Management and diagnosis of fatty liver disease.

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Expert Review of Gastroenterology & Hepatology Downloaded from informahealthcare.com by Nanyang Technological University on 04/26/15 For personal use only.

Management and diagnosis of fatty liver disease Expert Rev. Gastroenterol. Hepatol. 9(5), 671–683 (2015)

Amanda Tamar Schneier*, Caitlin Colleen Citti and Douglas T Dieterich Department of Liver Diseases, Icahn School of Medicine at Mount Sinai,1 Gustave Levy Place, New York, NY 10029, USA *Author for correspondence: [email protected]

Nonalcoholic fatty liver disease is a common cause of chronic liver disease and has been an increasingly studied topic of research as the obesity epidemic has been growing. There is a significant morbidity and mortality with uncontrolled steatohepatitis, which can progress to fibrosis, cirrhosis and hepatocellular carcinoma. The prevalence of this disease has been estimated to be roughly one-third of the western population, thought to be largely due to diet and sedentary lifestyle. Several treatments have been studied including vitamin E, insulin-sensitizing agents and ursodeoxycholic acid; however, the only treatment shown to improve the histologic changes of nonalcoholic fatty liver disease is weight loss. Given the proven benefit of weight loss, there may be reason to screen at-risk populations; however, limited availability of other disease-modifying treatments may limit the cost–benefit ratios. A better understanding of the diagnosis and management of this condition is required to alter the course of this modifiable disease. KEYWORDS: fatty liver disease . NAFLD . NASH . review . steatohepatitis

Definitions

Nonalcoholic fatty liver disease (NAFLD) refers to a spectrum of liver diseases whose hallmark, fat accumulation (or steatosis), cannot be attributed to secondary causes such as alcohol or certain drugs. NAFLD includes steatosis, steatohepatitis and cirrhosis. Nonalcoholic fatty liver (NAFL) refers to evidence of macrovesicular hepatic steatosis without signs hepatocellular injury such as hepatocyte ballooning or fibrosis. The term nonalcoholic steatohepatitis (NASH) denotes the presence hepatic inflammation and hepatocyte injury (seen as ballooning) with or without the presence of fibrosis. It is worthy of note that this pattern of inflammation can be histologically indistinguishable from alcoholic steatohepatitis. Cryptogenic cirrhosis (CC) refers to cirrhosis without evidence of etiology. In many of these patients, the evidence of NASH such as ballooning and inflammation, while at one time present, can no longer be seen; thus, the term ‘burned-out steatohepatitis’ is also sometimes used [1–3]. TABLE 1 summarizes the above terminology. Epidemiology

First described in 1980 [4], NAFLD has become the leading cause of chronic liver informahealthcare.com

10.1586/17474124.2015.1003209

disease in western developed countries, and is a growing cause of liver disease worldwide [5,6]. The numbers are likely even higher, as many patients with NAFLD are clinically silent and often have normal liver tests [7,8]. Prevalence

In recent studies looking at developed countries in Europe, the USA and Australia, the prevalence of NAFLD in the general population has been reported to be approximately 30% [8–10]. One study by Younossi et al. reported that the prevalence of chronic liver disease increased from 11.78 to 14.78% between 1988 and 2008 [5]. The study revealed that while viral and alcoholic etiologies remained relatively stable, the prevalence of NAFLD (defined in this case by elevated liver transaminases without any other explanation) doubled from 5.51 to 11.01%. Thus, the proportion of chronic liver disease due to NAFLD also increased from 46.8 to 75.1%, as shown in FIGURE 1. Another prospective study conducted in 2010 found that on ultrasound, the prevalence of NAFLD in adults aged 18– 70 was 46% [11]. The discrepancy between these two studies may be in the fact that imaging is a much more sensitive modality for diagnosing fatty liver disease that would otherwise be clinically silent.

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Schneier, Citti & Dieterich


Table 1. Defining conditions within the spectrum of non-alcoholic liver disease. NAFLD

Encompasses all forms of liver disease in patients without significant alcohol consumption, including simple steatosis, steatohepatitis and cirrhosis

NAFL

Evidence of hepatic steatosis without signs of hepatocellular injury such as hepatocyte ballooning or fibrosis

NASH

The presence of hepatic inflammation which may be histologically indistinguishable from alcoholic steatohepatitis with inflammation and hepatocyte injury (ballooning) ± fibrosis

deemed to be good surgical candidates. There are also studies in high-risk groups that can shed light on the prevalence of NASH. One such study looked at tissue obtained from morbidly obese patients undergoing bariatric surgery and found 35% prevalence of biopsy-proven NASH in this population [17]. Demographics

