Accepted Manuscript Non-alcoholic fatty liver disease, obesity and the metabolic syndrome Peter Dietrich, Claus Hellerbrand
PII:
S1521-6918(14)00086-9
DOI:
10.1016/j.bpg.2014.07.008
Reference:
YBEGA 1270
To appear in:
Best Practice & Research Clinical Gastroenterology
Received Date: 26 May 2014 Revised Date:
25 June 2014
Accepted Date: 5 July 2014
Please cite this article as: Dietrich P, Hellerbrand C, Non-alcoholic fatty liver disease, obesity and the metabolic syndrome, Best Practice & Research Clinical Gastroenterology (2014), doi: 10.1016/ j.bpg.2014.07.008. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Dietrich and Hellerbrand: NAFLD in Obesity
1
ACCEPTED MANUSCRIPT
Non-alcoholic fatty liver disease, obesity and the metabolic syndrome
RI PT
Peter Dietrich1 and Claus Hellerbrand2
1
Institute of Pathology, University Regensburg, 93053 Regensburg, Germany
2
SC
Department of Internal Medicine I, University Hospital Regensburg, 93053
M AN U
Regensburg, Germany
Corresponding author:
Claus Hellerbrand
Department of Internal Medicine I University Hospital Regensburg
TE D
93053 Regensburg, Germany Phone: +49 941 9447155
EP
Fax: +49 941 9447154
AC C
E-mail: [email protected]
Dietrich and Hellerbrand: NAFLD in Obesity
2
ACCEPTED MANUSCRIPT ABSTRACT
Nonalcoholic fatty liver disease (NAFLD) is now recognized as the most common cause of chronic liver disease worldwide. Its prevalence has increased to more than
RI PT
30% of adults in developed countries and its incidence is still rising. The majority of patients with NAFLD have simple steatosis but in up to one third of patients, NAFLD progresses to its more severe form nonalcoholic steatohepatitis (NASH). NASH is
SC
characterized by liver inflammation and injury thereby determining the risk to develop liver fibrosis and cancer. NAFLD is considered the hepatic manifestation of the
M AN U
metabolic syndrome. However, the liver is not only a passive target but affects the pathogenesis of the metabolic syndrome and its complications. Conversely, pathophysiological changes in other organs such as in the adipose tissue, the intestinal barrier or the immune system have been identified as triggers and
TE D
promoters of NAFLD progression. This article details the pathogenesis of NAFLD
EP
along with the current state of its diagnosis and treatment.
Key words: Nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis
AC C
(NASH), metabolic syndrome.
Dietrich and Hellerbrand: NAFLD in Obesity
3
ACCEPTED MANUSCRIPT DEFINITION
The definition “nonalcoholic fatty liver disease” (NAFLD) is associated with other terms like NAFL (“nonalcoholic fatty liver”), NASH (“nonalcoholic steatohepatitis”) and
RI PT
“hepatic steatosis”. Often, these terms are not clearly separated, which may result in confusion in clinical practice. According to the guidelines of the American Association for the Study of Liver Diseases (AASLD) the definition of NAFLD requires the
SC
presence of primary hepatic steatosis diagnosed either by imaging or by histology and that reasons for secondary hepatic fat accumulation (e.g. extensive alcohol
M AN U
consumption, steatogenic medication or hereditary disorders) are excluded [1]. Hepatic steatosis means cytoplasmatic micro-, macro- or mixed vesicular incorporation of lipids into hepatocytes [2]. Primary hepatic steatosis in NAFLD is associated with metabolic risk factors reflecting the metabolic syndrome (MS) - such
TE D
as obesity, insulin resistance and/or dyslipidemia - in the majority of patients [1]. If hepatic steatosis in NAFLD leads to inflammation and hepatocellular injury, “simple” steatosis has to be segregated from the more severe form nonalcoholic
EP
steatohepatitis (NASH). While NAFLD encompasses the whole spectrum of disease, NASH is defined as the presence of primary hepatic steatosis and inflammation with
AC C
hepatocellular injury (e.g. ballooning of the hepatocytes). NASH may progress to fibrosis, cirrhosis and hepatocellular carcinoma (HCC) [3,4] (Figure 1).
Dietrich and Hellerbrand: NAFLD in Obesity
4
ACCEPTED MANUSCRIPT EPIDEMIOLOGY
NAFLD is an emerging epidemic disease. Its prevalence has increased to more than 30% of adults in developed countries with an incidence still rising [5]. However, prevalence data concerning NAFLD range between 20% and 50% depending on
RI PT
definition criteria and diagnostic methods used in different studies [3,6–8]. Already today, NAFLD is the most common chronic liver disease worldwide and it is becoming a frequent cause of patient referral to gastroenterologists [9]. Indeed, it is
SC
by now the most common diagnosis in patients with elevated liver enzymes in Western countries although aminotransferase serum levels are normal in
M AN U
approximately 50% of NAFLD patients [3]. Furthermore, NAFLD constitutes a major risk factor for progression to end stage liver disease [10,11]. In children, the prevalence of NAFLD ranges between 13% and 80% showing strong positive
TE D
correlation to obesity [12].
