pages 1143-1148, June 2007

Genetics in liver diseases

  • Antonello Pietrangelo

      Affiliations

    • Center for Hemochromatosis, University Hospital of Modena, Via del Pozza 71, 41100 Modena, Italy
    • Corresponding Author InformationCorresponding author. Tel.: +39 05 9422 2714.
    • ,
  • Ronald Oude Elferink

      Affiliations

    • AMC Liver Center, Academic Medical Center, Amsterdam, The Netherlands
    • ,
  • Jesus Prieto

      Affiliations

    • Department of Medicine, University of Navarra, Pamplona, Spain
    • ,
  • Bruce R. Bacon

      Affiliations

    • Division of Gastroenterology and Hepatology, Saint Louis University, St. Louis, MO, USA

published online 05 April 2007.

Article Outline

In recent years, few fields in medicine have witnessed discoveries as momentous as those pertaining to the liver. Dramatic advances have been made, particularly in the areas of molecular biology and genetics. A joint EASL/AASLD Monothematic Conference was held on June 23rd–24th, 2006, in Modena, Italy, to bring the latest breakthroughs in different fields of genetics to hepatologists. This article reports the highlights of the conference and summarizes the main conclusions and implications for clinical and experimental Hepatology.

Keywords: Hereditary diseases, Polymorphisms, Gene therapy, Genetic screening, Quantitative trait loci

 

Back to Article Outline

1. Genetic screening and diagnosis: methods and strategies 

The completion of the human genome project and the development of new technologies for DNA testing have initiated a revolution within the classic diagnostic laboratory. Mutation detection is an important area of molecular diagnostics today and advances in DNA analysis have led to development of methods that are increasingly specific, sensitive, fast, simple, automatic and cost-effective. Dr. Maurizio Ferrari (Milan, Italy) reported on recent and exciting developments in the use of “DNA chips” for the identification of discrete mutations associated with human genetic disorders [1]. However, as the use for genetic testing is dramatically expanding in clinical settings, societal fears of misuse of genetic information are also growing. This occurs both in diagnostic settings, where the information obtained can be used to establish a specific diagnosis and have treatment implications, and in screening settings, where testing target populations is performed to detect future disease risks in individuals or their progeny for which preventive interventions may exist [2]. Vittorio Fineschi (Siena, Italy) detailed numerous aspects related to ethical issues in genetics including informed consent, genetic counseling, privacy and confidentiality or inappropriate access to genetic data by third parties, as well as stigmatization and discrimination [3].

In the research field, a new and fascinating area is the study of complex traits in humans. Paolo Gasparini (Trieste, Italy) discussed the use of isolated inbred populations to reduce disease heterogeneity of complex disorders, detect association of disease phenotypes with specific traits, and identify modifier or pathogenic genes. Large projects have been implemented using inbred populations from small villages, settled by only a few founders, and with a high percentage of endogamy. These projects involve full clinical and biochemical examination, along with the establishment of DNA, sera and urine banks, creation of genealogical data and pedigree drawings. While this approach looks very promising, at present, it remains extremely difficult to undertake a broad, unbiased search for modifying genes in a human population. As an alternate way to address this issue, Nancy C. Andrews (Boston, USA) reported exciting new data on an ongoing search for quantitative trait loci (QTLs) that modify iron loading in mice. The strategy involves the choice of quantitative parameters (e.g., liver iron loading and spleen iron loading), the analysis of such parameters in a variety of inbred mouse strains and intercrossed strains, followed by a genome-wide screen for linkage between characterized genetic markers and the quantitative phenotypes [4]. This has allowed Dr. Andrews and colleagues to identify discrete chromosomal regions which carry modifier gene(s), the cloning of the relevant gene products, and the determination of their functional assay as well as a directed search for analogous human modifier gene(s).

1.1. Take home messages 


1.While genetic testing is rapidly expanding, hepatologists should be aware of the potential misuse of genetic information and its inherent ethical, social, and legal consequences, particularly when dealing with monogenic diseases with low or uncertain phenotypic penetrance.

