MH 1-2013 - Diretoria.pmd - Grupo de Fígado do Rio de Janeiro

Transcrição

MODERNA HEPATOLOGIA
ISSN 19823150
Serviço de Hepatologia da Santa Casa do Rio de Janeiro (8ª Enfermaria)
Rua Santa Luzia, nº 206 – Castelo - 20020-020 – Rio de Janeiro-RJ - Tel.: (21) 2220-9649
E-mail: [email protected]
Grupo de Fígado do Rio de Janeiro
Rua Siqueira Campos, nº 93/802 - Copacabana –22031-070 - Rio de Janeiro-RJ
Tels.: (21) 2255-8282 e (21) 2236-4510 - e-mail: [email protected]
Ano 39 – Nº 1 – Janeiro/Junho de 2013
MODERNA HEPATOLOGIA
Editores Responsáveis
Cláudio G de Figueiredo Mendes
Eduardo Joaquim Castro
Conselho Editorial
Carlos Antônio R. Terra Filho, Carlos Eduardo Brandão-Mello, Cláudio G. de Figueiredo Mendes,
Cristiane Alves Villela Nogueira, Eduardo Joaquim Castro, Fernando Wendhausen Portella, Francesco Agoglia,
Henrique Sérgio M. Coelho, João Luiz Hauer, João Luiz Pereira, Joaquim Ribeiro Filho, Jorge André de Segadas Soares,
Letícia Cancella Nabuco, Paulo de Tarso A. Pinto, Renata de Mello Perez, Ricardo Cerqueira Alvariz,
Silvando Barbalho Rodrigues, Vera Lucia N. Pannain
DIRETORIA DO GRUPO DE FÍGADO
BIÊNIO 2011-2013
Presidente: Francesco Agoglia
Secretário: Eduardo Joaquim Castro
Tesoureiro: Marcio Fragoso Castro
Diretor Científico: João Luiz Pereira
Diretor de Divulgação: Silvando Barbalho Rodrigues
Comissões
Homepage: Paulo de Tarso A. Pinto
Moderna Hepatologia
Claudio G. de Figueiredo Mendes e Eduardo Joaquim Castro
Curso de Aperfeiçoamento em Hepatologia
Flavia Fernandes e Gustavo Henrique Pereira
Admissão: Carlos Antônio R Terra Filho e Clarice Gdalevici
Comissão Fiscal: Fernando Wendhausen Portella, Letícia Cancella Nabuco, Paulo de Tarso A. Pinto
PRODUÇÃO EDITORIAL E GRÁFICA DA MODERNA HEPATOLOGIA
Trasso Comunicação Ltda
Av. N. Sra. de Copacabana, 1059 sala 1201 – 22060-001– Rio de Janeiro-RJ – Tel/Fax.: (21) 2521-6905
[email protected] - www.trasso.com.br
Moderna Hepatologia –Vol 39– Nº 1 – Jan/Jun – 2013
1
MODERNA HEPATOLOGIA
ISSN 19823150
ÍNDICE
Prefácio
Syllabus do Congresso Brasileiro de Hepatologia ...................................................................................................................................................... 3
Henrique Sergio Moraes Coelho
Editorial
Mensagem do Presidente do GFRJ .............................................................................................................................................................................. 4
Francesco Agoglia
Trabalhos
Primary Biliary Cirrhosis – An Update .......................................................................................................................................................................... 5
Cynthia Levy
Hepatocellular Carcinoma: Enhancing clinical outcomes in Advanced HCCl .............................................................................................................. 8
Ghassan K. Abou-Alf
Non cirrhotic intrahepatic portal hypertension ........................................................................................................................................................... 11
Dominique Charles Valla
Como acompanhar o paciente HBV sem indicação de tratamento? ........................................................................................................................ 12
Luiz Guilherme Lyra
Esteatose: Como identificar os pacientes que progridem à esteato-hepatite ......................................................................................................... 15
Helena Cortez-Pinto
Terapia tríplice em Hepatite C: Fatores de risco para complicações ....................................................................................................................... 17
Moises Diago
Hepatite C – O que ainda precisa ser respondido? ................................................................................................................................................. 18
Moises Diago
Hepatocellular carcinoma in non-cirrhotic liver .......................................................................................................................................................... 19
Peter Robert Galle
Recurrent hepatitis C after liver transplantation ......................................................................................................................................................... 21
Marina Berenguer
Complicações metabólicas pós-transplante ............................................................................................................................................................. 23
Marina Berenguer
Cirrose – O que ainda precisa ser respondido? ........................................................................................................................................................ 25
André Castro Lyra
Hepatitis B and liver transplantation ........................................................................................................................................................................... 27
Marina Berenguer
Ascites ........................................................................................................................................................................................................................ 29
Florence Wong
Treatment of Hepatic Encephalopathy: Focus on Rifaximin ...................................................................................................................................... 32
Hitoshi Maruyama, Arun J. Sanyal
Iron and steatohepatitis ............................................................................................................................................................................................... 38
Antonello Pietrangelo
Diagnosis of Renal Failure in Cirrhosis ....................................................................................................................................................................... 41
Florence Wong
Hemochromatosis – Diagnosis and Treatment ........................................................................................................................................................... 43
Therapeutic Strategies for Budd-Chiari Syndrome ..................................................................................................................................................... 47
Portal vein thrombosis in cirrhosis .............................................................................................................................................................................. 49
Epidemiology of NAFLD in the Americas ..................................................................................................................................................................... 51
Karen V. Silva-Vidal; Jorge A. López-Velázquez; Varenka J. Barbero-Becerra; Norberto C. Chávez-Tapia;
Misael Uribe; Nahum Méndez-Sánchez
2
Moderna Hepatologia – Vol 39– Nº 1 – Jan/Jun – 2013
PREFÁCIO
SYLLABUS DO CONGRESSO BRASILEIRO DE HEPATOLOGIA
É
com imenso prazer que lhes apresento esta edição de Moderna Hepatologia,
comemorativa do XXII Congresso Brasileiro de Hepatologia e da XXII Semana de Fígado do
Rio de Janeiro. Neste número encontrarão diversos artigos escritos por nossos convidados
nacionais e internacionais abordando de forma mais resumida as palestras que proferirão
nestes eventos.
Além do inestimável valor científico e prático, esta edição permitirá rever conceitos
emitidos em aulas não presenciadas, pois o Congresso se desenvolverá em pelo menos
em três salas simultâneas.
Terão oportunidade de rever conceitos em áreas diversas da Hepatologia clínica e
cirúrgica, na opinião de renomados especialistas, que comparecerão ao Congresso num
total de 32 palestrantes internacionais e cerca de 120 nacionais. Isto mostra a pujança da
Hepatologia em nosso país.
Espero que esta edição, estendida também aos que não puderam comparecer ao
Congresso, possa os ajudar no desafio que é hoje manter-se atualizado em todos os
assuntos da Hepatologia, para melhor servir aos seus pacientes portadores de hepatopatias.
Agradeço aos editores desta revista a honra de prefaciar este número, ao mesmo
tempo em que os parabenizo pela iniciativa.
Henrique Sergio Moraes Coelho
Presidente da Sociedade Brasileira de Hepatologia e do
XXII Congresso Brasileiro de Hepatologia
Moderna Hepatologia – Vol. 39– Nº 1 – Jan/Jun 2013
3
EDITORIAL
PALAVRA DO PRESIDENTE DO GFRJ
Prezados Colegas
E
ste número da Moderna Hepatologia é sem dúvida ímpar e memorável. É editado
como "Syillabus" do Congresso Brasileiro de Hepatologia, que acaba de se iniciar aqui no
Rio de Janeiro, sob a presidência do Dr. Henrique Sérgio Moraes Coelho, membro fundador
do Grupo de Fígado do Rio de Janeiro - GFRJ. Este exemplar contém uma significativa
amostragem do alto teor científico que sem dúvida será a tônica deste Congresso.
Congresso este que, por coincidência e por logística, engloba também a XXII Semana
de Fígado do Rio de Janeiro, evento anual do GFRJ. Este ano, com grande satisfação,
ainda sob minha presidência, mesmo que em final de mandato. O GFRJ não tem poupado
esforços para que um evento desta magnitude tenha o sucesso esperado.
De igual forma, não me faltaram colaborações e esforços durante a condução do
GFRJ na gestão do biênio 2011-2013, pelos quais exprimo meus sinceros agradecimentos.
Meu entusiasmo e disposição, aliados à experiência da diretoria executiva, fizeram com
que as dificuldades e os obstáculos fossem vencidos ou pelo menos contornados. Carrego
na bagagem uma experiência profissional e pessoal, embora laboriosa, mas sem dúvida
gratificante e enriquecedora, por ter conseguido – espero! – agregar algo ao muito que já
havia sido construído pelas gestões anteriores.
Me sobra desejar ao próximo presidente eleito, Dr. Carlos Terra, um proveitoso trabalho,
bem como uma gestão cada vez mais inovadora e visionária. Para ele, para os editores da
Moderna Hepatologia e especialmente para o GFRJ, "AD MAIORA SEMPER".
Francesco Agoglia
Presidente do Grupo de Fígado do Rio de Janeiro
4
Moderna Hepatologia – Vol. 39 – Nº 1 – Jan/Jun 2013
PRIMARY BILIARY CIRRHOSIS – AN UPDATE
CIRROSE BILIAR PRIMÁRIA – UMA ATUALIZAÇÃO
Cynthia Levy, MD
Hepatology - Internal Medicine
Gastroenterology - Internal Medicine
INTRODUCTION
Primary biliary cirrhosis (PBC) is a chronic cholestatic
autoimmune liver disease characterized by inflammation
and progressive destruction of the intrahepatic bile ducts,
eventually leading to biliary cirrhosis and end stage liver
disease. PBC affects predominantly middle-aged females:
approximately 1:1,000 women over the age of 40 is
(1)
affected .
The disease is thought to result from a combination of
genetic predisposition and environmental triggers, with
molecular mimicry likely playing a major role in the
abnormal recognition of mitochondrial self-antigens by the
immune system. As such, anti-mitochondrial antibodies
(AMA), present in 90-95% of all patients, are directed
against the pyruvate dehydrogenase complex (PDC E2) in
the inner membrane of the mitochondria and constitute the
serologic hallmark of PBC.
The diagnosis of PBC requires the presence of 2 out
(2)
of 3 criteria :
(1) biochemical evidence of cholestasis with elevated
serum alkaline phosphatase for longer than 6 months,
(2) presence of AMA, and
(3) liver biopsy consistent with PBC. In AMA-negative
patients, the presence of a florid duct lesion, a
lymphoplasmacytic infiltrate that surrounds and infiltrates the
bile duct in the portal triad, is required for diagnosis.
The clinical course of PBC is highly variable. Four
distinct clinical phases have been described: pre-clinical,
asymptomatic, symptomatic and liver failure. Patients may
first present at any of these phases. Most are
asymptomatic at presentation, although after 20 years of
follow-up only 5% remain asymptomatic. The most
common symptoms are fatigue and pruritus; 10% of
patients complain of non specific right upper quadrant and
a minority already has evidence of portal hypertension at
the time of first presentation. The overall survival of
untreated patients is markedly decreased compared to
the general population, with approximately 60% 10-year
(3)
survival .
MEDICAL THERAPY
UDCA
Ursodeoxycholic acid (UDCA), a hydrophilic bile acid,
is the only approved therapy for PBC. Multiple mechanisms
(4)
of action have been demonstrated for UDCA in PBC :
1. Cytoprotective – By enriching bile with UDCA we
decrease the pool of hydrophobic bile acids, which
are known to be cytotoxic. UDCA has been shown to
protect against apoptosis
2. Choleretic – UDCA modulates synthesis and
membrane insertion of key transporters to increase
the rate of transport of intracellular bile acids across
the hepatocyte and into the canaliculus. UDCA also
stimulates bicarbonate secretion in the bile
3. Anti-inflammatory and immunomodulatory – UDCA
suppresses production of immunoglobulins, decreases
aberrant expression of MHCs and adhesion molecules,
inhibits cytokine release and interferes with NF-KB
activation.
In clinical trials, UDCA at 13-15 mg/kg/day has been
shown to improve liver biochemistries, cholesterol and
immunoglobulins, delay histological progression, delay
development of esophageal varices and improve survival
(2-5)
free of liver transplantation . As a result, the number of
patients being transplanted for PBC has been decreasing
in the United States. However, there is still a subset of
patients with PBC who will continue to progress despite
being on UDCA. These are so-called "non-responders" or
"incomplete responders" to UDCA, and represent up to
40% of all patients with PBC, of whom 10% will either die
or require a liver transplant.
Biochemical Response to UDCA
Several investigators attempted to identify those
patients who continued to progress and have a decreased
survival despite being on treatment with UDCA. Each
generated a set of criteria to define this group of non(6)
responders , as shown in Table 1. In addition to the alkaline
phosphatase and other liver biochemistries, young age,
male gender and Hispanic ethnicity may be additional
predictors of poor response to UDCA. Regardless of how
the non-responders are defined, it is clear that a subset of
patients with PBC will need adjuvant therapy.
Adjuvant Therapy
There is no consensus on how to treat patients with
incomplete response to UDCA. The European Association
5
LEVY C
drop in alkaline phosphatase. The lower dose of 10 mg/day
was equally effective to the higher dose of 50 mg/day.
The main adverse effect of OCA is pruritus, which is
dose-dependent, and only a small proportion of patients
receiving the lower dose had more intense pruritus than
the placebo group. We are currently waiting for the results
of a large phase 3 study.
PPAR-α
α agonists – Fibrates
for the Study of Liver (EASL) suggests use of budesonide
9 mg/day for incomplete responders who are not cirrhotic,
although large-scale studies are lacking. The American
Association for the Study of Liver Diseases (AASLD) does
not make specific suggestions; the addition of methotrexate
or colchicine is not recommended.
NOVEL THERAPIES CURRENTLY UNDER
EVALUATION
FXR agonists – Obeticholic Acid (OCA)
FXR (Farnesoid X Receptor) is a member of the
ligand-activated nuclear receptors superfamily. It
functions as an agonist-dependent transcriptional
transactivator of its direct target genes. FXR is a bile
sensor and bile acids are the natural ligands, especially
chenodeoxycholic acid (CDCA). Thus, FXR activation
leads to negative regulation of genes involved in bile acid
synthesis and uptake, and upregulation of those involved
in bile acid detoxification and excretion. OCA is a
synthetic potent FXR agonist, with chemical structure
very similar to CDCA. Preclinical studies indicate both
a choleretic and anti-fibrotic effect.
In patients with incomplete response to UDCA,
addition of OCA resulted in significant improvement in
(7)
serum alkaline phosphatase compared to placebo .
Similarly, studies with OCA monotherapy led to a 40%
6
When activated, PPAR-α binds to retinoid X receptor
to form a heterodimer, which then binds to its peroxisome
proliferator response elements present in the promoter
regions of its target genes, resulting in gene transactivation.
PPAR downregulates CYP7A1, which is involved in bile
acid synthesis, as well as transporters involved in bile acid
uptake in the basolateral membrane. In addition, PPAR
upregulates several canalicular transporters, all contributing
to lowering the concentration of bile acids within the
(8)
hepatocyte . A cross-talk between FXR and PPAR has
been described.
A pilot study involving 20 patients with incomplete
response to UDCA and treated with fenofibrate 160 mg/day
for 48 weeks showed a significant drop in serum alkaline
(9)
phosphatase and serum IgM levels . Once the drug
was discontinued, a rebound was noticed on serum
alkaline phosphatase. As expected, the biochemical
response was more pronounced in patients with early
histological disease. Larger placebo-controlled studies
are warranted.
Rituximab
Rituximab is a chimeric monoclonal anti-CD 20
antibody that depletes B cells by complement-dependent
and antibody-dependent cytotoxicity. In mouse models of
PBC, depletion of B cells resulted in amelioration of liver
inflammation.
Two studies conducted in the US and Canada
included a total of 20 patients who were treated with 2
infusions of rituximab, 2 weeks apart. In general,
approximately 25% of patients had a drop in alkaline
(10,11)
phosphatase
. As proof of concept, an increase in
regulatory T cells was noticed, along with decrease in
AMA titer and IgM levels. The alkaline phosphatase levels
were reduced for up to 36 weeks after drug
discontinuation. Although no serious adverse event
occurred, a couple of patients had to be withdrawn from
the study due to infections.
Others
Additional drugs under investigation include:
usterkinumab (IL-12 blocker), LUM001 (apical sodium
dependent bile salt transporter blocker), and pentoxifylline
(TNF blocker).
PRIMARY BILIARY CIRRHOSIS – AN UPDATE
CONCLUSION
PBC is effectively treated with UDCA 13-15 mg/kg/
day in approximately 60% of patients. Among those with
incomplete response, about 10% will go on to develop liver
failure and either die or require a liver transplant. Thus,
patients with incomplete response to UDCA should be
considered for adjuvant and novel therapies. Use of FXR
agonists and fibrates may lead to further improvement of
serum liver biochemistries and larger trials are awaited.
REFERENCES
1. Poupon R. Primary biliary cirrhosis: a 2010 update. J Hepatol
2010;52:745-58.
2. Lindor KD, Gershwin ME, Poupon R, et al. Primary biliary cirrhosis.
Hepatology 2009;50:291-308.
3. Kim WR, Lindor KD, Locke GR, 3rd, et al. Epidemiology and natural
history of primary biliary cirrhosis in a US community.
Gastroenterology 2000;119:1631-6.
4. Roma MG, Toledo FD, Boaglio AC, Basiglio CL, Crocenzi FA, Sanchez
Pozzi EJ. Ursodeoxycholic acid in cholestasis: linking action
mechanisms to therapeutic applications. Clin Sci (Lond)
2011;121:523-44.
5. EASL Clinical Practice Guidelines: management of cholestatic liver
diseases. J Hepatol 2009;51:237-67.
6. Czul F, Peyton A, Levy C. Primary biliary cirrhosis: therapeutic
advances. Clin Liver Dis 2013;17:229-42.
7. Mason A, Luketic V, Lindor K, et al. 2 farnesoid-x receptor agonists:
A new class of drugs for the treatment of pbc? An international
study evaluating the addition of int-747 to ursodeoxycholic acid.
Journal of hepatology 2010;52:S1-S2.
8. Honda A, Ikegami T, Nakamuta M, et al. Anticholestatic effects of
bezafibrate in patients with primary biliary cirrhosis treated with
ursodeoxycholic acid. Hepatology 2012.
9. Levy C, Peter JA, Nelson DR, et al. Pilot study: fenofibrate for
patients with primary biliary cirrhosis and an incomplete response
to ursodeoxycholic acid. Aliment Pharmacol Ther 2011;33:235-42.
10. Tsuda M, Moritoki Y, Lian ZX, et al. Biochemical and immunologic
effects of rituximab in patients with primary biliary cirrhosis and an
incomplete response to ursodeoxycholic acid. Hepatology
2012;55:512-21.
11. Myers RP, Swain MG, Lee SS, Shaheen AA, Burak KW. B-cell
depletion with rituximab in patients with primary biliary cirrhosis
refractory to ursodeoxycholic acid. Am J Gastroenterol
2013;108:933-41.
Correspondence to
Cynthia Levy, MD
Division of Hepatology
University of Miami Miller School of Medicine
1500 NW 12th Avenue, suite 1101, Miami, FL 33136
phone 305-243-2147 - fax: 305-243-3877
[email protected]
7
HEPATOCELLULAR CARCINOMA: ENHANCING CLINICAL
OUTCOMES IN ADVANCED HCC
CARCINOMA HEPATOCELULAR: MELHORAR OS RESULTADOS CLÍNICOS EM HCC AVANÇADO
Ghassan K. Abou-Alfa, MD
Memorial Sloan-Kettering Cancer Center, New York, NY, USA,
and Weill Medical College at Cornell University
INTRODUCTION
After the approval of sorafenib as a standard of care
for the treatment of advanced hepatocellular carcinoma
(HCC), there has been several single agent and
combination of biologic studies that so far have failed to
improve median overall survival beyond the 11 months of
sorafenib. While there are still certain attempts to improve
outcome with the combination of biologic plus
chemotherapy like in the example of sorafenib plus
doxorubicin, the focus has already changed to other
targets. c-met inhibition is now being extensively evaluated
in advanced HCC. While these efforts continue to evolve,
we continue to get close and closer to a custom-based
therapy in treating advanced HCC.
SORAFENIB
(1)
Sorafenib a multi-kinase inhibitor , that has already
been approved as a standard of care for advanced HCC
based on the positive outcome of two pivotal, multicenter,
double-blind, placebo-controlled, randomized phase III
(2,3)
studies of sorafenib versus best supportive . A phase
III study that was available mainly in the western
hemisphere called the SHARP trial enrolled 602 patients
with advanced HCC, Child-Pugh A, who did not receive
any prior systemic therapy, showed an improvement in
median overall survival of 10.7 months in favor of sorafenib
at 400 mg twice daily, versus 7.9 months for best
(3)
supportive care (HR = 0.69) . The Asia-Pacific Study was
a parallel study to the SHARP and operated mainly in
Asia had similar outcomes to the SHARP but with a
difference in magnitude of the median overall survival
benefit which was 6.5 and 4.2 months for patients receiving
(3)
sorafenib and placebo, respectively .
The patients included in the Asia-Pacific Study had
more advanced disease and worse performance status,
which may have influenced the lesser magnitude
improvement in survival. However specific viral etiologic
factor might have also have played a role. In the subset
8
analysis of the SHARP study, patients with HCC and
hepatitis C related who received sorafenib demonstrated a
greater clinical benefit, with substantial improvements over
placebo in overall survival (14.0 vs. 7.4 months), while
patients with median survival for patients with hepatitis B
related HCC who received sorafenib had a median overall
(4)
survival of 9.7 versus 6.1 months for the placebo group .
These findings may be explained by HCV core proteininduced upregulation of the sorafenib target CRAF, among
(5)
other kinases . Obviously more prospective work is
required. Nonetheless, it should be emphasized that the
utility of sorafenib depends on its multi-kinase targeting
and thus it remains the standard of care therapy, irrespective
of the underlying etiology of HCC.
NOVEL SINGLE AGENTS
Emerging results on several small molecule, multireceptor tyrosine kinase inhibitors with an ability to inhibit
VEGFR, have been disappointing.
Sunitinib a multi-kinase inhibitor with greater anti(6)
VEGFR-1/-2 potency than sorafenib , have been evaluated
in a randomized phase III study versus sorafenib in
treatment naïve patients with advanced HCC and Child
(7)
Pugh Class A liver function . The trial failed to meet its
non-inferiority endpoint of overall survival, with a median
overall survival of 8.1 months for sunitnib versus 10 months
for sorafenib (HR 1.31, 95%CI 1.13-1.52). The incidence of
drug-related adverse events was higher in the sunitinib arm
than in the sorafenib arm.
Brivanib, a dual inhibitor of VEGFR and FGFR, did
not show an improvement in overall survival when compared
to sorafenib, in a randomized phase III study in treatment
(8)
naïve patients with advanced HCC . The median survival
was 9.5 for the brivanib group versus 9.9 months for the
sorafenib group (hazard ratio [HR], 1.06; 95.8% CI, 0.93
(8)
to 1.22) .
Linifanib, a selective inhibitor of VEGFR and PDGFR,
faired similarly to brivanib. In a randomized phase III study
of sorafenib versus linifanib as a first line therapy for
advanced HCC who did not receive systemic therapy
(9)
previosuly . The trial failed to meet the both pre-specified
superiority and non-inferiority boundaries with a median
overall survival of 9.1 months for the linifanib versus 9.8
months for sorafenib. Serious adverse events were more
common in this cohort than compared with sorafenib.
HEPATOCELLULAR CARCINOMA: ENHANCING CLINICAL OUTCOMES IN ADVANCED HCC
COMBINATION STRATEGIES
Considering the disappointing results of rather more
precise or more potent anti-angiogenics than sorafenib,
focus has been also on combination therapies.
The potential VEGF up-regulation undermining anti25
EGFR therapy, led to a phase II trial evaluated the
combination of bevacizumab plus erlotinib in treatment naïve
advanced HCC patients that revealed PFS at 16 weeks
(primary endpoint) of 64% (95% CI 51-76), median PFS
was 7.2 months (95% CI 5.6-8.3), and median OS was
(10)
13.7 months (95% CI 9.6-19.7) . Based on this data, a
randomized phase II trial comparing bevacizumab and
erlotinib versus sorafenib in the first-line setting for advanced
HCC is currently underway (www.clinicaltrials.gov,
NCT00881751) In addition, a phase III trial attempted an
evaluation of a presumed similar combinaiton of sorafenib
plus erlotinib versus sorafenib failed to show a statistically
(11)
significant benefit to the combination arm . The median
overall survival was 9.5 months for the combination versus
8.5 months for single agent sorafenib (HR 0.929, 95% CI:
0.781-1.1.06, p=0.204 1-sided).
Combining anti-angiogenics plus chemotherapy is
another approach that already has been studied
extensively. A randomized double-blinded phase II study
of doxorubicin plus sorafenib and doxorubicin plus placebo
in patients with advanced HCC and Child-Pugh A cirrhosis
showed in an exploratory comparison an improvement in
median OS of 13.7 months for the combination of
doxorubicin plus sorafenib versus 6.5 months for
(12)
doxorubicin plus placebo (p = 0.006) . This led to a phase
III trial in HCC patients with no prior systemic therapy
and Child-Pugh A, comparing sorafenib plus doxorubicin
versus sorafenib (CALGB 80802) (www.clinicaltrials.gov,
