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 Archives depuis le 01/09/00 |
Noninvasive gene delivery to the liver by mechanical massage
Feng Liu, Leaf Huang
With the recent completion of the human genome project and the
tremendous growth of biotechnology, the desire to extract information
concerning gene expression, protein level, subcellular localization,
and functionality in the liver will demand the development of
efficient gene transfer to this organ with minimal toxicity. In
this report, we show that significant gene expression in the liver
could be achieved by simple mechanical massage after intravenous
injection of naked plasmid DNA into mice. This method is simple,
highly reproducible, repeatable, and, more importantly, free of
toxicity. Hepatic gene transfer with hepatocyte growth factor
(HGF) plasmid DNA prevented endotoxin-induced lethal fulminant
hepatic failure, leading to dramatically enhanced survival in
mice. (HEPATOLOGY 2002;35:1314-1319.)
Hepatic sinusoidal vasodilators improve transplanted cell engraftment
and ameliorate microcirculatory perturbations in the liver
Sanjeev Slehria, Pankaj Rajvanshi, Yoshiya Ito, Rana P. Sokhi,
Kuldeep K. Bhargava, Christopher J. Palestro, Robert S. McCuskey,
Sanjeev Gupta
After transplantation, hepatocytes entering liver sinusoids are
engrafted, whereas cells entrapped in portal spaces are cleared.
We studied whether hepatic sinusoidal dilatation will increase
the entry of transplanted cells in the liver lobule, improve cell
engraftment, and decrease microcirculatory perturbations. F344
rat hepatocytes were transplanted intrasplenically into syngeneic
dipeptidyl peptidase IV (DPPIV)-deficient rats. Animals were treated
with adrenergic receptor blockers (phentolamine, labetalol), a
calcium channel blocker (nifedipine), and splanchnic vasodilators
(nitroglycerine, calcitonin gene-related peptide [CGRP], glucagon).
Transplanted cells were localized by histochemistry. The hepatic
microcirculation was studied with in vivo videomicroscopy.
Changes in cell translocations were analyzed by injection of 99mTc-labeled
hepatocytes. Pretreatment with phentolamine and nitroglycerine
increased transplanted cell entry in liver sinusoids, whereas
labetalol, nifedipine, CGRP, and glucagon were ineffective. Increased
deposition of transplanted cells in sinusoids resulted in greater
cell engraftment. In vivo microscopy showed disruption
of sinusoidal blood flow immediately after cell transplantation
with circulatory restoration requiring more than 12 to 24 hours
after cell transplantation. However, in nitroglycerine-treated
animals, sinusoidal blood flow was perturbed less. Nitroglycerine
did not meaningfully increase intrapulmonary cell translocations.
In conclusion, these findings indicate that hepatic sinusoidal
capacitance is regulated by -adrenergic and nitroglycerine-responsive
elements. Sinusoidal vasodilatation benefited intrahepatic distribution
of transplanted cells and restored hepatic microcirculation after
cell transplantation. This shall facilitate optimization of clinical
cell transplantation and offers novel ways to investigate vascular
mechanisms regulating hepatic sinusoidal reactivity. (HEPATOLOGY
2002;35:1320-1328.)
Stimulation of 2-adrenergic receptor inhibits cholangiocarcinoma
growth through modulation of Raf-1 and B-Raf activities
Noriatsu Kanno, Gene LeSage, Jo Lynne Phinizy, Shannon Glaser,
Heather Francis, Gianfranco Alpini
Growth factor signaling, mediated by the mitogen-activated protein
kinase (MAPK) cascade, induces cell mitosis. Adenosine 3',5'-monophosphate
(cAMP) may inhibit or stimulate mitosis (depending on the cell
type) through the activation of MAPK and Raf proteins. Among Raf
proteins, Raf-1 and B-Raf differentially regulate mitosis. Our
aims were to evaluate the role and mechanisms of action of the
2-adrenergic agonist UK14,304 in the regulation of growth of the
human cholangiocarcinoma cell line Mz-ChA-1. Immunocytochemistry
and immunoblotting for 2A-, 2B-, or 2C-adrenergic receptor subtypes
showed positive reaction in Mz-ChA-1 cells. We found that physiological
concentrations of UK14,304 increased cAMP levels and inhibited
proliferation and MAPK activity in Mz-ChA-1 cells. Mz-ChA-1 cells
expressed Raf-1 and B-Raf. Epidermal growth factor (EGF) immediately
and transiently stimulated Raf-1 activity, whereas B-Raf activity
was increased with prolonged EGF stimulation. EGF-stimulated Raf-1
and B-Raf activities were both inhibited by UK14,304. UK14,304
did not affect Ras activity. In Mz-ChA-1 cells, 2-adrenoreceptor
stimulation causes up-regulation of cAMP, which inhibits EGF-induced
MAPK activity through an acute increase of Raf-1 and sustained
activation of B-Raf. In conclusion, because 2-AR inhibition of
growth occurred downstream of Ras, adrenergic stimulation or other
stimulants of cAMP may overcome the Ras mutations and offer a
new therapeutic approach for patients with cholangiocarcinoma.
(HEPATOLOGY 2002;35:1329-1340.)
Cell cycle deregulation in liver lesions of rats with and without
genetic predisposition to hepatocarcinogenesis
Rosa M. Pascale, Maria M. Simile, Maria R. De Miglio, Maria R.
Muroni, Diego F. Calvisi, Giuseppina Asara, Daniela Casabona,
Maddalena Frau, Maria A. Seddaiu, Francesco Feo
Preneoplastic and neoplastic hepatocytes undergo c-Myc up-regulation
and overgrowth in rats genetically susceptible to hepatocarcinogenesis,
but not in resistant rats. Because c-Myc regulates the pRb-E2F
pathway, we evaluated cell cycle gene expression in neoplastic
nodules and hepatocellular carcinomas (HCCs), induced by initiation/selection
(IS) protocols 40 and 70 weeks after diethylnitrosamine treatment,
in susceptible Fisher 344 (F344) rats, and resistant Wistar and
Brown Norway (BN) rats. No interstrain differences in gene expression
occurred in normal liver. Overexpression of c-myc, Cyclins
D1, E, and A, and E2F1 genes, at messenger RNA
(mRNA) and protein levels, rise in Cyclin D1-CDK4, Cyclin E-CDK2,
and E2F1-DP1 complexes, and pRb hyperphosphorylation occurred
in nodules and HCCs of F344 rats. Expression of Cdk4, Cdk2,
p16INK4A, and p27KIP1 did not change. In nodules
and/or HCCs of Wistar and BN rats, low or no increases in c-myc,
Cyclins D1, E, and A, and E2F1 expression, and
Cyclin-CDKs complex formation were associated with p16INK4A
overexpression and pRb hypophosphorylation. In conclusion, these
results suggest deregulation of G1 and S phases in liver lesions
of susceptible rats and block of G1-S transition in lesions of
resistant strains, which explains their low progression capacity.
(HEPATOLOGY 2002;35:1341-1350.)
Maturation of fetal hepatocytes in vitro by
extracellular matrices and oncostatin M: Induction of tryptophan
oxygenase
Akihide Kamiya, Nobuhiko Kojima, Taisei Kinoshita, Yasuyuki Sakai,
Atsushi Miyaijma
Previously, we described that embryonic day 14.5 (E14.5) mouse
fetal hepatocytes differentiate to express tyrosine amino transferase
(TAT) and glucose-6-phosphatase, which are expressed in the perinatal
liver, in response to oncostatin M (OSM) or in high-cell-density
culture. However, under such conditions, fetal hepatic cells failed
to express genes for adult liver-specific enzymes, such as tryptophan
oxygenase (TO). Although phenobarbital (PB) and dimethylsulfoxide
(DMSO) have been known to maintain the functions of adult hepatocytes
in vitro, they failed to induce TO expression in fetal
hepatic cells. Thus far, no system has been developed that reproduces
terminal differentiation of fetal hepatocytes in vitro.
Here, we describe that extracellular matrices derived from Engelbreth-Holm-Swarm
sarcoma (EHS) in combination with OSM or high-cell-density culture
induced expression of TO as well as cytochrome P450 genes that
are involved in detoxification. However, EHS alone was insufficient
to induce expression of TO, although it induced TAT expression
in fetal hepatocytes. In addition, high-density culture further
augmented differentiation. In conclusion, the combination of signals
by cytokines, cell-cell contact, and cell-matrix interaction is
required for induction of adult liver functions in fetal hepatocytes
in vitro. This primary culture system will be useful for
studying the mechanism of liver development. (HEPATOLOGY 2002;35:1351-1359.)
Role of MAP kinases and their cross-talk in TGF-1induced
apoptosis in FaO rat hepatoma cell line
Hyun-Jin Park, Byung-Chul Kim, Seong-Jin Kim, Kyeong Sook Choi
Transforming growth factor (TGF) 1 is a potent inducer of apoptosis
in the liver. During TGF-1induced apoptosis, 3 mitogen-activated
protein (MAP) kinases (extracellular signalregulated kinase
[ERK], c-Jun N-terminal kinase [JNK], and p38 kinase) showed
simultaneously sustained activation in FaO rat hepatoma cells.