2.New and potent high-throughput methods are being implemented in molecular diagnostics and mouse–human comparative genetics that allow the identification of susceptibility genes to complex diseases through discrete gene loci (Quantitative Trait Loci, QTLs) analysis.

3.However, before we move to the diagnostic applications, mathematical models for data analysis need to be standardized and interpretation validated through analysis of large databases in different patient populations.

Back to Article Outline

2. Genetic components in hepatic response to drugs and toxins 

The liver can be acutely or chronically exposed to a variety of damaging agents including natural toxins, environmental contaminants, drugs, viruses, and abnormally accumulated metabolites. Matias Avila (Pamplona, Spain) reviewed the liver defense mechanisms against injury and stress, with particular emphasis on novel cytokines and growth factors, such as cardiotrophin-1 and amphiregulin, involved in protection and regeneration [5], [6]. Recently, there has been a change in the understanding of how variations or mutations in genes involved in drug metabolism or disease pathophysiology affect response to therapy. Bruno Stieger (Zurich, Switzerland) discussed recent developments in pharmacogenetics and the genetic background in susceptibility to acquired forms of cholestasis, including drug-induced cholestasis [7]. Neil Kaplowitz and colleagues have focused on both intracellular metabolism and stress responses as well as intercellular interactions of the innate immune response using the well-characterized acetaminophen mouse model. It is striking how many genes turn out to modify the response to this model drug. They foresee an advancement of this field at the preclinical level by integrating transcriptomics, proteomics and metabonomics in comparing paired compounds and sensitive and resistant strains [8].

2.1. Take home messages 


1.The liver is central in drug metabolism. Yet, pharmacology of the drugs subject to inherited variability in metabolism is very complex and only partially understood. As an example the genetic predisposition towards certain drug–drug interactions (via nuclear receptors) must be increasingly taken into account.

2.While a few genotyping tests are regularly used in clinical practice, it is anticipated that studies will propel the routine use of many more tests in the future and ultimately lead to genetically guided decisions about drug therapies in patients at risk to develop drug-induced liver diseases.

Back to Article Outline

3. Genetic predisposition to liver diseases 

There are numerous examples in hepatology of how genetic components have profound effects on development and progression of an underlying disease. Liver fibrosis, which is common to many forms of liver injury and disease, is a highly dynamic process in which multiple genes interact with environmental factors. Transgenic mouse models and epidemiologic studies have revealed single nucleotide polymorphisms (SNPs) in many genes that modulate hepatic fibrosis, as reported by David A. Brenner (New York, USA) [9]. In specific disorders, such as alcoholic liver disease, many studies have focused on the association of disease progression with specific SNPs in different genes: alcohol dehydrogenase, cytochrome P4502E1 (CYP2E1), antioxidant enzymes (e.g., manganese superoxide dismutase or glutathione S-transferase), inflammatory cytokines (TNF-α, IL-1β, IL-10), cytokine modulating factors (IL-1R antagonist), the endotoxin receptor CD14 and cytotoxic T lymphocyte associated antigen-4 (CTLA-4) [10]. Emanuele Albano (Novara, Italy) reviewed this work and underscored that the results obtained are quite promising, but still non-conclusive. Similar data have been collected in NASH and NAFLD [11]. According to C.P. Day (Newcastle Upon Tyne, UK) recent reports of family clustering indicate that susceptibility to NAFLD may have genetic components. A discrete number of genes is likely to play a particular role in determining the development and progression of NAFLD, such as genes influencing the pattern and magnitude of adiposity and insulin resistance, the severity of steatosis, fatty acid oxidation, oxidative stress, the amount or effect of TNF-α and the severity of NAFLD-related fibrosis. Among different liver diseases, autoimmune hepatitis is likely one with very strong genetic associations that influence its occurrence, clinical phenotype and treatment outcome, as outlined by Albert J. Czaja (Rochester, MN USA) [12]. DRB1∗0301 and DRB1∗0401 are the susceptibility alleles for type 1 autoimmune hepatitis in white North American and northern European patients, while in other countries typically alleles of HLA DRB1∗4 are seen. Single amino acid substitutions at DRβ71 can enhance susceptibility (lysine, arginine), protect against the disease (alanine), or suggest another etiology (glutamic acid).