NCT01015833). An interim analysis was recently
completed and the study is continuing accrual.
TARGETING C-MET
c-MET overexpression in HCC have been associated
with transgene inactivation that lead to regression of
(13)
tumors . Tivantinib (ARQ197), a c-met tyrosine kinase
inhibitor, has been recently evaluated in a randomized
(14)
phase II study versus placebo in the second-line setting .
While the primary endpoint of TTP was not met (1.6 months
versus 1.4 months; hazard ratio [HR] 0.64, 90% CI 0.430.94; p=0.04), patients with MET-high tumors (≥2+ in ≥50%
of tumour cells), median time to progression was longer
with tivantinib than for those on placebo (2.7 months versus
1.4 months; HR 0.43, 95% CI 0.19-0.97; p=0.03).
Cabozantinib (XL184), a dual c-met/vascular endothelial
growth factor receptor-2 (VEGFR-2) inhibitor was also
evaluated in the second line setting in HCC as part of phase
(15)
II randomized discontinuation study . After 12 weeks of
therapy, patients with evident response continued on openlabel cabozantinib, those with stable disease were
randomized to cabozantinib versus placebo, and those with
progressive disease discontinued cabozantinib. Among 41
patients on study, median PFS was 4.4 months and median
OS 15.1 months.
Two second-line phase III trial evaluating tivantinib
(www.clinicaltrials.gov, NCT01755767) and cabozatinib
(www.clinicaltrials.gov, NCT01908426) in patients with
advanced HCC who failed prior therapy are already
announced.
CONCLUSION
Despite the availability of sorafenib as a standard of
care for HCC, there is a substantial need to enhance
therapies in the advanced setting. Despite that several,
high-profile, phase III clinical trials have failed to improve
on the current standard, the pipeline for drug development
is still extensive. We should all await further developments
in that respect.
REFERENCES
1. Wilhelm SM, Carter C, Tang L, Wilkie D, McNabola A, Rong H, et al:
BAY 43-9006exhibits broad spectrum oral antitumor activity and
targets the RAF/MEK/ERK pathway and receptor tyrosine kinases
involved in tumor progression and angiogenesis. Cancer Res. 2004
Oct 1;64(19):7099-109.
2. Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, et al.
Sorafenib in advanced hepatocellular carcinoma. N Engl J Med.
2008 Jul 24;359(4):378-90.
3. Cheng AL, Kang YK, Chen Z, Tsao CJ, Qin S, Kim JS, et al. Efficacy
and safety of sorafenib in patients in the Asia-Pacific region with
advanced hepatocellular carcinoma: a phase III randomised, doubleblind, placebo-controlled trial. Lancet Oncol. 2009 Jan;10(1):25-34.
4. Bruix J, Raoul JL, Sherman M, Mazzaferro V, Bolondi L, Craxi A, Galle
PR, Santoro A, Beaugrand M, Sangiovanni A, Porta C, Gerken G,
Marrero JA, Nadel A, Shan M, Moscovici M, Voliotis D, Llovet JM.
Efficacy and safety of sorafenib in patients with advanced
hepatocellular carcinoma: subanalyses of a phase III trial. J Hepatol.
2012 Oct;57(4):821-9.
5. Giambartolomei, S., Covone, F., Levrero, M. & Balsano, C. Sustained
activation of the Raf/MEK/Erk pathway in response to EGF in stable
cell lines expressing the Hepatitis C Virus (HCV) core protein.
Oncogene 20, 2606-2610, doi:10.1038/sj.onc.1204372 (2001).
6. Mendel, D. B. et al. In vivo antitumor activity of SU11248, a novel
tyrosine kinase inhibitor targeting vascular endothelial growth factor
and platelet-derived growth factor receptors: determination of a
pharmacokinetic/pharmacodynamic relationship. Clinical cancer
research : an official journal of the American Association for Cancer
Research 9, 327-337 (2003).
7. Cheng AL, Kang Y, Lin D, Park, J, Kudo M, Qin S, et al. Phase III study
of sunitinib versus sorafenib in advanced hepatocellular carcinoma.
J Clin Oncol 29: 2011 (suppl; abstr 4000)
8. Johnson PJ, Qin S, Park JW, Poon RT, Raoul JL, Philip PA, Hsu CH, Hu
TH, Heo J, Xu J, Lu L, Chao Y, Boucher E, Han KH, Paik SW, RoblesAviña J, Kudo M, Yan L, Sobhonslidsuk A, Komov D, Decaens T,
Tak WY, Jeng LB, Liu D, Ezzeddine R, Walters I, Cheng AL. Brivanib
Versus Sorafenib As First-Line Therapy in Patients With Unresectable,
Advanced Hepatocellular Carcinoma: Results From the Randomized
Phase III BRISK-FL Study. J Clin Oncol. 2013 Aug 26.
9
ABOU-ALFA GK
9. Cainap C, Qin S, Huang W-T, Chung I-J, Pan H, Cheng Y, et al.
Phase III trial of linifanib versus sorafenib in patients with
advanced hepatocellular carcinoma (HCC). J Clin Oncol 30: 2012
(suppl 34; abstr 249)
10. Kaseb AO, Garrett-Mayer E, Morris JS, Xiao L, Lin E, Onicescu G, et
al. Efficacy of bevacizumab plus erlotinib for advanced
hepatocellular carcinoma and predictors of outcome: final results
of a phase II trial. Oncology. 2012;82(2):67-74.
11. Zhu AX, Rosmorduc O, Evans J, Ross P, Santoro A, Carrilho FJ, et al.
SEARCH: A phase III, randomized, double-blind, placebo-controlled
trial of sorafenib plus erlotinib in patients with hepatocellular
carcinoma (HCC). Ann Oncol (2012) 23 (suppl 9):LBA2.
12. Abou-Alfa GK, Johnson P, Knox JJ, Capanu M, Davidenko I, Lacava
J,et al. Doxorubicin Plus Sorafenib vs Doxorubicin Alone in Patients
With Advanced Hepatocellular Carcinoma: A Randomized Trial. JAMA
2010 Nov 17;304(19):2154-2160
13. Wang R, Ferrell LD, Faouzi S, Maher JJ, Bishop JM. Activation of
the Met receptor by cell attachment induces and sustains
hepatocellular carcinomas in transgenic mice. J Cell Biol. 2001
May 28;153(5):1023-34.
14. Santoro A, Rimassa L, Borbath I, Daniele B, Salvagni S, Van Laethem
JL, Van Vlierberghe H, Trojan J, Kolligs FT, Weiss A, Miles S,
Gasbarrini A, Lencioni M, Cicalese L, Sherman M, Gridelli C, Buggisch
P, Gerken G, Schmid RM, Boni C, Personeni N, Hassoun Z,
Abbadessa G, Schwartz B, Von Roemeling R, Lamar ME, Chen Y,
Porta C. Tivantinib for second-line treatment of advanced
hepatocellular carcinoma: a randomised, placebo-controlled phase
2 study. Lancet Oncol. 2013 Jan;14(1):55-63.
15. Verslype C, Cohn AL, Kelley RK, Yang T-S, Su W-C, Ramies DA, et
al. Activity of cabozantinib (XL184) in hepatocellular carcinoma:
results from a randomized phase II discontinuation study. J Clin
Oncol 30, 2012 (suppl; abstr 4007).
Correspondence to
Ghassan K. Abou-Alfa, MD
Memorial-Sloan Kettering Cancer Center
300 East 66th Street
New York, NY 10065 - USA
Telephone: 646-888-4184
10
NON CIRRHOTIC INTRAHEPATIC PORTAL HYPERTENSION
HIPERTENSÃO PORTAL INTRA-HEPÁTICA NÃO CIRRÓTICA
Service d'Hépatologie, Hôpital Beaujon, AP-HP, Université ParisDiderot, and Inserm U773, Clichy-la-Garenne, France
Summary
Non cirrhotic intrahepatic portal hypertension is characterized
by disorders of the small intrahepatic vessels. Prothrombotic
conditions, disorders of immunity, exposure to certain
xenobiotics, infections with articular pathogens, and genetic
disorders have been implicated. The complications of portal
hypertension dominate the outcome of the disease. The risk
of portal vein thrombosis is particularly high. No specific
treatment is currently available.
Keywords: Portal hypertension; Portal vein thrombosis; Liver
transplantation; Anticoagulation therapy; Nodular
regenerative hyperplasia; Obliterative portal venopathy.
Non cirrhotic intrahepatic portal hypertension includes
diverse entities which encompass the non-cirrhotic but
advanced stages of common acute and chronic liver disease
(alcoholic liver disease, viral and autoimmune hepatitis,
chronic cholangitis, acute hepatitis, Budd-Chiari syndrome),
as well as other specific disorders, the manifestations of
which are almost exclusively related to portal hypertension
(schistosomiasis, sarcoidosis, congenital hepatic fibrosis).
The term idiopathic non-cirrhotic portal hypertension includes
the other disorders where portal hypertension is a major
feature but cirrhosis is absent. The presentation will focus
(1)
on this last category of disorders .
Idiopathic non cirrhotic portal hypertension is
associated with a variety of histopathological changes in
(2)
the liver . Some of them are likely to be instrumental in
causing portal hypertension: obliterative portal venopathy,
portal and perisinusoidal fibrosis, and regenerative changes
(including full blown nodular regenerative hyperplasia. Other
changes are likely to be the mere consequence of the
obstruction to portal venous inflow: sinusoidal dilatation,
increased number of venous channels in the portal tracts
and ectopically located vascular channels.
Several risk factors appear to play a role in the etiology
of idiopathic non-cirrhotic portal hypertension, including
prothrombotic disorders (particularly antiphospholipid
syndrome and myeloproliferative neoplasms), prolonged
exposure to certain agents (e.g. purine derivatives,
oxlitplatine, vitamin A, arsenicals, vinyl chloride monomers),
and a heterogeneous group of immune disorders (common
variable immunodeficiency syndrome, autoimmune
connective tissue diseases, HIV infection). However, the
relationship between these factors and idiopathic noncirrhotic portal hypertension is not straightforward. It is
tempting to speculate that a genetic predisposition is also
involved as familial forms, and an association with genetic
abnormalities (Turner syndrome in particular), have been
described.
Manifestations are dominated by the features of portal
hypertension (bleeding and encephalopathy), but ascites
(1-3)
and jaundice are uncommon . Still, some patients are
recognized only at the examination of the explant after
liver transplantation for decompensated liver disease. By
contrast, at the other end of the spectrum, the characteristic
histopathological changes can be found in patients with
abnormal laboratory tests but without clinical or imaging
features of portal hypertension. When portal hypertension
is managed according to the recommendations applying
to cirrhosis, the course of the disease is stable or slowly
progressive over 20 years. Longer term, however, data are
still lacking. Portal vein thrombosis is a very common
finding (40% of patients by 5-10 years).
No specific therapy has been subjected to a solid
(1)
evaluation . Besides prophylaxis for the complications of portal
hypertension, anticoagulation could be proposed in patients
developing portal vein thrombosis. Anticoagulation has also
been has been discussed as a means to prevent extrahepatic
portal vein thrombosis, as well as to limit the intrahepatic
progression of the disease. However, extreme caution should
be applied to the administration of anticoagulation in such
(1)
patients as data are essentially absent .
REFERENCES
1. Schouten JN, Garcia-Pagan JC, Valla, DC, Janssen HL. Idiopathic
noncirrhotic portal hypertension. Hepatology 2011 ; 54 : 1071-1081.
2. Cazals Hatem D, Hillaire S, Rudler M, Plessier A, Paradis V, et al.
Obliterative portal venopathy: portal hypertension is not always
present at diagnosis. J Hepatol 2011; 54: 455-461.
3. Hillaire S, Bonte E, Denninger MH, Casadevall N, et al. Idiopathic noncirrhotic intrahepatic portal hypertension in the West: a re-evaluation
in 28 patients. Gut 2002, 51: 275-280
Correspondence to
Dominique Valla
Service d'Hépatologie, Hôpital Beaujon
92118 Clichy, France
Tel: + 33 1 40 87 55 94
Fax: + 33 1 40 87 44 26
[email protected]
11
COMO ACOMPANHAR O PACIENTE HBV SEM INDICAÇÃO DE
TRATAMENTO?
HOW TO FOLLOW THE PATIENT WITHOUT HBV TREATMENT INDICATION?
Luiz Guilherme Costa Lyra
Prof. Titular Departamento de Medicina da Universidade Federal
da Bahia
Coord. Científico Hospital São Rafael - Bahia
INTRODUÇÃO
A infecção pelo vírus da Hepatite B (VHB) é um
importante problema de saúde pública, associado a
significante morbidade e mortalidade por doença crônica
do fígado. Admite-se que no mundo cerca de 400 milhões
de indivíduos estão com infecção crônica pelo VHB e
anualmente 500.000 óbitos estão relacionados a cirrose
ou carcinoma hepatocelular pelo VHB. Diante do exposto
torna-se imperativo tratar o paciente com infecção crônica
pelo o VHB, entretanto existem circunstâncias em que o
tratamento não está indicado e nesta situação impõe-se
uma conduta para acompanhar estes pacientes.
O ciclo do VHB inicia-se quando o vírus penetra no
hepatócito, elimina o envelope viral e libera a partícula viral
do nucleocapsídeo. No hepatócito o DNA é convertido
para um DNA circular covalente (cccDNA). O cccDNa é
estável e induz a transcrição dos RNas mensageiros para
a tradução de 7 proteínas virais, sendo 3 proteínas do
envelope viral que formam o HBsAg; uma proteína
correspondendo ao antígeno central (do core), o HBcAg;
uma proteína secretora, solúvel do nucleocapsídeo, o
antígeno "e" da hepatite B, HBeAg; uma proteína X e a
polimerase viral (Figura 1).
São determinados no soro:
1- HBsAg → significa a presença do vírus;
2- HBeAg → relacionado a replicação viral;
3-HBV DNA → em dosagem quantitativa representa
a carga viral
1
4- Anti-HBs → significa resolução da infecção viral.
Após a infecção pelo VHB os pacientes desenvolvem
hepatite aguda e subsequente cura em cerca de 92 a 95%
dos casos. Raramente evoluem para a forma fulminante.
Uma pequena proporção progride para infecção crônica,
com diferentes estágios evolutivos e apresentações
clínicas:
12
Na infecção crônica causada pelo vírus B as lesões
hepáticas são imunomediadas, através de citocinas,
expressando a tentativa do sistema imune de destruir o
agente viral. O cccDNA entretanto, persiste na célula
infectada, caracterizando não haver a cura virológica da
infecção crônica pelo VHB, mesmo quando há evidência
sorológica de "clearence viral" e a viremia está
indetectável.
11
O VHB replica a um estimado índice 10 virions/dia
o que resulta em elevadas taxas de mutação espontânea.
A infecção cônica viral pode ser devido a uma cepa nativa
(selvagem) ou uma cepa mutante, especialmente
associada a mutação na região pré-core do genoma e
que se caracteriza pela interrupção da produção da
proteína HBeAg mas mantendo índices de carga viral
(HBV DNA).
A depender da idade de aquisição da infecção, da cepa
do VHB se nativa ou mutante e do "status" imunológico
do paciente a infecção crônica pelo VHB manifesta-se em
diferentes formas evolutivas e de replicação viral:
Estado de imunotolerância: quando a infecção foi
adquirida precocemente na infância. Caracteriza-se pela
presença no soro do HBeAg com níveis bastante elevados
de HBVDNA, com ALT e AST normais ou próximas do
normal e lesão histológica mínima.
Hepatite crônica HBeAg-positivo: desenvolve quando
a infecção pelo VHB é adquirida na adolescência ou na
fase adulta. Os pacientes evoluem com presença do
HBeAg no soro e níveis elevados do HBV DNA e da ALT.
Moderna Hepatologia – Vol. 37 – Nº 2 – Jul/Dez 2011
COMO ACOMPANHAR O PACIENTE HBV SEM INDICAÇÃO DE TRATAMENTO?
Estado de portador inativo do HBsAg: observa-se
após a soroconversão do HBeAg para o anti-HBe. Têm
no perfil sorológico: HBsAg positivo, HBeAg negativo e
anti-HBe positivo. A replicação viral é discreta, com ALT
normal e apenas poucas alterações histológicas.
Hepatite crônica HBeAg-negativo: corresponde a
forma mutante do vírus sem produção do HBeAg, mas com
elevada carga viral ( HBVDNA).
Nos estados de imunotolerância e de portador inativo
a literatura não recomenda o tratamento antiviral, entretanto
estes pacientes devem permanecer sob acompanhamento
médico.
Estado de portador inativo do HBsAg.
Caracteriza-se pela persistência da infecção pelo VHB
sem significante inflamação necro-inflamatória. O portador
inativo não requer tratamento e pode ser confundido com
a hepatite crônica HBeAg negativo. A carga viral está abaixo
de 2.000UI/ml (10.000cp/genoma/ml), a ALT permanece
normal ou próxima do normal e as alterações histológicas
são mínimas.
Na hepatite crônica HBeAg negativo, à semelhança
do portador inativo, o HBsAg está presente no soro
associado a ausência do HBeAg, entretanto os níveis
séricos de HBVDNA estão ≥ 2.000UI/ml (10.000 cópias
de genoma/ml). Pacientes com hepatite crônica HBeAg
negativo tendem a ter doença hepática mais grave, mesmo
quando comparados aos com hepatite crônica HBeAg
positivo. Os níveis séricos da ALT podem estar elevados
ou intercalados com períodos de normalidade, porem com
o HBVDNA ≥2.000UI/ml. Alterações inflamatórias e fibrose
estão presentes em diferentes graus evolutivos e o
tratamento antiviral é mandatório.
A determinação quantitativa do HBV DNA (carga viral)
é indispensável para estabelecer o diagnóstico diferencial
entre o estado de portador inativo e a hepatite crônica HBeAg
negativo uma vez que o médico fica exposto a uma decisão,
entre definir o tratamento antiviral na hepatite crônica HBeAg
negativo, ou evitar a terapia antiviral no portador inativo. Os
ensaios para dosagem do HBV DNA são baseados na
amplificação da reação da cadeia da polimerase (PCR) e
têm sensibilidade variável desde a detecção de 15 a 200UI/
ml. Um valor arbitrário de até 2.000UI/ml (10.000cópias/ml)
foi atribuído como critério diagnóstico para diferenciar o
portador inativo da hepatite crônica HBeAg negativo, embora
não se tenha plena segurança quanto a este índice de corte
("cutoff"). Estudo de coorte realizado na China (Taiwan)
sugeriu o índice de corte de 2.000UI/ml (10.000cp/ml) para
diferenciar doença ativa do portador inativo. Considerando a
possibilidade dos pacientes apresentarem níveis flutuantes
de HBV DNA, a monitoração do HBVDNA com mais de
uma dosagem é essencial para estabelecer o diagnóstico
do portador inativo.
Além da carga viral, a definição do diagnóstico do
portador inativo tem respaldo nos níveis normais ou
próximos do normal das transaminases, no exame
físico sem manifestação de hepatopatia crônica e tem
alicerce na ausência de alterações necroinflamatórias
no fígado.
Em alguns pacientes pode não ser fácil o
diagnóstico diferencial com a hepatite crônica HBeAg
negativo quando a mesma evoluir de forma silenciosa
por vários anos, deixando de ser reconhecida
clinicamente. Neste pacientes, os níveis séricos do HBV
DNA podem elevar somente de forma transitória antes
dos níveis séricos da ALT aumentarem. Em geral, a
hepatite crônica HBeAg-negativo representa uma forma
de doença hepática crônica potencialmente progressiva
e grave associada a estágios variados de fibrose
hepática. Estudos que avaliaram a histologia do fígado
no momento que a hepatite crônica HBeAg negativo foi
diagnosticada, demonstraram inflamação moderada a
intensa em 50% dos pacientes e cirrose em 25% a
40%.dos pacientes. Por outro lado, o risco de
desenvolvimento do carcinoma hepatocelular tem relação
com os níveis mais elevados do HBV DNA e presença
de fibrose e cirrose, condições que não são observadas
nos pacientes portadores inativos.
CONDUTA NOS PORTADORES INATIVOS
DO HBSAG
Os portadores inativos geralmente são indivíduos mais
idosos e podem espontaneamente eliminar o HBsAg com
soroconversão para o anti-HBs. A maioria dos portadores
inativos permanece sem atividade de doença por muitos
anos se não indefinidamente, com prognóstico favorável,
particularmente se esta fase é alcançada precocemente
no curso da doença. Não há indicação para tratamento
antiviral do portador inativo. Todavia ao ser estabelecido o
diagnóstico inicial e considerando a natureza flutuante da
hepatite crônica HBeAg positivo, recomenda-se:
1- determinar os níveis de ALT e a carga viral do
HBVDNA a princípio em intervalos de 1 a 3 meses durante
o primeiro ano de observação. Posteriormente a cada 6
meses de intervalo para confirmar que o paciente permanece
em estado de portador inativo
2- Estudos longitudinais de portadores inativos
relatam que 15% a 20% desenvolvem hepatite crônica no
decorrer dos anos e 1 a 17% têm reversão sustentada
para positividade do HBeAg.
3- A replicação do HBV pode ser reativada em
portadores inativos de HBV em situações especiais,
quando os pacientes são submetidos a imunossupressão
ou quimioterapia. Nesta eventualidade ao iniciar a
imunossupressão/quimioterapia é imperativo estabelecer
o tratamento antiviral
13
LYRA LG
ESTADO DE IMUNOTOLERÂNCIA NA INFECÇÃO
PELO VHB
Pacientes que adquiriram precocemente a infecção
VHB na infância têm o perfil sorológico com presença do
HBeAg, níveis bastante elevados de HBVDNA, ALT e AST
normais ou próximas do normal e lesão histológica mínima.
Estudos posteriores reportaram histologia hepática normal
ou próxima do normal em pacientes abaixo de 35-40 anos
de idade. Nesta situação, os pacientes estão em fase de
imunotolerância, a biópsia não é recomendada e o
tratamento antiviral não está indicado.
Estudos focados na fase de imunotolerância reforçam
que a biópsia hepática e o tratamento antiviral não devem
ser indicados neste pacientes:
1- 33 a 49% dos pacientes quando submetidos a
biópsia hepática estavam em estágio 0 (F-0) de fibrose e
os remanescentes em estágio I (F-1).
2- Após seguimento de 5 anos 41 de 48 pacientes
permaneceram em fase de imunotolerância, sem alteração
na histologia
3- Não foi observado desenvolvimento de carcinoma
hepatocelular após um período de seguimento de 10,5 anos
em pacientes na fase de imunotolerância.
• Keefe EB, Dieterich DT,Han SB,Jacobson IM, Martin P, Schiff ER,Tobias
H Wright TL. A treatment algorithm for the management of chronic
hepatitis B Virus Infection in the United States: An Update. Clin
Gastroenterol Hepatol 2006;4:936-962.
• Lok ASF, and McMahon BJ. AASLD Practice Guideline Update. Chronic
Hepatitis B: Update 2009.l Hepatology 2009;50:661-662.
• Papatheodoridis GV, Manolakopoulos S, Liaw YF, Lok A. Follow-up
and indications of liver biopsy in HBeAg negative chronic hepatitis
B virus infection with persistently normal ALT: a systematic review.
J Hepatol. 2012, 57(1): 196-202.
• Andreani T, Serfaty L, Nohand D et al. Chronic Hepatitis B virus in the
immunotolerant phase of infection: histologic findings and outcomes.
Clin Gastroenterol Hepatol. 2007,5:636-641
• Hui CK, Leumg N, Yuen ST et al. Natural history and disease
progression in Chineese chronic hepatitis B patients in immiune
tolerant phase. Hepatology, 2007; 46:395-401
Correspondência
Luiz Guilherme Costa Lyra
Av. Juracy Magalhães Junior 2096
Centro Medico Aliança - Bairro Rio Vermelho
41920-000 - Salvador - BA
[email protected]
Por outro lado, nos pacientes que permanecem com
ALT normal após um período de 3-6 meses de observação,
apresentam níveis de HBV DNA no soro > 20.000UI/mL
(100.000cp/mL), mas estão acima de 35-40 anos de idade,
deve ser considerada a biópsia hepática pela possibilidade
de atividade necroinflamatória ou fibrose de moderada a
intensa. Nesta situação não há o estado de imunotolerância
e o tratamento antiviral é preconizado.
REFERÊNCIAS RECOMENDADAS
• Seeger C, Mason WS. Hepatitis B vírus biology. Microbiol Mol Biol Ver.
2000;64:51-68.
• European Association for the study of the Liver (EASL). Clinical
practice guidelines: management of chronic hepatitis B.J Hepatol;
2009;50:227-242.
• Liaw YF, Leung N, Guan R, Lau GKK, Merican I, McCaughan E, Gane
H, Kao J-H, Omata M. Asian-Pacific consensus statement on the
managememnt of chronic hepatitis B: a 2005 update. Liver Int
2005;25:472-489.
• Lok ASF and McMahon BJ. Chronic Hepatitis B. Hepatology
2007;45: 507-539.
• Sociedade Brasileira de Hepatologia. Consenso sobre condutas nas
hepatites B e C. GED 2005; vol 24 (supl) 1:1-16.
• Chen CJ, Yang HI, Su J, Jen CL, You SL, Lu SN, et al. Risk of
hepatocellular carcinoma across a biological gradient of serum
hepatitis B virus DNA level. JAMA 2006;295:65-73.
• Iloeje UH, Yang HI, Su J, Jen CL, You SL, Chen CJ. Predicting cirrhosis
risk based on the level of circulating hepatitis B viral load.
Gastroenterology 2006;130:678-686.
• European Association for the study of the Liver (EASL). EASL Clinical
Practice Guidelines: Management of chronic hepatitis B virus
infectionJ. Hepatology 2012,57:167-18.
14
ESTEATOSE: COMO IDENTIFICAR OS PACIENTES QUE PROGRIDEM
À ESTEATO-HEPATITE
STEATOSIS: HOW TO IDENTIFY PATIENTS TO PROSPER STEATOHEPATITIS
(1)
Helena Cortez-Pinto, MD, PhD
Professor, Senior Consultant
Departamento de Gastrenterologia, Hospital Santa Maria, CHLN;
Unidade de Nutrição e Metabolismo, Faculdade de Medicina de Lisboa,
IMM; Lisboa, Portugal
INTRODUÇÃO
A frequência do fígado-gordo não-alcoólico (FGNA) tem
vindo a aumentar rapidamente, sobretudo devido à epidemia
de obesidade, que tem atingido especialmente os países
desenvolvidos. Além disso, tornou-se prática frequente, a
realização de análises e de ultrassons, de rotina, levando
a uma frequência crescente da identificação do FGNA.
Dada a elevada frequência desta situação clínica, é
de grande importância para o clínico conseguir identificar
quais os casos que correspondem à forma mais frequente
e benigna de esteatose, e quais os que têm esteatohepatite
(EHNA), em que se associa à esteatose, a lesão
hepatocelular e graus variáveis de fibrose, podendo progredir
para cirrose hepática em cerca de um quinto dos casos, e
eventual carcinoma hepato-celular.
Verificou-se que a presença de FGNA se associou a
maior taxa de mortalidade que a população geral, com um
odds-ratio de 1,57. De notar que os doentes com EHNA
apresentaram como maior causa de mortalidade acrescida,
a doença hepática, tendo maior mortalidade de causa
hepática que os doentes com esteatose apenas (Odds
ratio de 5,7). Também os resultados do estudo de Eksted
e col., revelaram que os doentes com EHNA tinham uma
redução da sobrevivência por doença cardiovascular e
mortes por doença hepática.
FACTORES DE RISCO DE PROGRESSÃO
Existe evidência que o risco de progressão vai depender
da interação entre fatores genéticos e ambientais. Existem
uma série de factores genéticos que têm vindo a ser
investigados. Inicialmente, a investigação dos fatores
genéticos era baseada na seleção prévia dos potenciais
genes candidatos, selecionados com base na patogénese
da doença. No entanto, desde 2008 surgiram vários estudos
chamados genome wide association (GWAS), que
permitiram estudar a maioria da variabilidade do genoma
humano. Vários estudos GWAS surgiram, em 2008, de
Romeo, em 2010 por Chalasani e em 2011 por Speliotes .
Verificou-se assim que o alelo G do rs738409 da Patatinlike phospholipase domain-containing protein 3 (PNPLA3)
conferia risco aumentado de maior gravidade histológica do
FGNA. Também a Microsomal triglyceride transfer protein
(MTP), que é crítica para a síntese e secreção de VLDL no
fígado, foi investigada, tendo-se verificado num estudo inicial
que os doentes com EHNA tinham maior incidência do
2
genótipo G/G , o que não foi depois confirmado num estudo
3
posterior com maior número de doentes .
São ainda considerados classicamente como
fatores de risco de progressão da doença, a idade
superior a 45 anos, a presença de DM tipo 2 e a
2
Obesidade (IMC >30 kg/m ). De facto, um estudo recente
com cerca de 2,5 milhões de pessoas revelou que a
presença de diabetes aumentava duas vezes o risco de
4
doença hepática grave . Um outro estudo muito recente
de Pais, verificou que em 25 doentes com FGNA, não
NASH, os que tinham sobretudo inflamação lobular
5
progrediram para EHNA ou fibrose em ponte .
IDENTIFICAÇÃO DOS DOENTES COM ESTEATOSE
SIMPLES QUE VÃO PROGREDIR PARA EHNA
