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DOI:10.2214/AJR.07.2052
AJR 2008; 190:993-1002
© American Roentgen Ray Society

Review

Nonalcoholic Fatty Liver Disease

Chandana G. Lall1, Alex M. Aisen1, Navin Bansal1 and Kumaresan Sandrasegaran1

1 All authors: Department of Radiology, Indiana University School of Medicine, 550 N University Blvd., Ste. UH 0279, Indianapolis, IN 46202.

Received February 14, 2007; accepted after revision May 22, 2007.

 
CME

This article is available for CME credit. See www.arrs.org for more information.

Address correspondence to K. Sandrasegaran (ksandras{at}iupui.edu).


Abstract
Top
 Abstract
Introduction
 Epidemiology
 Natural History of Nonalcoholic...
 Clinical Diagnosis and...
 Imaging Tests in Nonalcoholic...
 Conclusions
 References
 
OBJECTIVE. The inflammatory subtype of nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, is becoming one of the most important causes of chronic liver disease. In this article, we discuss the epidemiology, pathogenesis, and clinical and radiologic diagnosis of the subtypes of nonalcoholic fatty liver disease.

CONCLUSION. We discuss the current and evolving imaging tests in the evaluation of hepatic fatty content, inflammation, and fibrosis.

Keywords: CT • fatty liver • MRI • nonalcoholic fatty liver disease • nonalcoholic steatohepatitis • sonography


Introduction
Top
 Abstract
 Introduction
Epidemiology
 Natural History of Nonalcoholic...
 Clinical Diagnosis and...
 Imaging Tests in Nonalcoholic...
 Conclusions
 References
 
Nonalcoholic fatty liver disease is a group of disease entities that are typified by macrovesicular fatty change in the liver, unrelated to significant alcohol intake. The spectrum includes hepatic steatosis, nonalcoholic steatohepatitis, and chronic fibrosis and cirrhosis.


Epidemiology
Top
 Abstract
 Introduction
 Epidemiology
Natural History of Nonalcoholic...
 Clinical Diagnosis and...
 Imaging Tests in Nonalcoholic...
 Conclusions
 References
 
Autopsy studies suggest that approximately 20% and 3% of American adults have hepatic steatosis and nonalcoholic steatohepatitis, respectively [1]. In the United States, 7–10% of patients undergoing liver biopsy have nonalcoholic steatohepatitis [2], compared with only 1.5% of liver biopsy patients in Japan [3]. Obesity is the biggest risk factor for nonalcoholic fatty liver disease. It is estimated that 70–80% of obese individuals have hepatic steatosis and 15–30% have nonalcoholic steatohepatitis [1, 4]. In 1999, 35% of adults were overweight (as defined by a body mass index of 25–30 kg/m2) and 30% were obese (body mass index of > 30 kg/m2) [5]. Obesity shows an epidemic rise in prevalence, and it is estimated that 50% of adults will be obese by 2025 [6]. Given the prevalence of nonalcoholic steatohepatitis in obese individuals, it is probable that more than 25 million Americans will have nonalcoholic steatohepatitis in the next 20 years. As a result, nonalcoholic steatohepatitis is expected to become the most common cause of chronic liver disease, surpassing hepatitis C.


Natural History of Nonalcoholic Fatty Liver Disease
Top
 Abstract
 Introduction
 Epidemiology
 Natural History of Nonalcoholic...
Clinical Diagnosis and...
 Imaging Tests in Nonalcoholic...
 Conclusions
 References
 
The progression of hepatic steatosis to nonalcoholic steatohepatitis is thought to be low [7–9] (Fig. 1). The proportion of fat in the liver is not thought to alter the risk of developing nonalcoholic steatohepatitis. Most cases of nonalcoholic steatohepatitis present de novo. The mortality rate from liver failure in nonalcoholic steatohepatitis is low, estimated to be 2–3% [8, 9]. Biopsy studies show that progression of nonalcoholic steatohepatitis (inflammation) to fibrosis occurs in approximately 40% of patients but most of these patients do not show clinical or biochemical deterioration [10]. The reported progression of nonalcoholic steatohepatitis to cirrhosis is 3–10% [8, 11, 12]. Thus, in comparison with alcoholic steatohepatitis, nonalcoholic steatohepatitis is a relatively benign disease. The 10-year survival rate of the former has been shown to be about 15%, compared with 60% for nonalcoholic steatohepatitis [10].


Figure 1
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  		Fig. 1 —Natural history of nonalcoholic fatty liver disease. Small proportion of patients with fatty liver develop nonalcoholic steatohepatitis. Less than 10% of nonalcoholic steatohepatitis patients develop cirrhosis. Current research is aimed at detecting early stages of fibrosis that are potentially reversible. aProbable percentage of patients with hepatic steatosis progressing to nonalcoholic steatohepatitis. bDisease progression (%) of all nonalcoholic steatohepatitis patients.