TGF-1induced apoptosis was markedly enhanced when ERK activation
was selectively inhibited by the mitogen-activated protein kinase/extracellular
signalregulated kinase kinase inhibitor PD98059. In contrast,
both interfering with p38 activity by overexpression of the dominant
negative (DN) MKK6 mutant and inhibition of the JNK pathway by
overexpression of the DN SEK1 mutant resulted in suppression of
mitochondrial cytochrome c release, abrogating TGF-1induced
apoptosis. In addition, antiapoptotic Bcl-2 blocked mitochondrial
cytochrome c release, suppressing TGF-1induced activation
of JNK and p38. Inhibition of ERK activity enhanced TGF-1induced
p38 and JNK activation. However, inhibition of the JNK pathway
suppressed p38 but induced transient ERK activation. Similarly,
interfering with the p38 pathway also attenuated JNK activation
but generated transient ERK activation in response to TGF-1. These
results indicate that disrupting one MAP kinase pathway affects
the TGF-1induced activation of other MAP kinases, suggesting
cross-talk among MAP kinase pathways. In conclusion, we propose
that the balance and integration of MAP kinase signaling may regulate
commitment to TGF-1induced apoptosis modulating the release
of cytochrome c from mitochondria. (HEPATOLOGY 2002;35:1360-1371.)
A novel mechanism for mitogenic signaling via protransforming
growth factor within hepatocyte nuclei
Bettina Grasl-Kraupp, Elisabeth Schausberger, Karin Hufnagl, Christopher
Gerner, Alexandra Löw-Baselli, Walter Rossmanith, Wolfram
Parzefall, Rolf Schulte-Hermann
Transforming growth factor (TGF) , an important mediator of growth
stimulation, is known to act via epidermal growth factor receptor
(EGF-R) binding in the cell membrane. Here we show by immunohistology,
2-dimensional immunoblotting, and mass spectrometry of nuclear
fractions that the pro-protein of wild-type TGF- occurs in hepatocyte
nuclei of human, rat, and mouse liver. Several findings show a
close association between nuclear pro-TGF- and DNA synthesis.
(1) The number of pro-TGF-+ nuclei was low in resting liver
and increased dramatically after partial hepatectomy and after
application of hepatotoxic chemicals or the primary mitogen cyproterone
acetate (CPA); in any case, S phase occurred almost exclusively
in pro-TGF-+ nuclei. The same was found in human cirrhotic
liver. (2) In primary culture, 7% of hepatocytes synthesized pro-TGF-,
which then translocated to the nucleus; 70% of these nuclei subsequently
entered DNA replication, whereas only 2% of pro-TGF-
hepatocytes were in S phase. (3) The frequency of hepatocytes
coexpressing pro-TGF- and DNA synthesis was increased by the hepatomitogens
CPA or prostaglandin E2 and was decreased by the growth inhibitor
TGF-1. (4) Treatment with mature TGF- increased DNA synthesis
exclusively in pro-TGF- hepatocytes, which was abrogated
by the EGF-R tyrosine kinase inhibitor tyrphostin A25. In conclusion,
TGF- gene products may exert mitogenic effects in hepatocytes
via 2 different signaling mechanisms: (1) the "classic"
pathway of mature TGF- via EGF-R in the membrane and (2) a novel
pathway involving the presence of pro-TGF- in the nucleus. (HEPATOLOGY
2002;35:1372-1380.)
Liver cell proliferation requires methionine adenosyltransferase
2A mRNA up-regulation
Covadonga Pañeda, Itziar Gorospe, Blanca Herrera, Toshikazu
Nakamura, Isabel Fabregat, Isabel Varela-Nieto
Regulation of liver cell proliferation is a key event to control
organ size during development and liver regeneration. Methionine
adenosyltransferase (MAT) 2A is expressed in proliferating liver,
whereas MAT1A is the form expressed in adult quiescent hepatocytes.
Here we show that, in H35 hepatoma cells, growth factors such
as hepatocyte growth factor (HGF) and insulin up-regulated MAT2A
expression. HGF actions were time- and dose-response dependent
and required transcriptional activity. Mitogen-activated protein
(MAP) kinase and phosphatidylinositol 3-phosphate kinase (PI 3-K)
pathways were required for both HGF-induced cell proliferation
and MAT2A up-regulation. Furthermore, in H35 cells treated with
HGF, the inhibition of these pathways was associated with the
switch from the expression of fetal liver MAT2A to the adult liver
MAT1A isoform. Fetal liver hepatocytes exhibited an identical
response pattern. Treatment of H35 hepatoma cells with MAT2A antisense
oligonucleotides decreased cell proliferation induced by HGF;
this decrease correlated with the decay in MAT2A messenger RNA
(mRNA) levels. Finally, growth inhibitors such as transforming
growth factor (TGF) blocked HGF-induced MAT2A up-regulation while
increasing MAT1A mRNA levels in H35 cells. In conclusion, our
results show that MAT2A expression not only correlates with liver
cell proliferation but is required for this process. (HEPATOLOGY
2002;35:1381-1391.)
Diminished hepatic expression of the HNF-6 transcription factor
during bile duct obstruction
Ai-Xuan L. Holterman, Yongjun Tan, Wooram Kim, Kyung W. Yoo, Robert
H. Costa
Hepatocyte nuclear factor 6 (HNF-6) is a member of the one
cut family of transcription factors and potentially regulates
expression of numerous target genes important for hepatocyte function.
In the liver, HNF-6 is expressed not only in hepatocytes, but
also in biliary epithelial cells (BEC). To evaluate the in
vivo function of HNF-6, we examined the hepatic expression
pattern of HNF-6 messenger RNA (mRNA) and protein after bile duct
ligation (BDL)mediated liver injury. We found that HNF-6
protein levels in BEC and hepatocytes were diminished within 15
hours of BDL injury and remained suppressed through the fifth
day of injury. The onset of BEC proliferation in response to bile
duct obstruction was associated with diminished HNF-6 protein
levels. To maintain hepatic HNF-6 protein levels during BDL liver
injury, we used mouse tail vein injections with recombinant adenovirus
expressing HNF-6 complementary DNA (cDNA) (AdH6). We found that
maintaining hepatic HNF-6 levels with AdH6 infection resulted
in significant decreases in BEC proliferation at 15 and 24 hours
after biliary obstruction compared with adenovirus control. Our
results showed that HNF-6 expression is diminished in BEC and
hepatocytes and that maintaining hepatic HNF-6 expression hinders
the normal biliary proliferative response to bile duct injury.
This suggests that diminished hepatic HNF-6 levels are required
for repair in response to biliary injury and that it regulates
expression of genes that possess differentiation-specific function
that are inhibitory to proliferation. In conclusion, we propose
a biologic role for diminished HNF-6 protein levels in bile duct
disease. (HEPATOLOGY 2002;35:1392-1399.)
Regulation of oxysterol 7-hydroxylase (CYP7B1) in primary cultures
of rat hepatocytes
William M. Pandak, Phillip B. Hylemon, Shunlin Ren, Dalila Marques,
Gregorio Gil, Kaye Redford, Darrell Mallonee, Z. Rano Vlahcevic
Conversion of cholesterol into 7-hydroxylated bile acids is a
principal pathway of cholesterol disposal. Cholesterol 7-hydroxylase
(CYP7A1) is the initial and rate-determining enzyme in the "classic"
pathway of bile acid synthesis. An "alternative" pathway
of bile acid synthesis is initiated by sterol 27-hydroxylase (CYP27)
with subsequent 7-hydroxylation of 27-hydroxycholesterol by oxysterol
7-hydroxylase (CYP7B1). The regulation of CYP7B1, possibly a rate-determining
enzyme in the alternative pathway, has not been thoroughly studied.
The aims of this study were to (1) study the regulation of liver
CYP7B1 by bile acids, cholesterol, adenosine 3', 5'-cyclic monophosphate
(cAMP), and phorbol myristate acetate (PMA) in primary rat hepatocytes
and (2) determine the effect of CYP7B1 overexpression on rates
of bile acid synthesis. The effects of different bile acids (3-150
µmol/L), cAMP (50 µmol/L), PMA (100 nmol/L; protein
kinase C stimulator), cholesterol (200 µmol/L), and squalestatin
(1 µmol/L; cholesterol synthesis inhibitor) on CYP7B1 expression
in primary rat hepatocytes were studied. Taurocholic acid and
taurodeoxycholic acid decreased CYP7B1 activity by 45% ±
10% and 36% ± 7%, respectively. Tauroursodeoxycholic acid
and taurochenodeoxycholic acid did not alter CYP7B1 activity.
Inhibition of cholesterol synthesis with squalestatin decreased
CYP7B1 activity by 35%, whereas addition of cholesterol increased
activity by 39%. Both PMA and cAMP decreased CYP7B1 activity by
60% and 34%, respectively, in a time-dependent fashion. Changes
in CYP7B1 messenger RNA (mRNA) levels correlated with changes
in specific activities. Overexpression of CYP7B1 led to a marked
increase in CYP7B1 mRNA levels and specific activity but no change
in rates of bile acid synthesis. In conclusion, in the rat, CYP7B1
specific activity is highly regulated but does not seem to be
rate limiting for bile acid synthesis. (HEPATOLOGY 2002;35:1400-1408.)