In both HBV and HCV infections, epidemiological research has revealed a number of factors which influence outcome and point to the host genetic background as being one of the key determinants. Identification of specific genes may provide novel therapeutic targets for the future. Functional candidates, which influence susceptibility to persistent infection, the rate of liver fibrosis induced by HCV or the response to interferon therapy, have recently been reported. In contrast, Mark Thursz has used a positional candidate approach in parallel with disease association studies and found a polymorphism in the IL-10 (and IL-22) receptor II gene strongly associated with HBV infection [13]. In patients with chronic viral infections, as reported by Marie Annick Buendia ( Paris, France), SNPs or haplotypes affecting tumor suppressors, cytokines, growth factors and several metabolic enzymes are associated with increased or reduced risk of hepatocellular carcinoma occurrence [14]. Besides viral infections, other conditions have been convincingly linked to an increased risk of developing HCC, including hereditary metabolic diseases, diabetes, and obesity. In addition, a number of germline mutations may confer susceptibility to HCC development and cooperate with environmental risk factors in increasing the probability of HCC incidence. A fascinating and rapidly developing area of research deals with the role of microfilaments in response to liver injury and disease progression. Bishr Omary (Palo Alto, CA, USA) showed how keratin variants may predispose to end stage liver disease and disease progression in patients with hepatitis C infection [15].

3.1. Take home messages 


1.Polymorphic variants in genes involved in the development and regulation of inflammation, apoptosis, regeneration and fibrosis have a role in susceptibility to different liver diseases.

2.In most cases, with a few notable exceptions (i.e. autoimmune hepatitis), the relative importance of these genes in liver disease progression remains to be defined and validated in well-controlled large scale studies involving different populations.

3.Genetic predisposition to disease may derive from abnormal gene expression or from gene mutations causing disturbed liver cell biology (due to changes in enzymes, receptors, ligands, transporters, cofactors, signaling molecules, cytoskeletal proteins, etc.) or altered immune reactivity. The time is getting ripe to compile all the reported genetic mutations and all the changes in gene expression relating predisposition to liver disease in order to construct potent molecular scans (of two types: to identify SNPs and to analyze changes in gene expression) that might help to better characterize the specific nature of the patient disorder.

4.Experience teaches now that studies reporting on a correlation between specific SNPs and complex clinical phenotypes must be interpreted with caution. In many cases the number of patients under study is too small and coincidental correlations often are found. Reported correlations must always be replicated in prospective studies with sufficient numbers of well-defined patients (see for discussion Ref. 31).

Back to Article Outline

4. Hereditary liver diseases 

The liver is central to many metabolic activities and in recent years the genetic basis for numerous diseases involving malfunction of this organ has been clarified. Dramatic progress has occurred in hemochromatosis, the most common hereditary metabolic disorder in adult whites. According to Antonello Pietrangelo (Modena, Italy), at least five genes have been identified whose mutation may lead to a hemochromatotic syndrome: HFE, Transferrin receptor 2 (TfR2), Hemojuvelin (HJV), Hepcidin and Ferroportin [16]. HFE, TfR2 and particularly HJV are required for transcription of hepcidin, the iron-regulatory hormone, in the liver; ferroportin is the hepcidin target–receptor. Lack of hepcidin leads to uncontrolled release of iron from intestine and macrophages, responsible for circulatory and tissue iron overload. Bruce Bacon (St. Louis, USA) reported that approximately 85–90% of patients with typical hemochromatosis are homozygous for the C282Y mutation in HFE (prevalence of 1:250/300 Caucasians). However, not all homozygotes have symptoms and many have very mild degrees of hepatic iron overload. A great deal of effort is ongoing, attempting to understand the contribution of environmental, physiological, and genetic cofactors in determining a fully expressed disease phenotype.