 
It is not clear why some patients with hepatic steatosis progress to nonalcoholic steatohepatitis and most do not. Hepatic steatosis develops when the supply of fatty acids to the liver exceeds the requirements of triglyceride, phospholipid, and cholesterol synthesis, and mitochondrial oxidation. A "two hit" theory has been proposed [13] (Fig. 2).


Figure 2
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  		Fig. 2 —Pathogenesis of nonalcoholic steatohepatitis. Currently popular "two-hit" theory. First hit is insulin resistance, which leads to hepatic steatosis. Fatty liver is less able to cope with oxidative stress, which is second hit, leading to chronic liver inflammation. Purported factors causing liver damage include free radical formation, cytokine release, iron overload, and altered mitochondrial energy production [71].

 

Clinical Diagnosis and Management
Top
 Abstract
 Introduction
 Epidemiology
 Natural History of Nonalcoholic...
 Clinical Diagnosis and...
Imaging Tests in Nonalcoholic...
 Conclusions
 References
 
The original definition of nonalcoholic fatty liver disease required liver biopsy findings as outlined and the absence of significant alcohol intake or hepatic C seropositivity. Disagreement exists as to the threshold of alcohol intake that would be expected to cause alcoholic liver disease. Currently, nonalcoholic steatohepatitis is diagnosed if the alcohol intake is less than 20g ({approx} 2 drinks) per day.

Liver biopsy finding of macrovesicular fat (single large vacuole) in the cytoplasm of hepatocytes displacing the nucleus peripherally is the hallmark of hepatic steatosis caused by alcohol, diabetes, and obesity [14]. In contradistinction, microvesicular steatosis is characterized by multiple small fatty inclusion bodies with a predominantly central nucleus and is associated with abnormalities of mitochondrial fatty acid oxidation, such as in acute fatty liver of pregnancy and Reye's syndrome [15]. In nonalcoholic steatohepatitis, additional histologic features are seen, including Mallory's bodies, cytoplasmic balloon degeneration, perisinusoidal (zone III) fibrosis, and neutrophilic infiltrate [14] (Fig. 3). However, many atypical findings may be found, such as the presence of lymphocytic infiltration and periportal fibrosis. It is not clear if these are different clinical entities that have been grouped as nonalcoholic steatohepatitis. Note that the histologic appearance of nonalcoholic steatohepatitis is identical to that of alcoholic liver disease, and the distinction between the two conditions has traditionally been made on the basis of the amount of alcohol intake.


Figure 3
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  		Fig. 3 —Photomicrograph shows histology of nonalcoholic steatohepatitis in 62-year-old woman. Mallory's hyaline bodies (pink filamentous structures, black arrowhead) are cytoplasmic inclusions in hepatocytes consisting of abnormal keratin, hyaline, and other proteins. They are usually found in hepatocytes that are ballooned (black arrow) and are morphologic hallmarks of alcoholic and nonalcoholic steatohepatitis. Mallory's bodies are not cause but rather consequence of cellular injury. Usually hepatocytes with Mallory's bodies do not contain large fat vacuoles, although microvesicular fat may be seen. In this frame, other hepatocytes are present, containing macrovesicular fat globules (white arrow), which occupy almost all cytoplasm, displacing nucleus (white arrowhead) to periphery. (H and E, x 400) (Courtesy of Romil Saxena, Department of Pathology, Indiana Universtiy School of Medicine)

 
Increasing evidence indicates that nonalcoholic fatty liver disease is the hepatic component of a systemic metabolic syndrome that includes obesity, insulin resistance, hyperlipidemia, and hypertension. Thus, it is possible to have patients who have both nonalcoholic fatty liver disease (in view of their metabolic status) and alcoholic liver disease, or nonalcoholic fatty liver disease, and chronic liver disease due to hepatitis C [16].

The general goals of treating nonalcoholic steatohepatitis are to correct risk factors with exercise and appropriate diet and to avoid drugs such as alcohol, tamoxifen, and steroids that exacerbate liver disease. Pharmacologic therapies that have been proposed include those that increase insulin sensitivity, such as glitazones and biguanides, and antihyperlipidemic drugs, such as gemfibrozil [17]. Bariatric surgery has also been shown to reduce the severity of hepatic steatosis and nonalcoholic steatohepatitis [18, 19]. Patients with nonalcoholic steatohepatitis who progress to end-stage liver disease become candidates for liver transplantation.


Imaging Tests in Nonalcoholic Fatty Liver Disease
Top
 Abstract
 Introduction
 Epidemiology
 Natural History of Nonalcoholic...
 Clinical Diagnosis and...
 Imaging Tests in Nonalcoholic...
Conclusions
 References
 
Assessment of Hepatic Fat Content
Sonographic findings of fatty liver change include increased echogenicity of liver, blurring of vascular margins, and increased acoustic attenuation. Hyperechogenicity is due to increased acoustic interfaces resulting from intracellular accumulation of lipid vesicles. Severe fatty liver, containing more than 30% fat by weight, is detected by sonography with a sensitivity and specificity of 67–84% and 77–100%, respectively [20, 21]. Hepatic steatosis may appear heterogeneous on sonography, with some areas of liver parenchyma spared by the steatosis. Sonography is poor in detecting smaller amounts of fat in liver. In addition, the degree of fatty change in the liver can only be subjectively classified as mild or severe on sonography. In general, severe steatosis is diagnosed when the hepatic parenchymal echogenicity obscures visualization of the walls of the hepatic and portal veins.

