HEPATOLOGY, Vol. 60, No. 4, 2014
proatherogenic factors, including homocysteine, thereby contributing to Hp-related CVD risk; Hp-I is associated with increased tumor necrosis factor alpha (TNF-a), a circulating cytokine able to exert its effects at a distance. TNF-a and interleukin (IL)26 (TNF-a is the main trigger for the production of IL-6 by a variety of cells) play important roles in the regulation of synthesis of other acute phase proteins, which are established risk factors for atherosclerosis, such as the mentioned fibrinogen and factor VIII;3 and circulating lipid peroxides, also associated with cardiovascular risk, are raised in Hp-positive patients.3 Therefore, Hp eradication might display a positive effect on Hprelated NAFLD and CVD development/progression by inhibiting various prothrombotic and proinflammatory agents partly in some Hp-positive ethnic subpopulations. Because there is a lack of literature showing any demonstrable evidence to support the aforementioned hypothesis, large-scale studies are warranted to elucidate our hypothesis. JANNIS KOUNTOURAS, M.D., PH.D. STERGIOS A. POLYZOS, M.D., PH.D. CHRISTOS ZAVOS, M.D., PH.D. GEORGIA DERETZI, M.D., PH.D. CONSTANTINOS KOUNTOURAS, PH.D. ELIZABETH VARDAKA, PH.D. PANAGIOTIS KATSINELOS, M.D., PH.D. ELENA TSIAOUSI, M.D. NIKOLAOS GRIGORIADIS, M.D., PH.D. IORDANIS ROMIOPOULOS, M.D. DIMITRIOS TZILVES, M.D., PH.D. EVANGELIA GIARTZA-TAXIDOU, M.D., PH.D. Department of Medicine Second Medical Clinic Aristotle University of Thessaloniki Ippokration Hospital Thessaloniki, Greece
CORRESPONDENCE
Our study results suggest increased levels of plasminogen activator inhibitor-1 (PAI-1) to be one of the possible mechanisms linking nonalcoholic fatty liver disease (NAFLD) to the development of cardiovascular disease (CVD) in obese subjects. The reflection by Kountouras et al. on the role of Helicobacter pylori (Hp) in the induction of PAI-1 and other prothrombotic and -inflammatory agents in NAFLD is interesting. Hp has indeed been associated with CVD, although some controversy does still exist.2,3 In addition, a link between obesity and Hp has been suggested,4 which could be interesting in light of our study results. Kountouras et al. also report on an association between Hp and fibrinogen and von Willebrand facor (vWF). However, in our study, we did not find an independent association between liver histology and fibrinogen and vWF when corrected for metabolic factors, which is hence not supportive for their hypothesis. In our article, we postulate on a few possible mechanisms linking NAFLD to increased PAI-1 levels, such as increased liver fat or inflammation parameters, as direct triggers for production of PAI-1 by hepatocytes. We did not assess the presence of Hp in our study population. Serology testing on spare samples would be the only way to test the hypothesis of Kountouras et al. on our study cohort, but serology does not reflect active infection and is hence inaccurate for this research question. We estimate that the potential link between NAFLD, Hp, and CVD should be assessed in appropriately designed studies. AN VERRIJKEN, M.SC.1 SVEN FRANCQUE, M.D., PH.D.2 ILSE MERTENS, PH.D.1 LUC VAN GAAL, M.D., PH.D.1 1 Department of Endocrinology, Diabetology and Metabolism Antwerp University Hospital University of Antwerp Antwerp, Belgium 2 Department of Gastroenterology and Hepatology Antwerp University Hospital University of Antwerp Antwerp, Belgium
References 1. Verrijken A, Francque S, Mertens I, Prawitt J, Caron S, Hubens G, et al. Prothrombotic factors in histologically proven NAFLD and NASH. HEPATOLOGY 2014;59:121-129. 2. Polyzos SA, Kountouras J, Zavos C, Deretzi G. Helicobacter pylori infection and insulin resistance. Helicobacter 2013;18:165-166. 3. Kountouras J, Polyzos SA, Deretzi G, Katsinelos P, Kyriakou P. Helicobacter pylori infection and the risk for cardiovascular disease. Eur J Intern Med 2011;22:e146-e147. C 2014 by the American Association for the Study of Liver Diseases. Copyright V View this article online at wileyonlinelibrary.com. DOI 10.1002/hep.27168 Potential conflict of interest: Nothing to report.