Altered localization and activity of canalicular Mrp2 in estradiol-17-D-glucuronideinduced
cholestasis
Aldo D. Mottino, Jingsong Cao, Luis M. Veggi, Fernando Crocenzi,
Marcelo G. Roma, Mary Vore
Estradiol-17-D-glucuronide (E217G), an endogenous metabolite of
estradiol, induces a potent dose-dependent and reversible inhibition
of bile flow in the rat. We analyzed the effect of a single dose
of E217G (15 µmol/kg, intravenously) to female rats on bile
flow and the endocytic retrieval and function of the canalicular
multidrug resistance-associated protein 2 (Mrp2) and the effect
of pretreatment with dibutyryl-cyclic AMP (DBcAMP; 20 µmol/kg)
on these measures. Bile flow was maximally inhibited by 85% within
10 minutes of E217G and returned to 50% and 100% of control levels
within 75 and 120 minutes, respectively. Western analysis of total
homogenates and mixed plasma and intracellular membranes suggested
partial internalization of Mrp2 during the acute phase of cholestasis
at 20 minutes and during the period of recovery from cholestasis
at 75 minutes, which returned to control levels by 180 minutes
after E217G. Confocal analysis confirmed Western studies and demonstrated
endocytic retrieval of Mrp2 from the canalicular membrane into
pericanalicular and intracellular domains. The biliary concentration
and excretion of the model Mrp2 substrate, dinitrophenyl-S-glutathione
(DNP-SG), was impaired in parallel with the extent of Mrp2 retrieval.
Pretreatment with DBcAMP partially protected against maximal E217G
cholestasis and the endocytic retrieval and decreased function
of Mrp2 at 20 minutes and significantly accelerated the exocytic
insertion of Mrp2 into the canalicular membrane and the recovery
of bile flow and biliary excretion of DNP-SG. In conclusion, these
data indicate that E217G induces endocytic internalization of
Mrp2, which occurs in parallel with decreased bile flow and Mrp2
transport activity. (HEPATOLOGY 2002;35:1409-1419.)
Cyclosporine a protects against arachidonic acid toxicity in
rat hepatocytes: Role of CYP2E1 and mitochondria
Defeng Wu, Arthur I. Cederbaum
Diets high in polyunsaturated fatty acids (PUFA) are important
for the development of alcoholic liver injury. The goal of this
report was to characterize toxicity by arachidonic acid (AA),
its enhancement by salicylate, and the role of mitochondrial injury
in the pathway leading to toxicity in hepatocytes from pyrazole-treated
rats. AA caused toxicity that was increased by sodium salicylate.
This synergistic toxicity was reduced by diallyl sulfide (DAS),
an inhibitor of CYP2E1; Trolox ([±] 6-hydroxy, 2, 5, 7,
8-tetramethylchroman-2-carboxylic acid), an inhibitor of lipid
peroxidation; Z-Val-Ala-Asp(OMe)-fluoromethylketone (ZVAD-FMK),
a pan caspase inhibitor; and by cyclosporine A (CsA), an inhibitor
of the mitochondrial permeability transition. Mitochondrial membrane
potential also was reduced, and this was prevented by cyclosporine,
diallyl sulfide, and Trolox. There was release of mitochondrial
cytochrome c into the cytosol and activation of caspase 3, which
were prevented by cyclosporine, diallylsulfide, and Trolox. Toxicity
was prevented by expression of catalase either in the cytosolic
or the mitochondrial compartment. Levels of CYP2E1 rapidly declined,
and this was partially prevented by salicylate. These results
are consistent with a model in which CYP2E1-dependent production
of reactive oxygen species enhances lipid peroxidation when AA
is added to hepatocytes. This results in damage to the mitochondria,
with initiation of a membrane permeability transition and a decline
in membrane potential, followed by release of cytochrome c, caspase
3 activation, and cellular toxicity. In conclusion, damage to
mitochondria appears to play an important role in the CYP2E1 plus
AA toxicity. (HEPATOLOGY 2002;35:1420-1430.)
Expression of GP73, a resident Golgi membrane protein, in viral
and nonviral liver disease (*Human Study*)
Raleigh D. Kladney, Xiaoyen Cui, Gary A. Bulla, Elizabeth M. Brunt,
Claus J. Fimmel
GP73 is a novel type II Golgi membrane protein of unknown function
that is expressed in the hepatocytes of patients with adult giant-cell
hepatitis (Gene 2000;249:53-65). Its expression pattern in human
liver disease and the regulation of its expression in hepatocytes
have not been systematically studied. The aims of the present
study were to compare GP73 protein levels in viral and nonviral
human liver disease and in normal livers, to identify its cellular
sources, and to study the regulation of its expression in hepatoma
cells in vitro. GP73 protein levels were quantitated in
explant livers of patients with well-defined disease etiologies
and compared with the levels in normal donor livers. GP73-expressing
cells were identified immunohistochemically. GP73 expression in
vitro was studied by Western blotting and immunofluorescence
microscopy in HepG2 and SK-Hep-1 cells and in the HepG2-derived,
hepatitis B virus (HBV)-transfected HepG2215 and HepG2T14.1 cell
lines. Whole organ levels of GP73 were low in normal livers. Significant
increases were found in liver disease due to viral causes (HBV,
HCV) or nonviral causes (alcohol-induced liver disease, autoimmune
hepatitis). In normal livers, GP73 was constitutively expressed
by biliary epithelial cells but not by hepatocytes. Hepatocyte
expression of GP73 was dramatically up-regulated in diseased livers,
regardless of the etiology, whereas biliary epithelial cell expression
did not change appreciably. GP73 was present at high levels in
HepG2215 cells (a cell line that supports active HBV replication),
but was absent in HepG2T14.1 cells (an HBV-transfected cell line
that does not support HBV replication) and in HBV-free HepG2 cells.
In SK-Hep-1 cells, GP73 expression was increased in response to
interferon gamma (IFN-), and inhibited by tumor necrosis factor
(TNF-). In conclusion, increased expression of GP73 in hepatocytes
appears to be a general feature of advanced liver disease, and
may be regulated via distinct pathways that involve hepatotropic
viruses or cytokines. (HEPATOLOGY 2002;35:1431-1440.)
Liver Failure and Liver Disease
Cardiovascular effects of canrenone in patients with preascitic
cirrhosis (*Human Study*)
Giorgio La Villa, Giuseppe Barletta, Roberto Giulio Romanelli,
Giacomo Laffi, Riccarda Del Bene, Francesco Vizzutti, Pietro Pantaleo,
Valeria Mazzocchi, Paolo Gentilini
In patients with cirrhosis and portal hypertension, standing induces
a reduction in cardiac index (CI) and an increase in systemic
vascular resistance index. Our previous studies indicate that
this abnormal hemodynamic response to standing is due to an altered
myocardial function, because cirrhotic patients are unable to
compensate for the reduced preload with an increase in left ventricular
(LV) ejection fraction (EF) and stroke volume. To evaluate whether
the cardiac dysfunction in cirrhosis is influenced by canrenone,
an aldosterone antagonist, 8 patients with preascitic, nonalcoholic
cirrhosis, and portal hypertension underwent echocardiographic
assessment of LV function and systemic hemodynamics and determinations
of plasma volume, urinary sodium excretion, and plasma renin activity
(PRA), aldosterone (PAC), and norepinephrine (PNE) when on a 150-mmol/d-sodium
diet (baseline), after 1 month on canrenone (100 mg/d) plus a
40-mmol/d-sodium diet and after 1 month on canrenone plus a 150-mmol/d-sodium
diet. Echocardiographic evaluation was performed with the patient
in the supine position and during active standing. At baseline,
patients had high plasma volume and normal renal function, PRA,
PAC, and PNE. CI, LVEF, and stroke volume index were also normal.
Standing caused a significant reduction in CI and LVEF. After
canrenone and either sodium diet, CI significantly decreased,
and PRA and PNE increased in the supine position. On standing,
LVEF and CI did not decrease further. Plasma volume significantly
decreased only after low-sodium diet plus canrenone. In conclusion,
canrenone normalizes the cardiac response to the postural challenge
in patients with preascitic cirrhosis. (HEPATOLOGY 2002;35:1441-1448.)
The mechanism of improved sodium homeostasis of low-dose losartan
in preascitic cirrhosis (*Human Study*)
Florence Wong, Peter Liu, Laurence Blendis
See Editorial on Page 1544
Renal sodium retention on standing is one aspect of the abnormal
renal sodium handling in preascitic, well-compensated patients
with cirrhosis. Recently, it has been shown that low doses (7.5
mg) of the angiotensin II (Ang II) receptor antagonist, losartan,
can reverse renal sodium retention on high, 200-mmol sodium/d
diet in these patients and restore them to sodium balance. Therefore,
the effect of 7.5 mg of losartan on sodium excretion, when changing
from supine to erect posture for 2 hours, was examined in 10 well-compensated
patients with cirrhosis and 9 age- and sex-matched controls on
the same sodium diet, under strictly controlled metabolic conditions.
In contrast to control subjects, in whom sodium excretion was
unaffected, single 7.5-mg doses of losartan again restored the
preascitic patients with cirrhosis to sodium balance. In addition,
it blunted the fall in erect posture induced renal sodium
excretion by a reduction in proximal and distal tubular reabsorption
of sodium. These changes occurred without any significant changes
in blood volumes, systemic and renal hemodynamics, or glomerular
filtration rate (GFR) and filtered sodium load compared with controls,
and despite activation of the systemic renin-angiotensin-aldosterone
system, which was still within normal levels. In conclusion, the
beneficial natriuretic effects of low-dose losartan on erect posture
induced sodium retention in preascitic cirrhosis supports
the suggestion that the pathophysiology of sodium retention in
preascites is in part caused by an intrarenal tubular effect of
Ang II in that posture. (HEPATOLOGY 2002;35:1449-1458.)