Metabolic syndrome is the main risk factor for NAFLD With the continued rise of obesity in the Western countries, the prevalence of NAFLD
EP
has followed a similar trend [13]. Since NAFLD is closely associated with obesity, insulin resistance, hypertension and dyslipidemia, it is regarded as the liver
AC C
manifestation of the metabolic syndrome (MS) [14,15]. Both excessive body mass index (BMI) and visceral obesity are recognized risk factors for NAFLD. In fact, nearly two thirds of patients with obesity and type-2-diabetes mellitus (T2DM) exhibit hepatic steatosis [16,17]. In another study, ultrasonography revealed fatty infiltration of the liver in approximately 50% of patients with hyperlipidemia [18]. Boza et al. showed that insulin resistance (IR) represents the main predictor of NASH and that obese patients undergoing gastric bypass surgery exhibit NASH on histological examination in more than 60% [19]. Other studies found even higher rates of NAFLD prevalence
Dietrich and Hellerbrand: NAFLD in Obesity
5
ACCEPTED MANUSCRIPT
in patients with severe obesity undergoing bariatric surgery, and 12% in this group of patients even had advanced hepatic fibrosis [20,21]. Among NAFLD patients, the MS has been associated with increased risk for NASH and fibrosis, and the risk of forthcoming liver failure [22,23].
RI PT
Apart from that, several studies revealed obesity-independent risk factors for development and progression of NAFLD. While in patients with T2DM the association with NAFLD is well established and recognized, there is a more limited appreciation
SC
of the condition among common endocrine diseases presenting with hormonal excess or deficiency [24]. For example, prevalence of NAFLD within obese patients
M AN U
with polycystic ovarian syndrome is elevated and estimated to be as high as 70% [25]. Interestingly, patients suffering from Cushing's syndrome present low prevalence of hepatic steatosis. This could result from the inhibition of the so-called low-grade chronic inflammation, mainly mediated by interleukin 6 (see pathogenesis),
TE D
due to an excess of cortisol [26]. Besides the metabolic syndrome, alcohol is the most frequent reason for fatty liver diseases, which will be discussed below. In addition, there are further less frequent reasons for secondary hepatic steatosis. The
EP
list of secondary causes for hepatic steatosis is detailed in excellent reviews by
AC C
Farrell et al. and Chitturi et al. [27,28].
Dietrich and Hellerbrand: NAFLD in Obesity
6
ACCEPTED MANUSCRIPT PATHOLOGY
Natural history The liver is the central organ of lipid and glucose metabolism; however, excess
RI PT
deposition of energy, and herein particularly of lipids, is associated with adverse effects on the liver and also other organs. The development of NAFLD (i.e. steatosis) results from an increased inflow of free fatty acids (FFA) derived from insulin resistant
SC
adipose tissue, altered hepatic processing of dietary lipids delivered by lipoproteins, increased hepatic de novo lipogenesis, or impaired lipid export out of the
M AN U
hepatocytes. In a fraction of patients, hepatic steatosis progresses to NASH with hepatocellular damage and inflammation, thereby obtaining the risk for further progression to fibrosis, cirrhosis and hepatocellular carcinoma (HCC) [29]. Day et al. have been the first describing the “two-hit-hypothesis” of NAFLD progression as a
TE D
model of NAFLD-progression. The "first hit” was defined as hepatocellular lipid accumulation (steatosis) resulting from an imbalance of cellular lipid uptake and combustion. The "second hit" was defined as additional inflammation (NASH)
EP
resulting from an imbalance of pro- and anti-inflammatory factors [30]. This was a valuable model to depict the pathogenesis of NAFLD, but soon it was recognized that
AC C
the pathophysiological changes are by far more complex with e.g. steadily flowing transitions and not only the results of two defined “hits”. In general, patients with "simple" steatosis (NAFL) reveal very slow or no histological progression, while NASH patients can exhibit histological and clinical progression to cirrhotic-stage disease including all known further complications of liver insufficiency [31]. However, current studies give evidence that all forms of NAFLD have a significantly increased risk of cirrhosis and HCC [32].
Dietrich and Hellerbrand: NAFLD in Obesity
7
ACCEPTED MANUSCRIPT Long-term outcomes and hepatic complications
The overall mortality of NAFLD patients is significantly increased because of both cardiovascular and liver-related complications; and the mortality of NASH patients is higher than in those patients with "simple" steatosis (NAFL) [33,34]. Furthermore,
RI PT
NAFLD has systemic consequences as it worsens insulin resistance, predicts the emergence of metabolic complications and increases the risk for cardiovascular events. Thus, liver-directed therapy likely also has beneficial effects on extra-hepatic
SC
metabolic complications. About 30% of patients with NAFL develop NASH, and in again about 30-40% of NASH patients the disease progresses to manifest fibrosis
M AN U
and cirrhosis. The latter has a 10-year-mortality of 25% and approximately 5% develop end-stage liver disease including HCC [35,36] (Figure 2). Thus, during the progression of NAFLD, the step from "simple" steatosis to NASH is the most critical and most challenging. Indeed, the presence of inflammation strongly predicts
TE D
progression to fibrosis, and herewith, the development of cirrhosis and cancer [37]. Apart from that, during the last years, it is getting more and more obvious that a significant number (>50%) of those patients with liver cirrhosis and the diagnosis
EP
"cryptogenic" cirrhosis have a NASH cirrhosis. Likely, numbers are even higher considering the fact that the typical histological criteria of NASH can be lost in
AC C
cirrhosis [38,39].
