Journal of Hepatology 46 (2007) 1143–1148

www.elsevier.com/locate/jhep

Meeting report

Genetics in liver diseases

Antonello Pietrangelo1,*, Ronald Oude Elferink2, Jesus Prieto3, Bruce R. Bacon4
1
Center for Hemochromatosis, University Hospital of Modena, Via del Pozza 71, 41100 Modena, Italy
2
AMC Liver Center, Academic Medical Center, Amsterdam, The Netherlands
3
Department of Medicine, University of Navarra, Pamplona, Spain
4
Division of Gastroenterology and Hepatology, Saint Louis University, St. Louis, MO, USA

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 Monothe-
matic 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.
 2007 Published by Elsevier B.V. on behalf of the European Association for the Study of the Liver.
Keywords: Hereditary diseases; Polymorphisms; Gene therapy; Genetic screening; Quantitative trait loci

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 dramati-
cally expanding in clinical settings, societal fears of
misuse of genetic information are also growing. This
occurs both in diagnostic settings, where the informa-
tion 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
*
Corresponding author. Tel.: +39 05 9422 2714.
E-mail address: pietrangelo.antonello@unimore.it (A. Pietrangelo).
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 pop-
ulations to reduce disease heterogeneity of complex dis-
orders, 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 endog-
amy. These projects involve full clinical and biochemi-
cal 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 quantita-