There is inconsistent data regarding gender and NAFLD. Most data have pointed to male predominance [7,15,18,19]; however, there is evidence that women make up a NAFL: Nonalcoholic fatty liver; NAFLD: Nonalcoholic fatty liver disease; NASH: Nonalcoholic steatohepatitis. larger proportion of NAFLD patients who are classified as lean [20]. NAFLD The prevalence of NAFLD in Asia appears to be as high as has been reported in all age groups, but most patients tend to in the west, that is, up to 30% [12–14]; however, it is more fre- be middle-aged [21]. quently seen in patients of lesser weight than in the west. But In the USA, there have been several studies examining the the definition of obesity in Asia has been changed to a BMI role that ethnicity plays in developing NAFLD. They have >25 instead of 30, based on anthropomorphic standards. There shown that Hispanic groups have the highest prevalence of is little data on NAFLD in South American, African and Mid- NAFLD at 21.2–58.3% [7,11–24] and also have the highest rates dle Eastern populations, but as the developing nations adopt of NASH, followed by non-Hispanic whites having an incidence western eating habits and have more access to diagnostic test- of 12.5–44.4% and African Americans having the lowest rates at ing, the documented prevalence will likely increase. 11.6–35.1% [20], as shown in FIGURE 2. As these were populationbased studies, the diagnostic criteria were based on imaging and Nonalcoholic steatohepatitis liver enzymes, and not on biopsy. There are several theories to Because NASH can only be diagnosed accurately on biopsy, explain why these differences occur, including the variation in there are few population-based studies that report the preva- traditional diet [25] and distribution of abdominal fat [18,26–28], lence of this more severe form of NAFLD. The prospective but the most likely determinants are genetic factors, such as carcohort study by Williams et al. did take biopsies of patients in rying the rs738409 G-allele of the patatin-like phospholipase a general population who had evidence of fatty liver on ultra- domain-containing protein 3 gene, or the PNPLA3 gene (also sound, and found NASH in 12.2% of the overall cohort and known as adiponutrin), which appears to modify the accumulain 29.9% of those with positive imaging [11]. Two other studies tion of hepatic triacylglycerol [29–31]. The link between NAFLD looked at biopsies from orthotopic liver donation candidates and insulin resistance has been extensively studied; however, in and found the prevalence to be 1.1–2.2% [15,16], although this terms of ethnicity, the data are inconsistent: while African Amermay be a low estimate as this population consisted of patients icans and Hispanics both have high rates of insulin resistance, African Americans actually have much lower prevalence of NAFLD [32,33], again supporting a genetic hypothesis. 16.00% Cryptogenic cirrhosis

14.00%

Cirrhosis without evidence of etiology. Many patients with ‘burnt-out’ steatohepatitis fall into this category as they no longer have signs of ballooning and inflammation

Chronic Liver disease NAFLD

Association with the metabolic syndrome

12.00% 10.00% 8.00% 6.00% 4.00% 2.00% 0.00%

1988

2008

Figure 1. Proportion of NAFLD as the etiology of chronic liver disease in the USA based on National Health and Nutrition Examination Survey data comparing 1988 and 2008 [5]. NAFLD: Nonalcoholic fatty liver disease.

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Risk factors for NAFLD include age, ethnicity, BMI, diabetes or insulin resistance, hypertension, dyslipidemia and visceral fat [4,34–37]. These risk factors are nearly identical to those of the metabolic syndrome, and many consider NAFLD to be a surrogate for the syndrome. For instance, Marchesini et al. reported that among patients with NAFLD but without diabetes, metabolic syndrome was diagnosed in 67% of NAFL patients and in 88% of patients with biopsy-proven NASH [34]. The link between NAFLD and metabolic syndrome has implications toward both mortality and treatment. Pathogenesis

The pathological processes in NAFLD can be thought of in the multi-hit hypothesis framework. A susceptible individual Expert Rev. Gastroenterol. Hepatol. 9(5), (2015)


Management & diagnosis of fatty liver disease

may be faced with environmental factors (diet, activity, gut flora) that then lead to a combination of pathologic processes. When discussing the pathogenesis of NAFLD, two processes have to be considered: the accumulation of intrahepatic fat, or steatosis, and the hepatotoxic process that leads to inflammation and fibrosis.

70

Steatosis

30

The accumulation of triglycerides in the liver causes hepatic steatosis. This can occur with increased supply of free fatty acids (FFAs) from the diet, de novo synthesis in the liver or increased delivery from the peripheral tissues. A link also exists between insulin resistance and the development of steatosis: insulin resistance in the periphery leads to lipolysis by adipose tissue, releasing FFAs to be delivered to the liver [38]. Also, insulin resistance can increase de novo synthesis of FFAs in the liver by upregulating the enzymes that catalyze lipogenesis. Normally, insulin also inhibits gluconeogenesis simultaneously [39]. With hepatic insulin resistance, there is a paradoxical effect in which the stimulatory effect of insulin on lipogenesis is retained but the inhibitory effect of insulin on glucose production in the liver is diminished and FFA accumulates, a phenomenon called selective insulin resistance [40]. Studies have shown that even without overt diabetes, NAFLD patients have decreased hepatic response to insulin [41]. Thus, in response to normal insulin signaling, these patients produce less glucose and accumulate more FFAs, and can acquire hepatic steatosis at a faster rate than their peers. In addition to increased production, decreased export of FFAs (via the transport lipid VLDL) can lead to steatosis. When synthesis of VLDL or its component protein apolipoprotein B is impaired (seen in protein deficiency), FFAs remain in the hepatocytes, leading to steatosis. There is evidence that patients with NASH may also have defects in the production of postprandial apolipoprotein B [42]. This may help explain how some lean individuals develop steatosis without increased dietary intake or insulin resistance. Inflammation & damage