Reply: We thank Dr. Kountouras et al. for their comment on our study, “Prothrombotic factors in histological proven nonalcoholic fatty liver disease and nonalcoholic steatohepatitis”.1
1451
References 1. Verrijken A, Francque S, Mertens I, Prawitt J, Caron S, Hubens G, et al. Prothrombotic factors in histologically proven NAFLD and NASH. HEPATOLOGY 2014;59:121-129. 2. Christodoulou DK, Milionis HJ, Pappa P, Katsanos KH, Sigounas D, Florentin M, et al. Association of Helicobacter pylori infection with cardiovascular disease—is it just a myth? Eur J Intern Med 2011;22:191-194. 3. Banic M, Franceschi F, Babic Z, Gasbarrini A. Extragastric manifestations of Helicobacter pylori infection. Helicobacter 2012;17(Suppl. 1):49-55. 4. Tan HJ, Goh KL. Extragastrointestinal manifesations of Helicobacter pylori infection: facts or myth? A critical review. J Dig Dis 2012;13:342-349. C 2014 by the American Association for the Study of Liver Diseases. Copyright V View this article online at wileyonlinelibrary.com. DOI 10.1002/hep.27167 Potential conflict of interest: Nothing to report.
Intrahepatic Cholestasis of Pregnancy and the Risk of Subsequent Hepatobiliary Disorders To the Editor: In a retrospective analysis of data collected from 1973 to 2009 in two nationwide health care registries in Sweden, Marschall
et al.1 concluded that women with a past history of intrahepatic cholestasis of pregnancy (ICP) have a higher risk to develop chronic hepatitis, liver fibrosis/cirrhosis, hepatitis C, gallstone disease, cholangitis, and other hepatobiliary disorders, as compared
1452
CORRESPONDENCE
with well-matched controls who did not have ICP. Due to the nature and design of the study, the data need to be interpreted with caution. A crucial question is whether the diagnosis of ICP was well documented in all those patients. The 11,349 ICP cases were identified from the Swedish Medical Birth Register that “collects data on maternal characteristics and complications during pregnancy, delivery, and the neonatal period.”2 For research purposes, current criteria for the diagnosis of ICP require a clinical and laboratory follow-up to verify that pruritus disappears after delivery and the biochemical abnormalities improve to normal values within 3 weeks.3 Besides, the diagnosis of ICP “should only be given after exclusion of preexisting liver disease.”1,3-6 Because discharge from obstetric wards usually occurs 1 to 3 days after delivery, patients in this study probably did not have a follow-up to fully document the diagnosis of ICP. Among patients with ICP, 42.7% were multiparous, with a range from 2 to 14 pregnancies. Important information would be to learn how many of them had recurrent ICP and whether it correlated with the incidence of subsequent hepatobiliary disorders. It would also be relevant to correlate the severity of ICP, estimated by clinical and laboratory markers such as early onset of pruritus in pregnancy, hyperbilirubinemia, and higher serum levels of bile salts, with the risk to develop other hepatobiliary disorders. Future reports extending this interesting population-based cohort study may consider the inclusion of these data. The final recommendation to test for hepatitis C in women with ICP may be expanded to all pregnant women in whom any clinical or laboratory sign suggest an underlying liver disorder. HUMBERTO REYES, M.D. Department of Medicine (Eastern Campus) and Institute of Biomedical Sciences University of Chile School of Medicine Santiago de Chile
References 1. Marschall H-U, Shemer EW, Ludvigsson JF, Stephansson O. Intrahepatic cholestasis of pregnancy and associated hepatobiliary disease: a population-based cohort study. HEPATOLOGY 2013;58:1385-1391. 2. Cnattingius S, Bergstr€om R, Lipworth L, Kramer MS. Prepregnancy weight and the risk of adverse pregnancy outcomes. N Engl J Med 1998;338:147-152. 3. Reyes H. Sex hormones and bile acids in intrahepatic cholestasis of pregnancy. HEPATOLOGY 2008;47:376-379. 4. Bacq Y, Sapey T, Brechot M-C, Pierre F, Fignon A, Dubois F. Intrahepatic cholestasis of pregnancy: a French prospective study. HEPATOLOGY 1997;26:358-364. 5. Lammert F, Marschall H-U, Glantz A, Matern S. Intrahepatic cholestasis of pregnancy: molecular pathogenesis, diagnosis and management. J Hepatol 2000;33:1012-1021. 6. Arrese M, Reyes H. Intrahepatic cholestasis of pregnancy: a past and present riddle. Ann Hepatol 2006;5:202-205. C 2014 by the American Association for the Study of Liver Diseases. Copyright V View this article online at wileyonlinelibrary.com. DOI 10.1002/hep.27041 Potential conflict of interest: Nothing to report.
