Preventive Female Sex Factors against the Development of Chronic Liver Disease


by

Ichiro Shimizu

DOI: 10.2174/97816080529361120101
eISBN: 978-1-60805-293-6, 2012
ISBN: 978-1-60805-409-1



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Indexed in: Book Citation Index, Science (BKCI-S), Web of Science, Scopus

Liver cancer, cirrhosis and nonalcoholic fatty liver disease are observed predominately in men. Being male or female is believed to be...[view complete introduction]

Table of Contents

Foreword

- Pp. i-ii (2)

Satoshi Mochida

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Preface

- Pp. iii

Ichiro Shimizu

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List of Contributors

- Pp. iv-v (2)

Ichiro Shimizu

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Chronic Liver Diseases Develop More Slowly in Females Than Males

- Pp. 3-18 (16)

Ichiro Shimizu, Tomomi Matsumoto, Nozomi Suzuki, Chiaki Sagara, Yui Koizumi, Tsutoshi Asaki, Yoshiki Katakura and Yosho Fukita

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Gender Difference in Clinicopathologic Features and Prognosis of Patients with Hepatocellular Carcinoma

- Pp. 19-31 (13)

Pisit Tangkijvanich, Kittiyod Poovorawan and Yong Poovorawan

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Body Iron and Chronic Liver Diseases

- Pp. 32-36 (5)

Ichiro Shimizu, Tomomi Matsumoto, Nozomi Suzuki, Chiaki Sagara, Yui Koizumi, Tsutoshi Asaki, Yoshiki Katakura and Yosho Fukita

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HCV Carriers With Normal Alanine Aminotransferase Levels

- Pp. 37-50 (14)

Claudio Puoti

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Innate Immune Response and Sex Hormones

- Pp. 51-60 (10)

Yoshiki Katakura, Tsutoshi Asaki, Yosho Fukita and Ichiro Shimizu

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Role of IL-6 in Gender Differences of Hepatocarcinogenesis

- Pp. 61-69 (9)

Hayato Nakagawa

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Estrogen Reduces Hepatic Fibrosis

- Pp. 70-85 (16)

Tsutoshi Asaki, Tomomi Matsumoto, Nozomi Suzuki, Chiaki Sagara, Yui Koizumi, Yoshiki Katakura, Yosho Fukita and Ichiro Shimizu

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Pharmacological Effects of Estrogen in Liver Cirrhosis-Induced Portal Hypertension

- Pp. 86-93 (8)

Takato Ueno

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Non-Alcoholic Fatty Liver Disease in Females and Males

- Pp. 94-106 (13)

Yosho Fukita, Tsutoshi Asaki, Yoshiki Katakura and Ichiro Shimizu

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Sex and Gender Specific Medicine in Chronic Liver Diseases

- Pp. 107-115 (9)

Sumiko Nagoshi

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Index

- Pp. 116-119 (4)

Ichiro Shimizu

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Foreword

The era of individualized medicine has arrived in the field of hepatology. Medicine based on genetic polymorphisms is a growing trend, especially for patients with chronic liver diseases arising from infection with hepatitis C virus (HCV), an endemic disease in Japan. In August 2009, single nucleotide polymorphisms (SNPs) of IL-28B, also known as interferon-λ, were shown to be an important host factor affecting the efficacy of ribavirin and pegylated interferon therapy in patients with chronic hepatitis C. As of July 2010, the Japanese Ministry of Health, Welfare, and Labor has allowed the use of these SNPs for advanced medical care to predict the therapeutic efficacy of given treatments in individual patients. Also in 2010, SNPs of the inosine triphosphatase (ITPA) gene were found to be a host factor determining the extent of hemolytic anemia caused by ribavirin, and it seems that genetic factors contributing to the development of other adverse effects, such as neutrocytopenia, thrombocytopenia and interstitial pneumonia, are likely to be identified in the near future. A genome-wide association study (GWAS) of SNPS will enable hepatologists to achieve such notable progresses, possibly clarifying the mechanisms involved in persistent infections of HCV.

While individualized medicine is a recent trend in hepatology, it has also been part of traditional approaches in ancient medicine traditions arising in Asian countries, including Japan. More than ten centuries ago in Europe, Christian clergies performed therapeutic procedures for various diseases based on their religious dogma. Phlebitis was performed for all patients, regardless of the type of disease and even among those afflicted with plague, according to the theory established by Galenus in Greece during the mid-second century AD. Such medical practices were performed in a uniform manner based on the hypothesis that all diseases developed as a result of imbalances among the four humors (blood, yellow bile, black bile, and phlegm) that had been described by Hippocrates during the fifth century BC. In contrast, in medieval Japan, traditional medicine was established by Buddhist priests based on superstitious divination as well as their religious world views. They used various types of herbs for therapeutic procedures, and different mixtures of numerous herbs were given to patients even if they had the same disease depending on their facial color and the size and strength of the pulse of each patient. These therapeutic approaches have evolved into modern Kanpo-medicine, a traditional form of individualized medicine in Japan.