Extra-hepatic consequences of the progression of NAFLD The liver is not only a passive target of the metabolic syndrome but steatohepatitis induces and enhances insulin resistance leading to a vicious cycle. Even if NASH does not lead to end stage liver disease it significantly affects morbidity via promotion of extra-hepatic sequels of the MS [40]. The concept that a fatty liver may drive the inflammatory cascade of atherosclerosis is gaining acceptance, and NASH is
Dietrich and Hellerbrand: NAFLD in Obesity
8
ACCEPTED MANUSCRIPT
recognized as an independent risk factor for cardiovascular and kidney diseases associated with the MS. Indeed, it was shown in several studies that NAFLD is not only associated with these diseases, but also precedes the manifestation of metabolic derangements [41]. Moreover, several lines of evidence indicate that
RI PT
hepatic steatosis and NASH are not only a plain consequence of insulin resistance (IR), but also play a causal role in the genesis or progression of IR. Intracellular lipid content in the liver reduces insulin clearance resulting in hyperinsulinemia, a feature
SC
of pre-diabetes [42]. In the general population, high aminotransferases (a surrogate marker for NAFLD) increased the long-term risk of incident diabetes, MS and
M AN U
cardiovascular events [43]. On a fat-enriched diet, steatosis and hepatic IR occurred earlier than peripheral IR suggesting that IR in the liver is one of the primary defects in the development of IR associated with obesity [44,45].
TE D
Individual factors associated with development and progression of NAFLD Age was reported to be associated with higher prevalence of NAFLD, and also NAFLD progression is faster in older patients [46,47]. Also male gender appears as
EP
risk factor for NAFLD development and progression [3,48–50], and it seems that estrogens may have protective effects against NAFLD in women [51]. Furthermore,
AC C
several studies reveal the ethnic background as an independent risk factor for development and progression of NAFLD. For example, NAFLD as well as elevated aminotransferase levels were most common in Hispanics and least common in African Americans compared to non-Hispanic whites in an obesity clinic population [52,53]. Furthermore, experimental and epidemiological studies revealed smoking as a risk factor for the development and progression of NAFLD [54-57]. The lifestyle favoring the development of the metabolic syndrome and NAFLD has been paralleled by the rise of chronic stress as the single most common contributor
Dietrich and Hellerbrand: NAFLD in Obesity
9
ACCEPTED MANUSCRIPT
to illness in modern societies [58]. Several studies indicate that chronic stress has implications on metabolic deficits such as obesity, T2DM and dyslipidemia [59]. Dysregulation of the hypothalamus-pituitary-adrenal axis, one of the major stress systems in the body, has been described in several metabolic disorders [60]. Thus,
RI PT
considering the high co-morbidity for the MS and NAFLD or NASH, it is likely that chronic stress indirectly promotes the progression of chronic liver disease. A study revealing positive correlation between psychosocial stress and the severity of chronic
SC
hepatitis C supports this hypothesis [61]. Psychosocial stress is also able to
M AN U
exaggerate inflammation and fibrosis in cirrhotic livers [62,63].
Extra-hepatic factors which affect the development and progression of NAFLD
Adipose tissue and adipokines
TE D
NAFLD is a multi-factorial disease coupled with clinical hallmarks including obesity, IR, and dyslipidemia [64]. Obesity is associated with elevated circulating levels of pro-inflammatory factors such as hormones or cytokines like tumor-necrosis-factor
EP
and interleukin-1. Hepatic lipid dysregulation, oxidative stress, and pro-inflammatory cytokines interact synergistically to promote hepatic fat accumulation over time [65]. It
AC C
is important to highlight that especially visceral adiposity is relevant for the development of NAFLD, because venous splanchnic blood flow directly leads to a high exposition of liver tissue to free fatty acids (FFA) and triglycerides resulting from lipolysis [66]. Moreover, in obesity, IR causes a decreased insulin dependent inhibition of lipolysis, leading to elevated levels of FFA, which in turn promote the proinflammatory state and subsequent enhancement of IR. Fatty infiltration of the liver results from increased hepatic lipid accumulation (from accelerated FFA influx and de novo lipid synthesis) and at the same time decreased
Dietrich and Hellerbrand: NAFLD in Obesity
10
ACCEPTED MANUSCRIPT
hepatic lipid clearance (free fatty acid oxidation and very low-density lipoprotein excretion). It is well established that adipose tissue has a strong impact on the accumulation of lipids in the liver, predominantly by the release of FFA, adipokines and cytokines. On the other hand, accumulation of intracellular lipids is one proposed
RI PT
mechanism of IR. Still, whether IR is a cause or consequence of lipid accumulation remains debated. In addition, especially the adipokine adiponectin has been shown to affect the regulation of hepatic inflammation in experimental studies. Support of the
SC
major role of adiponectin signaling in the pathogenesis of NAFLD and hepatic IR was also provided from clinical studies [67]. Moreover, further adipokines such as leptin
M AN U
have been suggested to be involved in the pathogenesis of NAFLD [68].