Unenhanced CT can show fatty change by a reduced attenuation of liver density. Fatty change is suspected when the density of liver is more than 10 H below that of the spleen. When IV contrast material was used, a difference in Hounsfield density of at least 20 units between liver and spleen (liver lower than spleen), at 80–100 seconds after the start of contrast injection, was found to have sensitivity and specificity of 86–87% in diagnosing fatty liver [22]. That study used 150 mL of iothalamate meglumine (Conray 60, Mallinckrodt) injected at a rate of 2 mL/s. However, another study reported lower sensitivity and specificity values of 50–75% [23]. Differences between these studies may be due to confounding factors such as iron, copper, or fibrous tissue that alter the Hounsfield density of liver, and differences in the rate of contrast injection and the timing of the scanning. In addition, CT is not sensitive in detecting mild or moderate elevations of hepatic lipid content (5–30%) [21]. Dual-energy CT has been reported to accurately determine the fatty content of liver in animals [24], although this finding has not been reproduced in humans [25, 26].

Water and fat protons have slightly different precessional frequencies in a magnetic field. As a result, MRI has the potential for diagnosing fatty infiltration both qualitatively and quantitatively. The most commonly used quantitative method is the acquisition of the so-called in- and out-of-phase imaging, or chemical shift imaging, in which different TE parameters are used in gradient-echo images so that the signal from fat protons is added or subtracted, respectively, from the signal from protons in water. With 1.5-T magnets, the fat and water protons are in phase or out of phase when the TE is an even or odd multiple, respectively, of 2.2 milliseconds. Reduction of signal on out-of phase T1-weighted images has been shown to be an accurate predictor of hepatic fat content (Figs. 4A and 4B), with correlation (r) of 0.86–0.91 compared with the histologic assessment of liver fat [27–29]. MRI is superior to sonography in assessing liver fat [30]. Chemical shift imaging has been shown to be useful in assessing reduction in fatty liver after insulin sensitizing therapy [31].


Figure 4
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  		Fig. 4A —Chemical shift MRI detection of hepatic fat in 56-year-old man with nonalcoholic steatohepatitis. Liver appears diffusely hypointense on out-of-phase gradient-echo sequence (TR/TE, 130/2.2; flip angle, 70°) (B) compared with in-phase sequence (130/4.9; flip angle, 70°) (A), indicating presence of fat.

 

Figure 5
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  		Fig. 4B —Chemical shift MRI detection of hepatic fat in 56-year-old man with nonalcoholic steatohepatitis. Liver appears diffusely hypointense on out-of-phase gradient-echo sequence (TR/TE, 130/2.2; flip angle, 70°) (B) compared with in-phase sequence (130/4.9; flip angle, 70°) (A), indicating presence of fat.

 

With 3-T MRI, the order in which in-phase and out-of phase echoes are acquired varies depending on the scanner vendor. In our practice, TEs of 2.5 and 6.2 milliseconds, respectively, are used for in-phase and out-of-phase imaging with the Magnetom Trio (Siemens Medical Solutions). With other 3-T MRI scanners, the out-of-phase echo may be acquired first. Susceptibility artifact from hepatic iron becomes more pronounced as the TE increases. Therefore, depending on the 3-T scanner, the presence of iron may variably affect the signal intensity of fatty liver. This confounding factor is less problematic when T2-weighted fast spin-echo sequences, which contain multiple refocusing pulses, are used. A study of cirrhotic and noncirrhotic patients performed at 1.5-T MRI found that the signal drop off on T2-weighted fast spin echo without and with fat saturation better correlated with fat content determined histologically than in- and out-of-phase T1-weighted gradient-recalled images (r = 0.76 vs r = 0.25; p < 0.01 in cirrhotic patients; r = 0.92 vs r = 0.69; p < 0.01 in noncirrhotic patients) [32].

It is possible to use specialized MR pulse sequences to quantitatively assess the degree of fat in the liver with greater accuracy than is possible with CT. The original approach was based on the Dixon technique, a spin-echo method analogous to in-phase and out-of-phase imaging, in which a pair of spin-echo images is acquired. In one of these, the timing of the 180° focusing pulse is altered so that both in-phase and out-of-phase images are obtained [33, 34]. These two images can then be mathematically added and subtracted to produce lipid-only and water-only images. With suitable calibration, quantification of fat is possible. Quantitative chemical shift imaging, based on an additional dimension of Fourier transformation to achieve separation water and fat signals, can also be used to measure lipid content [35]. Many additional approaches are described in the literature, including recent descriptions of quantitative gradient-echo methods that have been used to measure the degree of hepatic steatosis [36]. Many of these techniques are easy to perform and may be used as part of routine imaging assessment of the liver [32].