Many different mutations of the ATP7B gene are associated with Wilson disease (prevalence of approximately 1:30,000), a disorder characterized by impaired copper biliary excretion and reduced copper incorporation into ceruloplasmin. G. Loudians (Cagliari, Italy) reported that most mutations are rare or population specific and only a limited number are relatively frequent [17]. This limits the use of genetics in diagnostic settings. For symptomatic patients, treatment with chelating agents (d-penicillamine, trientine, tetrathiomolybdate) is first line therapy. Michael Schilsky (New York, USA) emphasized that targeted goals of therapy in symptomatic patients include stabilization of clinical disease, neurological or hepatic, biochemical normalization of circulating non-ceruloplasmin copper and stabilization of liver tests [18]. Liver transplantation is indicated for patients with acute liver failure and severe hepatic insufficiency not responsive to medical therapy, but remains controversial for patients with neurological disease.

Mutations in the UGT1A1 gene are responsible for both type I and type II Crigler-Najjar (CN) syndromes, characterized by very high serum levels of unconjugated bilirubin [19]. A dinucleotide TA insertion within the TATA box of the promoter region of UGT1A1 gene is responsible for the much milder Gilbert’s syndrome. CN1 patients are refractory to phenobarbital treatment, while in type II CN syndrome, enzyme activity can be induced by phenobarbital administration. Achille Iolascon (Naples, Italy) underscored that definitive diagnosis of the CN syndrome requires high performance liquid chromatography analysis of bile or liver enzyme assay, while genetics may confirm specific mutations in the five exons of the UGTA1 gene.

P. Harper (Stockholm, Sweden) nicely reviewed the porphyrias caused by deficiencies in the activity of specific enzymes in the heme biosynthetic pathway [20]. The most common porphyria is porphyria cutanea tarda, genetic or sporadic, caused by decreased activity of the hepatic enzyme uroporphyrinogen decarboxylase, and characterized by cutaneous and hepatic abnormalities, while iron overload, excess alcohol use, viral hepatitis or estrogen therapy are important aggravating factors.

Several forms of progressive familial intrahepatic cholestasis (PFIC) are caused by malfunction of the canalicular membrane [21], as reported by Ronald O. Elferink (Amsterdam, The Netherlands). This mainly involves canalicular ATP-dependent transport proteins such as the bile salt export pump (BSEP, mutated in PFIC2). The elucidation of these diseases has also highlighted the role of various proteins in the protection against toxic bile. Thus, the phospholipid flippase ABCB4 (mutated in PFIC3) translocates PC to the outer leaflet of the canalicular membrane to allow excretion which inactivates bile salt toxicity. Conversely, ATP8B1 (mutated in PFIC1) flips PS to the inner leaflet of the canalicular membrane so as to increase the rigidity of the outer leaflet and reduce bile salt sensitivity of the membrane. Mutations in various genes involved in bile salt synthesis also cause inherited cholestasis. Mario Strazzabosco (New Haven, USA) has highlighted the importance of CFTR in bile formation [22]. Mutation of the CFTR gene in cystic fibrosis causes impaired bile flow and progressive liver disease. In conjunction with other electrolyte transporters in the cholangiocyte membrane CFTR ensures bicarbonate excretion which drives water flow in the biliary tree.

In recent years, much has been learned about the physiological role of peroxisomes, thanks to the identification of a growing number of inherited diseases in man in which either the biosynthesis, or their metabolic functions, is disturbed [23]. R.J.A. Wanders (Amsterdam, The Netherlands) has reviewed the peroxisomal disorders (PDs), which include peroxisome biogenesis disorders (PBDs), whose prototype is Zellweger syndrome, and peroxisomal enzyme/transporter deficiencies (e.g., X-linked adrenoleukodystrophy). The genetic defects of peroxisomes involve fatty acid β- and α-oxidation, etherphospholipid biosynthesis and glyoxylate detoxification. Joost Drenth (Nijmegen, The Netherlands) discussed the impact of autosomal dominant polycystic liver disease (PCLD) in hepatology [24]. PCLD patients suffer from the appearance of numerous cysts spread throughout the liver resulting from overgrowth of biliary epithelium. Drenth and colleagues, using a positional cloning approach, have identified PRKCSH (protein kinase C substrate 80K-H) as the gene implicated in PCLD; its product participates in an ER protein processing pathway and is involved in the biliary epithelial luminal structure.