There are several mechanisms that have been proposed to explain the inflammation seen in more advanced forms of NAFLD. First, FFAs can themselves cause hepatotoxic free oxygen radical species by inducing microsomal lipoxygenases, or during beta-oxidation [43,44]. Defects in mitochondria have been proposed as a cause of increased free oxygen radicals during beta-oxidation, and electron microscopy has shown mitochondrial defects in patients with NASH but not in NAFL controls [45]. Reactive oxidative species lead to cell injury, apoptosis and necrosis, and are an important driver of inflammation and fibrosis in liver disease. A second mechanism that likely leads to liver inflammation in NAFLD patients is the interplay between the gut flora and the liver. There is evidence of increased gut permeability in patients with NASH and NASH risk factors [46–48]. The theoretical mechanism suggests that endotoxin may enter the portal informahealthcare.com

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60 50 40

20 10 0 White

Black

Hispanic

Figure 2. Comparing the prevalence of NAFLD across ethnicities as documented by percentage in population-based studies [7,11,18,20,22–24]. NAFLD: Nonalcoholic fatty liver disease.

blood, and induce hepatic injury via TNF-a [49,50]. Another area of research looks at the role of adiponectin, an adipokine that blocks the release of TNF-a, thus having antiinflammatory and anti-fibrotic effects on adipose and hepatic tissue [51–54]. An inverse relationship between NASH severity and adiponectin has been demonstrated [51,55], and its suppressive role in inflammation may be a key link in the progression from steatosis to steatohepatitis. Finally, recent studies have suggested that just as the case with other complications of the metabolic syndrome, endothelial damage within the liver and vascular dysfunction precedes the inflammation and fibrosis seen in NASH [56,57]. The inflammatory process in NAFLD and other liver diseases appears to be mediated mostly by NF-kB [58], natural killer T cells [59], the hedgehog pathway [60,61] and the activation of cytokines such as TNF-a [62]. Other players, such as myeloperoxidase [63], and activation of the complement system [64] have also been identified. A full discussion of the immune response from hepatic inflammation to liver fibrosis and cirrhosis is out of the scope of this review and can be found elsewhere [65–67]. Natural history

Simple steatosis (NAFL) and NASH behave differently. While there is evidence that without intervention simple steatosis can be progressive [68], NASH appears to have a more aggressive course. One prospective hospital cohort study looked at paired biopsies taken 36 months apart [69]. Of the 13 patients with steatosis at baseline, 23% continued to have simple steatosis while 15% regained normal histology; 39% progressed to borderline NASH and 23% developed clear NASH. Of the 17 patients with baseline NASH, however, only 6% returned to simple steatosis, indicating there may be a physiological ‘point of no return’. The risk of progression to liver fibrosis and cirrhosis appears to be relatively low in those with simple steatosis, compared to 673


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those with steatohepatitis [70,71]. A systematic review of 10 studies found that of 187 patients with NAFLD on biopsy, 17% of those with no evidence of inflammation went on to develop severe fibrosis on repeat biopsy, compared to 49% of those with initial inflammation [72]. Moreover, the median of time to the development of advanced fibrosis was 13.4 years for those with initial simple steatosis, compared to 4.2 years for those with inflammation. Additional paired biopsy studies have shown that up to 53% of patients with proven NASH will show significant progression within 7 years [71,73,74]. Finally, a recent systematic review by Singh et al. was published looking at 411 patients with biopsy-proven NAFLD from 11 cohort paired-biopsy studies [75]. It found that the annual fibrosis progression rate in NASH patients was double that of patients with an initial fibrosis level of 0 (0.14 stages/year compared to 0.07). Put another way, it would take an NAFL patient 14.3 years to progress to the next stage of fibrosis, compared to 7.1 years for patients with NASH. The mutation of the PNPLA3 gene mentioned above has been shown to affect not only hepatic fat content but also the rate of progression to fibrosis. A study by Valenti et al. found that the mutated allele was not only disproportionately expressed in patients who developed NALFD but also was strongly associated with NASH (odds ratio [OR]: 1.5) and fibrosis stage >1 (OR: 1.5), independent of other known risk factors [76]. Such other risk factors for progression appear to be age, elevated liver transaminases, diabetes, BMI and visceral fat [72,77–80]. Mortality