Microbiota, gut derived bacterial endotoxins and the immune system Alterations of the intestinal microbiota composition and barrier function resulting in an
TE D
increased permeation of bacterial endotoxin have been suggested to be critically involved not only in the onset but also progression of NAFLD [69]. Indeed, endotoxin levels were found to be elevated in portal plasma in mice with NAFLD and in
EP
peripheral blood of patients with NAFLD. Furthermore, the inhibition of endotoxinreceptors was associated with a marked protection against the onset of NAFLD in
AC C
various animal models of NAFLD [70,71]. These gut-derived bacterial products significantly contribute to the activation of inflammatory processes in the liver. Here, the innate immune system and the increased release of pro-inflammatory cytokines play a critical role in the progression of NAFLD.
Obstructive sleep apnoea syndrome The MS is often associated with obstructive sleep apnoea syndrome (OSAS). OSAS is correlated with an increased risk of NAFLD, NASH and fibrosis. Therefore, it has
Dietrich and Hellerbrand: NAFLD in Obesity
11
ACCEPTED MANUSCRIPT
been suggested that OSAS patients should be screened for the presence and severity of NAFLD [72]. As mentioned above, NAFLD is also common in children, with a strong correlation to obesity [12]. Likewise, OSAS and the severity/duration of hypoxemia in pediatric patients are associated with biochemical and histological
RI PT
measures of NAFLD severity [73,74].
Taken together, the complex etiology and pathophysiology of NAFLD has to be taken
SC
in account for individualized therapeutic intervention (Figure 3).
Effect of alcohol on the development and progression of NAFLD
M AN U
Per definition NAFLD excludes significant alcohol consumption in the past and in the present. However, definitions of "significant quantities" of alcohol promoting the development and progression of NAFLD are not equal around the world and the amount of alcohol that causes (alcoholic) fatty liver differs between individuals.
TE D
Moreover, it has to be noted that in western countries NAFLD-patients display very often a mixed picture of (components of the) MS and consumption of alcohol in moderate amounts. Still, as long as alcohol consumption is below "significant"
EP
quantities the diagnosis of NAFLD is correct in these patients. Nonetheless, it is important to recognize that even moderate alcohol consumption promotes NASH
AC C
development and progression [4,75]. Several studies in humans and animal models reveal that pre-existing NASH-conditions can be significantly aggravated after moderate alcohol intake/exposure [76,77]. We also developed an animal model that allows the investigation of isolated or joint effects of alcohol and high-fat diet on hepatic injury. Here, alcohol and high-fat diet appear to act synergistically on the development of hepatic fibrosis [78]. In line with this, other studies showed that overweight
and
obesity
increased
the
risk
of
alcohol-related
abnormal
aminotransferase levels [79]. Especially in older men and women, the combination of
Dietrich and Hellerbrand: NAFLD in Obesity
12
ACCEPTED MANUSCRIPT
obesity and alcohol is synergistic in increasing the risk of liver injury [80]. Finally, it has to be emphasized that patients with NASH cirrhosis have a greatly increased risk of liver cancer and that alcohol consumption, a modifiable risk factor, appears to be
AC C
EP
TE D
M AN U
SC
RI PT
the most significant factor associated with risk of HCC development [81] (Figure 4).
Dietrich and Hellerbrand: NAFLD in Obesity
13
ACCEPTED MANUSCRIPT DIAGNOSIS
Exclusion of significant alcohol consumption As mentioned above, the first and sometimes most challenging step of the diagnostic
RI PT
pathway for NAFLD is the exclusion of ongoing or prior consumption of significant amounts of alcohol, as patients tend to underestimate their alcohol intake. The threshold dose for significant hepatotoxic alcohol amount for the exclusion of
SC
alcoholic (fatty) liver disease (AFLD) or alcoholic steatohepatitis (ASH) varies among different cultures and individuals. The European Association for the Study of the Liver
M AN U
(EASL) defines 30 grams per day for men and 20 grams per day for women as significant hepatotoxic alcohol amounts [82]. American guidelines define significant alcohol consumption as > 21 drinks per week in men and > 14 drinks per week in
TE D
women over a 2-year period before the first diagnostic liver histology [1].
Clinical history and symptoms
Screening for NAFLD should be performed in individuals who are either obese,
EP
diabetic or have MS [83]. The majority of patients with NAFL or mild NASH are asymptomatic, sometimes they will complain about fatigue or slight epigastric feeling
AC C
of pressure. Most times, the disease may be detected via routine blood tests showing elevated liver enzymes or when ultrasound is performed and detects liver steatosis. The patient should be asked and screened for symptoms or diseases associated with the MS which make NAFLD more likely (obesity, hyperuricemia, T2DM/impaired glucose tolerance, arterial hypertension, hypertriglyceridemia, hypercholesterolemia). Furthermore, secondary causes for liver steatosis should be evaluated (medications, toxins, lipodystrophy, autoimmune and inflammatory diseases, malnutrition, severe
Dietrich and Hellerbrand: NAFLD in Obesity
14
ACCEPTED MANUSCRIPT
weight loss and re-feeding syndrome). In case of elevated serum transaminases, also other causes of liver injury, such as viral hepatitis have to be taken into account.