Perante o doente com FGNA o golden standard é ainda
a realização de biopsia hepática. Contudo, é impossível
fazer biopsia a todos os doentes, já que o procedimento
tem riscos, é desconfortável, caro, e com erros de
amostragem. Assim, temos que recorrer a métodos não
invasivos, entre os quais temos testes serológicos, scores
compostos, estudos imagiológicos, e avaliação da
elasticidade hepática. Após a realização destes testes,
poderemos então decidir da realização da biopsia hepática,
ou considerar que é dispensável.
Vários testes compostos são capazes de predizer
NASH. O NASH Test, que é o steato-test +AST, o índice
Palekar usa cinco variáveis incluindo idade, maior ou igual
2
a 50, sexo feminino, AST ≥45 IU/l, BMI ≥30 mg/kg , razão
AST/ALT ≥0.80, e ácido Hilauronico ≥55 microg/l. Outro
índice é o Shimada, que usa a adiponectina sérica, HOMA
IR, e o colagéneo tipo IV. Contudo, nenhum destes testes
foi validado de forma independente no FGNA ou está a ser
usado na prática clínica de rotina.
Os testes que têm despertado maior interesse são
os relacionados com os marcadores de apoptose como
os que incluem fragmentos CK18. Temos o modelo de Nice
15
CORTEZ-PINTO H
utilizando a presença de síndrome metabólico, ALT e os
fragmentos CK 18, proposto por Feldstein ou mais
recentemente a associação de CK18 e Fas sérico, como
6
publicado por Tamimi . Contudo, é justo dizer que nenhum
foi independentemente validado para o FGNA, ou está a
ser usado na rotina. Recentemente , uma meta-análise do
CK 18, mostrou uma especificidade agrupada de 0.83.
Quanto aos métodos de imagem, nenhum método é
ideal para distinguir a EHNA. No entanto, um score de
ultrassons, definiu um fatty liver index, em que os autores
7
verificaram que um valor superior a 4 podia predizer EHNA .
Também uma técnica cintigráfica, usando o tecnetium 99
parece ser útil na distinção entre EHNA e esteatose
simples. Tem ainda a vantagem de poder fazer-se em
simultâneo uma cintigrafia de perfusão do miocárdio,
8
permitindo dar informação em relação à função cardíaca .
Finalmente é muito importante predizer o grau de
fibrose. Existe um grande número de scores não-invasivos
para predizer fibrose avançada, sobretudo baseados na
razão AST / ALT, plaquetas e idade. Os dois scores que
mais foram estudados são o NAFLD fibrosis score que
usa também o índice de massa corporal, a evidência de
diabetes ou resistência à insulina e os níveis de albumina,
9,10
e o Bard score .
De notar, que num grande estudo multicêntrico, estes
scores não-invasivos e simples revelaram ser muito bons
em predizer a o prognóstico a longo termo, tanto no que
11
respeita acontecimentos hepáticos como mortalidade .
Em relação às técnicas de imagem existem
atualmente várias técnicas para avaliar a fibrose,
®
nomeadamente a Elastografia transitória (FibroScan ), a
Radiação acústica ARFI, Elastografia de ressonância
magnética e a Elastografia de tempo real. Em relação ao
Fibroscan, dois estudos revelaram uma boa correlação com
12,13
a histologia, sobretudo nos extremos, F0 e F4 . Um
avanço recente útil é a possibilidade de usar a sonda XL
que se associou a menor taxa de falência, mas também a
14
menor rigidez média . Isto é importante dado que uma
percentagem importante destes doentes são obesos. Outra
técnica não invasiva para avaliar a fibrose é o ARFI ou
Acoustic Radiation Force Impulse (ARFI), que tem a
vantagem de estar acoplada ao Ecógrafo e consegue
distinguir fibrose baixa grau (0-2) de alta (3-4) com uma
especificidade e sensibilidade de 90%. Outra técnica muito
recente é a elastografia de real-time onde se pode avaliar o
grau de fibrose pela razão entre 2 pontos fígado e no baço.
Em resumo, parece-nos que a conjunção de scores
relativamente simples, com métodos de avaliação da
fibrose, vai em muitos casos permitir definir com alguma
segurança, que estamos perante uma esteatose simples,
e dispensar a biopsia hepática. Também quanto existe
evidência clínica de cirrose, nos parece não ser necessário
a biopsia. Nos casos em que a dúvida permanece, só a
realização da biopsia permitirá esclarecer a situação.
16
REFERÊNCIAS
1. Speliotes EK, Butler JL, Palmer CD, Voight BF, Hirschhorn JN. PNPLA3
variants specifically confer increased risk for histologic nonalcoholic
fatty liver disease but not metabolic disease. Hepatology
2010;52:904-12.
2. Namikawa C, Shu-Ping Z, Vyselaar JR, et al. Polymorphisms of
microsomal triglyceride transfer protein gene and manganese
superoxide dismutase gene in non-alcoholic steatohepatitis. Journal
of Hepatology 2004;40:781-6.
3. Oliveira CP, Stefano JT, Cavaleiro AM, et al. Association of
polymorphisms of glutamate-cystein ligase and microsomal
triglyceride transfer protein genes in non-alcoholic fatty liver disease.
Journal of Gastroenterology and Hepatology 2010;25:357-61.
4. Porepa L, Ray JG, Sanchez-Romeu P, Booth GL. Newly diagnosed
diabetes mellitus as a risk factor for serious liver disease. CMAJ :
Canadian Medical Association journal 2010;182:E526-31.
5. Pais R, Charlotte F, Fedchuk L, et al. A systematic review of followup biopsies reveals disease progression in patients with nonalcoholic fatty liver. Journal of Hepatology 2013;59:550-6.
6. Tamimi TI, Elgouhari HM, Alkhouri N, et al. An apoptosis panel for
nonalcoholic steatohepatitis diagnosis. Journal of Hepatology
2011;54:1224-9.
7. Ballestri S, Lonardo A, Romagnoli D, et al. Ultrasonographic fatty
liver indicator, a novel score which rules out NASH and is correlated
with metabolic parameters in NAFLD. Liver international
2012;32:1242-52.
8. Masuda K, Ono M, Fukumoto M, et al. Usefulness of Technetium-99
m-2-methoxy-isobutyl-isonitrile liver scintigraphy for evaluating
disease activity of non-alcoholic fatty liver disease. Hepatology
research: the official journal of the Japan Society of Hepatology
2012;42:273-9.
9. Angulo P, Hui JM, Marchesini G, et al. The NAFLD fibrosis score: A
noninvasive system that identifies liver fibrosis in patients with
NAFLD. Hepatology 2007;45:846-54.
10. Harrison SA, Oliver D, Arnold HL, Gogia S, NeuschwanderTetri BA. Development and validation of a simple NAFLD clinical
scoring system for identifying patients without advanced
disease. Gut 2008;57:1441-7.
11. Angulo P, Bugianesi E, Bjornsson ES, et al. Simple Noninvasive
Systems Predict Long-term Outcomes of Patients With Nonalcoholic
Fatty Liver Disease. Gastroenterology 2013.
12. Yoneda M, Yoneda M, Mawatari H, et al. Noninvasive assessment
of liver fibrosis by measurement of stiffness in patients with
nonalcoholic fatty liver disease (NAFLD). Digestive and liver disease.
2008;40:371-8.
13. Wong VW, Vergniol J, Wong GL, et al. Diagnosis of fibrosis and
cirrhosis using liver stiffness measurement in nonalcoholic fatty
liver disease. Hepatology. 2010;51:454-62.
14. Myers RP, Pomier-Layrargues G, Kirsch R, et al. Feasibility and
diagnostic performance of the FibroScan XL probe for liver stiffness
measurement in overweight and obese patients. Hepatology.
2012;55:199-208.
Correspondence to
Helena Cortez-Pinto, MD, PhD
Departamento de Gastrenterologia, Hospital Santa Maria, CHLN;
Unidade de Nutrição e Metabolismo,
Faculdade de Medicina de Lisboa, IMM; Lisboa, Portugal
Tel: +351217985187 - Mobile: +351918188955
TERAPIA TRÍPLICE EM HEPATITE C: FATORES DE RISCO PARA
COMPLICAÇÕES
TRIPLE THERAPY FOR HEPATITIS C: RISK FACTORS FOR COMPLICATIONS
Moises Diago
Hospital General Valencia. España
Los efectos adversos más comunes de la doble terapia
incluyen fatiga, cefalea, fiebre y mialgias, asimismo anemia
y neutropenia son frecuentes. Los síntomas psíquicos de
depresión, irritabilidad e insomnio son atribuibles al interferón
y con menos frecuencia.
La adición de un antiviral (Telaprevir o boceprevir) al
anterior tratamiento produce mas efectos adversos como
son rash cutáneo, anemia y síntomas anorrectales en el
caso de Telaprevir y anemia y disgeusia en el caso de
Boceprevir.
No existen factores predictivos de aparición de dichos
efectos adversos salvo la anemia que en pacientes con triple
terapia se ha asociado a pacientes de mayor edad, menor
índice de mas corporal y niveles mas bajos de hemoglobina.
La variabilidad en los niveles de ITPA ( inosin trifosfato
pirofosfatasa) ha sido identificado como un factor para la
anemia tanto en la doble como en la triple terapia. Los
pacientes con niveles bajos de actividad de ITPA (que hidroliza
el inosin trifosfato) tienen menores tasas de anemia que
aquellos que presentan niveles altos, como puede verse en
(1)
Figura 1 .
No se conocen factores predictivos de aparición de
otros efectos adversos pero es posible que factores
genéticos hoy no conocidos pueden estar implicados.
Un hecho bien conocido con la doble terapia es que la
aparición de efectos adversos ,asi como su intensidad son
mayores en los pacientes con enfermedad hepática
(2)
avanzada como muestra el estudio de Vezali .Ver Tabla 1 .
Con la triple terapia los pacientes con menos fibrosis
presentan efectos secundarios menos intensos que
aquellos que tienen fibrosis avanzada como ha mostrado
(2)
un subanálisis del estudio Advance con Telaprevir .
(3)
Otro subanálisis del estudio Realize de Pol ha
mostrado efectos adversos mas severos en los pacientes
cirróticos que en aquellos con menos lesión
Los datos del programa de acceso temprano francés
a Telaprevir y boceprevir realizado en pacientes cirróticos
no respondedores han mostrado efectos adversos severos
(incluso descompensaciones,infecciones y muerte) con
este tratamiento. Un análisis de este estudio ha mostrado
que factores de riesgo de complicaciones severas son
tener menos de 100000 plaquetas y albumina inferior a
(4)
3,5 gr/L.Ver Tabla 2 .
REFERENCIAS
1. Sulkowski MS, et al. Hepatology 2011;54(Suppl. S1):798A
2. Vezali E, et al. Clin Ther 2010;32:2117-38
3. Pol S, et al. Hepatology 2011;54(Suppl. S1):374A
4. Héode C, et al. J Hepatology 2013;59:434-441.
Palabras clave: Hepatitis C. Terapia triple. Efectos adversos
El autor realiza ensayos clínicos con las siguientes compañías:
Gilead, BMS, MSD, Roche, Janssen, Vertex, Boeringher, Abbvie ,
GSK y Bayer.
17
HEPATITE C – O QUE AINDA PRECISA SER RESPONDIDO?
HEPATITIS C – WHAT STILL NEEDS TO BE ANSWERED?
Moises Diago
Hospital General Valencia. España
El tratamiento de la hepatitis C ha experimentado
notables mejoría en las dos últimas décadas sobre todo
en eficacia llegando actualmente a tasas de curación en
torno a 80% para genotipo 1. Sin embargo existen
problemas importantes que condicionan que el impacto
del tratamiento sobre el global de la población afecta de
hepatitis C es todavía muy pequeño ( se calcula que entre
el 6-10% de población afecta).
Las limitaciones más importantes vienen derivadas de:
1 - Diagnóstico insuficiente
2 - Aplicabilidad disminuida por las características del
tratamiento
3 - Eficacia limitada en algunas poblaciones
4 - Efectos adversos intensos
5 - Complejidad, coste y efectos secundarios de la
triple terapia
Diagnostico insuficiente
Al ser un proceso asintomático la detección de la
hepatitis C se hace en chequeos habitualmente y la tasa
de diagnostico viene a ser de un 30% de los afectados en
el mejor de los casos
Aplicabilidad disminuida por las características
del tratamiento
Un reciente estudio español (Crespo) ha mostrado
que el24% de pacientes infectados por VHC presentan
contraindicación al tratamiento y del 76% restante se
tratan un 44% de los mismos, en tanto el 56%no se trata
por decisión del paciente o restricciones en el
reeembolso.
Complejidad, coste y efectos secundarios de la
triple terapia
Lead-in, elevado número de comprimidos en 3 tomas
con alimentos, terapia guiada por respuesta, efectos
adversos manejables pero en ocasiones intensos ,
interacciones con otros fármacos y posibilidad de generar
resistencias en los pacientes con pobre respuesta o poco
adherentes hacen que el tratamiento sea difícil para
médicos poco experimentados. A ello se unen eficacia no
probada en pacientes diferentes de genotipo 1,en
transplantados, enfermedad renal crónica y coinfectados
con VIH.
El alto coste del tratamiento está condicionando una
baja aplicabilidad del tratamiento en muchos países.
Incluso en los países mas desarrollados se ha impuesto
restricciones al tratamiento por parte de los pagadores.
Sin duda nos dirigimos hacia la consecución de un
tratamiento mejor que seria libre de interferón, con menos
comprimidos y una dosis diaria, mejor tolerado, que no
genere resistencias o con alta barrera a la misma y con
acción pangenotipica, pero esto es algo que veremos a
medio o largo plazo.
Palabras clave: Hepatitis C. Retos Terapia antiviral.
El autor realiza ensayos clínicos con las siguientes compañías:
Gilead, BMS, MSD, Roche, Janssen, Vertex, Boeringher, Abbvie,
GSK y Bayer.
Correspondencia para
Moises Diago, MD
Hospital General Valencia
Avenida Tres Cruces, 2
46014 Valencia, Espanha
+34 961 97 20 00
[email protected]
Eficacia limitada en algunas poblaciones
Tanto la doble como la triple terapia muestra una
dependencia importante de la respuesta al interferón y en
consecuencia una menor eficacia en cirróticos,
afroamericanos, IL28 CT o TT, no respondedores previos a
interferón, hemodializados, transplantados.
Efectos adversos intensos
A los del interferón y ribavirina se unen los de los
antivirales de acción directa, como son mayor anemia, rash
,prurito anal, disgeusia,etc
18
HEPATOCELLULAR CARCINOMA IN NON-CIRRHOTIC LIVER
CARCINOMA HEPATOCELULAR EM FÍGADO NÃO-CIRRÓTICO
Peter Robert Galle
Department of Internal Medicine
University Medical Center of the Johannes Gutenberg University,
Mainz, Germany
SUMMARY
Hepatocellular carcinoma (HCC) is the third most
common cause of cancer-related mortality globally and the
leading cause of death amongst patients with liver cirrhosis,.
HCC develops in more than 80% of cases on the background
of a cirrhotic liver and liver cirrhosis itself represents the
main risk factor for the development of HCC. Nevertheless,
HCC may arise in non-cirrhotic liver in 15%-20% of cases
in Western countries. Compared to HCC in cirrhotic liver,
this tumor entity has some peculiarities such as a lower
male preponderance, a bimodal age distribution, or a lower
prevalence of established risk factors such as chronic viral
hepatitis or chronic alcohol abuse. Patients are diagnosed
in a more advanced tumor stage, often with a single large
hepatic mass detected by the occurrence of tumor-related
symptoms. Due to preserved liver function, extended liver
resection is possible in many cases; however, overall (OS)
and disease-free survival (DFS) are impaired by a high rate
of recurrence.
Almost all studies in this setting are reports from
surgical cohorts with patients undergoing solely liver
resection as primary treatment in a potentially curative
intent, and only a few studies have addressed the
management and outcomes in unselected cohorts or in
patients with metastatic disease. We have performed a
retrospective study in an unselected cohort of 105
consecutive patients with HCC in non-cirrhotic liver to define
clinicopathologic factors influencing patients' prognosis.
This short article summarizes the peculiarities of
hepatocellular carcinoma in non-cirrhotic liver.
DEMOGRAPHICS
Hepatocellular carcinoma is the leading cause of death
in cirrhotic patients. Liver cirrhosis per se is the main risk
factor for HCC in almost 80% of cases (due to continuous
necroinflammation and hepatocellular regeneration). However,
15%-20% of HCCs develop without underlying liver cirrhosis.
Occurrence ranges widely from 7% to 54% (mean 15%20%) across geographic regions and underlying liver
disease. There is a lower male preponderance (male/female
ratio of 1.3/2.1; compared with 3.2/8.1 in cirrhotic patients)
and a trend to less advanced mean age compared with
cirrhotic patients.
Cirrhotic patients display an unimodal age distribution
peaking at the 7th decade. In contrast, non-cirrhotic patients
show a bimodal age distribution with peaks at the 2nd
(fibrolamellar variant) and the 7th decade.
ETIOLOGY
A large proportion of patients with HCC in non-cirrhotic
livers have no identifiable risk factor. Alcohol abuse is
remarkably less frequent in non-cirrhotic patients. Likewise,
prevalence of HBsAg/anti-HBc and anti-HCV is lower in noncirrhotic HCC patients compared with HCC patients with
cirrhosis.
The role of non alcoholic steato hepatitis (NASH) is
increasingly acknowledged. HCCs in patients with features
of metabolic syndrome mainly occur in the absence of
significant fibrosis. They are more often well differentiated
and in some cases, they may arise from pre-existing liver
cell adenomas.
Genotoxic compounds play an additional role. Chemical
industrial carcinogens such as nitrosamines, vinyl chloride,
aromatic amines, pesticides, and arsenic contribute to
hepatocarcinogenesis. Tobacco consumption results in
benzopyrene exposure.
HCC development in non-cirrhotic liver has also
been described in inherited diseases (hereditary
hemochromatosis (HFE C282Y), alpha-1-antitrypsin
deficiency (also heterozygosity), porphyria,
hypercitrullinemia, type I glycogen storage disease
(adenoma-carcinoma sequence), in congenital disease such
as Alagille syndrome and congenital hepatic fibrosis and in
the context of altered hepatic vascular pathology (BuddChiari syndrome, nodular regenerative hyperplasia, hepatoportal sclerosis).
Sex hormones can contribute to HCC devlopment. This
has been shown for anabolic C17-alkylated androgenic
steroids but also - less evident - for contraceptive steroids,
which may lead to hepatocellular adenomas (HCA) which
in turn carry the risk of transformation.
PATHOLOGICAL FINDINGS
The non-tumoral liver of non-cirrhotic HCC patients in
most cases shows histological changes. This includes
19
GALLE PR
fibrosis, inflammation, steatosis, parenchymal iron overload
(> 50%) and large cell dysplasia.
The tumor is mostly a single large mass (10 cm) (49%85%) and less common multinodular. The trabecular type
is most common (41%-76%), the fibrolamellar type is found
in about 11%. AFP elevation is detected in 31%-67% of the
tumors compared to 59%-84% in cirrhotic patients.
HCCs in non-cirrhotic livers are also genetically distinct
from HCCs in cirrhotic livers: Compared with HCC in cirrhotic
liver they have a lower rate of p53 mutations, a higher
prevalence of ß-catenin mutations, a higher prevalence of
p14 inactivation, show global gene methylation, higher
prevalence of microsatellite instability (MSI) and
overrepresentation of copy number gain 8q5.
• Molecular hepatocarcinogenesis in non-cirrhotic
HCC is not well elucidated
• The non-tumoral liver shows histological alterations
in most cases
• Patients often present with a single large mass with
clinical symptoms
• More advanced tumor stage at the time of diagnosis;
however, much higher amenability to hepatic resection
• Overall and disease-free survivals after resection of
non-advanced tumors comparable to that achieved with
liver transplantation in cirrhotic patients carrying an early
tumor
• OS more strictly dependent on tumor burden (and
its recurrence rate after resection) and much less
influenced by liver function
DIAGNOSIS
LITERATURE
Diagnosis is often delayed due to lack of surveillance,
incidental detection (30%) at routine check-up is common.
Clinical symptomes are observed in 70% of the patients
and include abdominal pain, jaundice, nausea, toxic
syndrome (asthenia, malaise, fever, anorexia, weight loss)
and tumor rupture.
TREATMENT
The treatment of choice is hepatic resection with a
perioperative mortality of 0%-6% and morbidity of 8%40%.
The overall survival is dependent on tumor burden and
less influenced by liver function compared to cirrhotic
patients. This results in better overall survival (5 years: 25%81%) and better disease-free survival (24%-58%) compared
with cirrhotic patients with small tumors.
Recurrence is frequent (27%-73%), occuring in 2/3 of
the patients within 2 years (intrahepatic metastasis).
Recurrence is often treated by surgery (11%-39%). Thus,
stringent follow-up during the first 2 years after resection is
recommended.
Orthotopic liver transplantation shows poor outcome
with a 5-year survival rate of 11.2% and recurrence in 50%
of the cases (75% within 2 years) due to advanced tumor
stage at the time of OLT.
Marcus A. Wörns, Timon Bosslet, Anja Victor, Sandra Koch, Maria
Hoppe-Lotichius, Michael Heise, Torsten Hansen, Michael B. Pitton,
Ina M. Niederle, Marcus Schuchmann, Arndt Weinmann, Christoph
Düber, Peter R. Galle & Gerd Otto. Prognostic factors and outcomes
of patients with hepatocellular carcinoma in non-cirrhotic liver
Scandinavian Journal of Gastroenterology; June 2012, Vol. 47, No. 6,
718-728
This work was not supported by any grant or funding source.
The author has received travel funds from Bayer
Correspondence to
Peter R. Galle, MD, PhD,
Department of Internal Medicine I
University Medical Center of the Johannes Gutenberg
University Mainz
Langenbeckstrasse 1, 55101 Mainz, Germany
Tel. +49 6131 177275; Fax +49 6131 175595
[email protected]
CONCLUSIONS
• Lower male preponderance and a bimodal age
distribution
• A large proportion of patients have no identifiable
risk factors
• Lower prevalence of the main risk factors for HCC,
namely HBV, HCV, and chronic alcohol abuse
• Metabolic syndrome, obesity, and NASH are risk
factors for HCC in the non-cirrhotic liver
20
RECURRENT HEPATITIS C AFTER LIVER TRANSPLANTATION
HEPATITE C RECORRENTE APÓS TRANSPLANTE DE FÍGADO
Marina Berenguer
La Fe Hospital, University Valencia and Ciberehd
HCV remains the leading indication for liver
transplantation in most transplant centers; interestingly,
while the proportion of cases attributable to HCV appears
to have plateaued, those due to hepatocellular carcinoma
(HCC) are rapidly increasing, and most of these cases
are due to HCV. Unfortunately, the outcome of liver
transplantation is impaired in HCV-infected transplant
recipients due to recurrent hepatitis C. At least 30% of
these individuals may progress to advanced liver disease
over a 1 to 7-year period.
Many factors are associated with an increased risk
of disease progression, but only effective antiviral therapy
has proved to have a major impact on the natural history
of HCV-associated graft disease. Indeed, viral eradication
with antiviral therapy results in histologic, biochemical
and clinical improvement resulting in a substantial
decrease in the risk of graft-related mortality. Antiviral
therapy with interferon- based regimens is the standard
of care. Treatment is usually considered in patients with
F2 or F0-1 and significant inflammation based on protocol
graft biopsies ± non-invasive monitoring tools (particularly
fibroscan). Until very recently, dual therapy based on
pegylated interferon and ribavirin was the standard of care
for all HCV genotypes. In the last year, triple therapy with
new oral protease inhibitors, boceprevir and telaprevir, have
become the standard of care for genotype 1 infected
recipients.
Dual therapy with ribavirin results in sustained viral
response (SVR) rates in the range of 25-40% in patients
with HCV genotype 1 and 45-65% in non-1 HCV genotypes.
Viral kinetics predict treatment response; if an early viral
response evaluated at 12 weeks post-treatment initiation
is not achieved, it is highly unlikely that the patient will
achieve an SVR with the standard 12-month treatment.
Higher response rates are achieved in those who can
tolerate the complete course of aggressive regimens with
interferon and particularly ribavirin given at full doses, in
those treated before there is progression to cirrhosis, and
in those with IL28B CC polymorphism of both the donor
and the recipient. Side effects occur very frequently leading
to a constrained follow-up, frequent dose reductions or
discontinuations, use of granulocyte colony stimulating
Moderna Hepatologia – Vol. 39 – Nº 1 – Jan-Jun 2013
factor and erythropoietin, hospital admissions and blood
transfusions. Most side effects are of hematologic (anemia,
neutropenia, thrombocyotpenia), or psychiatric nature
(depression). In addition, rejection and "de novo
autoimmune hepatitis" can be triggered by the use of
interferon.
Data on triple therapies with either telaprevir or
boceprevir are still preliminary but promising. The main
findings from these early studies show that while
challenging, because targeting "difficult to treat" patient
population (prior non-response, advanced fibrosis, high
baseline HCV RNA), improved SVRs are expected since
high rates of extended rapid viral response (eRVR) (of
aobut 80%) and end-of-treatment responses (of about
65%) are being reported with a positive correlation between
eRVR and SVR reported by one group. Unfortunately,
adverse events are very common with triple therapy, even
more than with dual therapy resulting in frequent dose
reductions, constraint follow up and significant morbidity
and even mortality. Anemia is the most frequent side
effect reported occurring in almost all patients, resulting
in the use of growth factors in more than 50% of treated
patients and transfusions in about 30%. Infections are
worrisome since most deaths reported to date with triple
therapy were caused by severe infections. Renal
dysfunction is also reported, likely reflecting drug-drug
interactions. Drug-drug interactions between calcineurin
inhibitors and protease inhibitors a very relevant issue
that needs to be acknowledged. Boceprevir and Telaprevir
are metabolized via the Cytochrome P450 3a system
and compete with Cyclosporine, Tacrolimus, Everolimus
and Rapamycine for metabolism. Emerging data suggest
that the area under the curve for these immunosuppressive
agents is dramatically increased when given with Telaprevir
or Boceprevir. These interactions are particularly relevant
between tacrolimus and telaprevir, but can be managed
successfully with strict and frequent monitoring of
immunosuppressive levels. When starting protease
inhibitors, calcineurin inhibitors doses need to be reduced
to avoid toxicity while increase of the doses to pretreatment or even higher doses are required once protease
inhibitors are discontinued in order to avoid rejection
episodes. As in the non-transplant setting, there is great
hope for non-interferon based therapies. Apart for the
potential for significantly greater efficacy, it is the lack of
toxicity, the potential for greater applicability and the lack
of significant drug-drug interactions that make these
therapies very attractive.
21
BERENGUER M
REFERENCES
• Berenguer M, Charco R, Manuel Pascasio J, Ignacio Herrero J. Spanish
society of liver transplantation (SETH) consensus recommendations
on hepatitis C virus and liver transplantation. Liver Int.
2012;32(5):712-31
• Werner CR, Egetemeyr DP, Lauer UM, Nadalin S, Königsrainer A,
Malek NP, et al. Interleukin-28B polymorphisms are associated with
histological recurrence and treatment response following liver
transplantation in patients with hepatitis C virus infection. Hepatology
2011;53:317-324