0168-8278/$32.00  2007 Published by Elsevier B.V. on behalf of the European Association for the Study of the Liver.
doi:10.1016/j.jhep.2007.03.009
1144 A. Pietrangelo et al. / Journal of Hepatology 46 (2007) 1143–1148
tive 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 charac-
terized genetic markers and the quantitative pheno-
types [4]. This has allowed Dr. Andrews and
colleagues to identify discrete chromosomal regions
which carry modifier gene(s), the cloning of the rele-
vant gene products, and the determination of their
functional assay as well as a directed search for analo-
gous human modifier gene(s).
1.1. Take home messages
1. While genetic testing is rapidly expanding, hepatolo-
gists 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 phe-
notypic penetrance.
2. New and potent high-throughput methods are being
implemented in molecular diagnostics and mouse–
human comparative genetics that allow the identifica-
tion of susceptibility genes to complex diseases
through discrete gene loci (Quantitative Trait Loci,
QTLs) analysis.
3. However, before we move to the diagnostic applica-
tions, mathematical models for data analysis need
to be standardized and interpretation validated
through analysis of large databases in different
patient populations.
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 mecha-
nisms against injury and stress, with particular empha-
sis on novel cytokines and growth factors, such as
cardiotrophin-1 and amphiregulin, involved in protec-
tion 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 dis-
ease pathophysiology affect response to therapy. Bruno
Stieger (Zurich, Switzerland) discussed recent develop-
ments 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 advance-
ment of this field at the preclinical level by integrating
transcriptomics, proteomics and metabonomics in com-
paring paired compounds and sensitive and resistant
strains [8].
2.1. Take home messages
1. The liver is central in drug metabolism. Yet, phar-
macology of the drugs subject to inherited variabil-
ity in metabolism is very complex and only partially
understood. As an example the genetic predisposi-
tion 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 pro-
pel 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.
3. Genetic predisposition to liver diseases
There are numerous examples in hepatology of how
genetic components have profound effects on develop-
ment 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 fac-
tors. Transgenic mouse models and epidemiologic stud-
ies 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: alco-
hol dehydrogenase, cytochrome P4502E1 (CYP2E1),
antioxidant enzymes (e.g., manganese superoxide dis-
mutase or glutathione S-transferase), inflammatory
cytokines (TNF-a, IL-1b, 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 com-
ponents. A discrete number of genes is likely to play
a particular role in determining the development and
 A. Pietrangelo et al. / Journal of Hepatology 46 (2007) 1143–1148
progression of NAFLD, such as genes influencing the
pattern and magnitude of adiposity and insulin resis-
tance, the severity of steatosis, fatty acid oxidation,
oxidative stress, the amount or effect of TNF-a 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 substitu-
tions at DRb71 can enhance susceptibility (lysine,
arginine), protect against the disease (alanine), or sug-
gest another etiology (glutamic acid).
In both HBV and HCV infections, epidemiological
research has revealed a number of factors which influ-
ence 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 sus-
ceptibility to persistent infection, the rate of liver fibro-
sis 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 hapl-
otypes affecting tumor suppressors, cytokines, growth
factors and several metabolic enzymes are associated
with increased or reduced risk of hepatocellular carci-
noma 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 susceptibil-
ity to HCC development and cooperate with environ-
mental 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 kera-
tin 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 devel-
opment and regulation of inflammation, apoptosis,
regeneration and fibrosis have a role in susceptibility
to different liver diseases.
1145
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, cofac-
tors, 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 clini-
cal 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 repli-
cated in prospective studies with sufficient numbers
of well-defined patients (see for discussion Ref. 31).
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 hepci-
din, the iron-regulatory hormone, in the liver; ferropor-
tin 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 hemo-
chromatosis 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 contri-
bution of environmental, physiological, and genetic
cofactors in determining a fully expressed disease
phenotype.
1146 A. Pietrangelo et al. / Journal of Hepatology 46 (2007) 1143–1148
Many different mutations of the ATP7B gene are
associated with Wilson disease (prevalence of approxi-
mately 1:30,000), a disorder characterized by impaired
copper biliary excretion and reduced copper incorpora-
tion into ceruloplasmin. G. Loudians (Cagliari, Italy)
reported that most mutations are rare or population
specific and only a limited number are relatively fre-
quent [17]. This limits the use of genetics in diagnostic
settings. For symptomatic patients, treatment with che-
lating agents (d-penicillamine, trientine, tetrathiomolyb-
date) 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 normaliza-
tion of circulating non-ceruloplasmin copper and stabil-
ization 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 Iolas-
con (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 spe-
cific 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 abnormali-
ties, while iron overload, excess alcohol use, viral hepa-
titis or estrogen therapy are important aggravating
factors.
Several forms of progressive familial intrahepatic
cholestasis (PFIC) are caused by malfunction of the can-
alicular membrane [21], as reported by Ronald O. Elfer-
ink (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 high-
lighted 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 mem-
brane 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 identifi-
cation of a growing number of inherited diseases in man
in which either the biosynthesis, or their metabolic func-
tions, is disturbed [23]. R.J.A. Wanders (Amsterdam,
The Netherlands) has reviewed the peroxisomal disor-
ders (PDs), which include peroxisome biogenesis disor-
ders (PBDs), whose prototype is Zellweger syndrome,
and peroxisomal enzyme/transporter deficiencies (e.g.,
X-linked adrenoleukodystrophy). The genetic defects
of peroxisomes involve fatty acid b- and a-oxidation,
etherphospholipid biosynthesis and glyoxylate detoxifi-
cation. Joost Drenth (Nijmegen, The Netherlands) dis-
cussed 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 bili-
ary epithelium. Drenth and colleagues, using a posi-
tional cloning approach, have identified PRKCSH
(protein kinase C substrate 80K-H) as the gene impli-
cated in PCLD; its product participates in an ER pro-
tein processing pathway and is involved in the biliary
epithelial luminal structure.
Urea cycle disorders (UCDs), whose estimated prev-
alence is at least 1/30,000, are caused by enzymatic defi-
ciencies such as ornithine transcarbamylase deficiency
(OTC), N-acetyl glutamate synthetase (NAGS), carba-
myl 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 heteroge-
neous 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, argi-
nine 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
 A. Pietrangelo et al. / Journal of Hepatology 46 (2007) 1143–1148
of liver disease in children, were outlined by David H
Perlmutter. The classical form of the deficiency is caused
by a mutant protein, a1ATZ, that is retained in the
endoplasmic reticulum (ER) of liver cells. Accumulation
of a1ATZ activates a distinct profile of cellular
responses, including activation of the autophagic
response, NFjB, mitochondrial- and ER-caspases.
Liver injury/carcinogenesis results from a gain-of-toxic
function mechanism in which mutant a1ATZ 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 mecha-
nisms, 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 interac-
tions of environmental and host-related factors that
affect the rate and extent of phenotypic penetrance
of monogenic defects.
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, thera-
peutic levels of F.IX were achieved at the highest dose
1147
tested and duration of expression at therapeutic levels
was limited to a period of 8 weeks [27]. Gene ther-
apy 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 cyto-
kines such as IFN-a or IL-12, as reported by Gloria
Gonzalez-Aseguinolaza (Pamplona, Spain). Jesus Pri-
eto (Pamplona, Spain) showed the results of clinical
trials applying intratumor injection of a first genera-
tion adenoviral vector encoding IL-12 to treat hepato-
cellular 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) stim-
ulation 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.
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.
1148 A. Pietrangelo et al. / Journal of Hepatology 46 (2007) 1143–1148
The permissive or modifying effects of genetic determi-
nants on individual response(s) to drugs, toxins, patho-
gens, 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 estab-
lishing databases of genetic and clinical data in many
liver diseases across different geographical areas to dis-
sect 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 pathogen-
esis but also improve the management of hereditary liver
disease and, in general, of all liver disorders.
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