Though simple steatosis has been shown to progress to fibrosis, the mortality remains roughly the same as in the general population [81–83]. NASH, however, has been shown to have an increased liver-related mortality rate [84,85]. One study following 132 NAFLD patients found that after 8 years of follow-up, 2% of the non-inflammatory NAFLD developed liver-related mortality, compared to 11% of the NASH cohort [81]. After 18.5 years of follow-up in the same cohort, liver-related mortality had risen to 18% for NASH and 3% for non-NASH patients [86]. Predictably, the degree of liver damage has the most effect on mortality. An international, multicenter prospective study showed that among patients with Childs–Pugh Class A disease followed over a mean period of 85.6 months, 12.3% of NASH patients required transplant or died, which, when corrected for age and gender, was statistically similar to patients with untreated Class A hepatitis C [87]. It is important to note that as the metabolic syndrome commonly affects NAFLD patients, the leading cause of death in these patients is cardiovascular disease [84,86,88]. The study by Ekstedt et al. found that mortality from cardiovascular events was double that of a matched reference population, at 15.5% compared to 7.5%, which could be explained by the shared risk factors as the metabolic syndrome [84]. There is also evidence that NAFLD is associated with an increased risk of incident cardiovascular disease even after controlling for 674

components of the metabolic syndrome and other risk factors [87,89,90]. It appears that even following liver transplantation, NASH patients remained at increased risk for cardiovascular events independent of other traditional risk factors [91]. NAFLD & hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the most common primary liver cancer and the fifth most common malignancy worldwide [92]. Cirrhosis is present in approximately 80% of patients with HCC, being the largest risk factor for the malignancy regardless of its etiology [93]. An estimated 30–40% of HCC cases are not classified under hepatitis C virus (HCV), hepatitis B virus (HBV) or heavy ethanol intake [92]. Of these, NAFLD is assumed to be a large component, though it is often missed as the steatosis and necro-inflammation of NASH ‘burn out’ or fade with the scarring of cirrhosis by the time HCC is diagnosed [35]. Because NAFLD often has an indolent course, there are few prospective studies directly examining the progression from NAFLD to HCC, as they require long periods of follow-up. Case reports of progression from NAFL to HCC exist [94], and there are numerous case reports [95–100] describing the development of HCC several years after the NASH is diagnosed. One cohort study at the higher end of reported prevalence showed that among 420 NAFLD patients followed over a mean of 7.6 years, only 2 progressed to HCC, making the prevalence 0.5% (however, this represented 10% of the 21 patients with cirrhosis) [21]. A second, larger study showed that of 817 NAFLD patients followed over 8.4 years, the incidence and prevalence of HCC was 0% [101]. The above studies included mostly patients with NAFL and few cases of biopsyproven NASH. In regards to NASH, the risk of HCC is higher. Two studies, by Ekstedt et al. and Rafiq et al. [84,86], also specifically looked at patients with documented NASH, showing the prevalence of HCC in these patients to be 0–2.8%. Another prospective study followed known cirrhotics with various etiologies including NASH (either on histology or by lack of any other etiology + 3 known risk factors) over a mean period of 6.8 years and found the annual rate of development of HCC to be 0.46%, compared to 1.5% for HBV and 3.6% for HCV [102]. As fibrosis advances, so does the risk for HCC. A fourth study, looking at NASH patients with evident cirrhosis, found that over a median follow-up of 3.2 years, 12.8% developed HCC with a yearly cumulative incidence of 2.6% (compared to 4.0% in HCV cirrhotics) [103]. Interestingly, the PNPLA3 gene may also be implicated in the risk of progression to HCC. In a recent study by Liu et al., the mutated allele was identified in 100 patients with NAFLDrelated HCC and 275 controls with histology-proven NAFLD [31]. They found that when controlled for age, gender, diabetes, BMI and cirrhosis, carriage of each copy of the mutated allele conferred an additive risk for HCC (adjusted OR: 2.26; 95% CI: 1.23–4.14; p = 0.0082), with mutation homozygotes exhibiting a fivefold increased risk over the wild type. Expert Rev. Gastroenterol. Hepatol. 9(5), (2015)


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Table 2. Secondary causes of hepatic steatosis characterized by size of cytoplasmic vacuoles. Macrovesicular steatosis

Environmental

Hereditary

.

Excessive alcohol consumption Hepatitis C Starvation Parenteral nutrition Medications (amiodarone, methotrexate, tamoxifen, corticosteroids)

.

Reye’s syndrome Medications (valproate, anti-retroviral medications)

.

. .


. .

Microvesicular steatosis

. .

. .

. .