Figure 6
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  		Fig. 5A —Proton (1H) hepatic MR spectroscopy. Single-voxel spectrum in 39-year-old-woman with hepatic steatosis (A) and 29-year-old asymptomatic male volunteer (B). In healthy volunteer, only resonances of water (f) and methylene (b), found in hepatic triglycerides and fatty acids, are discernible. Normal liver contains less than 5% fat by weight. In patient with hepatic steatosis, amplitude of methylene resonance (b) is much higher. Several other lipid resonances are now visible. Note chemical shifts of various resonances in 1H MR spectroscopy at 1.5 T: a, terminal methyl (CH3): 0.8 ppm; b, methylene (CH2)n: 1.2 ppm; c, CH2-C = C: 1.9 ppm; d, C = C-CH2-C = C: 2.6 ppm; e, CH2-O-COR: 4.15 ppm; f, water (H2O): 4.7 ppm; g, CH = CH and CH = O: 5.2 ppm.

 


Figure 7
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  		Fig. 5B —Proton (1H) hepatic MR spectroscopy. Single-voxel spectrum in 39-year-old-woman with hepatic steatosis (A) and 29-year-old asymptomatic male volunteer (B). In healthy volunteer, only resonances of water (f) and methylene (b), found in hepatic triglycerides and fatty acids, are discernible. Normal liver contains less than 5% fat by weight. In patient with hepatic steatosis, amplitude of methylene resonance (b) is much higher. Several other lipid resonances are now visible. Note chemical shifts of various resonances in 1H MR spectroscopy at 1.5 T: a, terminal methyl (CH3): 0.8 ppm; b, methylene (CH2)n: 1.2 ppm; c, CH2-C = C: 1.9 ppm; d, C = C-CH2-C = C: 2.6 ppm; e, CH2-O-COR: 4.15 ppm; f, water (H2O): 4.7 ppm; g, CH = CH and CH = O: 5.2 ppm.

 


Figure 8
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  		Fig. 6A —Phosphorus (31P) hepatic MR spectroscopy in healthy patient at 1.5 T. (Reprinted with permission from Cortez-Pinto H, Chatham J, Chacko VP, Arnold C, Rashid A, Diehl AM. Alterations in liver ATP homeostasis in human nonalcoholic steatohepatitis: a pilot study. JAMA 1999; 282:1659–1664 [42]. Copyright American Medical Association © 1999. All rights reserved.) There are six main resonances. PME = phosphomonoesters, Pi = inorganic phosphate, PDE = phosphodiesters; {gamma}-ATP, {alpha}-ATP, and β-ATP = {gamma}, {alpha}, and β phosphates of adenosine triphosphate (ATP).

 


Figure 9
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  		Fig. 6B —Phosphorus (31P) hepatic MR spectroscopy in healthy patient at 1.5 T. (Reprinted with permission from Cortez-Pinto H, Chatham J, Chacko VP, Arnold C, Rashid A, Diehl AM. Alterations in liver ATP homeostasis in human nonalcoholic steatohepatitis: a pilot study. JAMA 1999; 282:1659–1664 [42]. Copyright American Medical Association © 1999. All rights reserved.) 15 minutes after fructose infusion, ATP resonances are reduced in amplitude but Pi is maintained.

 


Figure 10
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  		Fig. 6C —Phosphorus (31P) hepatic MR spectroscopy in healthy patient at 1.5 T. (Reprinted with permission from Cortez-Pinto H, Chatham J, Chacko VP, Arnold C, Rashid A, Diehl AM. Alterations in liver ATP homeostasis in human nonalcoholic steatohepatitis: a pilot study. JAMA 1999; 282:1659–1664 [42]. Copyright American Medical Association © 1999. All rights reserved.) 60 minutes after infusion, ATP resonances recover. In patients with nonalcoholic steatohepatitis this recovery is impaired (not shown).

 
Proton (1H) MR spectroscopy has been found to have good correlation with hepatic lipid content (Figs. 5A and 5B), as determined by liver biopsy, with correlation (r) values of 0.91–0.98 [37–39]. This technique is considered sensitive to small variation (as little as 0.5% change) in hepatic lipid content and has a potential use in assessing therapy of steatosis [39].

Detection of Inflammation in Nonalcoholic Steatohepatitis
Sonography, CT, and MRI are insensitive in differentiating hepatic steatosis from nonalcoholic steatohepatitis [21]. A small CT study of patients with nonalcoholic fatty liver disease found that those with nonalcoholic steatohepatitis had increased liver size and increased caudate lobe-to-right lobe size ratio, compared with those with steatosis only [40]. The caudate-to-right lobe size ratio was statistically higher in steatohepatitis (mean, 0.43; range, 0.31–0.55) compared with steatosis only (mean, 0.36; range, 0.22–0.47). However, measurements showed considerable overlap in both categories, and it is unlikely that these measurements will be useful in individual patients.

