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Since the liver generates the heart, if the liver is too strong, an extra burden will be placed on the heart, which
can potentially harm it. In other words, it behaves like high-output heart failure. Liver restricts the spleen, so if
the liver is too strong, it will inhibit the spleen which is considered important for digestion. Thus, a strong liver
will disturb digestion and gut function.
These concepts may seem confusing from the Western point of view. However, a practical application in
TCM, to use an example, is the association of the liver with anger. If the patient has heart disease, the heart/li ver
interaction will increase anger, thus aggravating heart disease. Moreover, the liver/anger effect on the spleen
will also impact digestion, leading to indigestion and stomach problems. The association of the liver with anger
is interestingly also a common theme in Medieval Western medicine.
In the ancient Western world, views of the body including the liver and heart used tetrad concepts. The natu-
ral world was thought to be composed of four substances: air, earth, water, and fire. These interacted both within
and outside of the body. Substances were dry, moist, hot, and cold. In this respect, they are very similar to the
Yin/Yang duality of Eastern philosophy. Finally, the human body was felt to be composed of four humors,
which created the essence of life: black bile, yellow bile, phlegm, and blood
[1]. Thus, black bile was felt to be
dry and cold; yellow bile was dry and hot; blood was moist and hot, and phlegm was moist and cold
[1].In
many respects, these natural states were similar to some of the tenets of TCM.
Perhaps the dominant physiologist and physician of the Western ancient era was Claudius Galenius
(129216?), known as Galen. Although Greek, he spent his career in Rome, the center of the Western world in
his time, rising to prominence as a physician, writer, and teacher, and eventually becoming the court physician
to the Emperor. He combi ned the known and presumed hypotheses and evidence into a unified view of physiol-
ogy that encompassed these humors
[2,3]. According to the Galenic view of the body, the liver played a key role
as it produced and circulated bile as well as venous blood. The heart made and circulated arterial blood
(
Fig. 1.1). These were felt to be separate and open-ended circulations. The lungs were warmed and nourished by
venous blood pumped from the liver via the right ventricle, and sent air to the left ventricle to be diffused by the
arteries. The left ventricle pumped arterial blood and air to the organs and tissues, and eventually, this blood/air
mixture essentially dissolved and was expelled continuously from the body. The interventricular septum had
invisible minute pores, which connected the two ventricles.
FIGURE 1.1 Concepts of the blood circulation according to Galen (left) and Harvey (right) [2]. Source: Adapted from Aird WC. Discovery of
the cardiovascular system: from Galen to William Harvey. J Thromb Haemost. 2011;9(1):118129.
4 1. The liverheart relationship: a history
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The liver in Galen’s concept made and circulated venous blood, albeit in a much less vigorous manner, rather
gently pushing it to-and-fro in veins. This blood nourished the tissues and unlike arterial blood, did not dissipate
into the air. As the liver made and controlled venous blood in addition to bile, and also was impressively the
largest and most visible solid organ in the body of humans and animals, it was felt to be the dominant organ in
the body
[1]. Indeed, it was given its name as it was deemed essential for life and was thought to be the seat of
the soul.
Because of restrictions and cultural taboos across all civilizations that lasted until almost the modern era, nec-
ropsies or disturbing the human body after death was impossible. Thus this relatively simple Galenic view of the
circulation held sway for 15 centuries until William Harvey published his seminal work on blood circulation in
1628
[2,3].
The medieval era
The medieval world of liverheart interactions can be summarized in the publications of two key individuals.
Although many other scientists and physiologists had preceded them and contributed vital ideas of human physi-
ology, these two persons provided the quantum leaps forward in understanding the heart and liver. The first was
the English physiologist and physician William Harvey (15781657) who in 1628 published the landmark work
entitled “Exercitatio Anatomica de Motu Cordis et Sanguinus in Animalibus” (Anatomical study of the motion of
the heart and blood in animals), known by its shorter name, “de Motu Cordis”(
Fig. 1.2). This small 72-page book
presented his radically different view of the blood circulation, as a closed circuit with the heart at the center con-
trolling both arterial and venous circulations (
Fig. 1.1). These were connected by minute vessels (capillaries), which
he could not visualize but correctly surmised must be present throughout the body. Of course, in this concept of
FIGURE 1.2 Front page of “de Motu Cordis,” by William Harvey, published in 1628. Source: From https://www.gla.ac.uk/myglasgow/library/
files/special/exhibns/month/june2007.html.