HEPATOLOGY, October 2014
The diagnostic criteria for ICP includes both clinical signs of otherwise unexplained pruritus as well as elevated bile acids and/or transaminases in the second or third trimester of pregnancy. We agree with Dr. Reyes that the diagnosis of ICP should exclude other liver disease. However, at the time of discharge from the hospital we do not know whether liver values will improve to normal levels within 3 weeks after delivery. Hence, there is a risk of misclassification of women, which may have influenced the findings. However, as most women with unexplained pruritus and elevated bile acids and/or transaminases spontaneously recover, the extent of misclassification is likely to be small leading to only a marginal influence of the findings. Dr. Reyes raised the important question about the incidence of hepatobiliary diseases in recurrent ICP. In our study group of 10,067 women with ICP, 1,172 (11.6%) were given this diagnosis more than once in subsequent pregnancies (1,165 twice; 158 three or more times). Indeed, recurrent ICP was correlated with a higher incidence of subsequent hepatobiliary disorders, rising from 14.5% to 18.9%. The hazard ratio (HR) of any hepatobiliary disorder in women with recurrent ICP was increased by 1.29 (95% confidence interval [CI], 1.12-1.49). Significantly increased risks in women with at least two pregnancies with ICP compared to women with one ICP pregnancy were found for chronic hepatitis (0.6% versus 0.2%; HR 3.79; 95% CI 1.53-9.42), liver fibrosis/cirrhosis (0.7% versus 0.3%; HR 2.89; 95% CI 1.29-6.49), gallstone disease (14.4% versus 11.4%; HR 1.25; 95% CI 1.07-1.48), and cholangitis (1.2% versus 0.6%; HR 2.18; 95% CI 1.20-3.95). The risk of a later diagnosis of hepatitis C (combined hepatitis non-A/non-B and C) did not differ significantly between women with ICP in one pregnancy compared to women with at least two ICP pregnancies. Interestingly, the diagnosis of ICP did not affect the number of subsequent pregnancies when compared to the 10 times larger control population without this diagnosis. Thus, one might conclude that ICP does not affect fertility and that women once exposed to cholestatic pruritus are not discouraged from further pregnancies. In the present study we were not able to estimate the severity of ICP, as we did not have access to levels of serum bile acids. We had information on gestational age at delivery but we could not be certain that preterm delivery was a consequence of ICP or due to other causes. As Dr. Reyes points out, it would be interesting in future research to correlate severity of ICP with later risk of hepatobiliary disorders. Finally, we strongly agree with Dr. Reyes’ recommendation to test for hepatitis C in any women featuring signs of underlying liver disease. HANNS-ULRICH MARSCHALL, M.D., PH.D.1 OLOF STEPHANSSON, M.D., PH.D.2 1 Sahlgrenska Academy Institute of Medicine Department of Molecular and Clinical Medicine University of Gothenburg Gothenburg, Sweden 2 Clinical Epidemiology Unit Department of Medicine, Solna Karolinska University Hospital and Institutet Stockholm, Sweden
Reference 1. Marschall HU, Wikstr€ om Shemer E, Ludvigsson JF, Stephansson O. Intrahepatic cholestasis of pregnancy and associated hepatobiliary disease: a population-based cohort study. HEPATOLOGY 2013;58:1385-1391.
Reply: We thank Dr. Reyes for his insightful comments on our HEPA1 TOLOGY article on the association between intrahepatic cholestasis of pregnancy (ICP) and prevalent or future hepatobiliary diseases.