Proteomic analysis and molecular characterization of tissue
ferritin light chain in hepatocellular carcinoma (*Human Study*)
Kang-Sik Park, Hoguen Kim, Nam-Gyun Kim, Sang Yun Cho, Kun-Ho
Choi, Je Kyung Seong, Young-Ki Paik
To investigate a molecular basis for iron depletion in human hepatocellular
carcinoma (HCC), 19 cases of HCC were analyzed by two-dimensional
electrophoresis (2DE) and matrix-assisted laser desorption ionization
mass spectrometry (MALDI-MS). Results were compared with those
of paired adjacent nontumorous liver tissues. Comparative analysis
of the respective spot patterns in 2DE showed that tissue ferritin
light chain (T-FLC), an iron-storage protein, was either severely
suppressed or reduced to undetectable levels in HCC, which was
further supported by Western blot and immunohistochemical analysis.
In contrast, transferrin receptor (TfR) was shown to be overexpressed
in the same HCC samples. Interestingly, the relative levels of
messenger RNA (mRNA) expression of T-FLC in HCC, which were measured
by a real-time quantitative reverse-transcription polymerase chain
reaction (PCR), exhibited almost the same levels as those in normal
tissues, suggesting that the translational or posttranslational
modification of T-FLC may be the cause of T-FLC suppression in
HCC. Furthermore, with PCR-based loss of heterozygosity analysis,
only 1 of 19 HCCs showed chromosomal deletions at 19q13.3-q13.4
where T-FLC is located, indicating that the suppression of T-FLC
is unlikely due to structural genomic changes with HCC. In conclusion,
both proteomic and genomic evidence support not only a basis for
the suppression of T-FLC in HCC but also provide a new clue to
the unresolved question of iron depletion during hepatocarcinogenesis.
(HEPATOLOGY 2002;35:1459-1466.)
Treatment of hepatocellular carcinoma with radiofrequency ablation:
Radiologic-histologic correlation during follow-up periods (*Human
Study*)
Manabu Morimoto, Kazuya Sugimori, Kazuhito Shirato, Atsushi Kokawa,
Naohiko Tomita, Takafumi Saito, Noriko Tanaka, Akinori Nozawa,
Masamichi Hara, Hisahiko Sekihara, Hiroshi Shimada, Toshio Imada,
Katsuaki Tanaka
To determine whether radiographic images after radiofrequency
(RF)-induced coagulation necrosis are correlated with the pathologic
effects, we evaluated the morphology and histologic characteristics
of RF ablation lesions over a 6-month follow-up period and compared
the results with those of radiologic studies. Thirty-three hepatocellular
carcinoma (HCC) tumors with a maximum diameter of 3 cm or less
were treated percutaneously by using RF ablation in 26 patients.
Six treated tumors were resected 4 weeks after ablation; the remaining
27 treated tumors underwent a biopsy procedure by using an 18-gauge
fine needle 3 days, 4 weeks, and 24 weeks after ablation. The
excised or biopsied lesions were examined by using histologic
methods; the findings were then compared with those of contrast-enhanced
computed tomography (CT). Three days after ablation, a core of
hypoattenuation surrounded by an enhanced/hemorrhagic rim was
observed on the contrast-enhanced CT images. Hematoxylin-eosinstained
specimens were inconclusive as to whether or not cellular viability
remained; however, cell viability as determined by the presence
of histochemical (lactate-dehydrogenase, maleate-dehydrogenase,
and the reduced form of nicotinamide-adenine dinucleotide phosphate
[NADPH]-diaphorase) stains was absent, suggesting 100% cellular
destruction in the ablated lesion. Four and 24 weeks after ablation,
the sizes of the ablated lesions were progressively smaller on
the CT images; the histochemical stains remained superior to the
hematoxylin-eosin stains for obtaining a definite diagnosis of
cell death. We conclude that irreversible cellular destruction,
as determined by the absence of positive histochemical staining
patterns, was useful for evaluating the pathologic thermal effect
of RF ablation. These pathologic findings can be correlated with
those of contrast-enhanced CT. (HEPATOLOGY 2002;35:1467-1475.)
TFDP1, CUL4A, and CDC16 identified as targets for amplification
at 13q34 in hepatocellular carcinomas (*Human Study*)
Kohichiroh Yasui, Shigeki Arii, Chen Zhao, Issei Imoto, Masakazu
Ueda, Hisaki Nagai, Mitsuru Emi, Johji Inazawa
We carried out molecular cytogenetic characterization of 11 cell
lines derived from hepatocellular carcinomas (HCCs) and 51 primary
HCCs. Comparative genomic hybridization (CGH) revealed frequent
amplification at 13q34, where we had detected amplification in
several other types of tumor, including esophageal squamous cell
carcinomas (ESC). Previously, we suggested possible involvement
of TFDP1, encoding a transcription factor DP-1, in the
13q34 amplification observed in a primary ESC. Therefore, we investigated
amplifications and expression levels of 5 genes mapped on the
amplified region, including TFDP1, for exploring amplification
targets at 13q34 in HCCs. 3 of those genes, TFDP1, CUL4A
(cullin 4A), and CDC16 (cell division cycle 16), showed
distinct amplification and consequent over-expression in some
cell lines. Moreover, each was amplified in 3 or 4 of the 51 primary
HCCs, and all 3 were amplified in 2 tumors, in which their expression
patterns correlated with amplification patterns. To elucidate
the functional role of TFDP1 in HCC, we examined expression
levels of genes downstream of TFDP1 with real-time quantitative
polymerase chain reaction (PCR). Expression of cyclin E gene (CCNE1)
correlated closely with that of TFDP1 in not only cell
lines, but also primary tumors. Treatment of HCC cells with the
antisense oligonucleotide targeting TFDP1 resulted in down-regulation
of CCNE1, suggesting that TFDP1 overexpression led
to up-regulation of CCNE1 that encoded a positive regulator
for cell cycle G1/S transition. In conclusion, our findings suggest
that TFDP1, CUL4A, and CDC16 are probable targets
of an amplification mechanism and therefore may be involved, together
or separately, in development and/or progression of some HCCs.
(HEPATOLOGY 2002;35:1476-1484.)
Survival, liver failure, and hepatocellular carcinoma in obesity-related
cryptogenic cirrhosis (*Human Study*)
Vlad Ratziu, Luminita Bonyhay, Vincent Di Martino, Frederic Charlotte,
Lucas Cavallaro, Marie-Hélène Sayegh-Tainturier,
Philippe Giral, André Grimaldi, Pierre Opolon, Thierry
Poynard
Despite the rising incidence of obesity and diabetes, there is
little emphasis on morbidity and mortality from obesity-related
cirrhosis, usually considered a rare and asymptomatic condition.
Our aim was to assess survival and the occurrence of hepatocellular
carcinoma and complications of hepatic insufficiency in obesity-related
cryptogenic cirrhosis compared with cirrhosis of other origins.
We analyzed retrospectively 27 overweight patients with cryptogenic
cirrhosis (CC-O), 10 lean patients with cryptogenic cirrhosis
(CC-L) and 391 patients with hepatitis C virus-related cirrhosis
(C-HCV). In CC-O patients, cirrhosis was detected later in life
than in C-HCV and CC-L patients. Severe liver disease was as frequent
in CC-O as in C-HCV patients as indicated by the proportion of
Child B or C or of episodes of hepatic decompensation. Survival
of CC-O patients was lower than that of untreated, age- and sex-matched
C-HCV controls (P < .02 at 30 months), with a higher
mortality of Child B or C patients. Hepatocellular carcinoma was
detected in 8 of 27 (27%) CC-O patients versus 21% of matched
C-HCV controls with a similar age cumulated incidence, suggesting
a comparable carcinogenic potential. In conclusion, obesity-related
cirrhosis should now be recognized as a distinct entity that can
cause severe liver disease and death. Increased awareness of and
better diagnostic strategies for nonalcoholic steatohepatitis
in overweight patients are urgently needed. (HEPATOLOGY 2002;35:1485-1493.)
Small-duct primary sclerosing cholangitis: A long-term follow-up
study (*Human Study*)
Paul Angulo, Yaakov Maor-Kendler, Keith D. Lindor
Some patients with inflammatory bowel disease (IBD) have chronic
cholestasis and hepatic histology compatible with primary sclerosing
cholangitis (PSC) but normal findings on cholangiography. These
patients with small-duct PSC have remained largely unstudied.
Our aim was to determine the prevalence and long-term outcomes
of patients with small-duct PSC. Eighteen patients with small-duct
PSC (7 female and 11 male patients; mean age, 39.9 ± 15.3
years [range, 13-68 years]) seen over a 4-year period were matched
blindly by age and sex to 36 patients with classic PSC and followed
up for 32.5 years. Small-duct PSC represented 5.8% of patients
(18 of 309) with sclerosing cholangitis. Subsequent endoscopic
retrograde cholangiography (ERC) performed in 5 patients with
small-duct PSC showed progression to typical PSC in 3 patients
at 4, 5.5, and 21 years of follow-up. None of the patients with
small-duct PSC but 4 of the patients with classic PSC developed
hepatobiliary malignancy. There were 3 deaths (17%) or liver transplantations
in patients with small-duct PSC (2 after progressing to classic
PSC) and 15 (42%) in the classic PSC group. Survival free of liver
transplantation was significantly greater in the small-duct than
in the classic PSC group (P = .04). Compared with the general
U.S. population, survival in patients with small-duct PSC was
similar (P = .4) but significantly lower in patients with
classic PSC (P < .001). In conclusion, small-duct PSC
may represent an earlier stage of PSC associated with a significantly
better long-term prognosis. Some patients, however, progress to
classic PSC and/or end-stage liver disease with the consequent
necessity of liver transplantation. (HEPATOLOGY 2002;35:1494-1500.)