5The medieval era
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blood circulation, the liver plays no significant role. Thus, the removal of the liver as a prime player in blood circu-
lation started the process of toppling it from its perch as the dominant organ in human physiology.
Two critical concepts formed the basis of his hypothesis (reviewed in 2). First, he estimated the daily amount
of blood made and pumped by the heart in the Galenic open-ended model. From necropsies, and his knowledge
of the approximate size of the human heart, he estimated the volume of the left ventricle as 2 ounces, and calcu-
lated a range of ejection fractions from 1/4 to 1/8. Further continuing this thought experiment, Harvey used the
most conservative ejection fraction of 1/8 and a heart rate of 33 bets/min, producing a cardiac output of 8.25 oz/
min (approximately 245 mL/min), and a daily total of 11,880 oz of blood, or about 742 pounds (337 kg). Even
back in the medieval world of violence and frequent bleeding, that amount must have seemed like an enormous
and impossible figure. In retrospect, we can only wonder how nobody had thought to try to estimate this
figure before him. In other words, why did no learned scholars ever ponder how so much blood could just van-
ish into thin air, and how such a small organ like the heart could make such an enormous volume of blood?
The second key concept resulted from actual experiments on humans. This is illustrated in the key figure of
the book (
Fig. 1.3) in which he reconfirmed that veins have one-way valves and verified that the direction of flow
was actually centripetal. How could the liver pump venous blood centrifugally when these valves impeded flow
in that direction?
Of course, Harvey’s major contribution was his discovery of circulation but it is not widely known that
amongst his other extensive works, in one paper he described several patients who were undoubtedly suffering
from cirrhosis
[4], with very accurate descriptions of this condition two centuries before Rene
´
La
¨
ennec. Thus as
pointed out by the accomplished medical historians the Chen brothers, we may consider Harvey the world’s first
hepatologist
[4].
The second important individual in the late medieval period was the Frenchman Rene
´
La
¨
ennec (17811826).
In 1819, his most important work “de l’Auscultation Me
´
diate” (On Indirect Auscultation) described not only the
invention of the stethoscope
[5] but also coined the word “cirrhosis” [6]. Thus he is revered by cardiologists and
hepatologists.
Until the invention of the stethoscope (
Figs. 1.4 and 1.5), the only way to listen to heart and lung sounds was
for the physician to place his ear directly on the chest of the patient. As all physicians were males in those times,
only male patients could be examined in this manner. Direct auscultation was generally not possible in female
patients or if absolutely required had to be done through several layers of clothing to preserve modesty and
decorum. Thus indirect auscultation refers to using an instrument, a long tube, one end placed on the patient’s
thorax and the other on the ear of the physician. It remains unclear exactly how he conceived of the idea of the
stethoscope, but it has been conjectured that he was inspired by the sound-amplifying qualities of the flute,
which he played.
La
¨
ennec was a polyglot, having learned five languages including classical Greek. In a footnote about one of
the patients described in the book, he described in detail the pathologic features of cirrhosis and coined the word
“cirrhosis” from the Greek word “kirrhus” (tawny yellow), based on the color of the cirrhotic liver. He was cer-
tainly not the first to characterize and describe cirrhosis, as the aforementioned Harvey and other physicians in
the 17th and 18th centuries had already done so
[6]. However, his use of the new word “cirrhosis” quickly
caught on and became widely adopted globally. Indeed, the term “Laennec’s cirrhosis” was frequently used dur-
ing most of the 20th century to describe alcohol-associated cirrhosis
[6]. Sadly for those who cherish medical his-
tory, that term has basically disappeared in the past quarter-century or so, replaced by simply “cirrhosis,” or far
worse, the horribly self-redundant expression “liver cirrhosis” (cirrhosis only affects the liver!).
FIGURE 1.3 Figure from “de Motu Cordis” demonstrating forearm venous valves and centripetal direction of blood flow. Source: From
https://www.gla.ac.uk/myglasgow/library/files/special/exhibns/month/june2007.html.