Routine laboratory investigation
RI PT
The most common abnormality of laboratory parameters in NAFLD are elevated serum levels of transaminases (Aspartate-aminotransferase (AST) and Alaninaminotransferase (ALT)). They are elevated in approximately 50% if NAFL is present
SC
and in up to 80% in NASH patients, which supports the diagnosis NAFLD if other causes of liver injury can be excluded [84,85]. Also an AST:ALT ratio
PII:
S1521-6918(14)00086-9
DOI:
10.1016/j.bpg.2014.07.008
Reference:
YBEGA 1270
To appear in:
Best Practice & Research Clinical Gastroenterology
Received Date: 26 May 2014 Revised Date:
25 June 2014
Accepted Date: 5 July 2014
Please cite this article as: Dietrich P, Hellerbrand C, Non-alcoholic fatty liver disease, obesity and the metabolic syndrome, Best Practice & Research Clinical Gastroenterology (2014), doi: 10.1016/ j.bpg.2014.07.008. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Dietrich and Hellerbrand: NAFLD in Obesity
1
ACCEPTED MANUSCRIPT
Non-alcoholic fatty liver disease, obesity and the metabolic syndrome
RI PT
Peter Dietrich1 and Claus Hellerbrand2
1
Institute of Pathology, University Regensburg, 93053 Regensburg, Germany
2
SC
Department of Internal Medicine I, University Hospital Regensburg, 93053
M AN U
Regensburg, Germany
Corresponding author:
Claus Hellerbrand
Department of Internal Medicine I University Hospital Regensburg
TE D
93053 Regensburg, Germany Phone: +49 941 9447155
EP
Fax: +49 941 9447154
AC C
E-mail: [email protected]
Dietrich and Hellerbrand: NAFLD in Obesity
2
ACCEPTED MANUSCRIPT ABSTRACT
Nonalcoholic fatty liver disease (NAFLD) is now recognized as the most common cause of chronic liver disease worldwide. Its prevalence has increased to more than
RI PT
30% of adults in developed countries and its incidence is still rising. The majority of patients with NAFLD have simple steatosis but in up to one third of patients, NAFLD progresses to its more severe form nonalcoholic steatohepatitis (NASH). NASH is
SC
characterized by liver inflammation and injury thereby determining the risk to develop liver fibrosis and cancer. NAFLD is considered the hepatic manifestation of the
M AN U
metabolic syndrome. However, the liver is not only a passive target but affects the pathogenesis of the metabolic syndrome and its complications. Conversely, pathophysiological changes in other organs such as in the adipose tissue, the intestinal barrier or the immune system have been identified as triggers and
TE D
promoters of NAFLD progression. This article details the pathogenesis of NAFLD
EP
along with the current state of its diagnosis and treatment.
Key words: Nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis
AC C
(NASH), metabolic syndrome.
Dietrich and Hellerbrand: NAFLD in Obesity
3
ACCEPTED MANUSCRIPT DEFINITION
The definition “nonalcoholic fatty liver disease” (NAFLD) is associated with other terms like NAFL (“nonalcoholic fatty liver”), NASH (“nonalcoholic steatohepatitis”) and
RI PT
“hepatic steatosis”. Often, these terms are not clearly separated, which may result in confusion in clinical practice. According to the guidelines of the American Association for the Study of Liver Diseases (AASLD) the definition of NAFLD requires the
SC
presence of primary hepatic steatosis diagnosed either by imaging or by histology and that reasons for secondary hepatic fat accumulation (e.g. extensive alcohol
M AN U
consumption, steatogenic medication or hereditary disorders) are excluded [1]. Hepatic steatosis means cytoplasmatic micro-, macro- or mixed vesicular incorporation of lipids into hepatocytes [2]. Primary hepatic steatosis in NAFLD is associated with metabolic risk factors reflecting the metabolic syndrome (MS) - such
TE D
as obesity, insulin resistance and/or dyslipidemia - in the majority of patients [1]. If hepatic steatosis in NAFLD leads to inflammation and hepatocellular injury, “simple” steatosis has to be segregated from the more severe form nonalcoholic
EP
steatohepatitis (NASH). While NAFLD encompasses the whole spectrum of disease, NASH is defined as the presence of primary hepatic steatosis and inflammation with
AC C
hepatocellular injury (e.g. ballooning of the hepatocytes). NASH may progress to fibrosis, cirrhosis and hepatocellular carcinoma (HCC) [3,4] (Figure 1).
Dietrich and Hellerbrand: NAFLD in Obesity
4
ACCEPTED MANUSCRIPT EPIDEMIOLOGY
NAFLD is an emerging epidemic disease. Its prevalence has increased to more than 30% of adults in developed countries with an incidence still rising [5]. However, prevalence data concerning NAFLD range between 20% and 50% depending on
RI PT
definition criteria and diagnostic methods used in different studies [3,6–8]. Already today, NAFLD is the most common chronic liver disease worldwide and it is becoming a frequent cause of patient referral to gastroenterologists [9]. Indeed, it is
SC
by now the most common diagnosis in patients with elevated liver enzymes in Western countries although aminotransferase serum levels are normal in
M AN U
approximately 50% of NAFLD patients [3]. Furthermore, NAFLD constitutes a major risk factor for progression to end stage liver disease [10,11]. In children, the prevalence of NAFLD ranges between 13% and 80% showing strong positive
TE D
correlation to obesity [12].