In the future, MR spectroscopy may offer a role in the diagnosis of nonalcoholic steatohepatitis. MR spectroscopic studies on hydrogen, phosphorus, and sodium have been reported. The latter two chemical species show promise.

The typical phosphorus (31P) hepatic MR spectroscopy at 1.5 and 3 T shows six dominant resonances, denoting phosphomon oe sters, inorganic phosphate (Pi), phosphodiesters, and three resonances from the nucleoside triphosphates that are mainly composed of adenosine triphosphate (ATP) (Figs. 6A, 6B, and 6C). When the signal from phosphocreatine is seen, this is most likely due to the erroneous incorporation of adjacent muscle in the voxel. Several studies have investigated the utility of phosphorus (31P) MR spectroscopy in the diagnosis of acute and chronic liver damage in animal models and humans [41–44]. Most studies show that phosphorus metabolite ratios (e.g., ATP/Pi) do not differ significantly between normal and damaged or diseased liver [42, 43]. Two problems are inherent to 31P MR spectroscopy. The spatial resolution, even with a 3-T magnet, is limited to 2–3 cm; thus, this technique is suitable only for assessing diffuse liver disease. In addition, several homeo static mechanisms maintain levels of phosphate metabolites and inorganic phosphate at constant levels and limit the sensitivity of 31P MR spectroscopy to pathophysiologic changes. To overcome this problem, the recovery of cellular energy mechanisms after the depletion of ATP by an IV infusion of fructose, a form of pharmacologic hepatic stress testing, has been investigated in rat models [41]. A study of nonalcoholic steatohepatitis patients showed that, after fructose-induced depletion, recovery of hepatic ATP is severely impeded [42] (Figs. 6A, 6B, and 6C). This technique may help differentiate patients with hepatic steatosis from those with nonalcoholic steatohepatitis. It also suggests that impairment of energy homeostasis may be an integral part of the progression from fatty liver to nonalcoholic steatohepatitis.


Figure 11
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  		Fig. 7A —Sodium (23Na) MRI. Sodium (23Na) has spin quantum number (I) of 3/2 and four possible spin orientations (-3/2, -1/2, +1/2, +3/2). Three single-quantum (SQ) transitions are possible: an "inner" or -1/2 {leftrightarrow} +1/2 transition, and two "outer" or -3/2 {leftrightarrow} -1/2 and + 1/2 {leftrightarrow} +3/2 transitions. When 23Na cation is transiently bound to macromolecules, electric field gradients created allow outer transitions to relax more quickly than inner transition. In these circumstances, double-quantum (DQ) or triple-quantum (TQ) transitions become possible. Multiple-quantum transitions tend to occur in intracellular space due to high concentration of macromolecules in this compartment. Normal extracellular space is aqueous and predominantly shows SQ transitions. In disease, accumulation of collagen, as in hepatic fibrosis, enables multiple-quantum transitions to occur in extracellular space as well.

 


Figure 12
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  		Fig. 7B —Sodium (23Na) MRI. In vivo multiple-quantum transfer coherence filtered 23Na images of control (B) and carbon tetrachloride (CCl4)-treated (C) rats. Treated rats develop chemical hepatitis similar to nonalcoholic steatohepatitis and show hepatic hyperintensity (arrowhead, C) not seen in untreated rats (arrow denoting site of liver, B) in multiple-quantum transfer coherence filtering image due to increase in intracellular sodium (Nai+). Sodium-23 techniques yield MR images as well as MR spectroscopy.

 


Figure 13
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  		Fig. 7C —Sodium (23Na) MRI. In vivo multiple-quantum transfer coherence filtered 23Na images of control (B) and carbon tetrachloride (CCl4)-treated (C) rats. Treated rats develop chemical hepatitis similar to nonalcoholic steatohepatitis and show hepatic hyperintensity (arrowhead, C) not seen in untreated rats (arrow denoting site of liver, B) in multiple-quantum transfer coherence filtering image due to increase in intracellular sodium (Nai+). Sodium-23 techniques yield MR images as well as MR spectroscopy.

 
Using energy-intensive processes, hepatocytes maintain intracellular sodium concentration (Nai+) of 20 mmol/L and an extracellular concentration (Nae+) of approximately 140 mmol/L. With hepatocellular damage, Nai+ concentration increases. Unfortunately, because sodium is ionic, Nai+ and Nae+ have the same resonance and cannot be separated on routine MR spectroscopy. Several techniques have been proposed to overcome this, of which the most promising in humans is multiple-quantum transfer coherence filtering [45, 46]. Sodium (23Na) has three quantum energy levels and four possible spin orientations (Figs. 7A, 7B, and 7C). When the 23Na cation is transiently bound to macromolecules, as happens in the intracellular compartment, double or triple quantum transitions can occur. In the normal extracellular space, which is predominantly aqueous, most quantum transitions are single. In liver disease, the multiple-quantum transfer coherence filtering 23Na signal may increase stepwise from benign fatty liver to hepatitis and then to cirrhosis. Initially, the spectral signal increases due to elevated Na +i concentration from cellular damage in hepatitis (Figs. 7A, 7B, and 7C) lead to multiple quantum transitions. With the onset of cirrhosis, the multiple-quantum transfer coherence filtering Na +e signal increases because of higher extracellular collagen content. Thus, sodium spectroscopy with multiple-quantum transfer coherence filtering may allow the noninvasive prediction of the progression of nonalcoholic steatohepatitis.