• Berenguer M, Roche B, Aguilera V, Duclos-Vallée JC, Navarro L,
Rubín A et al. Efficacy of the retreatment of hepatitis C virus
infections after liver transplantation: Role of an aggressive approach.
Liver Transpl. 2013;19(1):69-77
• Mutimer D. Understanding the switchbacks: the impact of direct
antivirals on the minimization of hepatitis C virus recurrence after
transplantation. Liver Transpl. 2012 Nov;18 Suppl 2:S47-51..
• McCaughan G. New therapies against HCV: expected risks and
challenges associated with their use in the liver transplant setting.
J Hepatol 2013 (in press).
• Berg CP. Telaprevir-based triple therapy in liver transplant patients
with hepatitis C virus: A 12-week pilot study providing safety and
efficacy data. Liver Transpl. 2012;18(12):1464-70.
• Coilly A, Roche B, Dumortier J, Botta?Fridlund , Leroy V, Pageaux GP,
et al. Efficacy and safety of protease inhibitors to treat Hepatitis C
recurrence after liver transplantation: A first multicentric experience.
Hepatology 2012 (Abstract 9, AASLD meeting 2012).
• Punpapong S, Murphy JL, Henry TM, Ryland K, Satyanaravana R,
Rosser B, Yataco ML, Keaveny A. Preliminary experience using
Telaprevir with Peginterferon and Ribavirin for treatment of HCV
genotype 1 after liver transplantation. Hepatology 2012 (Abstract
10, AASLD meeting 2012).
• Burton JR, O'Leary JG, Verna EC, Lai JC, Everson GT, Trotter JF, et al.
A Multicenter Study of Protease Inhibitor-Triple Therapy in HCVInfected Liver Transplant Recipients: Report From The CRUSH-C
Group. Hepatology 2012 (Abstract 211, AASLD meeting 2012).
• Magel B, Koning L, Charlton M, Carey EJ, Byrne TJ, Rakela J, Vargas
HE. Multicenter Preliminary Experience Utilizing Boceprevir with
Pegylated Interferon and Ribavirin for Treatment of Recurrent
Hepatitis C Genotype 1 after Liver Transplantation. Hepatology
2012 (Abstract, AASLD meeting 2012).
• Mantry PS, Wu C, Weinstein JS, Mubarak A, Nazario HE, Madani B, et
al. Early and End of Treatment Virologic Responses in Patients with
Hepatitis C (HCV)genotype I Recurrence After Liver Transplant
Treated with Triple Therapy using Telaprevir: A Single Center
Experience. Hepatology 2012 (Abstract, AASLD meeting 2012).
• O'Leary JG, McKenna GJ, Klintmalm G, Davis GL. 100% cEVR PostLiver Transplant with Telaprevir Triple Drug Therapy. Hepatology
2012 (Abstract, AASLD meeting 2012).
• Kiser JJ, Burton JR, Anderson PL, Everson GT. Review and
management of drug interactions with boceprevir and telaprevir.
Hepatology. 2012;2(13):25653.
Correspondence to
Marina Berenguer, MD
Servicio de HepatoGastroenterología, Hospital Universitario La Fe,
Avenida Campanar, 21, 46009 Valencia, Spain
22
Moderna Hepatologia – Vol. 39 – Nº 1 – Jan-Jun 2013
COMPLICAÇÕES METABÓLICAS PÓS-TRANSPLANTE
METABOLIC COMPLICATIONS POST-TRANSPLANT
Due to improvements in surgical techniques,
immunosuppression regimes, and management of
infections, survival following liver transplantation (LT) is
significantly better in recent years. Currently, median
survival is about 90% at one year and 60% at 10 years.
Most studies to date have focused on short and medium
term patient and graft survival, so that main causes of
patient mortality and graft dysfunction are now clearly
established and include, in the first years postLT,
infections and recurrent diseases. In the medium-long term
though non- hepatic causes such as de novo tumors or
cardiovascular events (CVE) represent the most frequent
causes of death. In a recent study by Rubin and col.
focusing on patients alive 10 years after LT, the authors
found that these non-hepatic causes become with time
the most important cause of morbidity and mortality. In
that study, metabolic complications, such as diabetes,
arterial hypertension, obesity and hyperlipidemia were very
common 10 years post-transplantation, and continued to
increase afterwards, rising along with increased life
expectancy after LT. In addition, cardiovascular events
occurred in a substantial proportion (17%) of these longterm survivors. In addition, several cardiovascular risk
factors coexisted in these long-term survivors, a condition
that increases the risk of CVE. Interestingly, chronic renal
dysfunction was very frequent among long-term survivors,
present in about one third of patients at 10 years, and
was independently associated with long-term survival as
well as development of CVE.
The prevalence of postLT diabetes ranges between
30% and 38% with de novo diabetes developing in 13% to
28% of patients. Factors related to the development of
postLT diabetes include pretransplant diabetes, treatment
with calcineurin inhibitors and steroids, as well as HCV
infection. Arterial hypertension is also very common
postLT, with a prevalence that varies between 35 and 75%
among series. Factors associated with this risk factor
include obesity, preexisting or worsening renal disease
and immunosuppressive drugs, particularly calcineurin
inhibitors. Hyperlipidemia is also very common postLT. In
particular, hypercholesterolemia is prevalent in 51 to 66%
of liver transplant recipients and hypertriglyceridemia in
up to 50% of patients. Factors associated with dyslipidemia
include obesity as well as immunosuppressive agents such
as mTOr inhibitors, steroids and calcineurin inhibitors.
Finally, obesity, a global epidemic, also is very relevant
in the LT setting. In one study, more than 15% of patients
who were transplanted with normal weight became obese
after the first year posttransplant and more than 25 at 3
years. PostLT weight gain is significantly greater in
patients over 50 yrs of age and those transplanted for
chronic liver disease as compared with fulminant liver
failure. As mentioned previously, these cardiovascular risk
factors increase with follow up after LT emphasizing the
need to prevent and treat them aggressively after LT.
The impact that these cardiovascular risk factors have
on postLT outcome is less clear. Studies to date have
included small series, short follow up and different
definition of cardio-vascular event. Overall though, the
incidence of cardiovascular events is about 10% at 3 yrs
postLT. In a study by Johnston et al, LT recipients had a
2-fold increased risk of cardiovascular deaths and 3-fold
increased risk of ischaemic events as compared to an
age and sex-matched population without liver
transplantation. In the previously mentioned study by Rubin
et al based on long-term survivors, at 10 years posttransplantation, most patients had at least 2
cardiovascular risk factors, and more than one third had
3 risk factors, and the cumulative rate of developing
cardiovascular events was greater than 15 % beyond 15
years. Risk factors associated with cardiovascular events
in the general population have also been implicated in the
transplant setting. In one recent metanalysis, the risk of
cardiovascular events in a LT recipient was found to be
13.56 (IC 95 % 8.98-18.15) (percentage of CV events every
10 patients-year) which is equivalent to a moderate-high
Framingham risk and significantly higher than that of the
non-transplanted population. In that metanalysis, the risk
of cardiovascular death every 10 persons-year was 4.50
(IC 95 % 3.01-5.98) for the transplant population. In
addition, patients transplanted for non-alcoholic
steatohepatitis were recently shown to be at greater risk
of cardiac-death postLT. Finally, overimmunosuppression
in the early postLT period was shown in a retrospective
study to increase the risk of cardiovascular death.
In summary, LT recipients have an increased risk of
developing cardiovascular risk factors, which increase the
risk of metabolic syndrome, resulting in an increased risk
of cardiovascular events and deaths due to cardiovascular
events. This is particularly true for patients with preLT
23
BERENGUER M
metabolic syndrome such as those transplanted for nonalcoholic steatohepatitis or in those overimmunosuppressed
postLT.
Measures to treat these cardiovascular risk factors
are similar to those used in the general population. These
measures should be put in place early after LT and mainly
focus lyfe-style, emphasizing the importance of exercise
and weight control. The aim in the control of diabetes is
to achieve a glycated haemoglobin of < 7% and fasted
glucose between 70 and 130 mg/dl. The first step in the
absence of renal disease is the use of oral antidiabetics.
If needed, insulin is the second step. Arterial tension
should be checked at every visit since misdiagnosis of
arterial hypertension appears to be quite common,
particularly among diabetic patients. A multicenter and
prospective Spanish study on "control of blood pressure
hypertension in almost 1000 liver transplant recipients
found that almost one third of the patients known to be
hypertensive have an inadequate control of their blood
pressure. Another remarkable result was that 25% of
patients never diagnosed as hypertensive after
transplantation had increased blood pressure at the time
of the study visit. The aim is to have blood pressure below
140/90 (in the diabetics, below 130/80). Most drugs used
include calcium antagonists, IECA and ARAII, diuretics
and cardioselective beta-blockers. More than 60%
hypertensive LT recipients require more than 2 drugs to
have an adequate control of the blood pressure. In terms
of treating hyperlipidemia, the measures that need to be
taken do not differ from the general population and should
be based on the presence or not of additional risk factors
as well as history of cardiovascular events. Statins and
fibrates are the drugs typically used. In order to avoid
statin toxicities in patients on immunosuppressive
therapies, statins should be started at the lowest possible
dosage and titrated upward slowly.
Antiagregation is required for secondary prevention.
In addition, diabetic patients with high cardiovascular risk
should receive primary prevention.
In conclusión, the presence of hypertension,
hyperelipidemia, diabetes and obesity after LT is very
common and is associated with a high risk of developing
cardiovascular morbidity and mortality. Treatment of
modifiable risk factors is required in this setting and should
be started early after LT and maintained over time. Healthier
diet, increased exercise, pharmacological therapies, and
modification of immunosuppression should be tailored to
the needs of the patients, taking into account their
cardiovascular risk profile.
24
REFERENCES
• Desai S, Hong JC, Saab S. Cardiovascular risk factors following
orthotopic liver transplantation: predisposing factors, incidence and
management. Liver Int.2010;30(7):948-57
• Ripoll C, Yotti R, Bermejo J, Banares R. The heart in liver transplantation.
J Hepatol 2011;54:810-822.
• Munoz SJ, Elgenaidi H. Cardiovascular risk factors after liver
transplantation. Liver Transpl 2005:S52-56.
• Martinez-Saldivar B, Prieto J, Berenguer M, de la Mata M, Pons JA,
Serrano T, Rafael-Valdivia L, et al. Control of blood pressure in liver
transplant recipients. Transplantation 2012;93:1031-1037
• Arekh J, Corley DA, Feng S. Diabetes, hypertension and hyperlipidemia:
prevalence over time and impact on long-term survival after liver
transplantation. Am J Transplant 2012;12:2181-2187.
• Albeldawi M, Aggarwal A, Madhwal S, Cywinski J, Lopez R, Eghtesad
B, Zein NN. Cumulative risk of cardiovascular events after orthotopic
liver transplantation. Liver Transpl 2012;18:370-375.
• Vanwagner LB, Bhave M, Te HS, Feinglass J, Alvarez L, Rinella ME.
Patients transplanted for nonalcoholic steatohepatitis are at
increased risk for postoperative cardiovascular events. Hepatology
2012;56:1741-1750.
• Rodriguez-Peralvarez M, Germani G, Papastergiou V, Tsochatzis E,
Thalassinos E, Luong TV, Rolando N, et al. Early tacrolimus exposure
after liver transplantation: relationship with moderate/severe acute
rejection and long-term outcome. J Hepatol 2013;58:262-270.
• Madhwal S, Atreja A, Albeldawi M, Lopez R, Post A, Costa MA. Is liver
transplantation a risk factor for cardiovascular disease? A metaanalysis of observational studies. Liver Transpl 2012;18:1140-1146
• Guckelberger O, Mutzke F, Glanemann M, Neumann UP, Jonas S,
Neuhaus R, Neuhaus P, et al. Validation of cardiovascular risk
scores in a liver transplant population. Liver Transpl 2006;12:394401.
• Watt KD, Charlton MR. Metabolic syndrome and liver transplantation:
a review and guide to management. J Hepatol 2010;53:199-206.
• Rubín A, Sánchez-Montes C, Aguilera V, Juan FS, Ferrer I, Moya A, et
al. Long-term outcome of 'long-term liver transplant survivors'.
Transpl Int. 2013;26(7):740-50
• Watt KD, Pedersen RA, Kremers WK, Heimbach JK, Charlton MR.
Evolution of causes and risk factors for mortality post-liver
transplant: results of the NIDDK long-term follow-up study. Am J
Transplant. 2010;10(6):1420-7.
Correspondence to
CIRROSE - O QUE AINDA PRECISA SER RESPONDIDO?
CIRRHOSIS - WHAT STILL NEEDS TO BE ANSWERED?
André Castro Lyra
Prof. Adjunto e Livre Docente do Departamento de Medicina da
Universidade Federal da Bahia
Coordenador do Serviço de Gastro-Hepatologia do Hospital São
Rafael
Resumo
A cirrose hepática é o resultado final de uma agressão continua
e prolongada contra o fígado por agentes etiológicos diversos,
sendo caracterizada pela substituição do tecido hepático
normal por fibrose que delimitam nódulos de hepatócitos
pouco ou não funcionais. A cirrose classicamente sempre foi
considerada como irreversível, todavia, recentemente, estudos
têm sugerido que, em situações particularizadas, pode ocorrer
a reversão, ainda que parcial, da cirrose hepática. Todavia,
em todas estas situações a reversão da fibrose ocorreu após o
controle ou eliminação do agente etiológico. O que precisa
ainda ser respondido neste contexto é o ponto exato de não
reversão da cirrose, e, uma vez atingido este ponto, quais as
terapias que apresentam potencial para reverter a fibrose. O
desenvolvimento de fibrose hepática está intimamente
associado com o aumento da regulação de citocinas
fibrogênicas, a elevação da permeabilidade intestinal e
neovascularização. Drogas com potencial anti-fibrótico são
ansiosamente aguardadas para os pacientes com cirrose
hepática em fase irreversível. A terapia celular tem sido
avaliada no tratamento das doenças hepáticas. Os resultados
dos estudos clínicos com terapia de células da medula óssea
têm demonstrado que este tratamento é aparentemente seguro
e exequível, pode promover um aumento da regeneração
hepática e melhorar parâmetros funcionais do fígado. No
entanto, como ainda estamos dando os primeiros passos em
direção ao desenvolvimento de uma nova terapia, muitos
aspectos devem ser endereçados para melhorar a eficácia,
incluindo a melhor população de células a ser usada, a dose
correta, a necessidade de doses repetidas e a melhor rota de
administração.
Palavras-chave: Cirrose; Fibrose hepática; Terapia celular
Moderna Hepatologia – Vol. 39 – Nº 1– Jan/Jun 2013
A cirrose hepática é o resultado final de uma agressão
continua e prolongada contra o fígado por agentes
etiológicos diversos, sendo caracterizada pela substituição
do tecido hepático normal por fibrose que delimitam nódulos
de hepatócitos pouco ou não funcionais. As principais
características morfológicas de cirrose incluem: fibrose
difusa, nódulos regenerativos, alteração da arquitetura
lobular e estabelecimento de “shunts” vasculares intrahepáticos entre vasos aferentes (veia porta e artéria
(1)
hepática) e eferentes (veias hepáticas) do fígado. Os
"shunts" vasculares são determinados pela topografia dos
septos fibróticos vascularizados e representam uma
(1)
característica essencial da cirrose.
Outras
características relevantes incluem: capilarização de
sinusóides e fibrose perissinusoidal, trombose vascular
e lesões obliterante em tratos portais e veias hepáticas,
perfusão inadequada do parênquima lobular e consequente
(1)
hipóxia tecidual. Em conjunto, estas alterações são
responsáveis pelo desenvolvimento de hipertensão portal
e suas complicações. A hipertensão portal é o principal
mecanismo que leva à morte dos pacientes cirróticos.
A cirrose é uma condição clinica que classicamente
sempre foi considerada como irreversível, todavia,
recentemente, estudos têm sugerido que, em situações
particularizadas, pode ocorrer a reversão, ainda que
parcial, da cirrose hepática. Na hepatite crônica B, o uso
de análogos dos nucleotídeos/necleosideos tem proporcionado benefícios significativos. Tal terapia não pode
apenas retardar a progressão da fibrose, mas revertê-la.
Recentemente, o impacto sobre a inflamação e fibrose do
fígado em pacientes que receberam pelo menos três anos
de terapia entecavir acumulada foi avaliada. Os autores
constataram que 96% dos pacientes com hepatite crônica
B que foram tratados com entecavir nesta coorte de longo
prazo alcançaram melhora histológica significativa e
(2)
regressão da fibrose ou cirrose. O uso do tenofovir, da
mesma forma, também está associado à regressão da
fibrose. Depois da utilização do tenofivir por cinco anos,
dos 96 pacientes com cirrose no início do estudo, 71
(74%) não apresentavam mais cirrose, enquanto três de
252 pacientes sem cirrose no início evoluíram para cirrose
(3)
em cinco anos.
Um subgrupo de pacientes com cirrose hepática por
hepatite C que obtém resposta virologica sustentada pode
(4)
apresentar regressão da fibrose. Em outras causas de
cirrose hepática, como hepatite autoimune e doença
alcoólica do fígado, da mesma forma tem sido descrita a
(5,6)
regressão da fibrose hepática.
25
LYRA AC
Todavia, em todas estas situações a reversão da
fibrose ocorreu após o controle ou eliminação do agente
etiológico. O que precisa ainda ser respondido neste
contexto é o ponto exato de não reversão da cirrose, que
parece estar associado ao surgimento da angiogênese e
dos "shunts" vasculares, e, uma vez atingido este ponto,
quais as terapias que apresentam potencial para reverter
a fibrose. O desenvolvimento da fibrose hepática está
intimamente associado com aumento da regulação de
citocinas fibrogênicas, como o TGF-B1, aumento da
permeabilidade intestinal e neovascularização. Inibidores
de TGF-B1 têm um potencial para tratamento em curto
prazo no sentido de atenuar a fibrose hepática. A inibição
da sinalização por meio de TLR4 LPS pode ser um alvo de
escolha para o tratamento prolongado de pacientes com
(7)
fibrose hepática. A associação estreita entre a fibrose
hepática e neovascularização pode permitir o tratamento
da fibrose com a inibição da neovascularização
inapropriada. Portanto, drogas com potencial antifibrótico
são ansiosamente aguardadas para os pacientes com
cirrose hepática em fase irreversível.
A terapia celular tem sido avaliada no tratamento da
cirrose hepática. Os resultados dos estudos clínicos com
terapia de células da medula óssea têm demonstrado que
este tratamento é aparentemente seguro e exequível, pode
promover um aumento da regeneração hepática e melhorar
parâmetros funcionais do fígado como os níveis séricos
da albumina, das bilirrubinas, o escore de Child-Pugh e o
(8-10)
escore MELD.
No entanto, a maioria dos dados
disponíveis é oriunda de estudos não randomizados com
um número pequeno de pacientes. São poucos os estudos
randomizados e controlados e ainda assim, nestes estudos
o numero de paciente é limitado. Embora os resultados
preliminares dos ensaios clínicos com terapia celular em
pacientes portadores de doenças crônicas do fígado sejam
encorajadores, estamos ainda longe de alcançar uma
reconstituição plena do fígado que foi lesado durante anos
ou décadas por processos patológicos crônicos. É possível
que este tipo de terapia seja mais eficiente em uma fase
inicial ou em etapas intermediárias da doença. Como ainda
estamos dando os primeiros passos em direção ao
desenvolvimento de uma nova terapia, muitos aspectos
devem ser endereçados para melhorar a eficácia, incluindo
a melhor população de células a ser usada, a dose (número
de células) correta, a necessidade de doses repetidas e a
melhor rota de administração. A compreensão dos mecanismos moleculares e celulares que levam à reparação do
fígado lesado pode abrir novas perspectivas para o
desenvolvimento de estratégias terapêuticas mais eficientes
e talvez menos invasivas. Neste contexto, é atraente a
possibilidade do uso de hormônios celulares para estimular
o reparo do fígado agredido, através do estímulo de células
residentes no próprio fígado ou pelo recrutamento de células
de outros tecidos.
26
REFERÊNCIAS
1. Pinzani M, Rosselli M, Zuckermann M. Liver cirrhosis. Best Pract
Res Clin Gastroenterol. 2011 Apr;25(2):281-90
2. Chang TT, Liaw YF, Wu SS, et al. Long-term entecavir therapy
results in the reversal of fibrosis/cirrhosis and continued histological
improvement in patients with chronic hepatitis B. Hepatology. 2010
Sep;52(3):886-93.
3. Marcellin P, Gane E, Buti M, Afdhal N, Sievert W, Jacobson IM,
Washington MK, Germanidis G, Flaherty JF, Schall RA, Bornstein
JD, Kitrinos KM, Subramanian GM, McHutchison JG, Heathcote EJ.
Regression of cirrhosis during treatment with tenofovir disoproxil
fumarate for chronic hepatitis B: a 5-year open-label follow-up
study Lancet. 2013 Feb 9;381(9865):468-75.
4. George SL, Bacon BR, Brunt EM, Mihindukulasuriya KL, Hoffmann
J, Di Bisceglie AM. Clinical, virologic, histologic, and biochemical
outcomes after successful HCV therapy: a 5-year follow-up of
150 patients. Hepatology. 2009 Mar;49(3):729-38.
5. Müting D, Kalk JF, Fischer R, Wiewel D. Spontaneous regression of
oesophageal varices after long-term conservative treatment.
Retrospective study in 20 patients with alcoholic liver cirrhosis,
posthepatitic cirrhosis and haemochromatosis with cirrhosis. J
Hepatol. 1990 Mar;10(2):158-62.
6. Valera JM, Smok G, Márquez S, Poniachik J, Brahm J. [Histological
regression of liver fibrosis with immunosuppressive therapy in
autoimmune hepatitis]. Gastroenterol Hepatol. 2011 Jan;34(1):10-5.
7. Kisseleva T, Brenner DA. Anti-fibrogenic strategies and the
regression of fibrosis. Best Pract Res Clin Gastroenterol. 2011
Apr;25(2):305-17.
8. Lyra AC, Soares MB, da Silva LF et al. Feasibility and safety of
autologous bone marrow mononuclear cell transplantation in patients
with advanced chronic liver disease. World J Gastroenterol. 2007
13(7):1067-73.
9. Lyra AC, Soares MB, da Silva LF, et al.: A pilot randomized controlled
study used to evaluate ef?cacy of autologous bone marrow
mononuclear cells transplantation in patients with advanced chronic
liver disease. Hepatology. 46(Suppl 1), 271A.
10. Amin MA, Sabry D, Rashed LA, Aref WM, El-Ghobary MA, Farhan
MS, Fouad HA, Youssef YA. Short-term evaluation of autologous
transplantation of bone marrow-derived mesenchymal stem cells
in patients with cirrhosis: Egyptian study. Clin Transplant. 2013
Jul;27(4):607-12.
Correspondência
Dr. André Lyra
Av. Juracy Magalhães Junior 2096
Centro Medico Aliança - Bairro Rio Vermelho
41920-000 - Salvador - BA
Moderna Hepatologia – Vol. 39 – Nº 1– Jan/Jun 2013
HEPATITIS B AND LIVER TRANSPLANTATION
HEPATITE B E O TRANSPLANTE DE FÍGADO
Prior to the early 90s, and in the absence of any
prophylaxis, survival for HBV was significantly lower than
that achieved by other indications, and this was caused by
HBV recurrence occuring in greater than 80% of cases.
For this reason, HBV disease was considered a CT for LT
in many centers. In only ten years, hepatitis B has become
a universally accepted indication with results similar to or
even better than those obtained by patients transplanted
for other indications
The first major advance was the introduction of HBIg
prophylaxis. In 1993, Prof. Samuel and colleagues from
Europe nicely showed that long-term HBIg prophylaxis
significantly reduced HBV recurrence when compared to
patients that did not receive prophylaxis or those treated
with short-term HBIg. On average the risk of recurrence
decreased from 75% to 30%. More recently, the results
have further improved, with the introduction of oral antivirals,
such that the combination of HBIg with antivirals, mainly
LAM has further reduced the rate of HBV recurrence to
less than 10%. Four meta-analyses and systematic reviews
showed that combination therapy with HBIg and lamivudine
is markedly better than HBIg alone or lamivudine alone for
the prevention of HBV recurrence. In turn, a recent review
has showed that combination therapy with HBIg and adefovir,
with or without lamivudine, resulted in a rate of HBV
recurrence of only 2% which was significantly lower than
the 6% obtained with HBIg and lamivudine, despite that the
proportion of patients with active HBV replication at the time
of LT was significantly higher in the adefovir group.
Current schedules of HBV prophylaxis are hence
shown to be extremely effective. To maximize cost-benefit
, though, several strategies have been attempted in the
last few years. These have mostly aimed to reducing and
or discontinuing HBIG, considered a costly and
cumbersome product. Four major options have been
evaluated, including the use of low doses of HBIg
administered im, the discontinuation of HBIG followed by
antiviral therapy, the use of prophylaxis based on antiviral
therapy without HBIg and finally the discontinuation of all
HBV prophylaxis.
In order to understand the benefits and limitations of
these different approaches, some fundamental concepts
need to be addressed. The first one is the persistence of
HBV DNA in intra and extrahepatic sites despite successful
antiHBs prophylaxis, suggesting that HBV prophylaxis
needs to be maintained life-long to suppress viral replication.
The second fundamental concept for individualized
prophylaxis is that patients can be divided into different
groups based on their risk of HBV recurrence, mainly on
the basis of viral replication and drug exposure at the time
of LT. The third fundamental concept is the importance of
treatment adherence.
The first approach used in many centers was to reduce
the total amount of HBIg with results, in general, favorable.
The most impressive results were obtained by the
Australasian group reported by Ed Gane in 2007. In this
study that included 147 patients, treatment with very low
doses of IM HBIg in combination with LAM resulted in an
actuarial risk of HBV recurrence of only 4% at 5 years. The
second strategy is the interruption of HBIg followed by
antiviral therapy. The results using this strategy reported
by several groups are also favorable with rates of HBV
recurrence in general lower than 10%. In one study from
Spain where HBIg was stopped and patients were then
maintained with lamivudine, recurrence in the lamivudine
group increased from 0% at 18 months to 15% at 83 months
of follow-up, with lack of compliance explaining the increased
risk of recurrence observed with duration of follow up. The
third strategy is the complete avoidance of HBIg using only
oral antivirals as prophylaxis. Results with lamivudine, the
first drug to be used as monotherapy, were disappointing
due to the high rates of recurrence, mostly in the context of