Partial external biliary diversion for intractable pruritus
and xanthomas in Alagille syndrome (*Human Study*)
Karan M. Emerick, Peter F. Whitington
Alagille syndrome (AGS) causes intractable pruritus and disfiguring
xanthomas because of retained bile acids and cholesterol. This
study was performed to determine whether partial external biliary
diversion (PEBD) is effective for relief of pruritus and xanthomas
in AGS patients who fail conventional medical therapy. Between
the years 1985 and 2001, 9 AGS patients underwent PEBD. Complete
follow-up data were available for all patients. The average age
at PEBD was 4.8 (range 1.4-10) years. The average duration of
follow-up was 7.5 (range 0.5-16.0) years. All 9 patients had severe,
mutilating pruritus (grade 4) prior to diversion. At 1 year post-PEBD,
the average pruritus score was 1.1; 8 patients had only mild scratching
when undistracted. Three patients with extensive xanthomas prior
to PEBD had complete resolution within 1 year. Mean serum bile
salt levels (n = 5) decreased from 136.5 to 37.1 µmol/L
and mean cholesterol (n = 7) from 724 to 367 mg/dL 1 year after
PEBD. A single 21-year-old patient with PEBD for 14 years experienced
an increase in pruritus from grade 1 to grade 4 within 2 months
of elective reversal of PEBD. In conclusion, PEBD is effective
for treating severe pruritus and hypercholesterolemia in AGS patients
without cirrhosis who did not respond to medical therapy. PEBD
should be considered as a therapeutic option for these patients
before referral for liver transplantation because of morbid complications.
(HEPATOLOGY 2002;35:1501-1506.)
Prevalence of gallbladder disease in American Indian populations:
Findings from the Strong Heart Study (*Human Study*)
James E. Everhart, Fawn Yeh, Elisa T. Lee, Michael C. Hill, Richard
Fabsitz, Barbara V. Howard, Thomas K. Welty
American Indians are believed to be at high risk of gallbladder
disease (GBD), but there has been no systematic evaluation of
its prevalence among diverse groups of American Indians. Therefore,
we determined the prevalence of GBD and associated risk factors
among specified American Indian populations using ultrasonography
of the gallbladder and standardized diagnostic criteria. Enrolled
members, aged 47 years and older, of 13 American Indian tribes
or communities in Arizona, Oklahoma, and South and North Dakota
who participated in the Strong Heart Study were analyzed. GBD
was the sum of gallstones (determined by ultrasound examination)
and cholecystectomy (determined by ultrasound and self-report).
The proportion of American Indian heritage was based on the heritage
of the grandparents of participants. GBD prevalence was determined
among 3,296 participants at the 3 sites. Among women, 17.8% had
gallstones, and 46.3% had evidence of a cholecystectomy, for a
total of 64.1% with GBD. Among men, 17.4% had gallstones, and
12.1% had evidence of a cholecystectomy, for a total of 29.5%
with GBD. When figures were adjusted for age and Indian heritage,
there was no significant difference in GBD prevalence across the
3 geographical areas. In multivariate logistic regression analysis,
age, American Indian heritage, and waist circumference were associated
with GBD among men, and age, American Indian heritage, diabetes,
and parity were associated with GBD among women. Body mass index
was not independently associated with GBD in either sex. In conclusion,
GBD was found in epidemic proportions in diverse American Indian
populations. (HEPATOLOGY 2002;35:1507-1512.)
Defective regulation of cholangiocyte Cl/HCO and Na+/H+
exchanger activities in primary biliary cirrhosis (*Human
Study*)
Saida Melero, Carlo Spirlì, Ákos Zsembery, Juan
F. Medina, Ruth E. Joplin, Elena Duner, Massimo Zuin, James M.
Neuberger, Jesús Prieto, Mario Strazzabosco
Primary biliary cirrhosis (PBC) is a disorder of unknown origin
with autoimmune features. Recently, impaired biliary secretion
of bicarbonate has been shown in patients with PBC. Here we have
investigated whether bile duct epithelial cells isolated from
PBC patients exhibit defects in transepithelial bicarbonate transport
by analyzing the activities of 2 ion exchangers, Cl/HCO anion
exchanger 2 (AE2) and Na+/H+ exchanger (NHE) in isolated cholangiocytes.
AE2 and NHE activities were studied in basal conditions and after
stimulation with cyclic adenosine monophosphate (cAMP) and extracellular
adenosine triphosphate (ATP), respectively. Cholangiocytes were
grown from needle liver biopsies from 12 PBC patients, 8 normal
controls, and 9 patients with other liver diseases. Also, intrahepatic
cholangiocytes were cultured after immunomagnetic isolation from
normal liver tissue (n = 6), and from recipients undergoing liver
transplantation for end-stage PBC (n = 9) and other forms of liver
disease (n = 8). In needle-biopsy cholangiocytes, basal AE2 activity
was significantly decreased in PBC as compared with normal livers
and disease controls. In addition, we observed that though cAMP
increased AE2 activity in cholangiocytes from both normal and
non-PBC livers, this effect was absent in PBC cholangiocytes.
Similarly, though in cholangiocytes from normal and disease control
livers extracellular ATP induced a marked enhancement of NHE activity,
cholangiocytes from PBC patients failed to respond to purinergic
stimulation. In conclusion, our findings provide functional evidence
that PBC cholangiocytes exhibit a widespread failure in the regulation
of carriers involved in transepithelial H+/HCO transport, thus,
providing a molecular basis for the impaired bicarbonate secretion
in this cholestatic syndrome. (HEPATOLOGY 2002;35:1513-1521.)
Viral Hepatitis
Long-term outcome after spontaneous HBeAg seroconversion
in patients with chronic hepatitis B (*Human Study*)
Yao-Shih Hsu, Rong-Nan Chien, Chau-Ting Yeh, I-Shyan Sheen, Hung-Yi
Chiou, Chia-Ming Chu, Yun-Fan Liaw
During the course of chronic hepatitis B virus (HBV) infection,
hepatitis B e antigen (HBeAg) seroconversion to its antibody (anti-HBe)
often coincides with normalization of liver biochemical test and
clinical remission, but data regarding long-term outcome after
spontaneous seroconversion are still scarce. Excluding patients
with other virus(es) concurrent infection, 283 patients with chronic
HBV infection were followed up for at least 1 year after spontaneous
HBeAg seroconversion to anti-HBe. Follow-up studies included clinical,
biochemical, and virologic evaluation and hepatocellular carcinoma
(HCC) screening with ultrasonography and -fetoprotein assay. During
a median follow-up period of 8.6 years (range, 1 to 18.4 years)
after HBeAg seroconversion in 283 patients, 189 (66.8%) showed
sustained remission, whereas the remaining 94 (33.2%) experienced
alanine aminotransferase (ALT) elevation over twice the upper
limit of normal: 12 (4.2%) associated with HBeAg reversion, 68
(24%) with detectable serum HBV DNA but HBeAg negative, and 14
(4.9%) of undetermined causes. Of the 269 patients without evidence
of cirrhosis at the time of HBeAg seroconversion, 21 (7.8%) developed
cirrhosis with a cumulative incidence and relative risk significantly
higher in patients developing active hepatitis than in patients
with sustained remission (P < .05). HCC developed in
6 (2.2%) of the 283 patients, also with a significantly higher
cumulative incidence in patients developing active hepatitis after
HBeAg seroconversion (P < .005). In conclusion, the
results suggest that spontaneous HBeAg seroconversion confers
favorable long-term outcomes. However, active hepatitis still
may develop and lead to cirrhosis and HCC. (HEPATOLOGY 2002;35:1522-1527.)
Increasing applicability of liver transplantation for patients
with hepatitis Brelated liver disease (*Human Study*)
Thomas Steinmüller, Daniel Seehofer, Nada Rayes, Andrea R.
Müller, Utz Settmacher, Sven Jonas, Ruth Neuhaus, Thomas
Berg, Uwe Hopf, Peter Neuhaus
Liver transplantation in patients with hepatitis B has been under
discussion for 20 years because of inferior results without reinfection
prophylaxis; therefore, we analyzed our overall experience with
liver transplantation in hepatitis B patients with immunoprophylaxis,
particularly the influence of the available antiviral treatment
in different periods. From 1988 to 2000, 228 liver transplants
in 206 hepatitis B patients were performed. Indications were acute
liver failure (10%), hepatitis B virus (HBV) cirrhosis alone (67%)
or with hepatitis D virus (HDV) (13%), or hepatitis C virus (HCV)
coinfection (7%). All patients received long-term immunoprophylaxis
(anti-HBs > 100 U/L). HBV DNApositive patients were treated
before and after surgery with famciclovir or lamivudine since
1993 and 1996, respectively. Since 1993, antivirals also were
used for HBV reinfection. The 1-, 5-, and 10-year patient survival
rates were 91%, 81%, and 73%. In patients with hepatocellular
carcinoma (HCC) (60% 5-year survival, P < .01) or HBV
reinfection (69% 5-year survival, P < .01) survival
was significantly impaired. Those with HDV or HCV coinfection
had a slightly better survival than with HBV monoinfection (P
> .05, not significant). Preoperative positive HBV DNA (hybridization-assay)
test results were associated with a slightly impaired patient
survival (78% 5-year survival, P > .05, not significant
versus DNA-negative). Preoperative positive hepatitis B e antigen
(HBeAg) predicted significantly worse survival (P <
.05 versus negative HBeAg). Graft loss caused by reinfection was
most frequent before the availability of antiviral drugs. Two-year
patient survival increased from 85% in era I (1988-1993) to 94%
in era III (1997-2000, P < .05). The 2-year recurrence
rates in these 2 periods were 42% and 8% (P < .05).