Often the physical evidence of NAFLD disappears by the time of HCC diagnosis, and many such cases have thus fallen under the term cryptogenic cirrhosis (CC). Because of this, the most robust evidence for an association between NASH and HCC is indirect, inferred from either retrospective studies connecting HCC risk with obesity and diabetes, the two conditions most strongly associated with NASH [104–107], or by evaluating the connection between HCC and CC, then selecting a subgroup of patients with NAFLD based on patient demographics [108–111]. One retrospective cohort study showed that CC accounted for the second-most common etiology of HCC after HCV, at 29% [108]. Of these CC patients, half had a prior histologic diagnosis of NASH or clinical diagnosis of NAFLD before the diagnosis of HCC, implying NAFLD was the underlying etiology in up to 13% of the patients with HCC evaluated. A systematic review has tried to pool data to give a clear sense of the incidence of HCC in the NAFLD population [112]. It looked at 17 cohort studies, 18 case–control and crosssectional studies and 26 case series, with the inclusion criteria of patients with NAFLD, NASH and CC suspected to be NASH. It found that cohorts with NASH and defined cirrhosis had a significant but inconsistent risk, with cumulative incidence ranging from 2.4% over 7 years to 12.8% over 3 years. Cohorts defined as NAFL or NASH without cirrhosis, however, had a minimal risk for HCC, with cumulative HCC mortality 0–3% for up to 20 years of follow-up. Screening

Despite the prevalence of NAFLD being close to 30% in the US population, the role of screening is controversial. Given the usually benign course of the condition, it would not be costeffective to screen even those deemed to be at high risk, such as patients with obesity, Type 2 diabetes or metabolic syndrome. Also, how to screen is also debatable: imaging is more sensitive, but is expensive and less specific, while liver enzymes may not reveal enough cases as often transaminases can be normal. Currently, the American Association for the Study of Liver Diseases (AASLD) does not recommend screening, even in families with high rates of the disease [113]. informahealthcare.com

Wilson’s disease Congenital lipodystrophy Abetalipoproteinemia

Inborn errors of metabolism (lecithin cholesterol acyltransferase (LCAT) deficiency, cholesterol ester storage disease, Wolman disease) Acute fatty liver of pregnancy HELLP syndrome

Diagnosis

Identification of at-risk individuals has been an area of great interest in the recent past. As the presence of metabolic syndrome is highly correlated with NAFLD, it should prompt further noninvasive diagnostic evaluation in patients with abnormal liver chemistries. Laboratory abnormalities such as elevated transaminases, though frequently seen with liver disease, are insufficient to make the diagnosis for NAFLD alone. Of importance, one must exclude alternative causes of liver disease or steatosis, including alcoholic liver disease [113]. Differentiated by the size of cytoplasmic vacuoles, examples of secondary causes of steatosis can be seen in TABLE 2. Alternative etiologies of liver disease include significant alcohol use, starvation, medication use, pregnancy, autoimmune hepatitis, hemochromatosis, and infections such as hepatitis A, B or C. If the clinical scenario lends itself to alternative diagnosis, further testing can be pursued to rule out Wilson’s disease, thyroid disorders, celiac disease, a-1 antitrypsin deficiency, HELLP Syndrome and Budd–Chiari syndrome. Imaging

Most often, the diagnosis of NAFLD is made radiographically with ultrasound, computed tomography (CT) or MRI. Findings consistent with fatty infiltration of the liver, without signs and symptoms of cirrhosis, are consistent with NAFL. Ultrasonographic findings include hyperechoic texture, or brightness of the hepatic parenchyma. Although biopsy remains the gold standard for diagnosis, a meta-analysis conducted in 2011 of 49 studies reported that ultrasound has a sensitivity of 85% and a specificity of 94% for the detection of NAFLD [114]. As ultrasound is a low-cost and reliable diagnostic tool, it has become the modality of choice. An important caveat is in the morbidly obese population (BMI 35–40 kg/m2), wherein one study revealed a 95.4% prevalence confirmed by liver biopsy at the time of bariatric surgery, but the sensitivity of pre-surgical detection by ultrasound was reduced to 49.1% [115]. There have been limited studies detailing the sensitivity and specificity of CT and MRI scanning, given the need for comparative histologic examination. One study including 131 patients with 675


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Normal liver


Steatosis

NASH

Figure 3. Histologic appearance of normal liver biopsy, simple steatosis and NASH, with hepatocyte ballooning and fibrosis seen on trichrome stain. NASH: Nonalcoholic steatohepatitis.