6 1. The liverheart relationship: a history
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FIGURE 1.4 Diagram from “de l’Auscultation Me
´
diate” showing a proposed stethoscope.
FIGURE 1.5 Photo of one of La
¨
ennec’s original stethoscopes. Source: From the Science Museum, London, UK; photo accessed from Wikipedia
entry on “stethoscope,” 8/8/2022.
7The medieval era
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The modern era
The liver in heart failure
The modern era of liverheart relationships dates to the 20th century. In the early part of the century, several
works described the condition of the liver when the heart fails
[7,8]. However, only around the mid-century, this
phenomenon was extensively studied and characterized. Notable among these is the 1951 publication
[9] by
Dame Sheila Sherlock, one of the founders of modern hepatology. However, most of the other publications were
produced by French or Belgian authors writing in French (
[10,11]; reviewed [12]). Although this condition goes
by different names in the English language such as cardiac hepatopathy, given the important French contribu-
tions to this condition, one of the present authors (SSL) recently proposed that we rename this condition as “foie
cardiaque”
[13]. After all, many medical terms sound much more elegant in French, notably the “torsade de
pointes” ventricular arrhythmia, as compared to the mundane English translation “twisting of the points.” Alas,
this proposal seems to have mostly been ignored. Several chapters in this book detail the functional, histological,
biochemical, and clinical manifestations of the liver when the heart is dysfunctional (Part 2).
The heart in liver failure
Hyperdynamic circulation of cirrhosis
Around the mid-20th century was also when a seminal paper by Kowalski and Abelmann launched the mod-
ern era of cardio-hepatology
[14]. This mainly concerns the converse situation, that is, what happens to the car-
diovascular system when the liver fails. These authors demonstrated that patients with cirrhosis unexpectedly
showed features of hyperdynamic circulation. In other words, the cardi ac output was increased and arterial pres-
sure and systemic vascular resistance decreased in these patients
[14]. In the three to four decades following the
Kowalski and Abelmann publication, a large number of papers detailed and studied the hyperdynamic circula-
tion of portal hypertension and cirrhosis (reviewed in
[15,16]). During that era, most of the studies in this area of
hyperdynamic circulation in chronic liver disease came from large liver centers headed by individuals such as
Sheila Sherlock, Roger Williams, Kunio Okuda, Didier Lebrec, Roberto Groszmann, Vicente Arroyo, Roberto de
Franchis, Laurie Blendis, Arieh Bomzon, Gustav Paumgartner, Mauro Bernardi, Jens Henriksen, Jurg Reichen,
Telfer Reynolds, and many others. The effect of liver failure on different aspects of the cardiovascular/renal/
hemostatic systems is described in detail in Part 3 of this book.
Cirrhotic cardiomyopathy
This syndrome originated with a research paper on cardiac beta-adrenergic receptors in a rat model of cirrho-
sis, emanating from Didier Lebrec’s lab in the late 1980s
[17]. One of the present authors (SSL) was the first
author on that paper, and in a 1989 paper coined the expression “cirrhotic cardiomyopathy” (CCM)
[15]. Thus, at
the risk of immodesty, this author is considered the “founding father” of the field
[18]. However, he recognizes
that his former mentor Lebrec essentially left this new field to him by not continuing research in this area, an act
of surpassing generosity. The syndrome of CCM is characterized as abnormal cardiac structure and function
associated with cirrhosis, in the absence of any primary heart disease (see Chapter 15).
Over the past three decades, many centers have undertaken clinical and translational investigations in cirrhotic
cardiomyopathy (reviewed
[19,20]). The first consensus meeting to formulate diagnostic criteria for CCM took
place at the Montreal World Congress of gastroenterology meeting in 2005. Fifteen years later, given the advances
in cardiac-imaging technology, extensively revised diagnostic criteria based on systolic and diastolic contractile
indices were published by the Cirrhotic Cardiomyopathy Consortium. We believe that the new 2020 criteria are
superior. A partial list of the investigators currently working in this field includes Mauro Bernardi, Florence
Wong, Kevin Moore, Richard Moreau, Mario Altieri, Soren Moller, Alexander Krag, Jing Zhang, Manuela Merli,
Francesco Salerno, Moreshwar Desai, Kym Watt, Manhal Izzy, Lisa VanWagner, Ahmad R. Dehpour, Ali Reza
Mani, and Markus Peck. Several of these persons have contributed chapters to this book.