In conclusion, excellent long-term results can be achieved in
hepatitis B patients after liver transplantation with modern strategies,
and survival rates are similar to other indications. Based on
our experience, hepatitis B patients, including those with active
viral replication, should not be excluded from liver transplantation.
(HEPATOLOGY 2002;35:1528-1535.)
Cell Biology, Metabolism and Transport
Takuo Tokairin et al.
A highly specific isolation of rat sinusoidal endothelial cells
by the immunomagnetic bead method using SE-1 monoclonal antibody
Background/Aims: To develop a specific isolation method of
hepatic sinusoidal endothelial cells (SEC), we applied the immunomagnetic
method using a monoclonal antibody (SE-1) that recognizes a membranous
antigen expressed only in rat SEC.
Methods: Cells were isolated by incubating mixed non-parenchymal cells, which were obtained by collagenase digestion of the liver, with SE-1-conjugated superparamagnetic polystyrene beads. The conventional Percoll method was also performed in parallel to compare with the immunomagnetic method. The isolated cells were cultured on glass coverslips coated with type I collagen in the presence of various growth factors for 6 days.
Results: Approximately 98% of the isolated cells were positive for SE-1 and the contamination of Kupffer cells or stellate cells was less than 1%. The purity was significantly better than that obtained by the Percoll method. The cultured cells showed typical SEC features, such as sieve plates and uptake of acetylated low-density lipoprotein. Although the cells continuously underwent apoptotic cell death after 2 days, they started robust cell growth after 3 days and were well maintained during the culture period.
Conclusions: Our simple and specific isolation method
enables us to culture SEC with high purity and should be useful
for the biological analysis of SEC.
Hitoshi Kunitani, Yukihiro Shimizu, Hiroyuki Murata, Kiyohiro
Higuchi and Akiharu Watanabe
Phenotypic analysis of circulating and intrahepatic dendritic
cell subsets in patients with chronic liver diseases
Background/Aims: Dendritic cells (DCs) are the most potent professional antigen-presenting cells. Although two subsets of circulating DCs, lineageCD11c+CD4low (CD11c+DCs) and lineage CD11cCD4+CD123+ (CD123+DCs) are identified in humans, the role of each DC subset in the immunopathogenesis of liver diseases is unknown.
Methods: We examined the numbers and activation status of each DC subset in the circulation and in the inflamed livers in patients with chronic liver diseases by flow cytometry and immunohistochemistry.
Results: The numbers of circulating CD11c+DCs were inversely correlated with serum alanine aminotransferase (ALT) levels in patients with chronic viral hepatitis, and that the expression of costimulatory molecules on circulating CD11c+DCs in patients with chronic viral hepatitis was significantly up-regulated in patients with high serum levels of ALT. Both DCs are also identified in the livers by flow cytometry, and the expression of costimulatory molecule CD40 on those DCs was significantly higher in liver DCs than that in circulating DCs. Moreover, the ratios of CD11c+DCs/CD123+DCs were higher in liver DCs (mean±SD, 7.2±6.0) than those of circulating DCs (4.0±4.6). Immunohistochemically, CD11c+ or CD123+ cells and CD83+ activated DCs were observed mostly in portal areas with mononuclear cell infiltration in various liver diseases. These overall data suggest that DCs, especially CD11c+DCs, could be associated with the necroinflammatory response in the liver of chronic viral liver diseases.
Conclusions: DCs, especially CD11c+DCs, may be involved
in the immunopathogenesis of chronic liver diseases.
Marieke H. Schoemaker et al.
Cytokine regulation of pro- and anti-apoptotic genes in rat
hepatocytes: NF-B-regulated inhibitor of apoptosis protein 2 (cIAP2)
prevents apoptosis
Background/Aims: In acute liver failure, hepatocytes are exposed
to various cytokines that activate both cell survival and apoptotic
pathways. NF-B is a central transcription factor in these responses.
Recent studies indicate that blocking NF-B causes apoptosis, indicating
the existence of NF-B-regulated anti-apoptotic genes. In the present
study the relationship between NF-B activation and apoptosis has
been investigated in hepatocytes.
Methods: Primary rat hepatocytes were exposed to a cytokine mixture of tumor necrosis factor , interleukin-1, interferon- and lipopolysaccharide. Modulation of signalling pathways was performed by using dominant negative adenoviral constructs. Apoptosis and NF-B activation were determined by caspase-3 activity, Hoechst staining and electrophoretic mobility shift assay, respectively. Furthermore, expression and regulation of apoptosis-related genes were investigated.
Results: (1) Inhibition of NF-B activation results in apoptosis. (2) Inhibitor of apoptosis protein (IAP) family members, inhibitor of apoptosis protein1 (cIAP1), and X-chromosome-linked IAP, are expressed in rat hepatocytes. cIAP2 is induced by cytokines in an NF-B-dependent manner and overexpression of cIAP2 inhibits apoptosis. (3) The anti-apoptotic Bcl-2 family member A1/Bfl-1 and the pro-apoptotic members Bak and Bid are induced by cytokines and NF-B-dependent. (4) Nitric oxide inhibits caspase-3 activity in hepatocytes.
Conclusions: In inflammatory conditions, hepatocyte
survival is dependent on NF-B activation and cIAP2 contributes
significantly to this protection.
Cirrhosis and its Complications
Anthony J. Donaghy, Patric J.D. Delhanty, Ken K. Ho, Roger Williams
and Robert C. Baxter
Regulation of the growth hormone receptor/binding protein,
insulin-like growth factor ternary complex system in human cirrhosis
Background/Aims: The liver is the central organ of the endocrine
growth hormone/insulin-like growth factor I (GH/IGF-I) axis and
cirrhosis effects a state of acquired GH resistance. Low IGF-I
levels are associated with adverse clinical outcomes in cirrhotic
patients and may be pathogenic to the complications of cirrhosis.
We examined the impact of cirrhosis on hepatic mRNA and serum
protein levels for the GH receptor (GHR)/binding protein (GHBP),
IGF-I, IGF binding protein (IGFBP)-3 and the acid-labile subunit
(ALS).
Methods: Fifty patients with cirrhosis were studied and liver tissue was obtained from 18. Gene expression was assessed by Northern analysis and serum protein levels by immunoassay.
Results: In cirrhotic liver GHR mRNA and GH binding to microsomal membranes were decreased by 61 and 56%, respectively. Serum GHBP levels were decreased only in severe disease, not correlating with GHR mRNA or GH binding. Hepatic IGF-I and ALS mRNA were significantly decreased by 84 and 68%, respectively, in parallel with serum protein, suggesting transcriptional regulation. Hepatic IGFBP-3 mRNA was unchanged but low serum IGFBP-3 suggested post-transcriptional regulation.
Conclusions: The decreased mRNA and serum levels for
the GH-dependent, hepatocyte produced proteins IGF-I and ALS confirm
the importance of GH receptor loss to the GH resistance of cirrhosis.
Inflammation and Fibrosis
Takahiro Kitano et al.
Altered response to inflammatory cytokines in hepatic energy
metabolism in inducible nitric oxide synthase knockout mice
Background/Aims: Production of nitric oxide (NO) in the liver
is believed to be a critical factor for carbohydrate and energy
metabolism in endotoxin shock. The present study focuses on the
involvement of NO produced by inducible nitric oxide synthase
(iNOS) in glycogen synthesis and energy metabolism stimulated
by insulin.
Methods: Primary hepatocytes prepared from wild-type and iNOS knockout (iNOS/) mice were employed.
Results: Incubation of wild-type hepatocytes with a combination of cytokines (interleukin-1, tumor necrosis factor- and interferon-) and lipopolysaccharide (cytokines/LPS) inhibited insulin-stimulated glycogen synthesis and adenosine triphosphate (ATP) increase, and decreased the ketone body ratio (KBR) at 8-12 h, concomitant with expression of iNOS protein and NO production. While the glycogen synthesis was suppressed by cytokines/LPS, reduction of the ATP increase and a decrease in KBR by cytokines/LPS were not observed in iNOS/ hepatocytes. Further, NG-monomethyl-L-arginine, a NOS inhibitor, reversed the inhibition of ATP increase and decrease in KBR by cytokines/LPS, but not the inhibition of glycogen synthesis. Conversely, addition of S-nitroso-N-acetylpenicillamine, a NO donor, inhibited the insulin-stimulated ATP increase synthesis in iNOS/ hepatocytes, but not the insulin-stimulated glycogen synthesis.
Conclusions: These results demonstrate that NO mediates
the suppression of insulin-stimulated energy metabolism, but not
glycogen synthesis, in cytokines/LPS-treated hepatocytes.
Kimihide Nakamura et al.
Antithrombin III prevents concanavalin A-induced liver injury
through inhibition of macrophage inflammatory protein-2 release
and production of prostacyclin in mice
Background/Aims: Recently, we have reported that macrophage
inflammatory protein-2 (MIP-2) plays a pivotal role in concanavalin
A (Con A)-induced liver injury. In this study, we investigated
the effect of antithrombin III (AT-III) on liver damage, and production
of MIP-2 and prostacyclin in this model.
Methods: Liver injury was induced by intravenous injection of Con A (15 mg/kg) and AT-III was administered (50, 250 and 500 units/kg, iv) 30 mm before Con A injection. Plasma levels of alanine aminotransferase (ALT), MIP-2 and 6-keto-prostaglandin F1 (6k-PG-F1), stable metabolite of prostaglandin I2 (prostacyclin), were determined.