Metabolic syndrome is the main risk factor for NAFLD With the continued rise of obesity in the Western countries, the prevalence of NAFLD
EP
has followed a similar trend [13]. Since NAFLD is closely associated with obesity, insulin resistance, hypertension and dyslipidemia, it is regarded as the liver
AC C
manifestation of the metabolic syndrome (MS) [14,15]. Both excessive body mass index (BMI) and visceral obesity are recognized risk factors for NAFLD. In fact, nearly two thirds of patients with obesity and type-2-diabetes mellitus (T2DM) exhibit hepatic steatosis [16,17]. In another study, ultrasonography revealed fatty infiltration of the liver in approximately 50% of patients with hyperlipidemia [18]. Boza et al. showed that insulin resistance (IR) represents the main predictor of NASH and that obese patients undergoing gastric bypass surgery exhibit NASH on histological examination in more than 60% [19]. Other studies found even higher rates of NAFLD prevalence
Dietrich and Hellerbrand: NAFLD in Obesity
5
ACCEPTED MANUSCRIPT
in patients with severe obesity undergoing bariatric surgery, and 12% in this group of patients even had advanced hepatic fibrosis [20,21]. Among NAFLD patients, the MS has been associated with increased risk for NASH and fibrosis, and the risk of forthcoming liver failure [22,23].
RI PT
Apart from that, several studies revealed obesity-independent risk factors for development and progression of NAFLD. While in patients with T2DM the association with NAFLD is well established and recognized, there is a more limited appreciation
SC
of the condition among common endocrine diseases presenting with hormonal excess or deficiency [24]. For example, prevalence of NAFLD within obese patients
M AN U
with polycystic ovarian syndrome is elevated and estimated to be as high as 70% [25]. Interestingly, patients suffering from Cushing's syndrome present low prevalence of hepatic steatosis. This could result from the inhibition of the so-called low-grade chronic inflammation, mainly mediated by interleukin 6 (see pathogenesis),
TE D
due to an excess of cortisol [26]. Besides the metabolic syndrome, alcohol is the most frequent reason for fatty liver diseases, which will be discussed below. In addition, there are further less frequent reasons for secondary hepatic steatosis. The
EP
list of secondary causes for hepatic steatosis is detailed in excellent reviews by
AC C
Farrell et al. and Chitturi et al. [27,28].
Dietrich and Hellerbrand: NAFLD in Obesity
6
ACCEPTED MANUSCRIPT PATHOLOGY
Natural history The liver is the central organ of lipid and glucose metabolism; however, excess
RI PT
deposition of energy, and herein particularly of lipids, is associated with adverse effects on the liver and also other organs. The development of NAFLD (i.e. steatosis) results from an increased inflow of free fatty acids (FFA) derived from insulin resistant
SC
adipose tissue, altered hepatic processing of dietary lipids delivered by lipoproteins, increased hepatic de novo lipogenesis, or impaired lipid export out of the
M AN U
hepatocytes. In a fraction of patients, hepatic steatosis progresses to NASH with hepatocellular damage and inflammation, thereby obtaining the risk for further progression to fibrosis, cirrhosis and hepatocellular carcinoma (HCC) [29]. Day et al. have been the first describing the “two-hit-hypothesis” of NAFLD progression as a
TE D
model of NAFLD-progression. The "first hit” was defined as hepatocellular lipid accumulation (steatosis) resulting from an imbalance of cellular lipid uptake and combustion. The "second hit" was defined as additional inflammation (NASH)
EP
resulting from an imbalance of pro- and anti-inflammatory factors [30]. This was a valuable model to depict the pathogenesis of NAFLD, but soon it was recognized that
AC C
the pathophysiological changes are by far more complex with e.g. steadily flowing transitions and not only the results of two defined “hits”. In general, patients with "simple" steatosis (NAFL) reveal very slow or no histological progression, while NASH patients can exhibit histological and clinical progression to cirrhotic-stage disease including all known further complications of liver insufficiency [31]. However, current studies give evidence that all forms of NAFLD have a significantly increased risk of cirrhosis and HCC [32].
Dietrich and Hellerbrand: NAFLD in Obesity
7
ACCEPTED MANUSCRIPT Long-term outcomes and hepatic complications
The overall mortality of NAFLD patients is significantly increased because of both cardiovascular and liver-related complications; and the mortality of NASH patients is higher than in those patients with "simple" steatosis (NAFL) [33,34]. Furthermore,
RI PT
NAFLD has systemic consequences as it worsens insulin resistance, predicts the emergence of metabolic complications and increases the risk for cardiovascular events. Thus, liver-directed therapy likely also has beneficial effects on extra-hepatic
SC
metabolic complications. About 30% of patients with NAFL develop NASH, and in again about 30-40% of NASH patients the disease progresses to manifest fibrosis
M AN U
and cirrhosis. The latter has a 10-year-mortality of 25% and approximately 5% develop end-stage liver disease including HCC [35,36] (Figure 2). Thus, during the progression of NAFLD, the step from "simple" steatosis to NASH is the most critical and most challenging. Indeed, the presence of inflammation strongly predicts
TE D
progression to fibrosis, and herewith, the development of cirrhosis and cancer [37]. Apart from that, during the last years, it is getting more and more obvious that a significant number (>50%) of those patients with liver cirrhosis and the diagnosis
EP
"cryptogenic" cirrhosis have a NASH cirrhosis. Likely, numbers are even higher considering the fact that the typical histological criteria of NASH can be lost in
AC C
cirrhosis [38,39].