Although the condition of the pulse and genomic polymorphisms are useful parameters in algorithms for individualized treatment in Kanpo-medicine and recent hepatology, respectively, all physicians would likely agree that the age and sex of the patients are the most important factors in the individualized treatment of various diseases. In patients with a persistent HCV infection, for example, liver fibrosis progresses more rapidly in men than in women. Thus, women with HCV infection generally tend to develop hepatocellular carcinoma later in life than men. Also, the efficacy of ribavirin and pegylated interferon therapy is well known to be superior in women than in men among patients with chronic hepatitis C in Europe and the United States, while the therapeutic efficacy has been shown to be superior in male patients than in female patients in Japan. Moreover, autoimmune hepatitis and primary biliary cirrhosis are frequent diseases among elderly women, but are rare in men of any age. Although the frequency of non-alcoholic fatty liver diseases is greater in men than in women in Japan, the incidence of non-alcoholic fatty liver diseases increases according to age only in women. These fundamental observations in clinical hepatology have prompted us to recognize that sex, as well as age, is an essential factor for establishing algorithms to perform individualized medicine in patients with liver diseases. All of these topics are discussed in the chapter of this book entitled, “Preventive Female Sex Factors against the Development of Chronic Liver Disease”.

This distinguished and challenging book was edited by Dr. Ichiro Shimizu, a pioneer in sex- and/or gender-specific medicine, especially for liver diseases, in Japan. Ten excellent articles written by specialists in various fields of hepatology, such as viral hepatitis, autoimmune liver diseases, alcoholic and non-alcoholic fatty liver disease, and hepatocellular carcinoma, are presented in this book. Readers of this book will be able to obtain consensus information regarding sex differences in liver diseases. I believe that this book will be useful for all researchers and clinicians working in the field of hepatology, serving as a bible for sex- and/or gender-specific medicine, and may contribute to progress in individualized medicine regardless of the therapeutic approach: either modern medicine focusing on genetic polymorphisms or Kanpo-medicine using various herbs.

Satoshi Mochida
Saitama Medical University
Saitama, Japan


Preface

Until the last decade, it seemed that women and men were essentially identical except for the differences in their reproductive function. Everywhere, however, researchers look for differences between the sexes, and they find them. Sex does really matter. One of the most compelling reasons for understanding the biological differences is that there are striking differences in human disease. The best-studied differences between the sexes are in the reproductive systems. Much less study has been done on sex differences in non-reproductive areas of biology. It should be noted that liver cancer is undeniably predominant in men and postmenopausal women.

Chronic hepatitis C virus and hepatitis B virus infections are recognized as a major causative factor of cirrhosis and liver cancer. Obesity is also associated with increased incidence rates for cirrhosis and liver cancer. In general, men have a greater risk of exposure to hepatitis viruses, a greater opportunity for drinking, and a higher preponderance of nutritional and exercise-related problems such as obesity. Although it has been speculated that such gender-specific lifestyles and social environments might contribute to the predominant incidence of liver cancer in men, few studies have been done on the biological mechanisms underlying the sex-associated differences observed in chronic liver disease. A characteristic feature of chronic hepatitis C and B, alcoholic liver disease and non-alcoholic fatty liver disease is fatty liver, or hepatic steatosis. Central obesity (android pattern) is a predictor of hepatic steatosis. Hepatic steatosis leads to an increase in lipid peroxidation in hepatocytes, which, in turn, activates hepatic stellate cells (HSCs). HSCs are located in close contact with hepatocytes, and are the primary target cells for inflammatory and oxidative stimuli in the injured liver. Activated HSCs are responsible for much of the collagen synthesis during fibrosis development to the end-stage cirrhosis. Cirrhosis is an important host-related risk factor for liver cancer. Chronic hepatitis C and B appear to progress more rapidly in males than in females. Women have lower hepatic iron stores before menopause, and their production of proinflammatory cytokines, such as tumor necrosis factor-α and interleukin-6, increases after menopause as a result of the decline in ovarian function. Iron is essential for life, but is toxic in excess, because it produces reactive oxygen species (ROS) that react readily with lipids and DNA, leading to cell death and DNA mutagenesis. In addition, hepatic steatosis and central obesity are observed in growth hormone deficiency in adults. Growth hormone secretion is greater in women and is stimulated by estrogen. Estrogen is a potent endogenous antioxidant and suppresses hepatic fibrosis. Estrogen also attenuates hepatocyte death and HSC activation by inhibiting the ROS generation. These lines of evidence suggest that the greater progression of hepatic fibrosis and liver cancer in men and postmenopausal women may be due, at least in part, to lower secretions of estrogen and growth hormone, higher hepatic iron stores and increased immune responses.