radiographic evidence of NAFLD on non-contrast CT, contrast-enhanced CT or MRI prior to partial hepatectomy showed sensitivities of 33, 50 and 88%, respectively, and specificities of 100, 83 and 63%, respectively [116]. In recent years, newer imaging modalities have been developed for the identification and risk stratification of NAFLD, including controlled attenuation parameter (CAP) fibroscan as well as magnetic resonance (MR)-proton density fat fraction. CAP is an ultrasound-based transient elastography technique approved in April 2014 by the US FDA for screening of liver disease. CAP has been shown in a recent meta-analysis to have good sensitivity (ranging from 79 to 92%) and adequate specificity (ranging from 75 to 92%) for the detection of hepatic steatosis, and detects advanced fibrosis in patients effectively [117,118]. Given the reliance on ultrasound, it is notable that this test is limited in those with greater depth of subcutaneous tissue. Similarly, MR-proton density fat fraction, which uses MR imaging to quantify hepatic fat content, has shown promise in the detection and grading of hepatic steatosis. However, it has limited accuracy when compared to liver biopsy in the setting of concomitant fibrosis, as it is only accurate with presence of >30% steatosis [119,120]. Biopsy

Radiographic studies are all limited in that one cannot differentiate fat content in the liver due to alcoholic disease and NAFLD [121]. In patients in whom radiographic studies and laboratory testing are inconclusive, liver biopsy remains the gold standard for diagnosis. Biopsy is the only method to demonstrate the severity of NAFLD [122]. Although limited by cost, sampling error and procedure-related complications, the information from a liver biopsy may facilitate education of patients about their disease and may serve to motivate appropriate treatment and or screening protocols in the case of cirrhosis. Risk stratification scores have been developed, including the NAFLD fibrosis score (including age, BMI, hyperglycemia, platelet count, albumin and aspartate transaminase/alanine transaminase ratio), which has been validated in a 2011 meta-analysis [123]. 676

The NAFLD fibrosis score uses clinical and biochemical parameters to reliably identify patients with advanced fibrosis. It is limited, however, by the prevalence of intermediate scores which compel further testing. The enhanced liver fibrosis panel has also been studied in the above meta-analysis [124], with a sensitivity of 80% and a specificity of 90%; this test, however, requires measurement of three matrix turnover proteins (hyaluronic acid, TIMP-1 and PIIINP). Also, circulating cytokeratin-18 has been studied [117], and found to have a sensitivity of 78% and specificity of 87% for steatohepatitis. This test, however, is not commercially available and, therefore, not of practical use presently. The AASLD consensus guidelines recommend biopsy for patients who are at risk of steatohepatitis or advanced fibrosis by NAFLD fibrosis score, enhanced liver fibrosis, or transient elastography, or those in whom a competing diagnosis cannot be excluded without tissue diagnosis [116]. Histologic findings of NAFLD require observation of ballooning, macrovesicular steatosis, intra-acinar and portal inflammation, and may include fibrosis. Examples of the histologic findings of steatosis and NASH can be found in FIGURE 3. A disease grading system, the NAFLD activity score (NAS), has been designed to further characterize NAFLD particularly for clinical research [124]. Based on the histologic scores for steatosis (0–3), lobular inflammation (0–3) and hepatocyte ballooning (0–2), an unweighted sum of NAS ‡5 is consistent with NASH and those less than 3 are consistent with ‘not NASH’. Fibrosis on liver biopsies is staged separately (0–4). The composite NAS and fibrosis stage together comprise the NASH Clinical Research Network scoring system. As fibrosis progresses to cirrhosis, biopsies may lose their distinct pattern of inflammation and may be labeled as CC. Management

Given that patients with NAFLD without steatohepatitis have an excellent prognosis, the goal for those patients remains control of comorbid disease processes: obesity, hyperlipidemia and insulin resistance. Treatment of patients with NASH will be discussed further here and the treatment trials are summarized in TABLE 3. Many therapies have been tried for treatment or prevention of progression of NASH; weight loss, however, remains the only therapy with good evidence to support safety and efficacy. A randomized control trial evaluating a combination of diet, exercise and behavioral modification, with a goal of 7–10% weight loss, found an improvement in 48-week NASH histologic activity score (NAS) of at least 3 points, particularly in those who achieved the weight loss goal [125]. Therefore, weight loss achieved by diet and exercise, supervised by a medical practitioner, is recommended for patients with NASH. A reasonable goal for weight loss is between 0.5 and 1 kg/ week, as more rapid weight loss and poor nutrition have been associated with worsening fibrosis [126]. Medication

Aimed at reducing oxidative stress and hepatocellular injury, vitamin E was seen in observational studies to improve surrogate end points such as transaminase levels [127]. Randomized Expert Rev. Gastroenterol. Hepatol. 9(5), (2015)

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Weight loss

Vitamin E

Pioglitazone

Metformin

UDCA

Vitamin E and UDCA

Orlistat

Probucol

Betaine

Atorvastatin

Pentoxifylline

Resveratrol

Ethyl-eicosapentanoic acid

Omega-3 fatty acid

Promrat et al. (2010)

Sanyal et al. (2010)

Boettcher et al. (2012)

Rakoski et al. (2010)

Leuschner et al. (2010)

Pietu et al. (2012)

Zelber-Sagi et al. (2006)

Merat et al. (2003)

Abdelmalek et al. (2009)

Foster et al. (2011)