Extra-hepatic consequences of the progression of NAFLD The liver is not only a passive target of the metabolic syndrome but steatohepatitis induces and enhances insulin resistance leading to a vicious cycle. Even if NASH does not lead to end stage liver disease it significantly affects morbidity via promotion of extra-hepatic sequels of the MS [40]. The concept that a fatty liver may drive the inflammatory cascade of atherosclerosis is gaining acceptance, and NASH is
Dietrich and Hellerbrand: NAFLD in Obesity
8
ACCEPTED MANUSCRIPT
recognized as an independent risk factor for cardiovascular and kidney diseases associated with the MS. Indeed, it was shown in several studies that NAFLD is not only associated with these diseases, but also precedes the manifestation of metabolic derangements [41]. Moreover, several lines of evidence indicate that
RI PT
hepatic steatosis and NASH are not only a plain consequence of insulin resistance (IR), but also play a causal role in the genesis or progression of IR. Intracellular lipid content in the liver reduces insulin clearance resulting in hyperinsulinemia, a feature
SC
of pre-diabetes [42]. In the general population, high aminotransferases (a surrogate marker for NAFLD) increased the long-term risk of incident diabetes, MS and
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cardiovascular events [43]. On a fat-enriched diet, steatosis and hepatic IR occurred earlier than peripheral IR suggesting that IR in the liver is one of the primary defects in the development of IR associated with obesity [44,45].
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Individual factors associated with development and progression of NAFLD Age was reported to be associated with higher prevalence of NAFLD, and also NAFLD progression is faster in older patients [46,47]. Also male gender appears as
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risk factor for NAFLD development and progression [3,48–50], and it seems that estrogens may have protective effects against NAFLD in women [51]. Furthermore,
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several studies reveal the ethnic background as an independent risk factor for development and progression of NAFLD. For example, NAFLD as well as elevated aminotransferase levels were most common in Hispanics and least common in African Americans compared to non-Hispanic whites in an obesity clinic population [52,53]. Furthermore, experimental and epidemiological studies revealed smoking as a risk factor for the development and progression of NAFLD [54-57]. The lifestyle favoring the development of the metabolic syndrome and NAFLD has been paralleled by the rise of chronic stress as the single most common contributor
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to illness in modern societies [58]. Several studies indicate that chronic stress has implications on metabolic deficits such as obesity, T2DM and dyslipidemia [59]. Dysregulation of the hypothalamus-pituitary-adrenal axis, one of the major stress systems in the body, has been described in several metabolic disorders [60]. Thus,
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considering the high co-morbidity for the MS and NAFLD or NASH, it is likely that chronic stress indirectly promotes the progression of chronic liver disease. A study revealing positive correlation between psychosocial stress and the severity of chronic
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hepatitis C supports this hypothesis [61]. Psychosocial stress is also able to
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exaggerate inflammation and fibrosis in cirrhotic livers [62,63].
Extra-hepatic factors which affect the development and progression of NAFLD
Adipose tissue and adipokines
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NAFLD is a multi-factorial disease coupled with clinical hallmarks including obesity, IR, and dyslipidemia [64]. Obesity is associated with elevated circulating levels of pro-inflammatory factors such as hormones or cytokines like tumor-necrosis-factor
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and interleukin-1. Hepatic lipid dysregulation, oxidative stress, and pro-inflammatory cytokines interact synergistically to promote hepatic fat accumulation over time [65]. It
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is important to highlight that especially visceral adiposity is relevant for the development of NAFLD, because venous splanchnic blood flow directly leads to a high exposition of liver tissue to free fatty acids (FFA) and triglycerides resulting from lipolysis [66]. Moreover, in obesity, IR causes a decreased insulin dependent inhibition of lipolysis, leading to elevated levels of FFA, which in turn promote the proinflammatory state and subsequent enhancement of IR. Fatty infiltration of the liver results from increased hepatic lipid accumulation (from accelerated FFA influx and de novo lipid synthesis) and at the same time decreased
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hepatic lipid clearance (free fatty acid oxidation and very low-density lipoprotein excretion). It is well established that adipose tissue has a strong impact on the accumulation of lipids in the liver, predominantly by the release of FFA, adipokines and cytokines. On the other hand, accumulation of intracellular lipids is one proposed
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mechanism of IR. Still, whether IR is a cause or consequence of lipid accumulation remains debated. In addition, especially the adipokine adiponectin has been shown to affect the regulation of hepatic inflammation in experimental studies. Support of the
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major role of adiponectin signaling in the pathogenesis of NAFLD and hepatic IR was also provided from clinical studies [67]. Moreover, further adipokines such as leptin
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have been suggested to be involved in the pathogenesis of NAFLD [68].