References
[1] Chen TS, Chen PS. Understanding the liver: a history. Westport, CT: Greenwood Press; 1984.
[2] Aird WC. Discovery of the cardiovascular system: from Galen to William Harvey. J Thromb Haemost. 2011;9(Suppl 1):11829.
8 1. The liverheart relationship: a history
1. Liver and heart
https://t.me/medicina_free
[3] Bestetti RB, Restini CB, Couto LB. Development of anatomophysiologic knowledge regarding the cardiovascular system: from Egyptians
to Harvey. Arq Bras Cardiol. 2014;103:53845.
[4] Chen TS, Chen PS. William Harvey as hepatologist. Am J Gastroenterol. 1988;83:12747.
[5] Laennec and the stethoscope. JAMA. 1919;73:422423.
[6]
Duffin JM. Why does cirrhosis belong to Laennec? CMAJ. 1987;137:3936.
[7] Jolliffe N. Liver function in congestive heart failure. J Clin Invest. 1930;8:41933.
[8] Meakins J. Distribution of jaundice in circulatory failure. J Clin Invest. 1927;4:13548.
[9] Sherlock S. The liver in heart failure; relation of anatomical, functional, and circulatory changes. Br Heart J. 1951;13:27393.
[10] Drouet PL, Verain M, Collesson L, Rauber G, Pernot C, Metz J, et al. Study of blood proteins by microelectrophoresis in tubes in alcoholic
hepatitis, cardiac liver, obstructive jaundice and retention jaundice caused by cancer; general review and personal data relating to 54
cases. Rev Med Nancy. 1956;81:26978.
[11] Tricot R, Benhamou JP, Guillemot R, Urbanczyk A. Hemodynamics of the cardiac liver. Pathol Biol. 1962;10:13614.
[12] Mirouze D, Michel H. Le foie cardiaque. Gastroenterol Clin Biol. 1982;6:1437.
[13] Lee SS. ’Foie cardiaque’: a new name for an old syndrome? Liver Int. 2008;28:7556.
[14] Kowalski HJ, Abelmann WH. The cardiac output at rest in Laennec’s cirrhosis. J Clin Invest. 1953;32:102533.
[15] Lee SS. Cardiac abnormalities in liver cirrhosis. West J Med. 1989;151:5305.
[16] Lebrec D, Moreau R. Pathogenesis of portal hypertension. Eur J Gastroenterol Hepatol. 2001;13:30911.
[17] Lee SS, Marty J, Mantz J, Samain E, Braillon A, Lebrec D. Desensitization of myocardial beta-adrenergic receptors in cirrhotic rats.
Hepatology. 1990;12:4815.
[18] Ma Z, Lee SS. Cirrhotic cardiomyopathy: getting to the heart of the matter. Hepatology. 1996;24:4519.
[19] Chahal D, Liu H, Shamatutu C, Sidhu H, Lee SS, Marquez V. Review article: comprehensive analysis of cirrhotic cardiomyopathy.
Aliment Pharmacol Ther. 2021;53:98598.
[20] Liu H, Yoon KT, Zhang J, Lee SS. Advances in cirrhotic cardiomyopathy. Curr Opin Gastroenterol. 2021;37:18793.
9References
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CHAPTER
2
Nonalcoholic fatty liver disease and
cardiovascular disease
Masahiro Koseki
Division of Cardiovascular Medicine, Department of Medicine, Osaka University Graduate School of Medicine,
Suita, Osaka, Japan
Introduction
Nonalcoholic fatty liver disease (NAFLD) is a pathological condition in which fatty liver is recognized by liver
biopsy or imaging, and other liver diseases such as alcoholic liver disorder are excluded. A series of liver condi-
tions including nonalcoholic fatty liver (NAFL), advanced steatohepatitis, cirrhosis, and hepatocellular carcinoma
(HCC) are defined as NAFLD. NAFLD/nonalcoholic steatohepatitis (NASH) is considered to be the phenotype
of the metabolic syndrome in the liver. With an increase in lifestyle-related diseases such as obesity, diabetes,
and dyslipidemia, NAFLD/NASH is also rapidly expanding. NAFLD includes (1) NAFL, which is histologically
macroscopic hepatic stea tosis and (2) NASH, which is pathologically inflammatory and progressive to cirrhosis
and/or liver cancer. In patients with viral hepatitis, CVD was less common, however, in individuals with
NAFLD, CVD may affect prognosis
[1,2].