Van Wagner et al. (2011)

Chachay et al. (2014)

Sanyal et al. (2014)

Scorletti et al. (2014)

Randomized controlled trial, n = 103








Pending results

No significant difference in histologic findings

No significant difference in insulin resistance, steatosis or abdominal fat distribution. Elevations in transaminases noted in treatment group

Statistically significant improvements in AST and ALT, steatosis and cellular ballooning. No overall statistically significant improvement in histology

Significant improvement in CT correlates of steatosis using atorvastatin in combination with vitamins C and E versus placebo (34.4 vs 70.4%, p = 0.001)

No significant difference in histologic findings

Statistically improved ALT. No significant difference in histologic findings

Statistically improved ALT, serum insulin and greater degree of reversibility on ultrasound. No significant difference in histologic findings

Normalization of AST, ALT and gamma-glutamyl transferase in 80, 70 and 65% of the patients, respectively

Retrospective cohort, n = 101

[134]

Metformin failed to improve any pooled outcome: steatosis, hepatocyte ballooning or ALT

[147]

[146]

[145]

[144]

[143]

[142]

[141]

[140]

[139]

[138]

[132]

Improvement in ballooning degeneration, lobular inflammation and steatosis, when compared to placebo, combined ORs of 2.11 (95% CI: 1.33–3.36), 2.58 (95% CI: 1.68–3.97) and 3.39 (95% CI: 2.19–5.25), respectively

No significant differences in overall histology at 18 months, significant improvement in lobular inflammation (modified Brunt score p = 0.011, NAS p = 0.005)

[128]

[125]

Improvement in 48-week NAS of at least 3 points (72 vs 30%, p = 0.03) Higher rate of improved NASH by histology versus placebo (43 vs 19%, p = 0.001)

Ref.

Results


Meta-analysis of nine trials: five with thiazolidinedione, three with metformin and one with combination therapy

Meta-analysis of four randomized control trials, n = 334



Study design, n

CT: Computed tomogram; NAS: NASH histologic activity score; NASH: Nonalcoholic steatohepatitis; OR: Odds ratio; UDCA: Ursodeoxycholic acid.

Intervention

Study (year)

Table 3. Summary of treatment trials for nonalcoholic fatty liver disease.



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controlled trials of 800 international units (IU) daily conducted later showed improved histologic findings when compared with pioglitazone, particularly in patients without diabetes [128]. The AASLD consensus guidelines now recommend 800 IU daily as first-line treatment for non-diabetic patients with biopsy-proven NASH [113]. Further studies are required to understand the long-term benefits of vitamin E therapy, as well as the utility in diabetic or cirrhotic patients. Insulin-sensitizing agents are thought to improve hepatic histology and biochemical markers by improving insulin resistance and, therefore, fatty deposition within the liver [128–131]. In a meta-analysis of four randomized trials of thiazolidinediones, such as pioglitazone, versus placebo, there was improved histology marked by reduced ballooning degeneration, lobular inflammation and steatosis, with a combined OR being 2.11 (95% CI: 1.33–3.36) [132]. Given the frequency of side effects from this medication class, however, including the risk of bladder cancer [133], they have been removed from French and German markets. Recommendations for use of these medications are limited to the diabetic patients who would otherwise be candidates for this drug class [113]. Metformin has similarly been evaluated for its utility in NAFLD [134], but was found to have an insignificant effect on liver histology. Recently, the glucagon-like peptide-1 receptor agonist, exenatide, has been shown to improve hepatic steatosis in murine models through the antiinflammatory mammalian sirtuin 1 pathway, thus suggesting exenatide may have a role in the treatment of NAFLD [135]. Another agent, ursodeoxycholic acid (UDCA), has also been studied. UDCA has been found to be anti-inflammatory, cytoprotective and anti-apoptotic due to activation of glucocorticoid and other survival pathways [136]; however, a large multicenter, randomized control trial in 2004 demonstrated no improvement in laboratory or histologic parameters [137]. Studies conducted later comparing high-dose UDCA (25–28 mg/kg/day) to placebo showed no statistically significant improvement in laboratory parameters or histology at 18 months [138]. Notably, however, a single-center long-term follow-up study has shown improved laboratory parameters after 10 years of dual therapy with vitamin E and low-dose UDCA [139]. The clinical relevance of these findings is unknown as the rates of progression to fibrosis or cirrhosis were not examined. Several other drugs have been studied for treatment of NASH, including orlistat [140], probucol [141], betaine [142], atorvastatin [143], pentoxifylline [144], resveratrol [145] and ethyleicosapentanoic acid [146]. None of the drugs studied has shown a definitive and/or reproducible benefit to be recommended as a primary treatment for NASH. A randomized, double-blind, placebo-controlled trial is underway to evaluate the long-term efficacy of w-3 fatty acid on hepatic fat composition [147], and investigation continues to identify and target new mechanisms to mitigate hepatic steatosis and inflammation.