Microbiota, gut derived bacterial endotoxins and the immune system Alterations of the intestinal microbiota composition and barrier function resulting in an
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increased permeation of bacterial endotoxin have been suggested to be critically involved not only in the onset but also progression of NAFLD [69]. Indeed, endotoxin levels were found to be elevated in portal plasma in mice with NAFLD and in
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peripheral blood of patients with NAFLD. Furthermore, the inhibition of endotoxinreceptors was associated with a marked protection against the onset of NAFLD in
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various animal models of NAFLD [70,71]. These gut-derived bacterial products significantly contribute to the activation of inflammatory processes in the liver. Here, the innate immune system and the increased release of pro-inflammatory cytokines play a critical role in the progression of NAFLD.
Obstructive sleep apnoea syndrome The MS is often associated with obstructive sleep apnoea syndrome (OSAS). OSAS is correlated with an increased risk of NAFLD, NASH and fibrosis. Therefore, it has
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been suggested that OSAS patients should be screened for the presence and severity of NAFLD [72]. As mentioned above, NAFLD is also common in children, with a strong correlation to obesity [12]. Likewise, OSAS and the severity/duration of hypoxemia in pediatric patients are associated with biochemical and histological
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measures of NAFLD severity [73,74].
Taken together, the complex etiology and pathophysiology of NAFLD has to be taken
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in account for individualized therapeutic intervention (Figure 3).
Effect of alcohol on the development and progression of NAFLD
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Per definition NAFLD excludes significant alcohol consumption in the past and in the present. However, definitions of "significant quantities" of alcohol promoting the development and progression of NAFLD are not equal around the world and the amount of alcohol that causes (alcoholic) fatty liver differs between individuals.
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Moreover, it has to be noted that in western countries NAFLD-patients display very often a mixed picture of (components of the) MS and consumption of alcohol in moderate amounts. Still, as long as alcohol consumption is below "significant"
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quantities the diagnosis of NAFLD is correct in these patients. Nonetheless, it is important to recognize that even moderate alcohol consumption promotes NASH
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development and progression [4,75]. Several studies in humans and animal models reveal that pre-existing NASH-conditions can be significantly aggravated after moderate alcohol intake/exposure [76,77]. We also developed an animal model that allows the investigation of isolated or joint effects of alcohol and high-fat diet on hepatic injury. Here, alcohol and high-fat diet appear to act synergistically on the development of hepatic fibrosis [78]. In line with this, other studies showed that overweight
and
obesity
increased
the
risk
of
alcohol-related
abnormal
aminotransferase levels [79]. Especially in older men and women, the combination of
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obesity and alcohol is synergistic in increasing the risk of liver injury [80]. Finally, it has to be emphasized that patients with NASH cirrhosis have a greatly increased risk of liver cancer and that alcohol consumption, a modifiable risk factor, appears to be
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the most significant factor associated with risk of HCC development [81] (Figure 4).
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Exclusion of significant alcohol consumption As mentioned above, the first and sometimes most challenging step of the diagnostic
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pathway for NAFLD is the exclusion of ongoing or prior consumption of significant amounts of alcohol, as patients tend to underestimate their alcohol intake. The threshold dose for significant hepatotoxic alcohol amount for the exclusion of
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alcoholic (fatty) liver disease (AFLD) or alcoholic steatohepatitis (ASH) varies among different cultures and individuals. The European Association for the Study of the Liver
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(EASL) defines 30 grams per day for men and 20 grams per day for women as significant hepatotoxic alcohol amounts [82]. American guidelines define significant alcohol consumption as > 21 drinks per week in men and > 14 drinks per week in
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women over a 2-year period before the first diagnostic liver histology [1].
Clinical history and symptoms
Screening for NAFLD should be performed in individuals who are either obese,
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diabetic or have MS [83]. The majority of patients with NAFL or mild NASH are asymptomatic, sometimes they will complain about fatigue or slight epigastric feeling
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of pressure. Most times, the disease may be detected via routine blood tests showing elevated liver enzymes or when ultrasound is performed and detects liver steatosis. The patient should be asked and screened for symptoms or diseases associated with the MS which make NAFLD more likely (obesity, hyperuricemia, T2DM/impaired glucose tolerance, arterial hypertension, hypertriglyceridemia, hypercholesterolemia). Furthermore, secondary causes for liver steatosis should be evaluated (medications, toxins, lipodystrophy, autoimmune and inflammatory diseases, malnutrition, severe
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weight loss and re-feeding syndrome). In case of elevated serum transaminases, also other causes of liver injury, such as viral hepatitis have to be taken into account.
Routine laboratory investigation
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The most common abnormality of laboratory parameters in NAFLD are elevated serum levels of transaminases (Aspartate-aminotransferase (AST) and Alaninaminotransferase (ALT)). They are elevated in approximately 50% if NAFL is present
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and in up to 80% in NASH patients, which supports the diagnosis NAFLD if other causes of liver injury can be excluded [84,85]. Also an AST:ALT ratio