YMDD mutants. Acceptable results though were observed
in low risk patients who were HBV DNA negative at time of
LT. With newer and more potent oral antivirals that have
replaced lamivudine and adefovir, the results are expected
to be better. Indeed, in a recent study where entecavir was
used as monotherapy after LT in 80 patients, and with a
follow-up of 26 months, 22 % of the patients were HBsAgpositive, but 17 of the 18 had undetectable HBV DNA. The
last strategy is the discontinuation of all prophylaxis. This
was attempted in one study based on 30 selected low-risk
patients. All patients were HBsAg-positive and HBeAgnegative in serum before LT, 6 (20%) were co-infected with
hepatitis C virus (HCV) and 7 (23%) with hepatitis D virus
(HDV). Median follow-up after transplant was 139 months
27
BERENGUER M
(range, 64-195). Nine (30%) patients were treated with 100
mg/day of lamivudine for an average of 16 ± 22 (range 4-92)
months before LT because of detectable serum HBV-DNA
at the time of listing. In 2 patients (6.6%), 10 mg/day of
adefovir-dipivoxil was added to lamivudine due to
development of YMDD lamivudine resistant mutants before
LT. All patients showed undetectable serum HBV-DNA at
the time of transplant. All patients received anti-HBV
prophylaxis with HBIg after transplant: in 28 in combination
with LAM and in 2 combined with LAM and ADV. In these
patients, several liver biopsies were performed in order to
subsequently interrupt all prophylaxis (first HBIg and 6
months later lamivudine). Only patients with stable liver
enzymes and undetectable total and ccc-DNA in liver
biopsies could have the prophylaxis withdrawn. Of the 30
patients with undetectable total and ccc-DNA at baseline
liver biopsy, 25 (83.3%) did not exhibit serological signs of
HBV recurrence after a median follow-up of 28.7 months.
Five patients (16.6%) became serum HBsAg-positive: one
shortly after HBIg withdrawal, while still on lamivudine,
and 4 after NUCs withdrawal. In the first patient with
HBsAg recurrence, HBIg were reinstituted with prompt
HBsAg negativization. Of the other 4, only one remained
HBsAg-positive and developed detectable HBV-DNA levels
2
(up to 5.6 x 10 IU/ml) with mild ALT elevation, and was
given tenofovir as a rescue therapy. In this case, sequencing
analysis of the entire HBV genome showed the same LAM
resistant virus (L180 M/L mutation) detected before
transplant. The other 3 patients had only transient, shortterm HBsAg serum positivity and always remained with
undetectable serum HBV-DNA, which did not allow HBV
genome sequencing. In addition, in all of them HBsAg
clearance was followed by anti-HBs sero-conversion, with
development of anti-HBs titer ranging from 25 to 100 IU/L
after a median follow-up of 7 months (range 4-9).
Interestingly, 23 patients without HBsAg recurrence had
undetectable total or ccc-DNA in all protocol biopsies.
In conclusion, individualized prophylaxis can be
certainly applied to HBV patients, but many factors,
including viral, drug and host factors that impact recurrence
or the impact that recurrence may have on clinical outcomes
should be taken into account, in order to define different
groups of risks and potential approaches to prevent
recurrence. Based on available data, in high risk patients,
4
that is patients with HBV DNA ≥10 IU/ml at LT, infected
with resistant mutants at LT, with adherence issues, HDV
coinfected (where treatment options are limited if recurrence
occurs) or HIV coinfected, low-dose HBIG + NUC long-term
combination therapy is the preferred prophylaxis strategy,
with selection of NUC based on drug-resistance profile. In
contrast, HBIg minimization strategies should be used in
low risk patients. Whether in these patients a mini-short
28
term of HBIg might be beneficial needs to be evaluated.
What is clear is tha,t in these cases, strict monitoring is
essential to early diagnose and treat recurrence.
REFERÊNCIAS
• Gane EJ, Angus PW, Strasser S, Crawford DH, Ring J, Jeffrey GP,
McCaughan GW; Australasian Liver Transplant Study Group.
Lamivudine plus low-dose hepatitis B immunoglobulin to prevent
recurrent hepatitis B following liver transplantation.
Gastroenterology. 2007;132(3):931-7.
• Katz LH, Paul M, Guy DG, Tur-Kaspa R. Prevention of recurrent hepatitis
B virus infection after liver transplantation: hepatitis B
immunoglobulin, antiviral drugs, or both? Systematic review and
meta-analysis. Transpl Infect Dis. 2010 1;12(4):292-308.
• Cholongitas E, Goulis J, Akriviadis E, Papatheodoridis GV. Hepatitis B
immunoglobulin and/or nucleos(t)ide analogues for prophylaxis
against hepatitis b virus recurrence after liver transplantation: a
systematic review. Liver Transpl. 2011;17(10):1176-90.
• Lenci I, Tisone G, Di Paolo D, Marcuccilli F, Tariciotti L, Ciotti M, et al.
Safety of complete and sustained prophylaxis withdrawal in
patients liver-transplanted for HBV-related cirrhosis at low risk of
HBV recurrence. J Hepatol. 2011;55(3):587-93.
• Fox AN, Terrault NA. The option of HBIG-free prophylaxis against
recurrent HBV. J Hepatol. 2012;56(5):1189-97.
• Fung J, Cheung C, Chan SC, Yuen MF, Chok KS, Sharr W, et al.
Entecavir monotherapy is effective in suppressing hepatitis B virus
after liver transplantation. Gastroenterology. 2011;141(4):1212-9.
• Cholongitas E, Papatheodoridis GV. High genetic barrier nucleos(t)ide
analogue(s) for prophylaxis from hepatitis B virus recurrence after
liver transplantation: a systematic review. Am J Transplant.
2013;13(2):353-62.
• Gane EJ, Patterson S, Strasser SI, McCaughan GW, Angus PW.
Combination of lamivudine and adefovir without hepatitis B immune
globulin is safe and effective prophylaxis against hepatitis B virus
recurrence in hepatitis B surface antigen-positive liver transplant
candidates. Liver Transpl. 2013;19(3):268-74.
• Fung J, Chan SC, Cheung C, Yuen MF, Chok KS, Sharr W, et al. Oral
nucleoside/nucleotide analogs without hepatitis B immune globulin
after liver transplantation for hepatitis B. Am J Gastroenterol.
2013;108(6):942-8.
Correspondence to
ASCITES
ASCITES
Florence Wong, MB BS, MD, FRACP, FRCPC
Professor, GI Division - Department of Medicine - University of
Toronto, Canada
Ascites is the most common complication of cirrhosis,
affecting approximately 10% of all cirrhotic patients at any
one time. It has been estimated that at 10 years after the
diagnosis of compensated cirrhosis, 50-70% of patients
will have developed ascites if the underlying cause of the
cirrhosis is left untreated. The presence of ascites not only
affects the quality of life of these patients, but also
predisposes to the development of various complications,
negatively affecting their survival.
The pathophysiological processes that lead to the
development of ascites in cirrhosis are complex. The
presence of portal hypertension leads to changes in
systemic and splanchnic hemodynamics. Together with
alterations in renal auto-regulation, a reduction in functional
liver cell mass and the development of cirrhotic
cardiomyopathy, these processes result in a gradual
increase in renal sodium and water retention. The presence
of portal hypertension then preferentially localizes the
excess fluid in the peritoneal cavity as ascites.
Therefore, the treatment of ascites involves correcting
one or more of these pathological processes. The following
is a summary of the stepwise approach to the medical
management of ascites.
DIETARY SODIUM RESTRICTION
Dietary sodium restriction is the mainstay of treatment
of ascites, since ascites development is the consequence
of avid renal sodium and water retention. Reduction of
ascites and edema requires the induction of negative
sodium balance, that is, the urinary sodium output plus
insensible loss has to exceed the oral sodium intake in
order to reduce the ascites.
Scenario I Urinary sodium excretion is 90 mmol/day
Insensible sodium loss is 10mmol/day
Na intake = 44 mmol/day
Na output = 100 mmol/day
Na balance = (44-100)mmol/day
= -56 mmol
Ascitic [Na] = 135 mmol/L (same as serum [Na])
Therefore fluid loss = -56 mmol / 135 mmol/L
= -0.41 L
Weight loss/day = 0.41 kg
Scenario II Urinary sodium excretion is 0 mmol/day
Insensible sodium loss is 10mmol/day
Na intake = 44 mmol/day
Na output = 10 mmol/day
Na balance = (44-10) mmol/day
=+34 mmol
Ascitic [Na] = 135 mmol/L (same as serum [Na])
Therefore fluid gain = +34 mmol/135 mmol/L
= 0.25 L
Weight gain/day = 0.25 kg
Education about the importance of dietary sodium
restriction is central to the management of cirrhotic ascites.
It is customary to prescribe an 88mmol (2 grams) of sodium
per day diet, and repeat dietary counselling will help to
reinforce the need for dietary sodium restriction. However,
as the cirrhotic process progresses, urinary sodium
excretion will decrease. These patients will also require
diuretics to increase the urinary sodium excretion in order
to reduce the ascites.
DIURETIC THERAPY
Diuretics block sodium reabsorption along the various
nephron sites, thereby increasing renal sodium excretion.
Water excretion then follows passively. The most successful
therapeutic regimen is the combination of a distal diuretic
such as spironolactone, which is an aldosterone
antagonist, and a loop diuretic such as furosemide,
beginning with 100mg and 40mg, respectively and
increased in a step-wise fashion, preferably maintaining
the same ratio of dosages, in order to maintain
normokalemia. The doses can be doubled if a clinical
response is not evident, which is defined as <1.5kg weight
loss in one week despite adherence to a low sodium diet
and no renal failure. Dose adjustments should not be made
more often than once every 5 to 7 days. This is because
the onset of action of spironolactone is delayed to 48 hours
and its peak effect is not seen for 2 weeks, related to the
prolonged half-life of spironolactone and its metabolites in
advanced cirrhosis. The dose response curve of furosemide
is sigmoidal. Therefore, once a maximum response is
reached, further increases in furosemide dose will not
increase the diuretic response. The maximum
recommended daily doses are spironolactone 400mg and
furosemide 160mg. Single-daily dosing giving both drugs
once per day in the morning also maximizes compliance
and minimizes nocturia.
29
WONG F
Patients on diuretic therapy need to be monitored
regularly for electrolyte abnormalities, over-diuresis and renal
failure. Weight loss in excess of 0.5kg per day means that
there is reduction of the intra-vascular volume, and therefore,
the patient is at risk for the development of renal failure
from over-diuresis. Patients with peripheral edema can
tolerate more rapid fluid loss until the edema has resolved.
Compliance with and response to sodium restriction and
diuretics can be evaluated by 24-hour urine collection for
sodium. Completeness of urine collection is indicated by
urinary creatinine levels of 15-20 mg/kg in males and
10-15 mg/kg in females. However, in patients with advanced
disease and muscle wasting and therefore lower rates of
creatinine excretion, a random urine sodium to potassium
ratio of > 1 predicts a greater than 78mmol/day sodium
excretion in 90% of patients. Non-compliance with a lowsodium diet is reflected by an adequate urinary sodium
excretion but without any weight loss. A low urinary sodium
excretion necessitates increasing the diuretics doses as
tolerated up to the maximum recommended level.
Diuretic doses should be reduced or even stopped if
the patient develops orthostatic symptoms, azotemia,
excess weight loss. In patients with alcoholic cirrhosis,
renal sodium retention may become less avid with
abstinence, and therefore the diuretic doses may be reduced
or even tapered off as the patient's overall condition
improves. In contrast, in patients with no reversible
component to their liver injury, ascites usually worsens
over time and progresses from being diuretic-sensitive to
diuretic-resistant.
REFRACTORY ASCITES
Refractory ascites is defined as ascites that cannot be
easily mobilized (less than 1.5kg weight loss per week)
despite daily doses of 400mg of spironolactone or 30mg of
amiloride plus 160mg of furosemide, and the patient has
been compliant with dietary sodium restriction of ≤90mmol
per day for at least 1 week. Patients who cannot tolerate
diuretics because of the development of complications are
defined as having diuretic intractable ascites. These patients
require treatments other than medical therapy such as
repeat large volume paracentesis, or the insertion of a TIPS.
LARGE VOLUME PARACENTESIS
Large volume paracentesis (LVP) is now recognized
as a safe and effective therapy for the treatment of refractory
ascites. However, there is no survival advantage of
paracentesis over diuretic therapy for ascites.
Patients who require LVP should not need to have more
than 6-8 litres of ascites removed every 2 weeks. Larger
volumes can be removed at one sitting in edematous
patients. Patients may develop a post-paracentesis
30
syndrome known as "circulatory dysfunction",
characterized by a further rise in renin-angiotensin activity.
The risk factors for the development of this paracentesis
induced circulatory dysfunction (PICD) are unknown, but
its incidence is higher with progressively larger volume of
ascites removed. PICD has been associated with the rapid
recurrence of ascites, the development of hepatorenal
syndrome, and hyponatremia. Albumin infusion of 6-8 g
per litre of ascitic fluid removed has been recommended
for repeated large volume paracenteses of >5 litres to reduce
the incidence of PICD
Requests for more frequent LVP of larger volume
suggest non-compliance with dietary sodium restriction. If
the patient is consuming <80mmol of sodium per day and
assuming that there is no renal sodium excretion, the daily
positive sodium balance is 80mmol. The amount of sodium
retained in 2 weeks is 1120mmol or 8 litres of ascites fluid
(the concentration of sodium in the ascitic fluid is the same
as that in the serum). A dietary history will often reveal
food items that are high in sodium contents, and
consultation with a dietician will often improve dietary
compliance.
There are no absolute contra-indications for performing
an LVP. Although cirrhotic patients may have coagulopathy
and thrombocytopenia, the incidence of clinically significant
intra-abdominal bleeding during an LVP is estimated to be
at 0.5%. Therefore, the routine use of fresh-frozen plasma
or platelet concentrates is not recommended. Leakage of
ascitic fluid through the puncture site is a relatively frequent
complication. The Z-tract technique should reduce its
occurrence. Ascitic fluid leakage post-LVP should be
managed by placing a purse-string suture around the
puncture site or applying skin adhesive, and instructing
the patient to lie with the puncture site uppermost. The
use of a colostomy bag to contain the ascites leak should
be discouraged.
ASCITES
TRANSJUGULAR INTRAHEPATIC PORTOSYSTEMIC
SHUNT (TIPS)
The insertion of a TIPS, which bridges a branch of
the portal vein and a branch of the hepatic vein,
significantly decreases the sinusoidal portal pressure,
thereby eliminating one of the pathogenetic mechanisms
of ascites formation. Even in the absence of diuretics,
sodium excretion begins after the first month after TIPS
insertion, and slowly increases thereafter, culminating
to a urinary sodium excretion of approximately 100
mmol/day at 12 months post-TIPS. Therefore, patients
will need to stay on a low sodium diet in the post-TIPS
period or must take diuretics in order to facilitate ascites
clearance. Within 6 months, complete resolution of
ascites occurs in approximately two-thirds of patients,
and a partial response in the other third. Further ascites
resolution can occur up to 12 months post-TIPS, with
ultimately approximately 80% of patients responding with
complete disappearance of ascites. Recent results have
shown that the presence of diastolic dysfunction, part of
the cirrhotic cardiomyopathy syndrome, is associated
with poor ascites clearance after TIPS. Successful TIPS
placement with elimination of ascites results in improved
renal function, better nutritional status and positive
nitrogen balance, resulting in improved in quality of life
for the patient.
Several meta-analyses have confirmed that TIPS is
better than LVP in the control of ascites, but can lead to
either the development of new hepatic encephalopathy or
worsening of existing hepatic encephalopathy. Apart from
hepatic encephalopathy, the insertion of TIPS is
associated with its unique set of complications.
Meta-analysis using individual patient data from the
4 larger randomized controlled trials showed that patients
receiving TIPS showed a significantly better survival than
patients receiving paracentesis. This is especially true in
patients who are young (<50 years of age), with normal
liver function as indicated by a low or normal serum
bilirubin, and with no circulatory dysfunction as indicated
by normal serum sodium. A recent study also showed
that a lower bilirubin confers a survival advantage in
patients undergoing TIPS. Therefore proper patient
selection for TIPS placement is crucial for a successful
outcome following TIPS.
Corespondence to
Florence Wong, MD
GI Division - Department of Medicine - University of Toronto
9N/983 Toronto General Hospital
200 Elizabeth Street - Toronto M5G2C4
Ontario, Canada
Phone: 416-340 3834 - Fax: 416-340 5019
[email protected]
LIVER TRANSPLANTATION
Once refractory ascites develops, the prognosis is
decreased further to 50% survival at 6 months, related to
hemodynamic instability and circulatory dysfunction.
Therefore, all patients with refractory ascites should be
considered for liver transplantation unless there is a
contraindication.
31
TREATMENT OF HEPATIC ENCEPHALOPATHY:
FOCUS ON RIFAXIMIN
TRATAMENTO DA ENCEFALOPATIA HEPÁTICA: FOCO NA RIFAXIMIN
Hitoshi Maruyama, Arun J. Sanyal
Division of Gastroenterology at Virginia Commonwealth
University Medical Center in Richmond, Virginia
Abstract
Hepatic encephalopathy is a major complication of liver
disease, which is characterized by neuropsychiatric and motor
abnormalities. Current approaches for the management of
hepatic encephalopathy consist of removal of major
precipitants, diet, nonabsorbable disaccharides, and
antibiotics. Rifaximin is a poorly absorbed antibiotic with an
antimicrobial activity against both aerobic and anaerobic
gram-positive and gram-negative microorganisms, and
tolerability profile similar to that of placebo. Several studies
show reduced blood ammonia levels and improved clinical
outcomes following rifaximin therapy of hepatic
encephalopathy. This article provides an overview of current
concepst of the application of rifaximin for the treatment of
hepatic encephalopathy.
Keywords: Hepatic encephalopathy; Cirrhosis; Rifaximin,
Ammonia
INTRODUCTION
Hepatic encephalopathy (HE) is an important
complication of acute or chronic liver dysfunction. It is a
neuropsychiatric disturbance characterized by impaired
cognition, consciousness, behavior, personality, sleep as
well as motor abilities, which influence patients' quality of
(1)
life . HE is detected in about 30 to 70% of cirrhosis
(2,3)
patients , and is considered as a prognostic factor; the
probability of transplant-free survival after the first episode
of acute HE is reported to be 42% at 1 year and 23% at 3
(4)
yeas . Another study reported that HE of grade 3 or higher
was associated with a 3.7-fold (95% confidence interval,
1.9-7.3, P<0.01) increase in the risk of death in the 223
patients who underwent TIPS, and HE of grade 2 or higher
was associated with 3.9-fold increase (95% confidence
interval, 2.6-5.7, p<0.01) in 271 patients hospitalized with
(5)
hepatic decompensation .
Optimal management of HE requires a clear
understanding of the pathophysiology of HE, its natural
history and clinically relevant outcomes. Rifaximin is a
32
minimally absorbed antibiotic, and is capable of controlling
serum ammonia which is a major neurotoxic product for
HE. In this review article, we outline the current knowledge
of HE, summarize the results of clinical studies regarding
the effect of rifaximin for HE, and provide a perspective on
the usage of rifaximin in the management of this
complication of cirrhosis.
PATHOPHYSIOLOGY OF HE
Although the underlying mechanisms of HE have not
been fully elucidated, ammonia is implicated as a major
(2)
factor in the genesis of HE . The other toxins that have
also been implicated include benzodiazepine-like
substances, short- and medium-chain fatty acids, phenols,
(3)
mercaptans, and manganese . The liver possesses two
pathways for detoxification of ammonia: (1) the urea-cycle
in the peri-portal hepatocytes, (2) glutamine synthesis in
(6)
peri-venous hepatocytes . In liver failure, dysfunction of
these two processes results in the increased serum
ammonia level. In addition, ammonia accumulates in the
systemic circulation in cirrhosis with advanced
portosystemic shunt because of the reduction of removal
(2,6)
of ammonia by liver .
The key sources of circulating ammonia also include
(6)
the intestine, kidney and striated muscle . Ureasecontaining gut flora such as klebsiella and proteus species
in the intestine are an important source of ammonia. The
kidney contains both glutaminase and glutamine synthetase,
and regulates ammonia. When renal function is impaired,
ammonia diffuses into the circulation. Striated muscle can
both take up ammonia and convert it into glutamine as well
as release ammonia by a reverse process. Decreased
muscle mass which is often present in patients with cirrhosis
also contributes to hyperammonemia due to an impaired
(6)
capacity to form glutamine from ammonia . Infection and
systemic inflammation are also known as precipitating factors
(7)
of HE .
CLASSIFICATION OF HE
A nomenclature of HE proposed in the 11th World
Congresses of Gastroenterology classified HE into three
groups (Table 1); type A for encephalopathy associated
with acute liver failure, type B for encephalopathy
associated with portal-systemic bypass and no intrinsic
TREATMENT OF HEPATIC ENCEPHALOPATHY: FOCUS ON RIFAXIMIN
GENERAL MANAGEMENT OF HE
hepatocellular disease, and type C for encephalopathy
associated with cirrhosis and portal hypertension/ or
(1)
portal-systemic shunts . Neurologic manifestations in
chronic liver disease are classified into three
subcategories according to the duration and/or
characteristics; episodic HE, persistent HE and minimal
HE. Minimal HE is a cognitive dysfunction without clinical
signs of overt HE, and patients with minimal HE have an
increased risk of unexpected accidents during activities
(7,8)
such as driving or working . The severity of HE has been
usually assessed by the West Haven Criteria, which has
four stages according to alternations in the state of
consciousness, intellectual function, behavior, and
(1)
neuromuscular signs . As minimal HE is not associated
with overt changes in consciousness, it is diagnosed by
specialized psychometric and neurophysiological
(9)
measures . In this way, it is analogous to the use of a
"stress test" for the brain to uncover subtle neurocognitive
dysfunction that is not obvious on routine clinical
assessment.
It is now appreciated that the neurocognitive
disturbance associated with cirrhosis represents a
spectrum of neurocognitive impairment which ranges from
subtle findings that can only be identified by special test
to overt alternations of sensorium to coma. The Spectrum
of Neuro-cognitive Impairment in Cirrhosis (SONIC) was
(8,10)
introduced to capture this spectrums
. Mental status,
specialized tests and asterixis are used to classify HE
within this system, and patients currently classified as
having minimal HE and Grade I HE would be classified as
having Covert HE, whereas those with apparent clinical
abnormalities would continue to be classified as overt HE
(Table 2).
When a subject with cirrhosis presents with acute
worsening of mental states, it is important to remove
major precipitants, such as volume depletion, azotemia
(11)
and hypokalemia . Traditionally, restriction of protein
of the diet has been believed to be effective for the
treatment of HE. However, a recent study has shown
that it might not be beneficial for cirrhosis patients during
(12)
an episode of HE .
Oral medication against the accumulated ammonia
is the mainstream of pharmacological treatment, and
nonabsorbable disaccharides such as lactulose or lactitol
(2,7,13)
are most widely used in patients with HE
. However,
a meta-analysis of 22 clinical studies showed that there
is insufficient evidence to determine whether nonabsorbable disaccharides are of benefit to patients with
(14)
HE . Considering the possible adverse events like
flatulence, diarrhea and nausea, the data to support this
routine use of non-absorbable disaccharides for HE is still
(15)
controversial .
Non- or poorly absorbable antibiotics are another
option to treat HE, because of suppression of ammonia(3-15)
producing flora
. Neomycin has been a popularly used
medicine; however, the reports of associated nephrotoxicity
(15)
have reduced its use in clinical practice . Similar results
have been reported in the other antibiotics, paromomycin,
(15)
metronidazole and vancomycin . Probiotics might be
another option for HE due to the reduction of ammonia(16)
producing colony .
Embolization of large portal-systemic shunts by the
interventional radiologic approach is effective in some of
the cases with advanced collateral vessels with relatively
well-preserved liver function. Transplantation may be
recommended for the patient with persistent and recurrent
episodes of HE which are not controllable with the other
treatments.
33
MARUYAMA H, SANYAL AJ
Rifaximin
Activity and pharmacokinetics
Rifaximin is a semisynthetic derivative of rifampicin. It
is poorly absorbed from the gastrointestinal due to an
additional pyridoimidazole ring, which account for its safety
and limited systemic interaction profile between drugs. It
has wide antimicrobial activity against both aerobic and
anaerobic gram-positive and gram-negative microorganisms
(17)
. Its poorly absorbable nature allows achievement of high
fecal levels of drug after oral administration. Hence, in
subjects with cirrhosis or liver failure, there is a modest
degree of absorption.
Clinical indications
The clinical indications of rifaximin include acute intestinal
bacterial infections, bacterial overgrowth syndrome, diverticular
disease of the colon, inflammatory bowel diseases, prevention
of post-operative infections after colorectal surgery as well as
(17)
HE (Table 3) . In the US, rifaximin has been applied for
afebrile non-dysenteric travelers' diarrhea, and was approved
for reduction in the risk of the recurrence of overt HE in patients
with advanced liver disease by the United States Food and
Drug Administration on March 24, 2010.
Doses and safety profile