Figure 14
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  		Fig. 8A —46-year-old man with nonalcoholic fatty liver disease. Progression of nonalcoholic fatty liver disease is shown in comparable axial images from CT studies in 2002 (A), 2003 (B), 2004 (C), and 2006 (D). Note progressive increase in hepatic fatty content between 2002 and 2004. In 2004, liver biopsy confirmed nonalcoholic steatohepatitis. No obvious morphologic changes are seen in liver contour during this period. In 2006, patient was diagnosed as having cirrhosis. Again, no obvious morphologic abnormality is evident other than reduction in hepatic fatty content.

 


Figure 15
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  		Fig. 8B —46-year-old man with nonalcoholic fatty liver disease. Progression of nonalcoholic fatty liver disease is shown in comparable axial images from CT studies in 2002 (A), 2003 (B), 2004 (C), and 2006 (D). Note progressive increase in hepatic fatty content between 2002 and 2004. In 2004, liver biopsy confirmed nonalcoholic steatohepatitis. No obvious morphologic changes are seen in liver contour during this period. In 2006, patient was diagnosed as having cirrhosis. Again, no obvious morphologic abnormality is evident other than reduction in hepatic fatty content.

 


Figure 16
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  		Fig. 8C —46-year-old man with nonalcoholic fatty liver disease. Progression of nonalcoholic fatty liver disease is shown in comparable axial images from CT studies in 2002 (A), 2003 (B), 2004 (C), and 2006 (D). Note progressive increase in hepatic fatty content between 2002 and 2004. In 2004, liver biopsy confirmed nonalcoholic steatohepatitis. No obvious morphologic changes are seen in liver contour during this period. In 2006, patient was diagnosed as having cirrhosis. Again, no obvious morphologic abnormality is evident other than reduction in hepatic fatty content.

 


Figure 17
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  		Fig. 8D —46-year-old man with nonalcoholic fatty liver disease. Progression of nonalcoholic fatty liver disease is shown in comparable axial images from CT studies in 2002 (A), 2003 (B), 2004 (C), and 2006 (D). Note progressive increase in hepatic fatty content between 2002 and 2004. In 2004, liver biopsy confirmed nonalcoholic steatohepatitis. No obvious morphologic changes are seen in liver contour during this period. In 2006, patient was diagnosed as having cirrhosis. Again, no obvious morphologic abnormality is evident other than reduction in hepatic fatty content.

 
Note that even if inflammation can be detected on spectroscopic or imaging tests, the findings may not be specific for nonalcoholic steatohepatitis and may be seen in hepatitis as a result of toxins or viral disease.

Demonstration of Fibrosis
Fibrosis is an end result in many types of chronic liver disease and is not specific for nonalcoholic fatty liver disease. The currently available imaging tests are neither sensitive nor specific for fibrosis resulting from nonalcoholic fatty liver disease.

Sonography is not useful for detecting the presence or extent of fibrosis [47, 48]. The fatty content of the liver may reduce with the onset of cirrhosis [8]. Doppler indexes of hepatic vasculature are also not reproducibly reliable in detecting and grading fibrosis [49]. Contrast-enhanced sonography using microbubbles has been reported to be helpful in differentiating the severity of fibrosis in patients with hepatitis C, with significantly lower hepatic vein transit times in cirrhotic patients than in those with milder fibrosis [50, 51]. This technique requires multicenter validation. Many signs of cirrhosis can be detected on CT, including altered morphology with hypertrophy of the left lobe, contour nodularity, and low-density regenerating nodules. Serial CT studies are useful in assessing changes in hepatic content in nonalcoholic steatohepatitis that occur with the onset of cirrhosis (Figs. 8A, 8B, 8C, and 8D).

Ultrasonic elastography (FibroScan, Echosens) is a noninvasive technique that measures liver stiffness. In this technique, the liver is scanned via a right intercostal approach using an instrument that consists of an ultrasonic transducer mounted on a vibrator. The vibrator emits low-amplitude sound waves at a frequency of 50 Hz and induces a shear wave that propagates through the liver. The real-time progression of the shear wave is monitored by the 3.5-MHz transducer. The velocity of the shear wave is related to tissue stiffness or elasticity and is measured in kilopascals (kPa), with higher velocities indicating increased stiffness. Studies have shown good specificity (85–91%) for detecting fibrosis in hepatitis C and alcohol-related liver disease, but with a sensitivity of 56–73% [52–55]. The test is more accurate for diagnosing severe liver fibrosis (stage F4) than lower grades of fibrosis [56]. The failure rate of the technique is about 6%, mainly due to obesity or ascites. The failure rate may be higher in nonalcoholic steatohepatitis patients who are in general more obese than those with other types of chronic liver disease. The advantages of the technique include its noninvasive nature and its ability to be conducted at bedside. Its disadvantages include its inability to detect histologic features other than fibrosis, such as inflammation and mild steatosis [54].