Urea cycle disorders (UCDs), whose estimated prevalence is at least 1/30,000, are caused by enzymatic deficiencies such as ornithine transcarbamylase deficiency (OTC), N-acetyl glutamate synthetase (NAGS), carbamyl phosphate synthetase (CPSI), argininosuccinic acid synthetase (ASS), argininosuccinic acid lyase (ASL) and arginase I (ARG1). Brendan Lee (Houston, TX, USA) discussed the genetic basis, pathogenesis, and heterogeneous clinical presentation of UCDs [25]. Classically, patients with null activity present in the neonatal period with severe hyperammonemia, whereas patients with residual enzyme activity present later with a variety of symptoms ranging from cyclic vomiting to psychiatric disorders. Urea cycle intermediates are also important in other pathways of metabolism. As an example, arginine is also the primary substrate for nitric oxide (NO) synthase; hence, clinical features of the UCDs that are not related to hyperammonemia may be due in part to dysregulation of NO synthesis. Some recent exciting developments in the molecular pathogenesis of alfa-1-antitrypsin deficiency, the most common genetic cause of liver disease in children, were outlined by David H Perlmutter. The classical form of the deficiency is caused by a mutant protein, α1ATZ, that is retained in the endoplasmic reticulum (ER) of liver cells. Accumulation of α1ATZ activates a distinct profile of cellular responses, including activation of the autophagic response, NFκB, mitochondrial- and ER-caspases. Liver injury/carcinogenesis results from a gain-of-toxic function mechanism in which mutant α1ATZ elicits cytotoxic effects on liver cells. Accumulation of this mutant protein in the ER also has profound effects on cell proliferation and survival that may explain the mechanism of hepatocarcinogenesis [26].

4.1. Take home messages 


•The genetic defect responsible for a variety of hereditary liver disorders has been identified and the underlying molecular pathogenesis clarified. While this teaches us much about disease mechanisms, these disorders generally represent relatively rare prototypic phenotypes. In the future emphasis will have to shift towards milder mutations in the respective genes and their role in predisposition towards more complex but also more frequent disease phenotypes.

•However, in numerous hereditary liver diseases a clear discrepancy exists between the presence of a pathogenic gene mutation and clinical expressivity.

•Research should be directed to dissect the interactions of environmental and host-related factors that affect the rate and extent of phenotypic penetrance of monogenic defects.

Back to Article Outline

5. Gene therapy 

Gene therapy is a plastic procedure consisting of the introduction of genes into cells to control disease through the use of vectors. Inder Verma (La Jolla, CA, USA) has presented data showing the potential of third generation lentiviral vectors able to transduce liver, brain, muscle and hematopoietic stem cells. The most promising applications for hepatic gene therapy are not only the correction of hereditary diseases of the liver but also non-hepatic genetic disorders (e.g., hemophilia) or acquired liver diseases. Hemophilia B is a bleeding diathesis caused by mutations in the gene encoding blood coagulation Factor IX (F.IX). Katherine A. High (Philadelphia, USA) undertook an open label, dose escalation study of AAV-F.IX delivered through the hepatic artery in seven subjects with severe hemophilia B. Vector infusion was not associated with acute or long-lasting toxicity, therapeutic levels of F.IX were achieved at the highest dose tested and duration of expression at therapeutic levels was limited to a period of ∼8weeks [27]. Gene therapy can also be applied to the treatment of chronic viral hepatitis using vectors enabling expression within the liver of transgenes encoding siRNA against viral transcripts or antiviral or immunomodulatory cytokines such as IFN-α or IL-12, as reported by Gloria Gonzalez-Aseguinolaza (Pamplona, Spain). Jesus Prieto (Pamplona, Spain) showed the results of clinical trials applying intratumor injection of a first generation adenoviral vector encoding IL-12 to treat hepatocellular carcinoma and liver metastasis of colorectal cancer [28], [29]. The therapy was well tolerated but antitumor effects were modest. This low efficacy was related to a short duration of transgene expression and to the development of neutralizing anti-adenoviral antibodies precluding repeated transduction of the neoplastic lesions. Clinical trials using long-term expression vectors equipped with inducible promoters should be performed in the future.