procedures (laparoscopic adjustable gastric banding), malabsorptive procedures, Roux-en-Y gastric bypass and biliointesinal diversion have been shown to improve aspects of the metabolic syndrome, such as Type 2 diabetes [148]. Histologic improvement has also been observed following bariatric surgery in obese patients with NASH. An initial study of 18 consecutive patients undergoing Roux-en-Y gastric bypass showed that with a mean excess weight loss of 60%, there was resolution of steatosis in 84%, hepatocyte ballooning in 50%, and findings of fibrosis in 75%, with a persistence of lobular inflammatory infiltrate in 81%, on 2-year interval liver biopsies [149]. A subsequent larger case series of 381 patients undergoing biliointestinal bypass, laparoscopic gastric banding or Roux-en-Y gastric bypass examined 5-year interval liver biopsies after bariatric surgery [150]. Mathurin et al. showed that fibrosis remained the same or worsened in >90% of patients after surgery, but there was sustained improvement in steatosis and ballooning. The study also showed no significant difference in the type of weight loss surgery on NAS score. In 2010, a Cochrane review concluded that there is limited evidence for bariatric surgery in the management of NAFLD due to the paucity of wellstructured, well-powered trials [151]. At this time, it is unclear whether bariatric surgery should be performed for primary treatment of NASH, or which type of bariatric surgery may confer benefit. Given the risk for worsening fibrosis, postoperative management of bariatric surgery patients should include close monitoring. Surveillance

Because survival after HCC becomes symptomatic is so low (0–10%, 5-year survival) [152], early detection is essential. Currently, there is little-to-no definitive data showing survival advantage with screening for HCC [153]. There are only two randomized controlled trials showing any survival benefit from screening, both looking exclusively at an HBV cohort in China, each with internal validity concerns [154,155]. Because of this, the AASLD has tried to explore a more pragmatic approach to screening. The goal of screening is to strike a balance between early detection, when intervention can prolong life, and the cost of screening the population in question. As a framework, it defines an effective intervention as one being able to prolong life by 100 days and a cost-effective intervention as one that costs US$50,000/year or less [156]. It has found that in patients with non-viral cirrhosis, screening becomes cost-effective when the annual incidence exceeds 1.5–2%. As reviewed above, the incidence of HCC in NASH cirrhotics is ill-defined, ranging anywhere from 2.4% over 7 years to 12.8% over 3 years [112]. Thus, while there are no definitive guidelines for NAFLD/ NASH per se, many practitioners choose to screen only once the diagnosis of cirrhosis is made. Expert opinion

Surgery

Surgical treatment of obesity has been proposed as the means to sustained weight loss in patients with NASH. Restrictive 678

There is no consensus regarding appropriate risk stratification for screening. Given the morbidity and mortality associated with cirrhosis and HCC, there is a clear role for such a tool. Expert Rev. Gastroenterol. Hepatol. 9(5), (2015)



Certainly, the prevalence of subclinical disease in patients with metabolic syndrome, those of Hispanic ethnicity, and those with a strong family history and may be even with PNPLA3 may benefit from earlier detection and optimization of modifiable risk factors. More robust prospective studies are required to predict both the natural history and the potential benefits of treatment. It is clear that liver biopsy has limited the enrollment of patients in such vital studies. With the recent development of MR-proton density fat fraction protocols, and the measurement of CAP, non-invasive diagnosis and serial examinations can be standardized for research. Such approaches will be more attractive to potential study participants, and may aid in a better understanding of this complex and common disease. Lastly, given the proven benefits of weight loss for NAFLD patients, bariatric surgery should be studied further as a potential curative strategy. It is not known whether there are sustained benefits from weight loss in patients with liver disease; however, both the increased incidence of obesity and weight loss surgery lend themselves to further study.

Review

Five-year view

With the recent development of tolerable and effective HCV treatments, and the spread of HBV vaccination, it is likely that non-viral etiologies of cirrhosis will become the norm, not the exception. As the obesity epidemic continues, there are models predicting that by 2030, in the USA, there will be 65 million more obese adults and an additional 6–8.5 million more cases of diabetes [157]. With this data in mind, it is projected that NAFLD will be the leading cause of liver transplantation by 2020 [158]. Thus, better understanding of the fateful step from NAFLD to NASH, and exploring new and effective therapeutic opportunities will be critical. Financial & competing interests disclosure

DT Dieterich has had research support and has acted as a consultant for Gilead, BMS, Merck and Abbvie. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.

Key issues .

Reviewing the pathogenesis and epidemiology of nonalcoholic fatty liver disease.

.

Understanding the transformation from nonalcoholic fatty liver to nonalcoholic steatohepatitis.

.

Interventions which may help stifle the transformation.

.

Prevention of complications such as cirrhosis and malignancy.

steatohepatitis. Clin Liver Dis 2009;13: 511-31

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