Based on the studies in the literature, rifaximin is used
at a dose of 200 to 800mg/day for the treatment of traveler's
diarrhea. Meanwhile, for HE, investigators used rifaximin at a
(14,18)
dose of 400 to 2400 mg/day
. 400 - 1200 mg is the dose
frequently used in the recent studies. The recommended dose
for adult is 200mg orally 3 times a day for traveler's diarrhea
and 550mg orally twice a day for HE in the US.
Rifaximin is well tolerated and has few safety
problems, probably due to its non-absorbable property. Most
adverse events in clinical studies with large patient
population (400-1200mg/d, for 3 days) were not severe,
and included flatulence, abdominal pain, tenesmus, fecal
incontinence, nausea, headache, and other non-specific
events. Importantly, the incidence of such effects is almost
(19,20)
similar to that in placebo group
.
Clinical studies of rifaximin for HE (Table 4)
Treatment of active HE
The initial study to examine the effect of rifaximin for
34
HE was performed in 1985 in Italy and showed similar
effectiveness between rifaximin and paramomycin in
controlling ammonia level and clinical findings of HE in20
(21)
cirrhosis patients . A double-blind, double-dummy study
in cirrhosis has shown significant improvement in the
symptoms of HE (mental state, "A" cancellation test),
changes in electroencephalographic irregularities,
changes in the degree of severity of HE and variations in
fasting serum ammonia in the rifaximin group (n=30; at a
dose of 1200mg/day, 15 days) compared to lactulose
(22)
group (n=28; at a dose of 30g/day, 15 days) . Another
prospective, randomized, double-blind, double-dummy,
controlled trial reported a significantly better evolution of
the portal-systemic encephalopathy index,
electroencephalogram abnormalities and ammonia level
in rifaximin (1200mg/day, 5-10d) than lactitol (60g/day,
5-10d), with similar global efficacy (81.6% in rifaximin
group and 80.4% in lactitol group) in 103 cirrhotic patients
(23)
with acute HE . It is also reported that combined use
of rifaximin (1200 mg/day) and sufficient lactulose
improved the clinical symptoms of HE in cirrhosis
(24)
patients .
Several studies compared rifaximin to other antibiotics,
e.g. neomycin which has a widely different antimicrobial
spectrum for the treatment of HE. A randomized, doubleblind, controlled trial in 49 cirrhotic patients compared
the neuropsychiatric signs and blood ammonia between
two treatments, rifaximin (400 mg/d) and neomycin (3.0g/
d). Both were administered in 14 consecutive days each
month, for a period of 6 months. Both treatments were
effective for the treatment of HE with no significant
difference between them, except for the improvement in
the Reitan test which was observed only in rifaximin group
(25)
(p<0.02) .
From the aspect of hospitalization and cost of
medical care, one retrospective study compared the
clinical efficacy and adverse events in the two different
periods; (1) rifaximin period (400mg, 3 times a day), (2)
lactulose period (30cc, twice daily) of 145 patients with
HE. Fewer hospitalization (0.5 vs 1.6; p<0.001), fewer
days hospitalized (2.5 vs 7.3; p<0.001), fewer total
weeks hospitalized (0.4 vs 1.8; p<0.001) and lower
hospitalization charges per patient ($14,222 vs $56,635)
were reported during the rifaximin period. In addition,
more patients had asterixis, diarrhea, flatulence, or
(26)
abdominal pain during the lactulose period (p<0.001) .
Another retrospective study has confirmed the difference
of hospitalization and medical care cost between
lactulose group (60g/d) and rifaximin group (1200mg/d)
in 39 patients with HE; higher total cost of therapy per
patients per year in lactulose group ($13,285) than in
rifaximin group ($7,958), and the shorter average length
of stay in rifaximin group (3.5 days, 3-4) than lactulose
(27)
group (5.0 days, 3-10; p<0.0001) .
35
MARUYAMA H, SANYAL AJ
Prevention of HE
A randomized, double-blind, placebo-controlled trial
was performed in 299 patients who were in remission from
recurrent HE due to chronic liver disease in US, Canada
(28)
and Russia . There were two groups, 140 patient in
refaximin group (550 mg/d) and 159 patients in placebo
group, both were comparable. The primary end point was
the time to the first breakthrough episode of HE and
secondary end point was the time to the first hospitalization
involving HE. Rifaximin significantly reduced the risk of an
episode of HE as compared with placebo, over a 6-month
period (hazard ratio with rifaximin, 0.42; 95% confidence
interval, 0.28 to 0.64; p<0.001). A breakthrough episode of
HE occurred in 22.1% of patients in the rifaximin group, as
compared with 45.9% of patients in the placebo group,
resulting in 58% reduction in the risk of a breakthrough
episode in rifaximin group during 6 months period (Figure
1). A total of 13.6% of the patients in the rifaximin group
had a hospitalization involving HE, as compared with 22.6%
of patients in the placebo group (hazard ratio, 0.50 , 95%
confidence interval, 0.29 to 0.87; p=0.01) (Figure 2).
Furthermore, the incidence of adverse events reported
during the study was similar in the rifaximin group (80.0%)
and the placebo group (79.9%). It is important to note that
in this study, both groups combined to receive lactulose
and that the total exposure to lactulose was similar across
study groups.
Treatment of minimal HE
Two small randomized controlled trials focused on the
impact of rifaximin for the treatment of minimal HE. The
first study was the trial conducted in 42 subjects (21
rifaximin at a dose of 550 mg/day, 21 placebo; 8 weeks).
Significantly greater improvements in avoiding total driving
errors (76% vs 31%; p=0.013), speeding (81% vs 33%;
p=0.005), and illegal turns (62% vs 19%, p=0.01) were
(29)
found in rifaximin group than placebo group . Cognitive
performance and social dimension of the Sickness Impact
Profile improved significantly in rifaximin group than
placebo group. The second study performed in 94 cirrhotic
subjects (rifaximin, 1200mg/day, n=49; placebo, n=45;
both for 8 weeks) has shown that reversal of minimal HE
was significantly more frequent in rifaximin group (75.5%,
(30)
37/49) than in placebo group (20%, 9/45, p<0.0001) .
The mean number of abnormal results in neuropsychometric
test was significantly lower in rifaximin group (baseline,
2.35 (95% confidence interval, 2.17-2.53); 2 weeks, 1.29
(95% confidence interval, 1.02-1.56), p=0.002; 8 weeks,
0.81 (95% confidence interval, 0.61-1.02), p=0.000) than
in placebo group (baseline, 2.31 (95% confidence interval,
2.03-2.59); 2 weeks, 2.03 (95% confidence interval, 1.742.31); 8 weeks, 1.97 (95% confidence interval, 1.69-2.25),
p>0.05). The mean total score of sickness impact profile
questionnaire also improved significantly in rifaximin group
36
(baseline 11.67 (95% confidence interval, 10.31-13.03); 8
weeks, 6.45 (I95% confidence interval, 5.59-7.30); p=0.000)
compared with placebo group (baseline, 9.86 (95%
confidence interval, 8.66-11.06); 8 weeks, 8.51 (95%
confidence interval, 7.35-9.67), p=0.82).
Impact of rifaximin on other complications of cirrhosis
Two recent studies focused on the long-term effects of
rifaximin in cirrhosis. One case-control study performed in
23 patients with alcohol-related decompensated cirrhosis
and controls found that rifaximin group (1200mg/d, 4 weeks
or more) had a significant lower risk of developing variceal
bleeding (35% vs 59.5%, p=0.011), hepatic encephalopathy
(31.5% vs 47%, p=0.034), spontaneous bacterial peritonitis
(5.5% vs 46%, p=0.027), and hepatorenal syndrome (4.5%
(31)
vs 51%, p=0.037) than controls . The five-year
cumulative probability of survival was also significantly
higher in rifaximin group than in controls (61% vs 13.5%,
p=0.012). Another study reported that 2-year survival in
patients who received rifaximin long term (550mg/d) for
secondary prevention of HE was better than that in
otherwise comparable end-stage liver disease patients with
mild HE (overall p=0.04) and similar to that in patients
(32)
without HE . The small number of subjects in these
trials warrants confirmation in large data sets.
Limitations in the analysis of the literature
A limitation in the design of the previous studies is the
lack of blinding because the patients and investigator know
what they were taking by the typical side effects of
lactulose. Also, it is difficult to assess the side effects of
rifaximin when subjects are also taking lactulose. Another
limitation is a heterogeneity of terminology and definition
in studies of HE. The current categorical approach for the
classification of HE is suboptimal because of subjectivity
in establishing thresholds and boundaries between stages.
The clinical relevance of subject specific findings such as
asterixis also remains controversial. There is a need for
better guidelines to conduct future trials regarding
management of episodic HE, secondary prophylaxis of HE,
and minimal HE, including the patient population, standard
of care, end point to define outcome. More efforts should
be focused on the future studies regarding the application
of rifaximin for the secondary prevention of HE, comparison
of rifaximin with the other antibiotics, long-term effect, and
the mechanism of rifaximin in the improvement of HE and
portal hypertension.
Summary
HE is a chronic disabling complication of cirrhosis.
Rifaximin is an effective treatment of HE. It improves clinical
symptoms and severity of HE, reduces the ammonia level,
and improves the electroencephalogram and neuropsychiatric
tests. These effects are statistically significant in comparison
with placebo or lactulose, and almost similar to those by
neomycin or paramomycin. In addition, a large study
demonstrated that rifaximin is effective for the prevention of
HE in chronic liver disease with recurrent HE, and two small
trials have shown the benefits of rifaximin for the treatment of
minimal HE. Another advantage of rifaximin is a better safety
and tolerability profile compared with the other medicines.
Rifaximin nearly also reduce the risk of other complications of
cirrhosis. This, however, requires validation.
REFERENCES
nonabsorbed antimicrobial in the therapy of travelers' diarrhea.
Digestion 1998; 59: 708-14.
20. Steffen R, Sack DA, Riopel L, et al. Therapy of travelers' diarrhea
with rifaximin on various continents. Am J Gastroenterol 2003; 98:
1073-8.
21. Testa R, Eftimiadi C, Sukkar GS, et al. A Non-absorbable rifaximin for
treatment of hepatic encephalopathy. Drugs Exp Clin Res 1985; 11:
387-92.
22. Bucci L, Palmieri GC. Double-blind,double-dummy comparison
between treatment with rifaximin and lactulose in patients with
medium to severe degree hepatic encephalopathy. Curr Med Res
Opin 1993;13:109-18.
1. Ferenci P, Lockwood A, Mullen K, et al. Hepatic encephalopathydefinition, nomenclature, and quantification: final report of the
working party at the 11th World Congress of Gastroenterology,
Vienna, 1998. Hepatology 2002; 35: 716-21.
23. Mas A, Rodés J, Sunyer L, et al. Comparison of rifaximin and lactitol
in the treatment of acute hepatic encephalopathy : results of a
randomized, double-blind, double-dummy, controlled clinical trial. J
Hepatol 2003 ; 38 : 51-58.
2. Poordad FF. The burden of hepatic encephalopathy. Aliment
Pharmacol Ther 2007; 25: Suppl 1, 3-9 .
24. Puxeddu A, Quartini M, Massimetti A, et al. Rifaximin in the treatment
of chronic hepatic encephalopathy. Curr. Med. Res. Opin. 1995; 13;
274-81.
3. Riordan SM, Williams R. Gut flora and hepatic encephalopathy in
patients with cirrhosis. N Engl J Med 2010; 362: 1140-2.
4. Bustamante J, Rimola A, Ventura PJ, et?al. Prognostic significance
of hepatic encephalopathy in patients with cirrhosis.J Hepatol
1999;30:890-5.
5. Stewart CA, Malinchoc M, Kim WR, et al. Hepatic encephalopathy
as a predictor of survival in patients with end-stage liver disease.
Liver Transpl 2007; 13: 1366-71
25. Miglio F, Valpiani D, Rossellini SR, et al, Rifaximin, a non-absorbable
rifamycin, for the treatment of hepatic encephalopathy. A doubleblind, randomized trial. Curr Med Res Opin 1997; 13: 593-601.
26. Leevy CB, Phillips JA. Hospitalizations during the use of rifaximin
versus lactulose for the treatment of hepatic encephalopathy.Dig
Dis Sci 2007;52:737-41.
6. Olde Damink SW, Deutz NE, Dejong CH, et al. Interorgan ammonia
metabolism in liver failure. Neurochem Int 2002 ; 41: 177-188
27. Neff GW, Kemmer N, Zacharias VC, et al. Analysis of hospitalizations
comparing rifaximin versus lactulose in the management of hepatic
encephalopathy. Transplant Proc 2006;38:3552-5.
7. Cordoba J, Minguez B. Hepatic encephalopathy. Semin Liver Dis
2008 ; 28 : 70-80.
28. Bass NM, Mullen KD, Sanyal AJ, et al. Rifaximin treatment in hepatic
encephalopathy. N Engl J Med 2010; 362: 1071-81.
8. Bajaj JS, Wade JB, Sanyal AJ. Specttrum of neurocognitive
impairement in cirrhosis : implications for the assessment of hepatic
encephalopathy. Hepatology 2009 ; 50 : 2014-21.
29. Bajaj JS, Heuman DM, Wade JB, et al. Rifaximin improves driving
simulator performance in a randomized trial of patients with minimal
hepatic encephalopathy. Gastroenterology 2011; 140: 478-87.
9. Ortiz M, Jacas C, Cordoba J. Minimal hepatic encephalopathy :
diagnosis, clinical significance and recommendations. J Hepatol
2005 ; 42 : Suppl : S45-53.
30. Sidhu SS, Goyal O, Mishra BP, et al. Rifaximin improves psychometric
performance and health-related quality of life in patients with minimal
hepatic encephalopathy (The RIME Trial). Am J Gastroenterol, DOI:
10.1038/ajg.2010.455.
10. Bajaj JS, Cordoba J, Mullen KD, et al. Review article: the design of
clinical trials in hepatic encephalopathy - an International Society
for Hepatic Encephalopathy and Nitrogen Metabolism (ISHEN)
consensus statement. Aliment Pharmacol Ther 2011; 33: 739-747.
11. Sanyal AJ, Bosch J, Blei A, et al. Portal hypertension and Its
complications. Gastroenterology 2008;134:1715-28.
12. Cordoba J, Lopez-Hellin J, Planas M, et al. Normal protein diet for
episodic hepatic encephalopathy: results of a randomized study. J
Hepatol 2004; 41: 38-43.
13. Sharma BC, Sharma P, Agrawal A, et al. Secondary prophylaxis of
hepatic encephalopathy: an open label randomized controlled trial
of lactulose versus placebo. Gastroenterology 2009;137:885-91.
14. Als-Nielsen B, Gluud LL, Gluud C. Non-absorbable disaccharides
for hepatic encephalopathy: systematic review of randomized trials.
BMJ 2004;328:1046.
15. Riordan SM, Williams R. Treatment of hepatic encephalopathy. N
ENgl J Med 1997; 337: 473-9.
16. Liu Q, Duan ZP, Ha DK, et al. Synbiotic modulation of gut flora :
effect on minimal hepatic encephalopathy in patients with cirrhosis.
Hepatology 2004 ; 39 : 1441-1449
31. Vlachogiannakos J, Viazis N, Vasianopoulou P, et al. Long-term
administration of rifaximin improves the prognosis of patients with
alcohol-related decompensated cirrhosis: a case-control study.
Hepatology 2010; 52 (suppl): 328-9A.
32. Leise MD, Pedersen R, Kamath PS, et al. Impact of rifaximin treatment
on survival in patients with end-stage liver disease. Hepatology
2010; 52 (suppl): 331A.
Corresponding author:
Sanyal AJ
Division of Gastroenterology and Hepatology, Virginia
Commonwealth University, 1101 E Marshall
St. Richmond, VA 23298, USA
E-mail: Maruyama H ([email protected])
Sanyal AJ ([email protected])
17. Huang DB, DuPont HL. Rifaximin-a novel antimicrobial for enteric
infections. J Infect 2005; 50: 97-106.
18. Williams R, James OF, Warnes TW, et al. Evaluation of the efficacy
and safety of rifaximin in the treatment of hepatic encephalopathy:
a double-blind, randomizes, dose-findning multi-center study. Eur J
Gastroenterol Hepatol 2000; 12: 203-8.
19. Dupont HL, Ericsson CD, Mathewson JJ, et al. Rifaximin: a
37
IRON AND STEATOHEPATITIS
FERRO E ESTEATO-HEPATITE
Antonello Pietrangelo, M.D., Ph.D
Division of Internal Medicine 2 and Center for Hemochromatosis,
University Hospital of Modena, Modena, Italy
Abstract
A variable degree of hepatic iron accumulation has long been
recognized in a number of chronic liver diseases. Both
alcoholic and non-alcoholic steatohepatitis display increased
iron deposits in the liver, with an hepatocellular, mesenchymal,
or mixed pattern. Recent reports have documented a
concomitant aberrant expression of hepcidin, the iron
hormone, which could be linked to different coincidental
pathogenic events (e.g. the etiological agent itself,
necroinflammation, metabolic derangements, genetic
predisposition) and responsible for increased iron deposition
in the liver. Excess hepatic iron in steatohepatitis has been
linked to enhanced oxidative stress, fibrogenesis and, in
general, accelerated disease progression. Moreover,
increased hepatic iron stores appears to exacerbate insulin
resistance and metabolic complications. The present article
reviews the pathogenic mechanisms of iron accumulation in
steatohepatitis during alcoholic and non-alcoholic liver
disease and their clinical implications.
Keywords: Steatohepatitis; Alcoholic liver disease; Fatty liver
disease; Hepcidin; Iron;
INTRODUCTION
In spite of the diverse etiology, alcoholic liver disease
(ALD) and non-alcoholic fatty liver disease (NAFLD) share
many epidemiological, clinical, and pathogenetic features.
They both represent major causes of chronic liver disease
worldwide and both encompass a spectrum of disorders
ranging from simple fatty liver (steatosis) to hepatocyte
injury and inflammation (alcoholic steatohepatitis [ASH]
and non-alcoholic steatohepatitis [NASH]), cirrhosis, and
HCC.
Hepatocellular and/or mesenchymal iron deposition,
usually slight or mild, might be found in chronic non-cirrhotic
(1)
liver disease, regardless of its cause Although the
pathogenic mechanisms underlying ALD and NAFLD are
increasingly elucidated, therapeutic strategies are limited.
Therefore, a further dissection of the role of iron in the
pathogenesis of ALD and NAFLD could generate alternative
and/or complementary therapeutic approaches for these
(2)
common liver diseases .
IRON IN ALCOHOLIC AND NON-ALCOHOLIC FATTY
LIVER DISEASE: EPIDEMIOLOGICAL AND CLINICAL
ASPECTS
Alcoholic Liver Disease
Varying degrees of hepatic iron burden have been
reported in patients with ALD. In alcohol users, serum iron
markers have been shown to be raised even at early age,
whereas, with increasing and persistent alcohol abuse, iron
eventually accumulates in the liver. Whole-body retention
studies have demonstrated that alcoholics have a twofold
increase in intestinal iron absorption. The degree of iron
overload in ALD is usually relatively mild, but sometimes,
particularly in the presence of cirrhosis, it is sufficiently
severe to be mistakenly attributed to hereditary
hemochromatosis. There might be different reasons for iron
accumulation in ALD and ASH. Both alcohol-induced ER
stress and inflammation might lead to upregulation of
hepcidin, the iron hormone, responsible for subsequent and
iron retention in liver macrophages which will then result in
perturbation of their function and release of pro(3)
inflammatory cytokines (Fig. 1) . However, alcohol seems
also to suppress hepcidin expression in the liver after both
acute and chronic exposure, in vivo and in vitro. This will
eventually lead to increased iron absorption and consequent
hepatocellular iron accumulation (Fig. 1). In fact, patients
with both acute and chronic ALD show decreased serum
38
IRON AND STEATOHEPATITIS
Figure 1. Molecular pathways leading to hepatic iron overload through
hepcidin modulation in alcoholic steatohepatitis (ASH) and non-alcoholic
steatohepatitis (NASH). Putative pathways that lead to hepcidin stimulation
or inhibition in ASH and NASH are shown, and the opposite effect and
diverse iron deposition pattern that might arise during individual disease
processes are emphasized. In addition, the role of iron excess into
hepatocytes or Kupffer cells and relevant molecular pathways leading to
disease progression and hepatocellular carcinoma are shown. ER,
endoplasmic reticulum; HCC, hepatocellular carcinoma; HFE, human
hemochromatosis gene HFE; LPS, lipopolysaccharide.
hepcidin levels, which progresses along with the progression
of the underlying liver disease. As to the effect of excess
iron on ALD progression, the presence of iron has been
(4)
(5)
reported to be predictive of death and HCC development
in alcoholic cirrhosis. Alcohol promotes the main
pathological features of ASH (i.e. hepatocyte injury and
death, inflammation, and fibrosis) by different mechanisms,
including alcohol/driven oxidative stress, lipopolysaccharide
toxicity, due the increased gut permeability, and ER stress.
However, iron itself generates reactive oxygen species,
inducing lipid peroxidation and oxidation of proteins and
nucleic acids, leading to cell death. On the basis of the
ability of both alcohol and iron to cause oxidative stress,
stellate cell activation, and hepatic fibrogenesis, a
synergistic effect on liver disease progression can be
postulated (Fig. 1).
NON ALCOHOLIC LIVER DISEASE
Variable degrees of hepatic iron accumulation, usually
mild or moderate, are common in NAFLD. The term
(6)
"dysmetabolic iron overload syndrome" (DIOS) , more
recently also referred to as "insulin resistance-associated
hepatic iron overload", was first introduced to define cases
of unexplained hepatic iron excess characterized by high
serum ferritin levels, normal serum iron, and associated
metabolic abnormalities. The histological pattern of DIOS
was described as mixed parenchymal and mesenchymal
in 85% of patients. In two large, recent series of NAFLD
patients, hepatic iron deposition was found in approximately
50% and 35% of cases, respectively, with an hepatocytic,
mesenchymal, or mixed pattern. Serum ferritin levels are
commonly raised in NAFLD, due to hepatic iron overload,
hepatic or systemic inflammation, oxidative stress, and
likely insulin resistance. As DIOS and hyperferritinemia
associated with the MS or NAFLD share many clinical and
epidemiological features, they could be considered two
different faces of the same health problem.
Although hepatic iron excess is common in NAFLD
patients, its cause and clinical significance are still being
(2,3)
debated . Recent reports have suggested that hepcidin
might be directly responsible for iron disturbances during
NAFLD. Ectopic expression of hepcidin has been shown
in white adipose tissue in obese individuals; hepcidin mRNA
levels were increased and correlated with the inflammatory
state, independently of steatosis and NASH. Moreover,
leptin, which is commonly increased in obesity, was
demonstrated to enhance hepcidin mRNA expression in
vitro, and a significant positive correlation between serum
leptin and hepcidin has been reported in obese children.
Additional factors that might contribute to hepatic iron
excess in NAFLD are necrosis, or the induction of hepcidin
by inflammatory cytokines, causing iron accumulation in
KC (Fig. 1). In agreement with this hypothesis, increased
hepcidin levels compared to matched controls has been
reported in patients with metabolic syndrome, with and
without NASH. An additional trigger for hepcidin activation
in these patients is likely ER stress (a known activator of
hepcidin expression), which has been associated with
NAFLD and its main risk factors, namely obesity and type
2 diabetes (Fig. 1).
In summary, in analogy with ALD, during the dynamic
evolution of NAFLD, diverse signals might arise that
modulate hepcidin expression in the opposite direction,
depending on patient genetic determinants, comorbidities,
timing and entity of the primary liver injury, and liver disease
stage or inflammatory activity. So far, available data seem
to indicate that in NAFLD hepcidin induction by systemic
inflammation (related to obesity), intrahepatic inflammation,
(7)
and/or intrahepatic cytokine-related stress and ER stress
(secondary to excessive free FA influx) has a central role
in iron retention in the liver, and likely in white adipose
tissue (Fig. 1).
As to the effect of hepatic iron accumulation on disease
progression, a recent study showed that hepatocellular iron
accumulation was associated with more severe liver
(8)
fibrosis . Another study reported that reticuloendotelial iron
accumulation is correlated with the histological features of
NASH (inflammation, hepatocyte ballooning, and fibrosis)
(9)
and with advanced fibrosis . Finally, a significant
relationship between hepatic iron content and HCC
progression has been reported, suggesting a carcinogenic
(10)
or cocarcinogenic role for iron in NASH .
39
PIETRANGELO A
Both free fatty acids (FFA) and iron excess in the
liver have been demonstrated to induce oxidative injury,
indicating that when hitting the liver together, they might
exert a synergistic hepatotoxic effect. A number of studies
suggest that hyperglycemia, hyperinsulinemia, and
adipokines secreted by the adipose tissue might have a
direct fibrogenic role, independently of hepatocyte injury
and stellate cell activation. Hepatic iron excess might
contribute to the impairment of glucose homeostasis by
influencing insulin signaling. In fact, iron removal by
phlebotomy or iron chelators has been shown to improve
insulin sensitivity and/or metabolic control in healthy
individuals, type 2 diabetics, and NAFLD patients. Ferritin
levels also have been shown to correlate with the severity
of NAFLD, both in the absence or presence of hepatic iron
load, and independently of type 2 diabetes, body mass
index, age, sex, and hepatic iron deposition. This suggests
that ferritin per se might exert a role on disease progression
in NASH through still undefined mechanisms.
CONCLUSIONS AND FUTURE PERSPECTIVES
Both ALD and NAFLD are commonly associated with
varying degrees and diverse patterns of hepatic iron
deposition, whose cause and significance are being
progressively elucidated.
In both conditions, a direct modulation of hepcidin
expression by the causative agent (alcohol or fat) might
play a role in the modification of systemic and/or intrahepatic
iron traffic, leading to tissue iron load. While during the
long-lasting course of ALD and NAFLD opposite regulatory
forces on hepcidin expression might cause diverse patterns
of hepatic iron accumulation, alcohol induced hepcidin
downregulation seems to play a dominant role inhepatocytic
iron loading in ALD, while necroinflammation favors
preferential iron deposits in KC in NAFLD. Once liver iron
burden is established, it might act at both the hepatocellular
and mesenchymal levels to maintain and enhance liver
injury and disease progression, regardless of its cause
(Fig. 1). Further studies are needed to elucidate the
molecular events that link iron excess and the clinical
features of ALD and NAFLD, or the consequence of different
patterns of tissue iron accumulation on disease severity.
Nevertheless, in view of the available experimental and
clinical data, it is time to consider the use of iron removal