Using gender and sex as a unique prism through which to observe and better understand normal function and the experience of disease is one of the most important new ideas in medicine. This e-Book constitutes a collection of selected clinical and scientific topics in conjunction with the sex-associated differences of the liver disease. After considering the data and examples presented in the e-Book, anyone will be able to use new opportunities to obtain a better understanding of the sex-associated differences of chronic liver disease. Some of these differences can be explained by what we now know. Some are unexplained and point to important questions for future study. Being female or male is an important basic human variable that affects health and liver disease throughout the life span. A better understanding of the biological mechanisms underlying the differences in chronic liver disease between the sexes would provide valuable information to design care of health and liver disease more effectively for individuals, both females and males.

Ichiro Shimizu
Department of Gastroenterology
Seirei Yokohama Hospital
Kanagawa, Japan

List of Contributors

Editor(s):
Ichiro Shimizu
Department of Gastroenterology
Seirei Yokohama Hospital
Kanagawa
Japan




Contributor(s):
Chiaki Sagara
Support Center for Medical Sciences
Seirei Yokohama Hospital
215 Iwai-cho
Hodogaya-ku
Kanagawa, 240-8521
Japan


Claudio Puoti
Professor of Department of Internal Medicine and Liver Unit
Marino Hospital
Viale XXIV Maggio, 00047 Marino
Roma
Italy


Hayato Nakagawa
Department of Gastroenterology
University of Tokyo
7-3-1 Hongo, Bunkyo-ku
Tokyo, 113-8655
Japan


Ichiro Shimizu
A.G.A.F., Department of Gastroenterology
Seirei Yokohama Hospital
215 Iwai-cho
Hodogaya-ku, Kanagawa, 240-8521
Japan


Kittiyod Poovorawan
Department of Medicine
Faculty of Medicine
Chulalongkorn University
Bangkok, 10330
Thailand


Nozomi Suzuki
Support Center for Medical Sciences
Seirei Yokohama Hospital
215 Iwai-cho
Hodogaya-ku, Kanagawa, 240-8521
Japan


Pisit Tangkijvanich
Associate Professor of Department of Biochemistry
Faculty of Medicine
Chulalongkorn University
Bangkok, 10330
Thailand


Satoshi Mochida
Professor & Chairman, Department of Gastroenterology & Hepatology
Faculty of Medicine, Saitama Medical University
38 Morohongo, Moroyama-machi
Saitama
Iruma-gun, 350-0495
Japan


Sumiko Nagoshi
Professor of Department of Gastroenterology & Hepatology
Faculty of Medicine
Saitama Medical University
38 Morohongo, Moroyama-machi
Saitama
Iruma-gun, 350-0495
Japan


Takato Ueno
Professor of Research Center for Innovative Cancer Therapy
Kurume University
67 Asahi-machi
Kurume, 830–0011
Japan


Tomomi Matsumoto
Support Center for Medical Sciences
Seirei Yokohama Hospital
215 Iwai-cho
Hodogaya-ku, Kanagawa, 240-8521
Japan


Tsutoshi Asaki
Department of Gastroenterology
Seirei Yokohama Hospital
215 Iwai-cho
Hodogaya-ku, Kanagawa, 240-8521
Japan


Yong Poovorawan
Professor of Center of Excellence in Clinical Virology
Faculty of Medicine
Chulalongkorn University
Bangkok, 10330
Thailand


Yoshiki Katakura
Department of Gastroenterology
Seirei Yokohama Hospital
215 Iwai-cho
Hodogaya-ku, Kanagawa, 240-8521
Japan


Yosho Fukita
Department of Gastroenterology
Seirei Yokohama Hospital
215 Iwai-cho
Hodogaya-ku, Kanagawa, 240-8521
Japan


Yui Koizumi
Support Center for Medical Sciences
Seirei Yokohama Hospital
215 Iwai-cho
Hodogaya-ku, Kanagawa, 240-8521
Japan




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