The definition of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis
According to the NAFLD guidance published from American Association for the Study of Liver Diseases,
there must be evidence of hepatic steatosis (HS), either by imaging or by histology, and lacks of secondary causes
of hepatic fat accumulation such as significant alcohol consumption, long term use of a steatogenic medication,
or monogenic hereditary disorders. Importantly, NAFLD can be categorized histologically into NAFL or NASH.
NAFL is defined as the presence of ^ 5% HS with out evidence of hepatocellular injury in the form of hepatocyte
ballooning. NASH is defined as the presence of ^ 5% HS and inflammation with hepatocyte injury (e.g., balloon-
ing), with or without any fibrosis
[3].
Similarly in Japanese guideline documents, NAFLD is characterized by evidence of HS either by imaging or histol-
ogy and by appropriate exclusion of other liver diseases such as alcoholic liver disease. NAFLD is diagnosed when
the alcohol daily consumption is lower than 20 g in women and 30 g in men. NAFLD is histologically characterized
by macrovesicular steatosis and further categorized into NAFL and NASH. NAFL is mostly a benign and nonpro-
gressive clinical entity while NASH can progress to cirrhosis or even HCC. NASH is histologically characterized by
HS associated with evidence of liver cell injury (ballooning degeneration) and inflammation
[4].
The clinical practice guidelines published by the European Association for the Study of the Liver, European
Association for the Study of Diabetes, and European Association for the Study of Obesity state that NAFLD is also
defined by the presence of steatosis in . 5% of hepatocytes, according to histological analysis or by a proton density
fat fraction .5.6% assessed by proton magnetic resonance spectroscopy or quantitative fat- or water-selective mag-
netic resonance imaging. Likewise, NAFLD is defined to include two pathologically distinct conditions with different
11
Cardio-Hepatology.
DOI:
https://doi.org/10.1016/B978-0-12-817394-7.00011-5 © 2023 Elsevier Inc. All rights reserved.
https://t.me/medicina_free
prognoses: NAFL and NASH, where the latter covers a wide spectrum of disease severity, including fibrosis, cirrho-
sis, and HCC
[5,6].
It has been noted that inflammation as well as lipid accumulation is an important pathogenic mechanism in
cardiovascular disease (CVD), especially atherosclerosis. It is well remembered that the Canakinumab
Antiinflammatory Thrombosis Outcome Study (CANTOS) trial has nicely demonstrated that suppression of the
proinflammatory cytokine IL-1β with the neutralizing antibody, canakinumab alone suppressed cardiovascular
events without any intervention against dyslipidemia
[7]. Therefore, it may be quite reasonable to consider that
among NAFLD, NASH is more likely associated with CVD than NAFL. However, it has been difficult to perform
clinical studies on NASH and CVD because it was difficult to perform liver biopsy against the CVD patients,
who are often administrated antiplatelet and/or anticoagulant agents. I would like to emphasize that many pre-
vious clinical studies have been performed on CVD in NAFLD rather than on CVD in NASH.
Association between nonalcoholic fatty liver disease/nonalcoholic steatohepatitis and
cardiovascular disease
Targher et al. analyzed 2103 patients with type 2 diabetes without a history of CVD and conducted a 5-year pro-
spective observational study, after which 248 patients had nonfatal myocardial infarction and coronary artery revas-
cularization, ischemic stroke or cardiovascular death occurred. The presence of NAFLD was significantly
associated with increased cardiovascular risk after adjusting for age, gender, smoking history, history of diabetes,
HbA1c, low-density lipoprotein (LDL)-cholesterol, liver enzymes, and oral medications [odds ratio (OR) 1.84, 95%
confidence interval (CI) 1.42.1, P, .001)
[8]. A meta-analysis performed by Musso et al. has demonstrated that
patients with NAFLD had an approximately two-fold increase OR for incident CVD compared to controls
[9].