C 2014 by the American Association for the Study of Liver Diseases. Copyright V View this article online at wileyonlinelibrary.com. DOI 10.1002/hep.27040 Potential conflict of interest: Nothing to report.
proatherogenic factors, including homocysteine, thereby contributing to Hp-related CVD risk; Hp-I is associated with increased tumor necrosis factor alpha (TNF-a), a circulating cytokine able to exert its effects at a distance. TNF-a and interleukin (IL)26 (TNF-a is the main trigger for the production of IL-6 by a variety of cells) play important roles in the regulation of synthesis of other acute phase proteins, which are established risk factors for atherosclerosis, such as the mentioned fibrinogen and factor VIII;3 and circulating lipid peroxides, also associated with cardiovascular risk, are raised in Hp-positive patients.3 Therefore, Hp eradication might display a positive effect on Hprelated NAFLD and CVD development/progression by inhibiting various prothrombotic and proinflammatory agents partly in some Hp-positive ethnic subpopulations. Because there is a lack of literature showing any demonstrable evidence to support the aforementioned hypothesis, large-scale studies are warranted to elucidate our hypothesis. JANNIS KOUNTOURAS, M.D., PH.D. STERGIOS A. POLYZOS, M.D., PH.D. CHRISTOS ZAVOS, M.D., PH.D. GEORGIA DERETZI, M.D., PH.D. CONSTANTINOS KOUNTOURAS, PH.D. ELIZABETH VARDAKA, PH.D. PANAGIOTIS KATSINELOS, M.D., PH.D. ELENA TSIAOUSI, M.D. NIKOLAOS GRIGORIADIS, M.D., PH.D. IORDANIS ROMIOPOULOS, M.D. DIMITRIOS TZILVES, M.D., PH.D. EVANGELIA GIARTZA-TAXIDOU, M.D., PH.D. Department of Medicine Second Medical Clinic Aristotle University of Thessaloniki Ippokration Hospital Thessaloniki, Greece
CORRESPONDENCE
Our study results suggest increased levels of plasminogen activator inhibitor-1 (PAI-1) to be one of the possible mechanisms linking nonalcoholic fatty liver disease (NAFLD) to the development of cardiovascular disease (CVD) in obese subjects. The reflection by Kountouras et al. on the role of Helicobacter pylori (Hp) in the induction of PAI-1 and other prothrombotic and -inflammatory agents in NAFLD is interesting. Hp has indeed been associated with CVD, although some controversy does still exist.2,3 In addition, a link between obesity and Hp has been suggested,4 which could be interesting in light of our study results. Kountouras et al. also report on an association between Hp and fibrinogen and von Willebrand facor (vWF). However, in our study, we did not find an independent association between liver histology and fibrinogen and vWF when corrected for metabolic factors, which is hence not supportive for their hypothesis. In our article, we postulate on a few possible mechanisms linking NAFLD to increased PAI-1 levels, such as increased liver fat or inflammation parameters, as direct triggers for production of PAI-1 by hepatocytes. We did not assess the presence of Hp in our study population. Serology testing on spare samples would be the only way to test the hypothesis of Kountouras et al. on our study cohort, but serology does not reflect active infection and is hence inaccurate for this research question. We estimate that the potential link between NAFLD, Hp, and CVD should be assessed in appropriately designed studies. AN VERRIJKEN, M.SC.1 SVEN FRANCQUE, M.D., PH.D.2 ILSE MERTENS, PH.D.1 LUC VAN GAAL, M.D., PH.D.1 1 Department of Endocrinology, Diabetology and Metabolism Antwerp University Hospital University of Antwerp Antwerp, Belgium 2 Department of Gastroenterology and Hepatology Antwerp University Hospital University of Antwerp Antwerp, Belgium
References 1. Verrijken A, Francque S, Mertens I, Prawitt J, Caron S, Hubens G, et al. Prothrombotic factors in histologically proven NAFLD and NASH. HEPATOLOGY 2014;59:121-129. 2. Polyzos SA, Kountouras J, Zavos C, Deretzi G. Helicobacter pylori infection and insulin resistance. Helicobacter 2013;18:165-166. 3. Kountouras J, Polyzos SA, Deretzi G, Katsinelos P, Kyriakou P. Helicobacter pylori infection and the risk for cardiovascular disease. Eur J Intern Med 2011;22:e146-e147. C 2014 by the American Association for the Study of Liver Diseases. Copyright V View this article online at wileyonlinelibrary.com. DOI 10.1002/hep.27168 Potential conflict of interest: Nothing to report.