Results: The elevated plasma ALT levels 8, 16, 24 h after Con A injection were inhibited by AT-III pretreatment. The elevated plasma MIP-2 levels were significantly inhibited by AT-III pretreatment compared with vehicle treatment. The inhibitory effect of AT-III on plasma ALT and MIP-2 in Con A-induced liver injury was attenuated by indomethacin (5 mg/kg, ip). Plasma concentration of 6k-PG-F1 at 2 h after AT-III injection was significantly elevated compared with baseline and vehicle pretreatment.
Conclusions: These findings suggest that AT-III prevents
Con A-induced liver injury through an inhibition of MIP-2 release
and a production of prostacyclin.
Liver Growth and Cancer
Tsuyoshi Ohno et al.
Microwave coagulation therapy accelerates growth of cancer
in rat liver
Background/Aims: Although microwave coagulation therapy (MCT)
has been performed for liver cancer, there has been no report
examining the influence of this therapy on the growth of possible
remnant cancer.
Methods: A solid cube of AH-130 cells (ascites hepatoma cell line) was implanted into the left lateral lobe of the rat liver. Five days later, MCT was applied to the middle liver lobe of these rats. Tumor growth and cytokine levels in plasma and the liver were compared between rats that underwent MCT and rats that did not.
Results: The mean tumor weight in the MCT group (222.6±51.5 mg, mean±SD) was significantly greater than that in the control group (126.7±19.7 mg, P<0.01) at postoperative day (POD) 5. Immunohistochemistry for anti-proliferating cell nuclear antigen showed the labeling index in the MCT group (90.4%) to be higher than that in the control group (76.7%, P<0.01). Liver basic fibroblast growth factor and transforming growth factor-beta 1 levels in the MCT group on POD 3 were significantly higher than levels in the control group.
Conclusions: The present study suggests the clinically
important finding that MCT accelerates the growth of small residual
tumors in the liver.
Yoko Ukita, Masako Kato and Tadashi Terada
Gene amplification and mRNA and protein overexpression of c-erbB-2
(HER-2/neu) in human intrahepatic cholangiocarcinoma as detected
by fluorescence in situ hybridization, in situ hybridization,
and immunohistochemistry
Background/Aims: The human proto-oncogene c-erbB-2 (also called
HER-2/neu) is located on chromosome 17q21-22. There have been
no studies on gene amplification or mRNA expression of c-erbB-2
in human intrahepatic cholangiocarcinoma (CC) hitherto.
Methods: We investigated c-erbB-2 gene amplification by fluorescence in situ hybridization (FISH), c-erbB2 mRNA expression by ISH, and c-erbB-2 protein expression by immunohistochemistry in 22 archival cases of CC.
Results: FISH revealed that c-erbB-2 gene signals were increased in CC. ISH showed that c-erbB-2 mRNA signals were located in the nuclei and cytoplasms of cancer cells and were increased in cancer cells compared with non-cancerous bile ducts where no signals were present. Immunohistochemistry showed that the c-erbB-2 protein was expressed in the cell membrane of cancer cells, and was increased compared with non-cancerous bile ducts where no expression was found. There was a positive significant correlation between c-erbB-2 mRNA and protein expression. Clinicopathologically, there were no correlations between the c-erbB-2 expression and various pathological features.
Conclusions: These data suggest that c-erbB-2 gene amplification
does occur in CC, and that there is an overexpressed c-erbB-2
protein through the enhanced mRNA expression. The c-erbB-2 gene
amplification may be related to the oncogenesis or tumor progression
of CC.
Munechika Enjoji et al.
The tumor-associated antigen, RCAS1, can be expressed in immune-mediated
diseases as well as in carcinomas of biliary tract
Background/Aims: RCAS1, which is recognized by the specific
antibody 22-1-1, was first identified as a tumor-associated antigen
in gynecological carcinomas. RCAS1 is the ligand of a putative
receptor present on lymphocytes, the expression of which is enhanced
by lymphocyte activation. RCAS1 inhibits the growth of receptor-bearing
cells and induces apoptotic death. Here we examined RCAS1 expression
in biliary diseases.
Methods: RCAS1 expression was immunohistochemically examined on tissue samples. Apoptotic death was analyzed by DNA fragmentation detection method. RCAS1 production by cell lines was investigated by flow cytometry, enzyme-linked immunosorbent assay, and reverse transcription-polymerase chain reaction.
Results: All cholangiocarcinoma cell lines examined clearly expressed RCAS1 at both the protein and RNA level. Immunohistochemically, RCAS1 was expressed in a high percentage of biliary adenocarcinomas (85.9% of intrahepatic cholangiocarcinomas, 96.4% of extrahepatic cholangiocarcinomas and gallbladder carcinomas). Apoptotic tumor-infiltrating lymphocytes could be found in these specimens. RCAS1 expression was frequently detected also in biliary epithelial cells in cases of immune-mediated cholangitis (74.2% in primary biliary cirrhosis, 66.6% in graft-versus-host disease), although the staining pattern for RCAS1 was different compared with cancer cells.
Conclusions: RCAS1 is highly expressed not only in cancer
cells but also in non-tumor bile duct cells subjected to immune
attack.
Transplantation and Surgery
Santiago Tomé et al.
Influence of superimposed alcoholic hepatitis on the
outcome of liver transplantation for end-stage alcoholic liver
disease
Background/Aims: Alcoholic cirrhosis is a common indication
for liver transplantation. The present study was aimed to assess
the influence of superimposed alcoholic hepatitis on the outcome
of liver transplantation in patients with alcoholic cirrhosis.
Methods: Survival rates of 68 patients transplanted for alcoholic cirrhosis were compared with those of 101 patients transplanted for miscellaneous causes. Within the alcoholic group, explanted livers were searched for data of acute alcoholic hepatitis. The survival rate of patients with alcoholic hepatitis superimposed on liver cirrhosis was compared to that of patients with liver cirrhosis alone. Clinical severity of alcoholic hepatitis was assessed with Maddrey's score.
Results: Survival was similar in alcoholics and patients with other causes of liver disease. Among patients transplanted for alcoholic cirrhosis, survival was similar in patients with superimposed alcoholic hepatitis (n=36) and in cases with liver cirrhosis alone (n=32). There was no difference in survival between patients with mild (n=26) and severe (n=10) alcoholic hepatitis. Seven alcoholics (10%) returned to ethanol consumption. Recidivism was not associated with either alcoholic hepatitis in the explanted liver or graft loss.
Conclusions: Survival after liver transplantation in
patients with alcoholic cirrhosis plus alcoholic hepatitis detected
in the explanted liver is similar to that of patients transplanted
for other reasons. Even the presence of severe alcoholic hepatitis
does not worsen the outcome of liver transplantation for end-stage
alcoholic liver disease.
Viral Hepatitis
Teresa Santantonio et al.
Lamivudine/interferon combination therapy in anti-HBe positive
chronic hepatitis B patients: a controlled pilot study
Background/Aims: In this study, lamivudine-interferon (LAM/IFN)
combination therapy was compared to LAM monotherapy to verify
if the combination treatment might improve efficacy and reduce
the emergence of LAM-resistant mutants.
Methods: Fifty patients with anti-HBe-positive chronic hepatitis B were treated for 12 months with LAM at 100mg/day (26 pts) or with IFN at 5MU t.i.w.+LAM 100mg/day (24 pts). Serum ALT, HBV DNA and IgM anti-HBc were monitored during treatment and a 6-month follow-up. The polymerase gene was amplified by PCR and the region coding for YMDD motif was directly sequenced.
Results: All patients normalized ALT and cleared HBV DNA during treatment. The response was maintained until the end of therapy in the LAM/IFN group, while in 5/26 initial responders treated with LAM alone, a virological and biochemical breakthrough was observed after 6-10 months, and selection for YMDD variants resulted. After therapy discontinuation, most patients relapsed; the response rate after 6 months was 17% in the LAM/IFN group and 19% in the LAM group.
Conclusions: In anti-HBe-positive chronic hepatitis
B, a 12-month course of LAM/IFN combination therapy is as beneficial
as LAM monotherapy, however, the combination regimen appeared
to prevent or delay the emergence of YMDD variants.
Sanjiv K. Jain et al.
Oxidative stress in chronic hepatitis C: not just a feature
of late stage disease
Background/Aims: Chronic hepatitis C infection is a major
world-wide problem, frequently progressing to cirrhosis, liver
failure or hepatoma. The pathological mechanisms of disease progression
are unclear but oxidant stress may play a role.
Methods: Markers of lipid peroxidation, antioxidant status, hepatic fibrogenesis and liver function were measured in blood or urine from 42 chronic hepatitis C patients. Fibrosis was graded histologically in a subgroup of 33 patients.
Results: The lipid peroxidation marker 8-isoprostane and the ratio of oxidized to reduced glutathione were significantly elevated (P<0.001, P=0.006). The antioxidants glutathione, selenium and vitamins A, C and E were significantly decreased (all P<0.001) compared to age and sex matched controls. Abnormal values were more marked in cirrhotics, but significant changes were also observed in the non-cirrhotic group. The fibrosis score correlated positively with urinary 8-isoprostane and type III procollagen peptide and negatively with vitamin A.
Conclusions: Oxidant stress, as reflected in blood and
urine by a wide range of pro- and antioxidant markers, is a significant
feature of hepatitis C infection. Although more severe in the
cirrhotic group, there was clear evidence of oxidant stress in
non-cirrhotic patients. Antioxidant therapy may therefore have
a role in slowing disease progression to cirrhosis.