Ballestri et al. revi ewed the literatures on NAFLD or NAFL and CVD published between 1990 and 2013, and
found that NAFLD was not only linked to liver-related morbidity and mortality, but also associated with coro-
nary artery disease, cardiac dysfunction such as left ventricular dysfunction and hypertrophy, valvular heart dis-
ease such as aortic sclerosis, and arrhythmias such as atrial fibrillation. They assume severe NAFLD exacerbate
systemic/hepatic insulin resistance, cause atherogenic dyslipidemia, and lead to various cardiac complications
and arrhythmias, due to the release of the proinflammatory, procoagulant, and profibrotic mediator
[10].
Importantly, Angulo et al. have retrospectively analyzed 619 patients diagnosed with NAFLD between 1975
and 2005. With a median follow-up of 12.6 years, 193 patients (33.2%) had died or had a liver transplant. The
number of cardiovascular deaths was 38.3%, which was more than the number of liver-related deaths (8.3%).
However, we have to pay attention that statins had not been developed during the firtst half of the follow-up
period and it may differ from the current risks under the statin treatment for dyslipidemia
[11].
Kim et al. have investigated whether NAFLD was associated with coronary artery calcification (CAC), which is
used as a surrogate marker for coronary atherosclerosis measured by computed tomography. Out of 5648 subjects,
4023 subjects without known liver disease or a history of ischemic heart disease were enrolled. On univariate
analysis, the presence of CAC (score .0) was significantly associated with age, sex, body mass index, aspartate
aminotransferase, alanine aminotransferase, high-density lipoprotein cholesterol (HDL-C), triglycerides (TG), and
increased risk of diabetes, hypertension, smoking, and NAFLD. Importantly, multivariable ordinal regression
analysis in the subgroup showed that the increased CAC scores were significantly associated with the presence of
NAFLD (OR, 1.28, 95% CI, 1.04-1.59; P = 0.023), independent of the CT-measured visceral adipose tissue area.
Increasing CAC scores (0, ,10, 10100, $ 100) were also associated with higher prevalence of NAFLD (OR, 1.84;
95% CI, 1.612.10; P , .001)
[12].
To screen the subjects with NAFLD, the fatty liver index (FLI) calculated by gamma-glutamyl-transferase
(GGT), body mass index (BMI), waist circumference, and triglycerides has been reported useful by Bedogni et al
[13]. Recently, Pais et al. have investigated the relationship between FLI and site of atherosclerosis, multiple ath-
erosclerosis, and Framingham risk score (FRS), which is a predictive risk of coronary artery disease, for 10 years
in 2554 individuals. The proportion of patients with steatosis increased gradually with the number of atheroscle-
rosis sites: 34% at one site, 38% for at two sites, and 40% at three sites (P=.0 25). Conversely, the proportion of
patients with multiple-site atherosclerosis increased across FLI tertiles (46%, 55%, and 56%; P , .001). In univari-
ate analysis, the age-adjusted OR of steatosis for multiple-site atherosclerosis was 1.32, 95% CI 1.111.58. Among
traditional cardiovascular risk factors (CVRFs), dyslipidemia, tobacco, and clustering of CVRFs ( $ 4 CVRFs) had
the greatest age-adjusted OR for multiple-site atherosclerosis: OR 5 2.15 (1.692.74), OR 5 1.73 (1.362.19), and
OR 5 2.50 (1.863.35). In multivariate analysis, steatosis predicted multiple-site atherosclerosis independent of
12 2. Nonalco holic fatty liver disease and cardiovascular disease
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age, individual, or clustering of CVRFs. Interestingly, 40% of patients had three or more CVRFs. The proportion
of patients with multiple CVRFs gradually increased across FLI tertiles: 25%, 42%, and 54%; P , .001. Patients
with steatosis had significantly higher FRS than those without. FRS gradually increased across FLI tertiles
(6% 6 5%, 10% 6 6%, and 14% 6 8%; P , .001). They have concluded that after adjusting for age and sex, steatosis
was associated with FRS beyond the traditional CVRFs or individual atherosclerosis sites among coronary
plaque, femoral plaque, and CAC
[14].