Reply: We thank Dr. Kountouras et al. for their comment on our study, “Prothrombotic factors in histological proven nonalcoholic fatty liver disease and nonalcoholic steatohepatitis”.1
1451
References 1. Verrijken A, Francque S, Mertens I, Prawitt J, Caron S, Hubens G, et al. Prothrombotic factors in histologically proven NAFLD and NASH. HEPATOLOGY 2014;59:121-129. 2. Christodoulou DK, Milionis HJ, Pappa P, Katsanos KH, Sigounas D, Florentin M, et al. Association of Helicobacter pylori infection with cardiovascular disease—is it just a myth? Eur J Intern Med 2011;22:191-194. 3. Banic M, Franceschi F, Babic Z, Gasbarrini A. Extragastric manifestations of Helicobacter pylori infection. Helicobacter 2012;17(Suppl. 1):49-55. 4. Tan HJ, Goh KL. Extragastrointestinal manifesations of Helicobacter pylori infection: facts or myth? A critical review. J Dig Dis 2012;13:342-349. C 2014 by the American Association for the Study of Liver Diseases. Copyright V View this article online at wileyonlinelibrary.com. DOI 10.1002/hep.27167 Potential conflict of interest: Nothing to report.
Intrahepatic Cholestasis of Pregnancy and the Risk of Subsequent Hepatobiliary Disorders To the Editor: In a retrospective analysis of data collected from 1973 to 2009 in two nationwide health care registries in Sweden, Marschall
et al.1 concluded that women with a past history of intrahepatic cholestasis of pregnancy (ICP) have a higher risk to develop chronic hepatitis, liver fibrosis/cirrhosis, hepatitis C, gallstone disease, cholangitis, and other hepatobiliary disorders, as compared
1452
CORRESPONDENCE
with well-matched controls who did not have ICP. Due to the nature and design of the study, the data need to be interpreted with caution. A crucial question is whether the diagnosis of ICP was well documented in all those patients. The 11,349 ICP cases were identified from the Swedish Medical Birth Register that “collects data on maternal characteristics and complications during pregnancy, delivery, and the neonatal period.”2 For research purposes, current criteria for the diagnosis of ICP require a clinical and laboratory follow-up to verify that pruritus disappears after delivery and the biochemical abnormalities improve to normal values within 3 weeks.3 Besides, the diagnosis of ICP “should only be given after exclusion of preexisting liver disease.”1,3-6 Because discharge from obstetric wards usually occurs 1 to 3 days after delivery, patients in this study probably did not have a follow-up to fully document the diagnosis of ICP. Among patients with ICP, 42.7% were multiparous, with a range from 2 to 14 pregnancies. Important information would be to learn how many of them had recurrent ICP and whether it correlated with the incidence of subsequent hepatobiliary disorders. It would also be relevant to correlate the severity of ICP, estimated by clinical and laboratory markers such as early onset of pruritus in pregnancy, hyperbilirubinemia, and higher serum levels of bile salts, with the risk to develop other hepatobiliary disorders. Future reports extending this interesting population-based cohort study may consider the inclusion of these data. The final recommendation to test for hepatitis C in women with ICP may be expanded to all pregnant women in whom any clinical or laboratory sign suggest an underlying liver disorder. HUMBERTO REYES, M.D. Department of Medicine (Eastern Campus) and Institute of Biomedical Sciences University of Chile School of Medicine Santiago de Chile
References 1. Marschall H-U, Shemer EW, Ludvigsson JF, Stephansson O. Intrahepatic cholestasis of pregnancy and associated hepatobiliary disease: a population-based cohort study. HEPATOLOGY 2013;58:1385-1391. 2. Cnattingius S, Bergstr€om R, Lipworth L, Kramer MS. Prepregnancy weight and the risk of adverse pregnancy outcomes. N Engl J Med 1998;338:147-152. 3. Reyes H. Sex hormones and bile acids in intrahepatic cholestasis of pregnancy. HEPATOLOGY 2008;47:376-379. 4. Bacq Y, Sapey T, Brechot M-C, Pierre F, Fignon A, Dubois F. Intrahepatic cholestasis of pregnancy: a French prospective study. HEPATOLOGY 1997;26:358-364. 5. Lammert F, Marschall H-U, Glantz A, Matern S. Intrahepatic cholestasis of pregnancy: molecular pathogenesis, diagnosis and management. J Hepatol 2000;33:1012-1021. 6. Arrese M, Reyes H. Intrahepatic cholestasis of pregnancy: a past and present riddle. Ann Hepatol 2006;5:202-205. C 2014 by the American Association for the Study of Liver Diseases. Copyright V View this article online at wileyonlinelibrary.com. DOI 10.1002/hep.27041 Potential conflict of interest: Nothing to report.