Figure 18
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  		Fig. 9A —Detection of fibrosis on contrast-enhanced 3D fat-suppressed T1-weighted gradient-echo MRI (TR/TE, 4.85/2.48; flip angle, 12°) in 42-year-old woman with nonalcoholic steatohepatitis and cirrhosis. Arterial phase MR image shows capsular retraction (arrowhead) and hyperenhancing band (arrow) in anterior right lobe.

 


Figure 19
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  		Fig. 9B —Detection of fibrosis on contrast-enhanced 3D fat-suppressed T1-weighted gradient-echo MRI (TR/TE, 4.85/2.48; flip angle, 12°) in 42-year-old woman with nonalcoholic steatohepatitis and cirrhosis. Hypervascular band becomes isointense on venous phase image. Appearance suggests confluent fibrosis. In 10% of cases, fibrotic bands are hypervascular. More often, regions of confluent fibrosis show enhancement on delayed images (> 2 minutes).

 
Routine MRI is more sensitive for detecting fibrosis than CT. Gadolinium chelates show delayed enhancement of fibrous septa (Figs. 9A and 9B). Superparamagnetic iron oxide particles (SPIO) accumulate in the liver parenchyma containing Kupffer cells and cause preferential T2* shortening of spared liver tissue. On spoiled gradient-echo images with long TE ({approx} 7 milliseconds), fibrotic bands are seen as hyperintense foci. SPIO is usually given as a slow infusion over 30 minutes. Delayed scanning after infusion of gadolinium chelates (3 minutes after infusion) and SPIO have been reported to improve sensitivity for detecting hepatic fibrosis [57] (Figs. 10A and 10B). Nevertheless, neither CT nor conventional MRI has been shown to have high sensitivity for early fibrosis.


Figure 20
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  		Fig. 10A —Use of combined superparamagnetic iron oxide (SPIO) and gadolinium enhancement of liver fibrosis in 46-year-old man with fibrosis score of 4 (cirrhosis). (Reprinted with permission from Aguirre DA, Behling CA, Alpert E, Hassanein TI, Sirlin CB. Liver fibrosis: noninvasive diagnosis with double contrast material-enhanced MR imaging. Radiology 2006; 239:425–437 [57]) Transverse 2D spoiled gradient-recalled echo (SPGR) MR image obtained 30 minutes after infusion of diluted ferumoxide (Feridex, Berlex) (TR/TE,220/6.6; flip angle, 70°) (A) and double-enhanced 2D SPGR MR image (140/4.76, 70°) obtained 180 seconds after further infusion of gadodiamide (Optimark, Mallinckrodt) (B) show diffuse hyperintense reticulations throughout liver parenchyma that are more visible on image obtained after both SPIO and gadolinium infusions. Note aortic ghost artifact (arrow).

 

Figure 21
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  		Fig. 10B —Use of combined superparamagnetic iron oxide (SPIO) and gadolinium enhancement of liver fibrosis in 46-year-old man with fibrosis score of 4 (cirrhosis). (Reprinted with permission from Aguirre DA, Behling CA, Alpert E, Hassanein TI, Sirlin CB. Liver fibrosis: noninvasive diagnosis with double contrast material-enhanced MR imaging. Radiology 2006; 239:425–437 [57]) Transverse 2D spoiled gradient-recalled echo (SPGR) MR image obtained 30 minutes after infusion of diluted ferumoxide (Feridex, Berlex) (TR/TE,220/6.6; flip angle, 70°) (A) and double-enhanced 2D SPGR MR image (140/4.76, 70°) obtained 180 seconds after further infusion of gadodiamide (Optimark, Mallinckrodt) (B) show diffuse hyperintense reticulations throughout liver parenchyma that are more visible on image obtained after both SPIO and gadolinium infusions. Note aortic ghost artifact (arrow).

 
Magnetization transfer contrast imaging is an MRI technique that, by implementing on-resonance or off-resonance radiofrequency pulses before the conventional imaging pulse sequence, investigates the cross-relaxation of macromolecular and free-water protons in a specific tissue [58]. Extracellular accumulation of collagen and fibrin in cirrhosis was postulated to alter magnetization transfer contrast. However, the results obtained in both animal models and human studies have been discouraging [59–61]. It is likely that magnetization transfer contrast is a complex function influenced by several pathologic processes, such as fatty infiltration, edema, and iron accumulation, and not solely affected by collagen levels.