Patrice Cacoub et al.
Impact of treatment on extra hepatic manifestations
in patients with chronic hepatitis C
Background/Aims: Fatigue and other extra hepatic manifestations
of hepatitis C have never been studied prospectively in a large
cohort. The aim was to assess the prevalence of these symptoms
prior to any treatment, and on prolonged follow-up in treated
and untreated patients.
Methods: A single-center cohort of consecutive patients with chronic hepatitis C was investigated prior to any treatment. A questionnaire was completed every 6 months for 18 months of follow-up.
Results: Of 1614 patients, 431 met the inclusion criteria (56% male; age 49 years; 60% with significant fibrosis or cirrhosis; 46% with cryoglobulinemia). Seventy-six were untreated; of the treated patients, 83 were sustained responders, 47 relapsers and 225 non-responders. At baseline, fatigue and other extrahepatic manifestations were present in 254 (59%) and 225 (52%) patients. Fatigue was improved in 29 of 83 (35%) responders versus 75 of 348 (22%) patients with detectable hepatitis C virus (HCV)-RNA (P=0.01). The impact of virologic response on fatigue persisted after adjusting for age, gender, fibrosis stage, and depression (odds ratio: 0.34, P<0.001). A cryoglobulin was detectable in two of 34 (6%) responders versus 38 of 115 (33%) patients with detectable HCV-RNA (P<0.001).
Conclusions: In hepatitis C, a sustained virologic response
is associated with a reduction in fatigue and cryoglobulin, but
fatigue frequently persists despite a virologic response.
Victor de Lédinghen et al.
Daily or three times per week interferon -2b in combination
with ribavirin or interferon alone for the treatment of patients
with chronic hepatitis C not responding to previous interferon
alone
Background/Aims: We compared the efficacy and safety of the
combined therapy of daily interferon -2b and ribavirin with those
of interferon -2b three times per week alone or in combination
with ribavirin in non-responder patients with hepatitis C virus
(HCV) infection.
Methods: A total of 376 patients were randomly assigned to receive interferon -2b (6MU three times per week for 24 weeks followed by 3MU three times per week for 24 weeks) alone (group A) or in combination with ribavirin for 48 weeks (group B), or daily interferon -2b (3MU per day for 24 weeks followed by 3MU three times per week for 24 weeks) and ribavirin (group C).
Results: After 24 weeks of therapy, HCV RNA was undetectable in 11.7, 24.0, and 37.8% for groups A, B, and C, respectively. Sustained virological response was more frequent in patients who received combination therapy with three times weekly interferon (20.9%) or daily interferon (26.0%) than in patients who received interferon alone (5.8%) (P<0.001). The predictive HCV parameters for sustained response were a low viral load on day 7 and a negative HCV RNA on week 12.
Conclusions: In conclusion, in non-responder patients
with chronic hepatitis C, virological response with daily interferon
and ribavirin, compared to interferon monotherapy, was significantly
improved during treatment, although sustained virological response
was similar for both combination therapies with ribavirin and
three times a week or daily interferon.
Case Report
Olivier Loréal et al.
Aceruloplasminemia: new clinical, pathophysiological and therapeutic
insights
Aceruloplasminemia is an autosomal recessive disease of iron overload
associated with mutation(s) in the ceruloplasmin gene. We report
here a new case of aceruloplasminemia in a woman who is a compound
heterozygote for two new mutations. Besides this novel genotypic
profile, this observation provides new insights on: (i) iron metabolism
with normal erythroid repartition, in the absence of serum non-transferrin-bound
iron and with an increase of 59Fe plasma clearance; (ii) hepatic
abnormalities associated with the presence of iron-free foci;
(iii) the therapeutic management of the disease, chronic subcutaneous
infusion of deferrioxamine being remarkably effective at reducing
hepatic iron overload.
Are selective COX 2 inhibitors superior to traditional non
steroidal anti-inflammatory drugs?
Peter Jüni, Anne WS Rutjes, and Paul A Dieppe
BMJ 2002; 324: 1287-1288. [Full
text]
Selective cyclo-oxygenase 2 (COX 2) inhibitors, including
celecoxib (Celebrex) and rofecoxib (Vioxx), are hypothesised to
have a lower risk of gastrointestinal complications than traditional
non-steroidal anti-inflammatory drugs.1 In September 2000 the
celecoxib long term arthritis safety study, better known as CLASS,
was published in JAMA.2 This trial, widely cited and distributed,
concluded that a COX 2 inhibitor was associated with a lower
incidence of complications than traditional non-steroidal anti-inflammatory
drugs. What was much less widely publicised were criticisms that
contradicted this conclusion.
Potential alternatives to COX 2 inhibitors
M M Skelly and C J Hawkey
BMJ 2002; 324: 1289-1290. [Full
text]
For many years, non-steroidal anti-inflammatory drugs were
regarded as a treatment for which there was no gain in arthritis
without the pain of gastroduodenal toxicity. This reflected the
understanding that non-steroidal anti-inflammatory drugs (NSAIDs)
were cyclo-oxygenase inhibitors that reduced prostaglandin synthesis
both in inflamed joints with benefit and in the stomach with detriment
(figure). Recognition that a highly inducible enzyme, cyclo-oxygenase-2,
largely subserved the former and a constitutive enzyme, cyclo-oxygenase-1,
the latter provided an obvious selective target. The consequent
success of cyclo-oxygenase-2 (COX 2) inhibitors arises, in part,
from the conceptual simplicity of this idea. The journey from
concept to reality has, however, inevitably been more complex,
and one controversial issue is dealt with in an accompanying editorial.1
The failure of the celecoxib long term arthritis safety study
(the CLASS study) may have more to do with the design of the trial
than with inadequacies of cyclo-oxygenase-2 inhibitors. Other
limitations of these agents may eventually deserve more attention.
In particular, it was never likely that they would go beyond the
indication of pain and arthritis that characterises NSAIDs, given
that the goal was to mimic their action more selectively.
RAS
Analysis of minichromosome maintenance proteins as a novel
method for detection of colorectal cancer in stool [Full
Text]
R Justin Davies, Alex Freeman, Lesley S Morris, Sheila Bingham,
Stephen Dilworth, Ian Scott, Ronald A Laskey, Richard Miller,
Nicholas Coleman
Colorectal cancer is a common disease, and more reliable screening
methods are needed for early detection. We aim to develop a non-invasive,
stool-based assay that can identify colorectal cancer by detection
of minichromosome maintenance protein 2 (MCM2) expression in colonocytes
retrieved from the faecal surface. We devised a cell line model
to investigate methods and conditions for optimum colonocyte retrieval.
In our clinical evaluation study, MCM2-positive cells were retrieved
from 37 of 40 patients with symptomatic colorectal cancer, but
from none of 25 healthy control individuals. These results suggest
that immunocytochemical analysis of retrieved colonocytes might
enable accurate detection of colorectal cancer in stool. Lancet
2002; 359: 1917-19
Helicobacter pylori and peptic-ulcer disease [Full
Text]
*J R Boulton-Jones, C J Hawkey
Their conclusions on the prevalence of endoscopically detected
ulcers are based on four or five studies selected from 16 that
met their inclusion criteria. Although they state reasons for
excluding reports, six of those not selected do not support their
findings. Furthermore, the conclusions of other well designed
studies addressing this question, which did not meet their inclusion
criteria, differ from their own. Moreover, in the selected studies,
no control who had an ulcer was negative for H pylori and
NSAID use. This zero rate required statistical modelling by adding
a constant pseudo count. Therefore, data calculated by comparison
are distorted pseudo estimates. Clinical trials, which provide
a far larger, more rigorous, controlled, prospective data source
were not analysed. In such studies, results have shown effects
that range from increased risk of ulceration in H pylori-positive
patients taking NSAIDs2 to no effect and greater effectiveness
of acid-suppression,2 and overall do not support Huang and colleagues'
conclusions. Selection bias may also exist in the analysis of
ulcer bleeding. A large study that was not analysed shows an opposite
effect to that of Huang and colleagues.3 Again, clinical trials
in which clinically important ulcer complications were the primary
endpoint do not support a role for H pylori,4 whereas a
significant reduction in such events, in patients on NSAIDs or
rofecoxib in endoscopic studies, has been reported.5 If these
papers had been included, no additive risk between H pylori
and NSAIDs on ulcer bleeding would have been evident. The aims
and methods of the included studies are heterogeneous, which makes
it debatable whether meta-analysis, defined as combined analysis
of similar studies to produce a unifying conclusion, is an appropriate
statistical tool. For reasons that are unclear, the primary conclusion
of the nine studies of ulcer bleeding differ from Huang and colleagues'
conclusions (reduced ulceration in two, reduced gastric ulceration
in one, no effect in four, enhanced ulcer risk in one, and lowered
subgroup risk in one). Prescribers need to know what to do when
an NSAID user presents with a clinical event such as a bleeding
peptic ulcer. Trial data show that 18·8% of such patients
will have a further ulcer bleeding episode if they have H pylori
eradication and continue taking an NSAID, compared with 4·4%
if they continue taking NSAIDs and a protective proton-pump inhibitor
and do not have H pylori eradication. Since there are no
data, prescribers can make their own decisions about giving H
pylori eradication as well as proton-pump inhibitor, but should
bear in mind that H pylori eradication will reduce the
effectiveness of proton pump inhibitors at lowering the concentration
of intragastric acid by a hundred-fold.
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