In the editorial of this paper, Patel has mentioned the interplay between NAFL and atherosclerosis.
Development of NAFLD is associated with increased production and secretion of large triglyceride-laden very
low-density lipoprotein (VLDL) particles from the liver. In circulation, VLDL particles are slowly metabolized
and subjected to an exchange process that removes cholesteryl ester from the particle core, replacing it with tria-
cylglycerides, which leads to the formation of highly atherogenic small, dense low-density lipoprotein (sd-LDL)
particles
[15].
Dyslipidemia as causative factors for nonalcoholic fatty liver disease/nonalcoholic steatohepatitis and
cardiovascular disease
Cholesterol has been considered as a major risk factor developing atherosclerosis. The first study was con-
ducted by Anitschkow N. and he fed cholesterol extracted from egg yolks to rabbits for 139 days and observed
atherosclerotic lesions in the aorta, cholesterol deposition in lesions, and foam-cell formation in lesions acceler-
ated by cholesterol. This is the first study to prove that atherosclerosis is caused by cholesterol deposition
[16,17].
After that, the Framingham Heart Study, the world’s first epidemiological study, has demonstrated that serum
total cholesterol is a risk factor of atherosclerotic heart diseases, as well as gender, aging, hypertension, obesity,
and smoking
[18]. It was almost half a century later, in 2001, that Iso et al. first reported that hypertriglyceride-
mia (high TG) is a risk factor for coronary artery disease
[19].
On the other hand, the relationship between NAFLD and dyslipidemia was reported. Hamaguchi et al. con-
ducted a prospective observational study of 4401 patients whose health was examined and found that low high
density lipoprotein-cholesterol (HDL-C) and high TG were associated with the prevalence of NAFLD at enroll-
ment and new onset of NAFLD
[20]. It was also reported that low HDL-C and high TG were associated with the
atherosclerotic risk factors for developing coronary artery disease
[1921]. Therefore, dyslipidemia might be con-
sidered as a causative linking mechanism between NAFLD/NASH and CVDs.
More recently, lipoprotein subfraction analysis by high-performance liquid chromatography were performed
by Imajo et al. and examined the difference in the LDL-migration index (LDL-MI), which is an index of small
dense-LDL (sd-LDL). The analysis of 156 patients with NAFLD (53 NAFL patients, 103 NASH patients) showed
a significant increase in LDL-MI levels in patients with NASH
[22]. Because sd-LDL is a notorious risk factor of
atherosclerosis
[23,24], this might also be a sharing pathology between NASH and atherosclerosis.
Possible underlining molecular mechanisms between nonalcoholic steatohepatitis and atherosclerosis
It has been reported that inflammatory cytokines such as TNF- and IL-6 were induced in macrophages by free
cholesterol loading mediated by acetylated LDL and acyl-CoA:cholesterol acyltransferase inhibitor
[25]. This
model may suggest the relationship between cellular free cholesterol (FC) accumulation and inflammatory
response in macrophages.
HDL mediates choles terol efflux through the cholesterol transporter, the ATP-binding cassette protein A1
(ABCA1) on plasma membrane. ABCA1-deficiency results in lack of HDL-mediated cholesterol efflux. We previ-
ously examined secretion of inflammatory cytokines in ABCA1-knouckout macrophages. Interestingly, we have
confirmed that lipopolysaccharides (LPS)-induced secretion of inflammatory cytokines was markedly enhanced
in ABCA1-knockout macrophages due to FC accumulation by deficiency of HDL-mediated cholesterol efflux.
Thus, excess free cholesterol might be harmful although cholesterol is an essential molecule
[26].
Then I asked the question is: “What is the majority of lipid in the liver of patients with NAFL and NASH?”
Puri et al. have quantified and compared hepatic free fatty acid (FFA), diacylglycerol (DAG), triacylglycerol
(TAG 5 triglyceride), F C, cholesterol esters (CE), and phospholipid content in obese patients with normal liver,
NAFL, or NASH. In NAFL and NASH, DAG and TAG were markedly increased. Although the majority of hepatic
lipid is TAG, interestingly, a stepwise increase was found in hepatic FC, but not CE
[27].
13Possible underlining molecular mechanisms between nonalcoholic steatohepatitis and atherosclerosis
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