5.1. Take home messages 


1.Adeno-associated viruses (AAV), third generation (gutless) adenoviruses and lentiviruses represent the most promising tools for long-term expression of transgenes in liver cells. For specific transgenes the use of inducible promoters would be mandatory to ensure proper control on gene expression. Hurdles that remain to be taken are immune responses against the transgene product as well as against viral proteins (as in the case of AAV).

2.Future gene therapy strategies to combat cancer should include the use of long-term expression vectors encoding transgenes directed against different targets leading to: (a) interference with tumor biology by blocking survival factors or neutralizing angiogenic molecules, (b) direct destruction of tumor cells by using suicide genes or oncolytic virotherapy, (c) stimulation of antitumor immunity, (d) inhibiting the mediators of the immune tolerance to tumors (e.g., Tregs). Possibly, success may depend on the proper combination on several of these strategies. Much research should be done using animal models with tumors closer to the human counterpart than the transplantable tumors that are so frequently employed for the preclinical proof of concept.

Back to Article Outline

6. Conclusions and perspectives 

The EASL/AASLD Monothematic conference has brought together for the first time clinicians, geneticists, epidemiologists, bioethicists and molecular biologists to discuss key aspects related to genetics and liver disorders. The permissive or modifying effects of genetic determinants on individual response(s) to drugs, toxins, pathogens, or their role in progression of many acquired liver diseases have been recognized. These advances have also transformed the way we screen, diagnose and cure hereditary liver diseases. There is now a need for establishing databases of genetic and clinical data in many liver diseases across different geographical areas to dissect the complex interplay of genetic and environmental factors in determining disease phenotype and disease progression. It is anticipated that a joint effort of EASL and AASLD in supporting research and implementing epidemiological studies in large patient populations will greatly enhance our understanding of disease pathogenesis but also improve the management of hereditary liver disease and, in general, of all liver disorders.