strategies as adjuvant therapy in patients with ASH and
NASH. Ideally, iron removal should be achieved by using
permeable, hepatotropic iron chelators able to target the
redoxactive intracellular iron pool in hepatocytes and KC
without affecting the circulatory iron pool or systemic iron
stores (the drawback of phlebotomy).
40
REFERENCES
1. Deugnier Y, Turlin B. Pathology of hepatic iron overload. Semin.
Liver Dis. 2011; 31: 260-71.
2. Pietrangelo A. Iron in NASH, chronic liver diseases and HCC: how
much iron is too much? J. Hepatol. 2009; 50: 249-51.
3. Pietrangelo A. Hepcidin in human iron disorders: therapeutic
implications. J. Hepatol. 2011; 54: 173-81.
4. Ganne-Carrié N, Christidis C, Chastang C et al. Liver iron is predictive
of death in alcoholic cirrhosis: a multivariate study of 229
consecutive patients with alcoholic and/or hepatitis C virus cirrhosis:
a prospective follow up study. Gut 2000; 46: 277-82.
5. Nahon P, Sutton A, Rufat P et al. Liver iron, HFE gene mutations, and
hepatocellular carcinoma occurrence in patients with cirrhosis.
Gastroenterology 2008; 134: 102-10.
6. Moirand R, Mortaji AM, Loreal O, Paillard F, Brissot P, Deugnier Y. A
new syndrome of liver iron overload with normal transferrin
saturation. Lancet 1997; 349: 95-7.
7. Vecchi C, Montosi G, Zhang K, Lamberti I, Duncan SA, Kaufman RJ,
and Pietrangelo A. ER stress controls iron metabolism through
induction of hepcidin." Science 325 2009: 877-880.
8. Valenti L, Fracanzani AL, Bugianesi E et al. HFE genotype, parenchymal
iron accumulation, and liver fibrosis in patients with nonalcoholic
fatty liver disease. Gastroenterology 2010;138:905-12.
9. Nelson JE, Wilson L, Brunt EM et al. Relationship between the
pattern of hepatic iron deposition and histological severity in
nonalcoholic fatty liver disease. Hepatology 2011; 53: 448-57.
10. Sorrentino P, D'Angelo S, Ferbo U, Micheli P, Bracigliano A, Vecchione
R. Liver iron excess in patients with hepatocellular carcinoma
developed on non-alcoholic steato-hepatitis. J. Hepatol. 2009; 50:
351-7.
Conflict of interests disclosure: I have no conflict of interests to
disclose related to this work.
Correspondence to
Director, Division of internal Medicine 2 and Center for
Hemochromatosis, University Hospital of Modena,
Via del Pozzo 71, 41100 Modena, Italy
Tel. +390594224356 email [email protected]
DIAGNOSIS OF RENAL FAILURE IN CIRRHOSIS
DIAGNÓSTICO DE FALÊNCIA RENAL NA CIRROSE
Florence Wong MBBS, MD, FRACP, FRCPC
University of Toronto, Canada
Renal dysfunction is a common complication in liver
cirrhosis, estimated to occur in approximately 20% of
patients with advanced cirrhosis and ascites admitted to
hospital. While structural renal disease can occur in
patients with cirrhosis, leading to acute renal dysfunction,
most of the cases of renal failure in cirrhosis are functional
in nature, that is, there is no underlying structural
abnormality in the kidneys; rather, the renal dysfunction is
the result of hemodynamic changes that are prevalent in
advanced cirrhosis. Most episodes of functional renal
disorder are responsive to intravascular volume
replacement, with return of the renal function to the baseline
level. Patients with volume responsive functional renal
impairment are cases of pre-renal renal failure. Hepatorenal
syndrome (HRS) is the most severe form of functional renal
failure and it is not responsive to intravascular volume
challenge. Hepatorenal syndrome is diagnosed with a set
of rigid criteria, which demand the serum creatinine to reach
an absolute elevated value. Recent literature suggests that
it is the change in serum creatinine rather than the absolute
serum creatinine value that will determining patient
outcome. These cases are called acute kidney injury (AKI).
Currently the hepatology community is still trying to sort
out whether to follow the diagnostic criteria of the Acute
Kidney Injury Network's (AKIN) definition of AKI, which has
3 stages depending on the extent of serum creatinine
increase. There are also urinary criteria, which may be
difficult to fulfil as cirrhotic patients usually have decreased
urine output. The International Ascites Club (IAC) and the
Acute Dialysis and Quality Initiative (ADQI) Group have
proposed to adopt a definition of AKI in cirrhosis as a acute
rise in serum creatinine of ≥0.3mg/dL within 48 hours or a
50% increase in serum creatinine from baseline, defined
as a stable serum creatinine in the past 6 months. Both
the IAC/ADQI and the AKIN criteria are not validated in
cirrhosis. The diagnosis of acute or type 1 HRS requires a
serum creatinine to reach 2.5mg/dl (233µmol/l) in <2 weeks
and only if the renal impairment is not responsive to fluid
challenge, and structural renal disease has been excluded.
Therefore, work-up of a patient with cirrhosis and AKI
requires diligent search for structural renal disease and
volume replacement in order to determine whether the
patient has organic or volume responsive functional renal
impairment. HRS type 1 is diagnosed only after all other
causes of AKI have been excluded. There is also type 2
HRS, which is the chronic form of renal failure. It usually
occurs in patients with cirrhosis and refractory ascites.
The renal dysfunction is related to a slow deterioration of
renal hemodynamics, the result of a relative reduction of
the intravascular volume, consequent upon worsening of
systemic arterial vasodilatation, leading to activation of
various compensatory mechanisms including
vasoconstrictor systems, causing renal vasoconstriction
and hence renal failure. Diagnosis requires a slow rise in
the serum creatinine to reach 1.5mg/dL (133µmol/L).
Patients with type 2 HRS usually have more problems
dealing with their refractory ascites than with their renal
dysfunction, and treatment strategies should aim at
relieving the refractory ascites
41
DIAGNOSIS OF RENAL FAILURE IN CIRRHOSIS
Diagnostic criteria of hepatorenal syndrome
1. Cirrhosis with ascites;
2. Serum creatinine >133 µmol/L (1.5 mg/dl);
3. No improvement of serum creatinine (decrease to a
level of 133 µmol/L or less) after at least two days with
diuretic withdrawal and volume expansion with albumin.
The recommended dose of albumin is 1 g/kg of body
weight per day up to a maximum of 100 g/day;
4. Absence of shock;
5. No current or recent treatment with nephrotoxic drugs;
6. Absence of parenchymal kidney disease as indicated
by proteinuria >500 mg/day, microhematuria (>50 red
blood cells per high power field), and/or abnormal renal
ultrasonography.
7. Type 1 HRS: Acute rise in serum creatinine ≥2.5mg/dL
in <2 weeks
8. Type 2 HRS: Slow rise in serum creatinine ≥1.5mg/dL
over several weeks to months
Corespondence to
Florence Wong, MD
GI Division - Department of Medicine - University of Toronto
9N/983 Toronto General Hospital
200 Elizabeth Street - Toronto M5G2C4
Ontario, Canada
Phone: 416-340 3834 - Fax: 416-340 5019
[email protected]
42
HEMOCHROMATOSIS – DIAGNOSIS AND TREATMENT
HEMOCROMATOSE – DIAGNÓSTICO E TRATAMNETO
Antonello Pietrangelo,, M.D., Ph.D,
Division of Internal Medicine 2 and Center for Hemochromatosis,
University Hospital of Modena, Modena , Italy
Abstract
In the late 1800s hemochromatosis was considered an odd
autoptic finding. More than 1 century later, it was finally
recognized as a hereditary, multi-organ disorder associated
with a polymorphism that is common among Caucasians: a
845G-A change in HFE that results in C282Y in the gene
product. Hemochromatosis is now a well-defined syndrome
characterized by normal iron-driven erythropoiesis and the toxic
accumulation of iron in parenchymal cells of liver, heart, and
endocrine glands. It can be caused by mutations that affect
any of the proteins that limit the entry of iron into the blood: loss
of the iron hormone hepcidin, transferrin-receptor 2 (Tfr2) and
hemojuvelin (Hjv) (which all sense the accumulation of iron
that hepcidin corrects) or ferroportin (Fpn) (the cellular ironexporter down-regulated by hepcidin) also result in full-blown
hemochromatosis. Unlike these rare instances, in Caucasians,
homozygotes for C282Y polymorphism in HFE are numerous,
but they are only predisposed to hemochromatosis; complete
organ disease develops in a minority, when these individuals
abuse alcohol or from other unidentified modifying factors. HFE
gene testing can be used to diagnose hemochromatosis, but
analyses of liver histology and clinical features are still required
to identify patients with rare, non-HFE forms of the disease. The
role of hepcidin in the pathogenesis of hemochromatosis
reveals its similarities to endocrine diseases such as diabetes
and indicates new approaches to diagnosis and manage this
common disorder in iron metabolism.
Keywords: Steatohepatitis; Alcoholic liver disease; Fatty liver
disease; Hepcidin; Iron;
INTRODUCTION
Iron is a transition metal that is essential for the survival
of most organisms, particularly those existing in an
environment that is rich in oxygen. There is a requirement
for exquisite conservation and regulation of body iron, given
both the body's absolute need for iron and the fact that the
human does not have a physiological iron excretion
mechanism. This inability to dispose excess iron sets the
basis for the common occurrence of iron overload in humans
(Table 1).
The classic example of iron overload in human
pathology is Hemochromatosis (HC) (synonymous for
Hereditary Hemochromatosis, HH) and particularly the form
associated to HFE.
In the mid-1800s, hemochromatosis was described
from an autopsy of a patient with diabetes by the French
physician Armand Trousseau, who was struck by the
(1)
"bronze-like appearance of [the patient's] countenance."
The term "hemochromatosis" was coined in 1889 by Von
Recklinghausen to describe the necroscopic finding of
massive organ damage associated with dark tissue staining
caused by what he believed to be a blood-borne pigment
(2)
. In 1935, Joseph Sheldon described the syndrome's
multivisceral nature and the probable role of iron among its
(3)
causes . He was also the first to suggest that the disease
resulted from an inherited metabolic defect. Researchers
like MacDonald questioned the hereditary nature of HC and
advocated the pathogenic role of alcohol and dietary iron
until 1975 when Simon et al. linked the syndrome to the
(4)
Major Histocompatibility Complex on chromosome 6 .
Twenty years later, Feder et al. cloned HFE, leading to
genetic studies in humans and mice that provided important
(5)
new information about iron metabolism and HC . In 1996
when Feder et al. discovered a polymorphism (a 845G-A
change that results in C282Y in the gene product) involving
(2)
a novel MHC class I-like gene, named HFE . The C282Y
polymorphism was present in the majority of patients with
HC throughout the world.
Today "hemochromatosis" or "hereditary
hemochromatosis" is a well-defined syndrome
characterized by normal iron-driven erythropoiesis and toxic
accumulation of iron in parenchymal cells of vital organs
that can lead to severe organ diseases such as diabetes,
(6)
cirrhosis and HCC, or hearth failure . The syndrome is
usually caused by mutations in any gene that limits the
synthesis or activity of hepcidin, the iron hormone produced
by the liver that normally inhibits iron entry into the blood
43
PIETRANGELO A
by degrading the iron exporter ferroportin. In humans, in
addition to the C282Y homozigosity of HFE, loss of the
iron hormone hepcidin itself, transferrin-receptor 2 (Tfr2)
and hemojuvelin (Hjv) or ferroportin (Fpn), led to HC.
EPIDEMIOLOGICAL AND CLINICAL ASPECTS
Epidemiology
HFE-related HC is the most common form of HC and
the most frequently inherited metabolic disorder found in
whites. The reported allelic frequency of C282Y across
(7)
several screening studies is around 6% . The estimated
prevalence of the C282Y polymorphism is 1:200-300 in
Caucasians. The prevalence is much lower in Hispanics,
Asian Americans, Pacific Islanders, and black persons.
The proportion of C282Y homozygous males with ironoverload-related disease is substantially higher than for
women (28% vs. 1%). The disease likely arose from a
chance mutation occurring in a single individual, probably
a Celtic or Viking ancestor inhabiting northwestern Europe.
The prevalence of C282Y is higher in certain patient groups,
such as those with liver disease (5 to 10-fold higher than in
the general population), type 1 diabetes, chondrocalcinosis
or porphyria cutanea tarda. Even higher C282Y frequencies
44
can be found in patients with hepatocellular carcinoma, a
known complication of HC. Nearly 20% of patients with
hemochromatosis have the disease in absence of C282Y,
and they may carry mutations in TfR2, HJV, HAMP or FPN.
None of the related non-HFE HC appears to be restricted
to Northern Europeans. A form of hereditary iron overload
distinct from HC, "the ferroportin disease", is most
commonly due to mutations of the FPN gene and has
(8)
distinct clinical and pathogenic features .
Clinical aspects
In HFE-HC, the clinical presentation, usually in midlife, varies from simple biochemical abnormalities to severe
organ damage and disease. The variations in symptoms
occur because C282Y HFE homozygosity only
predisoposes an individual to hemochromatosis-additional
host or environmental factors, particularly alcohol abuse,
(9)
are required . Elevated liver enzymes can be found in
30% of C282Y homozygote males, liver fibrosis in 18% of
males and 5% of females, cirrhosis, in 6% and 2%,
respectively. It is important to recall that, variations
notwithstanding, all of the genetic mutations causing HC
result in the same syndrome and the targets of iron toxicity
are identical (i.e., liver, heart, endocrine glands, joints).
IHEMOCHROMATOSIS - DIAGNOSIS AND TREATMENT
HC should be suspected in a middle-aged men presenting
with unexplained cirrhosis of the liver, bronze skin, diabetes
and other endocrine failure, or joint inflammation and heart
disease. However, this classical syndromic presentation
is rare. Today diagnosis is made at earlier stages as an
effect of screening and enhanced case detection due to
greater clinician awareness and higher index of suspicion.
The most common presenting symptoms are now fatigue,
malaise, and arthralgia, while hepatomegaly is one of the
earliest physical signs.
Elevated transferrin saturation (TS), which precedes
increased serum ferritin (SF), and moderately increased
transaminase levels are common biochemical
abnormalities. Increasing SF levels herald iron
accumulation in tissues, and values above 1000 µg/L may
indicate underlying liver fibrosis in HFE-HC, even when
transaminase levels are normal. The presence of cirrhosis
places patients at an increased risk for the development of
hepatocellular carcinoma.
In individuals suffering from juvenile forms of HC, the
heart and endocrine glands, which are more susceptible
to iron toxicity, succumb to its effects earlier, and their
failure will dominate the clinical picture. These individuals
usually present with hypogonadism, which is inevitably
found in those aged 20 or over with juvenile-onset
hemochromatosis. Cardiomyopathy and endocrine
disorders, including diabetes, appear earlier than they do
in adult-onset forms.
In patients with signs and symptoms and/or organ
disease suggestive of HC, the diagnosis is based on the
presence of C282Y homozygosity and iron overload.
Therefore, C282Y homozygosity is required for the
diagnosis of HFE-HC. Today the demonstration of C282Y
homozygosity in a subject with high TS and SF levels is
sufficient for diagnosis, even without a liver biopsy. C282Y
homozygosity (particularly in those over age 40) with SF
above 1000 µg/L, together with increased transaminases
and hepatomegaly, may be an indication for liver biopsy to
rule out hepatic fibrosis or cirrhosis. Liver iron content (LIC)
can be assessed noninvasively by MRI over a wide range
of iron concentrations. Figure 1 shows an algorithm to
diagnose C282Y-HC (see also ref. 10).
Symptomatic subjects with clear signs of circulatory
and tissue iron overload but negative HFE gene testing
may carry pathogenic mutations in other HC genes. Genetic
testing for non-HFE HC is complex and it is not widely
available. An alternative approach for diagnosis in these
cases is based on biopsy demonstration of a
hemochromatotic pattern of hepatic iron load.
If patients present with hyperferritinemia but TS is
normal or low, the presence or absence of iron overload
will guide further diagnostic work up (Figure 2). Assessment
of liver iron stores by direct means (i.e. MRI or liver biopsy)
is recommended. If the liver iron concentration is increased,
Figure 1. Algorithm for the diagnostic management of patients with
C282Y homozygosity (from ref. 10).
non HC- hereditary iron overload diseases can be considered
(e.g. ferroportin disease, aceruloplasminemia). If liver iron
concentration is normal, genetic testing for L ferritin gene
mutations (to investigate the hyperferritinemia-cataract
syndrome) can be carried out.
TREATMENT
Phlebotomy is the standard treatment of all forms of
HC. One unit (400-500 ml) of blood contains approximately
200-250 mg of iron. There are no studies from which to
45
PIETRANGELO A
give an evidence base to the optimal time to start
therapeutic venesection. Threshold SF is currently
empirically chosen as above the normal range. The goal of
bloodletting during the iron-depletion stage is generally the
induction of a mildly iron-deficient state. Weekly
phlebotomy can restore safe blood levels of iron (reflected
by SF levels of less than 20-50 µg/L and TS below 30%)
within one-two years. Maintenance therapy, which typically
involves removal of 2-4 units a year, must then be continued
to keep SF normal. Despite its nonspecificity, SF should
always be monitored during phlebotomy.
Non-expressing C282Y homozygotes should be
monitored by SF once a year; if the SF is increasing , a full
clinical work-up should be implemented and phlebotomy
started.
Blood taken from patients with HC at phlebotomy
should be made available for national blood transfusion
services , if there is no medical contraindication and the
patient has given consent.
If phlebotomy is contraindicated or poorly tolerated,
other strategies can be considered, such as the use of
iron chelation. Patients with classic HC are at risk of
developing serious organ diseases and complications,
including hepatocellular carcinoma (2-2.5 fold higher risk
than in other liver diseases). Survival of treated HC patients
without cirrhosis and diabetes seems equivalent to that
of the normal population, whereas those with these
complications have significantly reduced survival. Elevated
transaminases, skin pigmentation and hepatic fibrosis
seem to improve after phlebotomy. In studies of individuals
with biopsy-proven liver fibrosis, phlebotomy has been
associated with improvement of liver fibrosis in 13% to
50% of treated patients, particularly those with the mildest
fibrosis at baseline. It is recognized, however, that several
clinical features are unlikely to improve with iron depletion,
in particular arthralgia. Hypogonadism, cirrhosis,
destructive arthritis, and insulin-dependent diabetes
associated with HC are usually irreversible, though
phlebotomy may improve certain aspects of these
diseases (e.g., daily insulin requirements, elevated
aminotransferase levels, weakness, lethargy, abdominal
pain). End-stage liver disease or hepatocellular carcinoma
secondary to HC is frequently treated by orthotopic liver
transplantation, but survival after liver transplantation might
be expected to be reduced when compared to non-ironloaded patients.
4. Simon M, Pawlotsky Y, Bourel M, Fauchet R, Genetet B. Idiopathic
hemochromatosis associated with HL-A 3 tissular antigen. Nouv
Presse Med. 1975;4:1432.
5. Feder JN, Gnirke A, Thomas W, Tsuchihashi Z, et al. A novel MHC
class I-like gene is mutated in patients with hereditary
haemochromatosis. Nature Genetics. 1996;13:399-408.
6. Pietrangelo A. Hereditary hemochromatosis--a new look at an old
disease. N Engl J Med. 2004;350:2383-97.
7. Merryweatherclarke AT, Pointon JJ, Shearman JD, Robson KJH. Global
prevalence of putative haemochromatosis mutations. J Med Genet.
1997;34:275-8.
8. Pietrangelo, A. The ferroportin disease." Blood Cells Mol Dis. 2004;
32:131-8.
9. Pietrangelo A. Hereditary hemochromatosis: pathogenesis, diagnosis,
and treatment. Gastroenterology. 2010; 139:393-408.
10. EASL clinical practice guidelines for HFE hemochromatosis. J Hepatol
2010;53(1):3-22.
Conflict of interests disclosure: I have no conflict of interests to
disclose related to this work.
Corespondence to
Director, Division of internal Medicine 2 and Center for
Hemochromatosis, University Hospital of Modena, Via del Pozzo 71,
41100 Modena, Italy
Tel. +390594224356 email [email protected]
REFERENCES
1. Trousseau A. Glycosurie; diabete sucre. Clinique Med de l'Hotel de
Paris 1865;2:663-698.
2. von Recklinghausen FD. Uber Haemochromatose. Taggeblatt der
(62) Versammlung deutscher Naturforscher and Aerzte in
Heidelberg 1889:324-325.
3. Sheldon J. Haemochromatosis. Oxford University Press, 1935.
46
THERAPEUTIC STRATEGIES FOR BUDD-CHIARI SYNDROME
ESTRATÉGIAS TERAPÊUTICAS PARA A SÍNDROME DE BUDD-CHIARI
Summary
Budd-Chairi syndrome is a potentially lethal disease generally
due to thrombosis of hepatic veins or inferior vena cava.
Multiple underlying prothrombotic conditions are usually
present. It has been shown that a strategy where interventions
are implemented by order of increasing invasiveness, based
on the response to previous, less invasive therapy, can achieve
high survival rates. Anticoagulation and TIPS play a central
role in this strategy. Long-term outcome is increasingly
determined by the underlying prothrombotic conditions and
de novo hepatocellular carcinoma.
Keywords: Thrombosis; TIPS; Prothrombotic conditions;
Anticoagulation therapy; Liver transplantation; Angioplasty
Primary Budd-Chiari syndrome (BCS) is characterized
by an obstruction of the hepatic venous outflow tract by
(1)
thrombosis . Therefore, treatment should be directed both
at correcting the cause for thrombosis, and at relieving the
consequences of the outflow blockade. In the last decade,
several options have been shown of interest for these
purposes. As a consequence, the issue has become to
determine on which patients or in what order the various
therapeutic options should be targeted in order to achieve
the optimal benefit risk-ratio.
The recognition of a multifactorial etiology, and of a
prominent role of myeloproliferative diseases in causing
(2)
hepatic vein and inferior vena cava (IVC) thrombosis , has
lead to a proposal for routine anticoagulation in all patients.
Indeed, beside an obvious rationale, there is some
circumstantial evidence for an improved survival in patients
(3)
treated with rapid and permanent anticoagulation .
However the risk inherent to long term anticoagulation has
not been fully evaluated yet. The rationale for treatment of
underlying myeloproliferative disorder is also obvious.
However, there is no direct evidence for an improved
prognosis in such patients. Furthermore, what should be
the target level in peripheral blood cell counts remains
unclear as BCS patients with underlying myeloproliferative
disease often present with normal blood cell counts. The
possibility to quantify the size of the JAK2-mutated clone
will hopefully allow for providing an answer to this question
(4)
in a near future .
BCS is currently recognized in patients without clinical
(1)
signs and symptoms in about 15% of patients . The goal
for therapy in such patients is to prevent extension or
recurrence of thrombosis. Other patients present with a
well compensated disease acute or chronic condition, or
rapidly improve on medical treatment for gastrointestinal
bleeding or ascites. The rest of the patients have a severe
liver disease that may present with an acute or a chronic
illness. Up-to 30% of patients with pure hepatic vein
involvement, and 60% of those with IVC obstruction, have
a short length stenosis that is theoretically amenable to
angioplasty with or without thrombolysis, with or without
stenting. Whereas side to side porto caval shunt has been
shown to be efficient to relieve intrahepatic hypertension,
gain in long term survival has been compromised by an
overriding operative mortality. However, TIPS has been
shown to be feasible in patients with pure obstruction of
the hepatic veins, and to be followed by medium term
(5)
control of the disease when covered stents are used .
Last, transplantation, when combined with early and
permanent anticoagulation, has been associated with
(6)
excellent medium term results .
There has been some debate on to whether patients
with the most severe disease should be offered rapidly and
directly TIPS, or even transplantation. Recently, however,
data from several groups have showed that a progressive
approach aiming at minimal invasiveness was able to achieve
(5,7,8,9)
excellent 5 year survival rates (about 80%)
. According
to this approach, (a) the therapeutic options are
implemented by order of increasing invasiveness: medical
therapy, then angioplasty, then TIPS and finally
transplantation; and (b) the indications are based on
response to previous therapy rather than on the actual
(8)
severity of the disease . In all patients, anticoagulation
and treatment for underlying disease are initiated as soon
as possible and maintained permanently. Of note is the
fact that the patients with the most severe forms of BCS
(10)
appear to benefit most from this strategy . As the early
and medium term outcome of BCS improves, the attention
is drawn to long-term complications. It appears that the
risk of hepatocellular carcinoma is similar to that seen in
other chronic liver diseases, affecting almost exclusively
(11)
patients with an obstruction of suprahepatic IVC .
Hepatocellular carcinoma is a difficult differential diagnosis
of the frequent benign macroregenerative nodules. Further,
lethal transformation of the underlying myeloproliferative
47
VALLA D
disease may affect up to 30% of the patients beyond 10
(12)
years of follow-up .
REFERENCES
1. Plessier A, Valla DC. Budd-Chiari syndrome. Semin Liver Dis
2008;28:259-269.
2. Kiladjian JJ, Cervantes F, Leebeek FW, Marzac C, Cassinat B, Chevret
S, Cazals-Hatem D, et al. The impact of JAK2 and MPL mutations on
diagnosis and prognosis of splanchnic vein thrombosis: a report on
241 cases. Blood 2008;111:4922-4929.
3. Valla DC. Primary Budd-Chiari syndrome. J Hepatol 2009;50:195203.
4. Kiladjian JJ, Cassinat B, Chevret S, Turlure P, Cambier N, Roussel M,
Bellucci S, et al. Pegylated interferon-alfa-2a induces complete
hematologic and molecular responses with low toxicity in
polycythemia vera. Blood 2008;112:3065-3072.
5. Garcia-Pagan JC, Heydtmann M, Raffa S, Plessier A, Murad S,
Fabris F, Vizzini G, et al. TIPS for Budd-Chiari syndrome: long-term