Diffusion-weighted imaging has been used to assess hepatic fibrosis and cirrhosis. Diffusion can be studied with sensitizing gradients that are typically strong bipolar gradients (i.e., two identical gradient pulses separated by a 180° radiofrequency pulse) that impart a phase shift to protons. For static protons, the phase shift imparted by the first pulse of the gradient is reversed by the second lobe of the gradient. With protons in random motion, the reversal is incomplete and results in some signal loss. Thus, rapidly diffusing protons, especially those in aqueous extracellular space, have reduced signal on diffusion-weighted images. The accumulation of extracellular collagen, as happens with liver fibrosis, may restrict proton motion and lead to reduced diffusion. If several images are acquired at the same anatomic plane with varying gradient magnitudes and durations (different b values), the degree of diffusion may be quantified, yielding measurements called "apparent diffusion coefficients" (ADCs). There appears to be a wide variation of ADC values in normal livers, ranging from 69 to 228 x 10-5 mm2/s [62–68]. However, in all these studies, the ADC values of cirrhotic livers were significantly lower, ranging from 60 to 190 x 10-5 mm2/s. The methodology of these studies varied; it may be necessary to standardize the technique of diffusion weighting. The traditional diffusion-weighted sequence is single-shot echo-planar imaging. Newer methods such as single/multishot fast spin-echo or periodically rotated overlapping parallel lines with enhanced reconstruction (PROPELLER) fast spin echo are being tried. Breath-hold diffusion-weighted sequences are possible, particularly at 3-T MRI using parallel imaging. Details of these techniques [69, 70] are beyond the scope of this review.

MR elastography, similar to ultrasonic elastography described previously, uses a sound wave generator applied to the right lateral aspect of the patient in the magnet bore. The effect of shear waves on the liver is detected using phase-contrast sequences [71] (Figs. 11A and 11B). The technique is in its early stage of development. Standardized sound wave generators and pulse sequences have not been established [71, 72]. Potential advantages compared with sonographic elastography include the ability to scan obese patients and larger volumes of liver (hence reducing error due to geographic variability of fibrosis) and the detection of complications, such as hepatocellular cancer, in the same study using other MRI sequences.


Figure 22
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  		Fig. 11A —MR elastography. (Reprinted with permission from Rouviere O, Yin M, Dresner MA, et al. MR elastography of the liver: preliminary results. Radiology 2006; 240:440–448 [71]) 21-year-old healthy volunteer patient (transcostal approach, 20-mm orthogonal plane). Rectangle indicates position of driver. Double-headed arrows indicate vibrational motion of driver. Phase-difference image shows shear waves propagating in liver. Note short wavelength, as shown by spacing of single-headed arrows.

 

Figure 23
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  		Fig. 11B —MR elastography. (Reprinted with permission from Rouviere O, Yin M, Dresner MA, et al. MR elastography of the liver: preliminary results. Radiology 2006; 240:440–448 [71]) 60-year-old patient (transcostal approach, 20° oblique plane). Rectangle indicates position of driver. Double-headed arrows indicate vibrational motion of driver. Phase-difference image shows shear waves (single-headed arrows) in liver. Wavelength is large, as indicated by spacing of single-headed arrows. This indicates increased liver stiffness. On basis of wavelength measurements, mean liver stiffness was estimated at 19.2 kPa. Liver biopsy, performed 4 months earlier, showed cirrhosis.

 

Fibrous collagen is difficult to visualize directly with MRI because of its short T2 relaxation time. MR spectroscopy has been studied to indirectly assess fibrosis, with the goal of differentiating early liver fibrosis from cirrhosis. Both proton (1H) [73] and phosphorus (31P) [43, 74] spectroscopy have been shown to predict the grade of chronic liver disease in small studies. Further research is required to verify these preliminary findings.


Conclusions
Top
 Abstract
 Introduction
 Epidemiology
 Natural History of Nonalcoholic...
 Clinical Diagnosis and...
 Imaging Tests in Nonalcoholic...
 Conclusions
References
 
There is still much that is not known about nonalcoholic fatty liver disease. This group may encompass different diseases with different natural histories and causes. Imaging tests are useful in diagnosing the presence of severe fatty liver. MRI sequences such as T1-weighted in- and out-of-phase sequences, T2-weighted fast spin-echo without and with fat saturation, and proton spectroscopy are useful to monitor the fat content of liver after therapy for nonalcoholic fatty liver disease. Sonography and CT are inaccurate in diagnosing nonalcoholic steatohepatitis or nonalcoholic steatohepatitis-related fibrosis. MR spectroscopy has shown some value in detecting hepatitis and in predicting the severity of cirrhosis. Ultrasonic and MR elastography and diffusion-weighted MRI show early promise in determining the degree of hepatic fibrosis. However, the specificity of these tests has not been proven, and they remain research tools. At present, the diagnosis and grading of liver fibrosis or cirrhosis are best achieved by biopsy.


References
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 Abstract
 Introduction
 Epidemiology
 Natural History of Nonalcoholic...
 Clinical Diagnosis and...
 Imaging Tests in Nonalcoholic...
 Conclusions
 References
 

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