Back to Article Outline

References 

  1. Ferrari F, Foglieni B, Arosio P, Camaschella C, Daraio F, Levi S, et al. Microelectronic DNA chip for hereditary hyperferritinemia cataract syndrome, a model for large-scale analysis of disorders of iron metabolism. Hum Mutat. 2006;27:201–208
  2. Burke W. Genetic testing. N Engl J Med. 2002;347:1867–1875
  3. van Leeuwen DJ, Bernat JL. Ethical, social and legal implications of genetic testing in liver disease. Hepatology. 2006;43:1195–1201
  4. Abiola O, Angel JM, Avner P, Bachmanov AA, Belknap JK, Bennett B, et al. The nature and identification of quantitative trait loci: a community’s view. Nat Rev Genet. 2003;4:911–916
  5. Diehl AM. Cytokine regulation of liver injury and repair. Immunol Rev. 2000;174:160–171
  6. Berasain C, Garcia-Trevijano ER, Castillo J, Erroba E, Santamaria M, Lee DC, et al. Novel role for amphiregulin in protection from liver injury. J Biol Chem. 2005;280:19012–19020
  7. Pauli-Magnus C, Stieger B, Meier Y, Kullak-Ublick GA, Meier PJ. Enterohepatic transport of bile salts and genetics of cholestasis. J Hepatol. 2005;43:342–357
  8. Kaplowitz N. Idiosyncratic drug hepatotoxicity. Nat Rev Drug Discov. 2005;4:489–499
  9. Bataller R, North KE, Brenner DA. Genetic polymorphisms and the progression of liver fibrosis: a critical appraisal. Hepatology. 2003;37:493–503
  10. Stickel F, Osterreicher CH. The role of genetic polymorphisms in alcoholic liver disease. Alcohol Alcohol. 2006;41:209–224
  11. Day CP. The potential role of genes in nonalcoholic fatty liver disease. Clin Liver Dis. 2004;8:673–691xi
  12. Donaldson PT, Czaja AJ. Genetic effects on susceptibility, clinical expression, and treatment outcome of type 1 autoimmune hepatitis. Clin Liver Dis. 2002;6:707–725
  13. Frodsham AJ, Zhang L, Dumpis U, Taib NA, Best S, Durham A, et al. Class II cytokine receptor gene cluster is a major locus for hepatitis B persistence. Proc Natl Acad Sci USA. 2006;103:9148–9153
  14. Kato N, Ji G, Wang Y, Baba M, Hoshida Y, Otsuka M, et al. Large-scale search of single nucleotide polymorphisms for hepatocellular carcinoma susceptibility genes in patients with hepatitis C. Hepatology. 2005;42:846–853
  15. Ku NO, Lim JK, Krams SM, Esquivel CO, Keeffe EB, Wright TL, et al. Keratins as susceptibility genes for end-stage liver disease. Gastroenterology. 2005;129:885–893
  16. Pietrangelo A. Hereditary hemochromatosis. Annu Rev Nutr. 2006;26:251–270
  17. Panagiotakaki E, Tzetis M, Manolaki N, Loudianos G, Papatheodorou A, Manesis E, et al. Genotype–phenotype correlations for a wide spectrum of mutations in the Wilson disease gene (ATP7B). Am J Med Genet A. 2004;131:168–173
  18. Ala A, Schilsky ML. Wilson disease: pathophysiology, diagnosis, treatment, and screening. Clin Liver Dis. 2004;8:787–805viii
  19. Bosma PJ. Inherited disorders of bilirubin metabolism. J Hepatol. 2003;38:107–117
  20. Thunell S, Harper P. Porphyrins, porphyrin metabolism, porphyrias. III. Diagnosis, care and monitoring in porphyria cutanea tarda – suggestions for a handling programme. Scand J Clin Lab Invest. 2000;60:561–579
  21. Oude Elferink RP, Paulusma CC, Groen AK. Hepatocanalicular transport defects: pathophysiologic mechanisms of rare diseases. Gastroenterology. 2006;130:908–925
  22. Spirli C, Fiorotto R, Song L, Santos-Sacchi J, Okolicsanyi L, Masier S, et al. Glibenclamide stimulates fluid secretion in rodent cholangiocytes through a cystic fibrosis transmembrane conductance regulator-independent mechanism. Gastroenterology. 2005;129:220–233
  23. Wanders RJ, Waterham HR. Biochemistry of mammalian peroxisomes revisited. Annu Rev Biochem. 2006;75:295–332
  24. Drenth JP, Martina JA, van de Kerkhof R, Bonifacino JS, Jansen JB. Polycystic liver disease is a disorder of cotranslational protein processing. Trends Mol Med. 2005;11:37–42
  25. Scaglia F, Brunetti-Pierri N, Kleppe S, Marini J, Carter S, Garlick P, et al. Clinical consequences of urea cycle enzyme deficiencies and potential links to arginine and nitric oxide metabolism. J Nutr. 2004;134:2775S–2782Sdiscussion 2796S-2797S
  26. Rudnick DA, Perlmutter DH. Alpha-1-antitrypsin deficiency: a new paradigm for hepatocellular carcinoma in genetic liver disease. Hepatology. 2005;42:514–521
  27. Manno CS, Pierce GF, Arruda VR, Glader B, Ragni M, Rasko JJ, et al. Successful transduction of liver in hemophilia by AAV-Factor IX and limitations imposed by the host immune response. Nat Med. 2006;12:342–347
  28. Wang l, Hernandez-Alcoceba R, Shankar V, Zabala M, Kochanek S, Sangro B, et al. Prolonged and inducible transgene expression in the liver using gutless adenovirus: a potential therapy for liver cancer. Gastroenterology. 2004;126:278–289
  29. Peñuelas I, Mazzolini G, Boán JF, Sangro B, Martı´-Climent J, Ruiz M, et al. Positron emission tomography imaging of adenoviral-mediated transgene expression in liver cancer patients. Gastroenterology. 2005;128:1787–1796

PII: S0168-8278(07)00182-1

doi:10.1016/j.jhep.2007.03.009

Journal of Hepatology
Volume 46, Issue 6 , Pages 1143-1148, June 2007

Article Tools