HEPATOLOGY, October 2014
The diagnostic criteria for ICP includes both clinical signs of otherwise unexplained pruritus as well as elevated bile acids and/or transaminases in the second or third trimester of pregnancy. We agree with Dr. Reyes that the diagnosis of ICP should exclude other liver disease. However, at the time of discharge from the hospital we do not know whether liver values will improve to normal levels within 3 weeks after delivery. Hence, there is a risk of misclassification of women, which may have influenced the findings. However, as most women with unexplained pruritus and elevated bile acids and/or transaminases spontaneously recover, the extent of misclassification is likely to be small leading to only a marginal influence of the findings. Dr. Reyes raised the important question about the incidence of hepatobiliary diseases in recurrent ICP. In our study group of 10,067 women with ICP, 1,172 (11.6%) were given this diagnosis more than once in subsequent pregnancies (1,165 twice; 158 three or more times). Indeed, recurrent ICP was correlated with a higher incidence of subsequent hepatobiliary disorders, rising from 14.5% to 18.9%. The hazard ratio (HR) of any hepatobiliary disorder in women with recurrent ICP was increased by 1.29 (95% confidence interval [CI], 1.12-1.49). Significantly increased risks in women with at least two pregnancies with ICP compared to women with one ICP pregnancy were found for chronic hepatitis (0.6% versus 0.2%; HR 3.79; 95% CI 1.53-9.42), liver fibrosis/cirrhosis (0.7% versus 0.3%; HR 2.89; 95% CI 1.29-6.49), gallstone disease (14.4% versus 11.4%; HR 1.25; 95% CI 1.07-1.48), and cholangitis (1.2% versus 0.6%; HR 2.18; 95% CI 1.20-3.95). The risk of a later diagnosis of hepatitis C (combined hepatitis non-A/non-B and C) did not differ significantly between women with ICP in one pregnancy compared to women with at least two ICP pregnancies. Interestingly, the diagnosis of ICP did not affect the number of subsequent pregnancies when compared to the 10 times larger control population without this diagnosis. Thus, one might conclude that ICP does not affect fertility and that women once exposed to cholestatic pruritus are not discouraged from further pregnancies. In the present study we were not able to estimate the severity of ICP, as we did not have access to levels of serum bile acids. We had information on gestational age at delivery but we could not be certain that preterm delivery was a consequence of ICP or due to other causes. As Dr. Reyes points out, it would be interesting in future research to correlate severity of ICP with later risk of hepatobiliary disorders. Finally, we strongly agree with Dr. Reyes’ recommendation to test for hepatitis C in any women featuring signs of underlying liver disease. HANNS-ULRICH MARSCHALL, M.D., PH.D.1 OLOF STEPHANSSON, M.D., PH.D.2 1 Sahlgrenska Academy Institute of Medicine Department of Molecular and Clinical Medicine University of Gothenburg Gothenburg, Sweden 2 Clinical Epidemiology Unit Department of Medicine, Solna Karolinska University Hospital and Institutet Stockholm, Sweden
Reference 1. Marschall HU, Wikstr€ om Shemer E, Ludvigsson JF, Stephansson O. Intrahepatic cholestasis of pregnancy and associated hepatobiliary disease: a population-based cohort study. HEPATOLOGY 2013;58:1385-1391.
Reply: We thank Dr. Reyes for his insightful comments on our HEPA1 TOLOGY article on the association between intrahepatic cholestasis of pregnancy (ICP) and prevalent or future hepatobiliary diseases.
C 2014 by the American Association for the Study of Liver Diseases. Copyright V View this article online at wileyonlinelibrary.com. DOI 10.1002/hep.27040 Potential conflict of interest: Nothing to report.