results and prognostics factors in 124 patients. Gastroenterology
2008;135:808-815.
6. Mentha G, Giostra E, Majno PE, Bechstein WO, Neuhaus P, O'Grady
J, Praseedom RK, et al. Liver transplantation for Budd-Chiari
syndrome: A European study on 248 patients from 51 centres. J
Hepatol 2006;44:520-528.
7. Eapen CE, Velissaris D, Heydtmann M, Gunson B, Olliff S, Elias E.
Favourable medium term outcome following hepatic vein
recanalisation and/or transjugular intrahepatic portosystemic shunt
for Budd Chiari syndrome. Gut 2006;55:878-884.
8. Plessier A, Sibert A, Consigny Y, Hakime A, Zappa M, Denninger MH,
Condat B, et al. Aiming at minimal invasiveness as a therapeutic
strategy for Budd-Chiari syndrome. Hepatology 2006;44:1308-1316.
9. Valla DC. Prognosis in Budd Chiari syndrome after re-establishing
hepatic venous drainage. Gut 2006;55:761-763.
10. Seijo S, Plessier A, Hoekstra J, Dell'era A, Mandair D, Rifai K, Trebicka
J, et al. Good long-term outcome of Budd-Chiari syndrome with a
step-wise management. Hepatology 2013; 57:1962-1968.
11. Moucari R, Rautou PE, Cazals-Hatem D, Geara A, Bureau C, Consigny
Y, Francoz C, et al. Hepatocellular carcinoma in Budd-Chiari
syndrome: characteristics and risk factors. Gut 2008;57:828-835.
12. Chait Y, Condat B, Cazals-Hatem D, Rufat P, Atmani S, Chaoui D,
Guilmin F, et al. Relevance of the criteria commonly used to diagnose
myeloproliferative disorder in patients with splanchnic vein
thrombosis. Br J Haematol 2005;129:553-560.
Correspondence to
Dominique Valla
Tel: + 33 1 40 87 55 94
Fax: + 33 1 40 87 44 26
[email protected]
48
PORTAL VEIN THROMBOSIS IN CIRRHOSIS
TROMBOSE DE VEIA PORTALNA CIRROSE
5,6
Summary
Portal vein thrombosis is an increasingly recognized feature
of severe cirrhosis. A prothrombotic state associated with the
coagulopathy of cirrhosis, a decreased blood flow velocity and
underlying thrombophilia may participate in pathogenesis.
The impact of portal vein thrombosis on the severity of liver
disease is unclear. Portal vein thrombosis is a factor of poor
prognosis post-transplant. Anticoagulation and TIPS appear
to be relatively safe and to allow recanalization. However,
their impact on major outcomes of cirrhosis remains to be
shown.
Keywords: Portal vein flow; Prothrombotic disorders;
Anticoagulation therapy; TIPS; Liver transplantation; Prognosis
Portal vein thrombosis (PVT) has recently emerged
as a factor associated with an increased severity of
cirrhosis, and thus a possible target for various therapeutic
interventions. The purpose of this presentation is to critically
review the data relevant to these issues.
FACTORS ASSOCIATED WITH THE OCCURRENCE
OF PVT IN PATIENTS WITH CIRRHOSIS
PVT incidences of 7-16% per year have been reported
in patients with cirrhosis. Cross-sectional studies in
patients with cirrhosis indicate a PVT prevalence varying
1
from 5 to 20%, depending on the context. An occlusive
thrombus has been present in only one fourth to one third
.2,3
of PVT patients, the rest having non occlusive thrombi
The factors thus far reported include (i) an advanced stage
of liver disease as assessed using MELD or Child-Pugh
1,4
score or their components , (ii) the slowing of blood flow
1
the portal vein , and (iii) an underlying inherited risk factors
1
for venous thrombosis , particularly factor II Leiden (mutation
G20210A in prothrombin gene). These 3 factors appear to
4
have some independent predictive value. However, a
comprehensive and simultaneous evaluation of all 3 factors
in a large group is lacking. Liver disease appears to produce
a prothrombotic state by increasing procoagulant factor
VIII plasma levels, while concurrently decreasing
Moderna Hepatologia – ol. 39 – Nº 1 – Jan/Jun 2013
anticoagulant protein C plasma levels. In line with this
procoagulant state, a slight but statistically significant
increase in the risk of venous thromboembolism has been
documented in patients with cirrhosis.
PVT AS A DEBATABLE CAUSE FOR THE
AGGRAVATION OF CIRRHOSIS
PVT has been associated with smaller liver weights at
liver transplantation, as well as with more severe ascites,
refractory variceal bleeding, encephalopathy, and as
1,6
mentioned above, high Child-Pugh/MELD scores.
However, the cross sectional studies available have not
permitted an analysis of causality. In selected patients with
occlusive PVT listed for liver transplantation, data on the
1,7
risk of death while on the waiting list are inconsistent.
Therefore, it remains unclear whether PVT actually causes
an aggravation in liver disease, or whether it is a mere
1,6
reflection of the severity of the underlying liver disease.
The fact that portal vein embolization causes apoptosis of
the liver cells in the embolized lobe undergoing atrophy,
suggests that PVT might induce a decrease in liver cell
mass. However, embolization of a large portal branch is
not an equivalent to a thrombus occurring in the main portal
vein, and even less so to a partial thrombus. PVT has
generally been associated with a poorer outcome after liver
7
transplantation. Interestingly, this poorer outcome has
7
been associated to a lower pretransplantation MELD score.
TREATMENT OPTIONS FOR THE RECANALIZATION
OF THE PORTAL VEIN
Data on TIPS, anticoagulation and thrombolysis are
available. Studies on TIPS have mostly consisted in
retrospective evaluations of PVT patients with cirrhosis,
having undergone the procedure for refractory bleeding or
1,8
ascites. Findings have been consistent in showing that
(i) insertion of the TIPS is possible whenever intrahepatic
portal branches were visible; and (ii) clearance of partial
thrombi occurs even in the absence of added
anticoagulation therapy. Studies on anticoagulation therapy
have mostly consisted in retrospective evaluations of
patients having received anticoagulation therapy for PVT,
with or without concurrent complications of cirrhosis, being
3,6,8
listed or not for liver transplantation. Recanalization has
been obtained in about 40% of patients. Factors suggested
to be associated with recanalization include the degree of
occlusion of the portal vein, the delay in initiation and the
49
VALLA D
duration of anticoagulation therapy. Interruption of
anticoagulation after recanalization has been associated
with recurrence in about one third of patients in one report.3
A small case series of systemic thrombolysis for PVT
9
reported recanalization in half of patients.
THE IMPACT OF TREATMENT FOR PVT ON THE
OUTCOME OF PATIENTS WITH CIRRHOSIS
TIPS has achieved beneficial and deleterious effects
1,8
as commonly as in patients without PVT. However none
of the reports on TIPS, anticoagulation therapy, or systemic
thrombolytic therapy have been designed to evaluate their
impact on patient or disease outcome. Furthermore, it has
not yet been clearly shown that recanalization on
anticoagulation before transplantation will improve post
transplant course.
A randomized controlled study has investigated the
prevention of PVT occurrence with enoxaparine versus no
10
treatment in patients with Child-Pugh score 7 to 10.
Complications and death were delayed in the treated group.
The benefit for complications was much greater than for
PVT, which suggests an effect independent from the
prevention of PVT per se.
THE SAFETY OF TREATMENT FOR PVT
Generally, anticoagulation has been considered
1, 3, 6, 8
safe.
The incidence of gastrointestinal bleeding in patient
submitted to the recommended prophylaxis for portal
hypertension-related bleeding was reported to be low. In
the current state of limited experiences, fatal bleeding has
not been reported. However, adequately powered study will
have to be performed to evaluate this aspect. It is likely
that the incidence of bleeding unrelated to portal
hypertension will be similar to that in other populations
receiving anticoagulation therapy.
indicated by refractory complications of portal hypertension.
Randomized controlled trials with robust clinical endpoints
are eagerly waited.
REFERENCES
1. Francoz C, Valla D, Durand F. Portal vein thrombosis, cirrhosis, and
liver transplantation. J Hepatol 2012;57:203-12.
2. Maruyama H, Okugawa H, Takahashi M, Yokosuka O. De novo
Portal Vein Thrombosis in Virus-Related Cirrhosis: Predictive Factors
and Long-Term Outcomes. Am J Gastroenterol 2013;108:568-74.
3. Delgado MG, Seijo S, Yepes I, Achecar L, Catalina MV, GarciaCriado A, Abraldes JG, de la Pena J, Banares R, Albillos A, Bosch J,
Garcia-Pagan JC. Efficacy and safety of anticoagulation on patients
with cirrhosis and portal vein thrombosis. Clin Gastroenterol Hepatol
2012;10:776-83.
4. Englesbe MJ, Schaubel DE, Cai S, Guidinger MK, Merion RM. Portal
vein thrombosis and liver transplant survival benefit. Liver Transpl
2010;16:999-1005.
5. Tripodi A, Anstee QM, Sogaard KK, Primignani M, Valla DC.
Hypercoagulability in cirrhosis: causes and consequences. J
Thromb Haemost 2011;9:1713-23.
6. Huard G, Bilodeau M. Management of anticoagulation for portal vein
thrombosis in individuals with cirrhosis: a systematic review. Int J
Hepatol 2012;2012:672986.
7. Englesbe MJ, Kubus J, Muhammad W, Sonnenday CJ, Welling T,
Punch JD, Lynch RJ, Marrero JA, Pelletier SJ. Portal vein
thrombosis and survival in patients with cirrhosis. Liver Transpl
2010;16:83-90.
8. Senzolo M, T MS, Rossetto V, Burra P, Cillo U, Boccagni P, Gasparini
D, Miotto D, Simioni P, Tsochatzis E, K AB. Prospective evaluation of
anticoagulation and transjugular intrahepatic portosystemic shunt
for the management of portal vein thrombosis in cirrhosis. Liver Int
2012;32:919-27.
9. De Santis A, Moscatelli R, Catalano C, Iannetti A, Gigliotti F, Cristofari
F, Trapani S, Attili AF. Systemic thrombolysis of portal vein thrombosis
in cirrhotic patients: a pilot study. Dig Liver Dis 2010;42:451-5.
10. Villa E, Camma C, Marietta M, Luongo M, Critelli R, Colopi S, Tata C,
Zecchini R, Gitto S, Petta S, Lei B, Bernabucci V, Vukotic R, De
Maria N, Schepis F, Karampatou A, Caporali C, Simoni L, Del Buono
M, Zambotto B, Turola E, Fornaciari G, Schianchi S, Ferrari A, Valla
D. Enoxaparin prevents portal vein thrombosis and liver
decompensation in patients with advanced cirrhosis.
Gastroenterology 2012;143:1253-60 e1-4.
CONCLUSION
It is still far from clear that recanalization of a
thrombosed portal vein is associated with improved survival.
Therefore, PVT per se still cannot represent an indication
for anticoagulation therapy, even though this treatment will
achieve recanalization in many patients. PVT in candidates
to liver transplantation constitutes the most logical situation
for using anticoagulation therapy, aiming at recanalization
and prevention of rethrombosis, in order to facilitate the
surgical procedure and hopefully improve posttransplant
survival. It appears that with adequate prophylaxis
anticoagulation does not increase the risk of portal
hypertension related bleeding. On the other hand portal
vein thrombosis is not a contraindication or a limitation to
attempting TIPS insertion when this procedure is otherwise
50
Correspondence to
Dominique Valla
Tel: + 33 1 40 87 55 94
Fax: + 33 1 40 87 44 26
[email protected]
Moderna Hepatologia – ol. 39 – Nº 1 – Jan/Jun 2013
EPIDEMIOLOGY OF NAFLD IN THE AMERICAS
EPIDEMIOLOGIA DE NAFLD NAS AMERICAS
Karen V. Silva-Vidal; Jorge A. López-Velázquez;
Varenka J. Barbero-Becerra; Norberto C. Chávez-Tapia;
Misael Uribe; Nahum Méndez-Sánchez
Liver Research Unit. Medica Sur Clinic & Foundation. Mexico
City, Mexico
Abstract
Non-alcoholic fatty liver disease (NAFLD) is an alarming public
health problem in America, which is rising worldwide with the
increasing incidence of obesity. The prevalence of NAFLD in
general population has been estimated between 20-30%.
Several factors determine the epidemiology of NAFLD such
as sex, ethnic groups, genetic factors and geographic regions.
We aimed to clearly understand the prevalence of NAFLD in
America, in order to have a detailed understanding of this
disease which could improve our screening and develop of
effective treatment or prevention strategies in our population.
Keywords: Non-alcoholic fatty liver disease, obesity,
metabolic syndrome.
INTRODUCTION
Non-alcoholic fatty liver disease (NAFLD) is the most
common cause for chronic liver disease around the world.
NAFLD definition involves the presence of lipid accumulation
into hepatocytes exceeding 5% of the total liver weight, as
well as no evidence from significant alcohol consumption,
(1)
steatogenic medication or hereditary disorders .
Clinically, NAFLD comprises a wide spectrum from
simple fatty liver (which in most cases is a benign condition),
fatty liver accompanied by inflammation and hepatocellular
necrosis (non-alcoholic steatohepatitis), collagen deposition
and the consequent lost of liver function (cirrhosis), and in
(2)
a few cases the development of hepatocellular carcinoma .
The aim of this review is to analyze the available
information about epidemiology of NAFLD in the Americas.
EPIDEMIOLOGY
The epidemiology of NAFLD is an extensive area of
research and currently with information lacking. Several
noninvasive markers with diagnostic purposes, but certain
(3)
limitations, have been proposed . Nevertheless, the best
non-invasive method to diagnose steatosis seems to be
the abdominal ultrasound; despite its proposal as the prior
method, it presents important disadvantages such as the
decrease in accuracy in some conditions (e.g. in high BMI
and steatosis <10%). Nuclear magnetic resonance
spectroscopy and liver biopsy are the most sensitive
(4)
techniques for fatty liver diagnosis . Actually, the former
is considered the gold standard, however, it is an invasive,
(5)
costly and operator dependent technique .
In most patients, NAFLD is mainly associated with
metabolic risk factors like obesity (75-95%), diabetes
mellitus and/or insulin resistance (70%) and dyslipidemia
(6)
(50%) .
Nowadays, NAFLD is considered the hepatic
(7)
manifestation of metabolic syndrome . Approximately 90%
of patients diagnosed with NAFLD develops more than one
component of metabolic syndrome; meanwhile, a third of
(8,9)
the population has this condition .
NAFLD is a complex condition that involves, ethnical,
genetic, and environmental factors , which determine its
development and progression. The prevalence of NAFLD
increases with age, being highest in males between 40
and 65 years-old, as well as between races, Hispanics
present a higher prevalence than African-Americans;
indeed, it has been shown an important difference between
(10)
continents . It is noteworthy that family members of
NAFLD patients present a higher risk to develop NAFLD,
(11)
regardless of age and BMI .
Some variants of different genes have been shown to
(12)
present a risk for NAFLD develop and progression . The
microsomal triglyceride transfer protein (MTP) regulates
synthesis and secretion of very low density lipoprotein
(VLDL) in the liver and it has been demostrated that a
genetic variation (G/G) affects susceptibility to the
(13)
development and severity of NAFLD . Furthermore,
adiponutrin (PNPLA3), a triacylglycerol lipase, mainly
expressed on the surface of lipid droplets in hepatocytes
and adipocytes; have been shown that I148M polymorphism
plays a strong role in the development of fatty liver and
(14)
also in the severity of disease . Actually, other study
suggests that ethnic and genetic differences in hispanic
population make them more prone to develop hepatic
steatosis and steatosis- related liver injury compared with
(10)
other ethnic groups .
Currently, there are different definitions of metabolic
syndrome such as the International Diabetes Federation,
the American Heart Association/ National Heart, Lung and
Blood Institute and the Adult Treatment Panel III (ATP III),
51
SILVA-VIDAL KV; JLÓPEZ-VELÁZQUEZ JA; BARBERO-BECERRA VJ; CHÁVEZ-TAPIA NC; URIBE M; MÉNDEZ-SÁNCHEZ N
generally include the same components, but they differ in
the assignment of each component importance for the
diagnosis.
ATP III is one of the most accepted and used
international definitions; however, it does not establish a
hierarchal relationship between the five components that
comprise: abdominal obesity, glucose alterations,
hypertension, hypertriglyceridemia and low HDL cholesterol
levels. According to this definition, some studies have
estimated the prevalence of metabolic syndrome in several
(15
countries ). Approximately 35% was reported in United
(16)
States ; meanwhile Mexico showed a 45% accordingly
(17)
to National Health and Nutrition Survey 2012 . Other
studies using the NCEP-ATPIII criterion have reported the
highest prevalence of metabolic syndrome in Brazil (47.3%),
Costa Rica (43%) and Puerto Rico (43.3%), probably due
to the adjustment of glucose level (>100 mg/dL).
The prevalence in Latin-America countries has been
(18)
estimated at 24.9% in 2011 . In 2008, the CARMELA
Study has estimated the prevalence between 14-27%, in
which Mexico and Venezuela were the countries which
present the highest prevalence value, 27% and 26%
(19)
respectively .
In the last 20 years, the prevalence of NAFLD in
America has increased dramatically; this could be due to
economic and demographic changes that may have
occurred especially in South-America. Furthermore,
lifestyle and dietary habits promote this status, which in
consequence, several profound changes have occurred in
epidemiological profiles of certain chronic diseases,
especially NAFLD, whose prevalence has increased
(20)
significantly .
In addition, obesity degree has shown a high
correlation with NAFLD prevalence and severity.
Accordingly, obesity prevalence in the Americas is higher
than in the rest of the world.
NAFLD prevalence assessed by the last two sensitivetechniques described before has been estimated between
(21)
20-32% in United States and Canada . In Mexico, a
prevalence of 32% was estimated accordingly to obesity
(17)
prevalence ; whereas, in Central-America countries,
prevalence is estimated close to 15-20%, and increases
up to 30% in Belize, Cuba, Trinidad and Tobago, Dominican
Republic and Puerto Rico since its high obesity prevalence.
Finally, in South-America, the prevalence has been
(19)
estimated as follows : 30% in Brazil, Paraguay and
Venezuela; approximately 25% in Guyana, Uruguay, Chile,
Argentina and Ecuador, and <20% in the rest of the
(19,22-34)
countries in that region
.
The increasing obesity prevalence in American
countries could lead to a non-stop increased prevalence of
NAFLD; this will present a challenge over the next years in
terms of public health costs. In summary, NAFLD is
undoubtedly closely associated with obesity. The lack of
52
current available treatments, as well as accurate diagnostic
method to reduce this burden disease, suggest that
prevention should be considered as the key step to control
this condition.
In conclusion, we found that United States, Mexico
and Brazil were the countries with the highest prevalence
of NAFLD and obesity, by the other hand Brazil, Puerto
Rico and Costa Rica showed the most increased metabolic
syndrome prevalence in the continent.
Figure 1. Prevalence of obesity and NAFLD in the Americas. NAFLD
prevalence was estimated by the assumption that 80% of obesity people
could have NAFLD.
Figure 2. Prevalence of metabolic syndrome in the Americas. Metabolic
syndrome is reported using the original criteria of the Adult Treatment
Panel III criteria.
REFERENCES
1. Angulo P. GI epidemiology: nonalcoholic fatty liver disease. Aliment
Pharmacol Ther. 2007;25:883-9.
2. Méndez-Sánchez N, Arrese M, Zamora-Valdés D, Uribe M. Current
concepts in the pathogenesis of nonalcoholic fatty liver disease.
Liver Int. 2007;27:423-33.
3. Musso G, Gambino R, Cassader M, Pagano G. Meta-analysis: natural
history of non-alcoholic fatty liver disease (NAFLD) and diagnostic
accuracy of noninvasive tests for liver disease severity. Ann Med
2011;43:617-649.
4. Pérez-Gutiérrez OZ, Hernández-Rocha C, Candia-Balboa RA, Arrese
MA, Benítez C, Brizuela-Alcántara DC, et al. Validation study of
systems for noninvasive diagnosis of fibrosis in nonalcoholic fatty
liver disease in Latin population. Ann Hepatol. 2013; 12: 416-24.
EPIDEMIOLOGY OF NAFLD IN THE AMERICAS
5. Machado MV, Cortez-Pinto H. Non-invasive diagnosis of nonalcoholic fatty liver disease. A critical appraisal. J Hepatol. 2013
;58: 1007-19.
23. The Central America Diabetes Initiative (CAMDI). Survey of Diabetes,
Hypertension and Chronic Disease Risk Factors. Pan American
Health Organization 2009.
6. Schindhelm RK, Heine RJ, Diamant M. Prevalence of nonalcoholic
fatty liver disease and its association with cardiovascular disease
among type 2 diabetic patients. Diabetes Care. 2007;30: 94-95.
24. Williams ES, Baylin A, Campos H. Adipose tissue arachidonic acid
and the metabolic syndrome in Costa Rican adults Clin Nutr.
2007;26:474-82. Epub 2007/ Encuesta Nacional de Nutricion, Costa
Rica. 2008-2009 Instituto Costarricense de Investigación y
enseñanza en nutrición y salud.
7. Medina-Santillán R, López-Velázquez JA, Chávez-Tapia N, TorresVillalobos G, Uribe M, Méndez-Sánchez N. Hepatic manifestations
of metabolic syndrome. Diabetes Metab Res Rev. 2013 Mar 7. doi:
10.1002/dmrr.2410.
8. Hamaguchi M, Kojina T, Takeda N et al. The metabolic syndrome as
a predictor of nonalcoholic fatty liver disease. Ann Intern Med 2005;
143: 722-8.
25. Pérez CM, Guzmán M, Ortiz AP, Estrella M, Valle Y, Pérez N, Haddock
L, Suárez E. Prevalence of the metabolic syndrome in San Juan,
Puerto Rico. Ethn Dis. 2008 Autumn; 18: 434-41./ Epidemiology
Aspects of Cardiology, Obesity, and Diabetes in Puerto Rico. Health
Department of Puerto Rico,2007
9. Almeda-Valdes P, Cuevas-Ramos D, Aquilar-Salinas CA. Metabolic
syndrome and nonalcoholic fatty liver disease. Ann Hepatol 2009;
8: 18-24.
26. Encuesta Nacional de Demografía y Salud 2008, Ministerio de Salud,
La Paz-Bolivia.
10. Browning JD, Szczepaniak LS, Dobbins R, Nuremberg P, Horton JD,
Cohen JC, Grundy SM, Hobbs HH. Prevalence of hepatic steatosis
in an urban population in the United States: impact of ethnicity.
Hepatology. 2004;40:1387-95.
28. Brazilian group for the study of the NAFLD-Sociedade Brasileira de
Hepatologia-Brazil 2011.
11. Ratziu V, Bellentani S, Cortez-Pinto H, Day C, Marchesini G. A position
statement on NAFLD/NASH based on the EASL 2009 special
conference. J Hepatol. 2010;53:372-84.
30. Romero C. El síndrome metabólico Rev Méd Urug 2006; 22: 2./ FAO,
2012.
12. Puppala J, Siddapuram SP, Akka J, Munshi A. Genetics of
nonalcoholic Fatty liver disease: an overview. J Genet Genomics.
2013; 20: 15-22.
13. Namikawa C, Shu-Ping Z, Vyselaar JR, Nozaki Y, Nemoto Y, Ono M,
et al. Polymorphisms of microsomal triglyceride transfer protein
gene and manganese superoxide dismutase gene in non-alcoholic
steatohepatitis. J Hepatol. 2004; 40: 781-6.
14. Sookoian S, Pirola CJ. Meta-analysis of the influence of I148M
variant of patatin-like phospholipase domain containing 3 gene
(PNPLA3) on the susceptibility and histological severity of
nonalcoholic fatty liver disease. Hepatology. 2011; 53: 1883-94.
15. Expert Panel on Detection, Evaluation, and Treatment of High
Blood Cholesterol in Adults (2001) Executive summary of the third
report of The National Cholesterol Education Program (NCEP)
Expert Panel on Detection, Evaluation, and Treatment of High Blood
Cholesterol in Adults (Adult Treatment Panel III). JAMA2001; 285:
2486-2497.
16. McCullough AJ. Epidemiology of the metabolic syndrome in the
USA. J Dig Dis. 201;12: 333-40.
17. Rojas R, Aguilar-Salinas CA, Jiménez-Corona A, Shama-Levy T,
Rauda J, Ávila-Burgos L, Villalpando S, Lazcano-Ponce E.
Metabolic syndrome in Mexican adults. Results from the National
Health and Nutrition Survey 2006. Salud Publica Mex 2010; 52:
S11-S18./ Encuesta Nacional de Salud. Secretaria de Salud, México
2012.
18. Márquez-Sandoval F, Macedo-Ojeda G, Viramontes-Hörner D,
Fernández Ballart JD, Salas Salvadó J, Vizmanos B. The prevalence
of metabolic syndrome in Latin America: a systematic review. Public
Health Nutr. 2011; 14: 1702-13.
19. Pramparo P, Boisson C, Schargrodsky H. Evaluation of
Cardiovascular Risk in Seven Cities in Latin America: The Main
Conclusions of the Carmela Study. Rev Argent Cardiol 2011; 79:
377-382.
20. Méndez-Sánchez N, Villa AR, Chávez-Tapia NC, Ponciano-Rodriguez
G, Almeda-Valdés P, González D, Uribe M. Trends in liver disease
prevalence in Mexico from 2005 to 2050 through mortality data.
Ann Hepatol. 2005; 4: 52-5.
21. Ong JP, Younossi ZM. Epidemiology and natural history of NAFLD
and NASH. Clin Liver Dis. 2007; 11: 1-16.
22. Bank of America Merrill Lynch Global Research, World Health
Organization. Globesity - the global fight against obesity. Report.
21 June 2012.
27. Encuesta Nacional de Salud, Ministerio de Salud, Chile 2009-2009.
29. Sistema de Información del Estado Nutricional (CIES), Instituto
Nacional de Salud, Ministerio de Salud, 2010.
31. Segunda Encuesta Nacional de Sobrepeso y Obesidad (ENSO 2)
2009
32. López P, Araujo C, Leguizamón C, Ayala A, Scott A, Maldonado D.
Prevalencia de Síndrome Metabólico en Adolescentes con
Sobrepeso u Obesidad Pediatr 2012; 39:1. /Primera Encuesta
Nacional de Factores de Riesgo No Transmisibles. MSP y BS,
Paraguay 2011
33.Riediger N. Prevalence of metabolic syndrome in the Canadian adult
population CMAJ 2011. DOI:10.1503.
34.DeBoer M, Chen D, Burt D, Ramirez-Zea M, Guerrant R, Stein A, et al.
Early childhood diarrhea and cardiometabolic risk factors in
adulthood: the Institute of Nutrition of Central America and Panama
Nutritional Supplementation Longitudinal Study. Annals of
Epidemiology 2013; 23: 314-320.
Abbreviations
ATP III, Adult treatment panel III
BMI, body mass index
CARMELA, Cardiovascular Risk Factor Multiple Evaluation in
Latin America
HDL, high-density lipoprotein
MTP, microsomal triglyceride transfer protein
NAFLD, non-alcoholic fatty liver disease
NCEP, National Cholesterol Education Program
PNPLA3, Patatin-like phospholipase domain containing 3 gene
TG, triglycerides
VLDL, very-low density lipoprotein
Correspondence should be addressed to: Prof. Nahum
Méndez-Sánchez, MD,MSc,PhD. Liver Research Unit.
Medica Sur Clinic & Foundation. Puente de Piedra 150,
Colonia Toriello Guerra, 14050 Tlalpan, Mexico City,
Mexico. [email protected]
53

MH 1-2013 - Diretoria.pmd - Grupo de Fígado do Rio de Janeiro

Transcrição

Documentos relacionados

É tempo de analisar e fazer uma completa reflexão sobre a vida

SET LIST | INTERNATIONAL Hotel California

hepatobiliary fascioliasis - Sociedade Portuguesa de Radiologia e

Pedro Campos Costa, Paula Sousa, Louis Mariette, Benoit

Sentinela - Zelia Fonseca

Inglês - Conteúdos - Etapa 2 - Campus São João Evangelista

Mother Road(Route 66 #1) by Dorothy Garlock

Por favor, não matem a cotovia Realizador

12 de Junho!

religiões comparadas da ásia

Revisión Nutritional support for fulminant hepatitis

View presentation

Expression of iron metabolism - related genes in a

EASL Recommendations on Treatment of Hepatitis C 2015