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Nonalcoholic Fatty Liver Disease

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

View larger version (8K): [in this window] [in a new window] [as a PowerPoint slide]   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.

View larger version (15K): [in this window] [in a new window] [as a PowerPoint slide]   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].

View larger version (120K): [in this window] [in a new window] [as a PowerPoint slide]   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)

View larger version (110K): [in this window] [in a new window] [as a PowerPoint slide]   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.

View larger version (104K): [in this window] [in a new window] [as a PowerPoint slide]   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.

View larger version (24K): [in this window] [in a new window] [as a PowerPoint slide]   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.

View larger version (23K): [in this window] [in a new window] [as a PowerPoint slide]   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.

View larger version (13K): [in this window] [in a new window] [as a PowerPoint slide]   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; -ATP, -ATP, and β-ATP = , , and β phosphates of adenosine triphosphate (ATP).

View larger version (11K): [in this window] [in a new window] [as a PowerPoint slide]   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.

View larger version (11K): [in this window] [in a new window] [as a PowerPoint slide]   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).

View larger version (7K): [in this window] [in a new window] [as a PowerPoint slide]   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 +1/2 transition, and two "outer" or -3/2 -1/2 and + 1/2 +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.

View larger version (54K): [in this window] [in a new window] [as a PowerPoint slide]   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.

View larger version (54K): [in this window] [in a new window] [as a PowerPoint slide]   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.

View larger version (107K): [in this window] [in a new window] [as a PowerPoint slide]   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.

View larger version (108K): [in this window] [in a new window] [as a PowerPoint slide]   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.

View larger version (111K): [in this window] [in a new window] [as a PowerPoint slide]   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.

View larger version (101K): [in this window] [in a new window] [as a PowerPoint slide]   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.

View larger version (143K): [in this window] [in a new window] [as a PowerPoint slide]   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.

View larger version (166K): [in this window] [in a new window] [as a PowerPoint slide]   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).

View larger version (153K): [in this window] [in a new window] [as a PowerPoint slide]   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).

View larger version (153K): [in this window] [in a new window] [as a PowerPoint slide]   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).

View larger version (52K): [in this window] [in a new window] [as a PowerPoint slide]   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.

View larger version (53K): [in this window] [in a new window] [as a PowerPoint slide]   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.

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