Noninvasive Assessment of Liver Disease in Patients With Nonalcoholic Fatty Liver Disease

Gastroenterology 2019;-:1–19 Noninvasive Assessment of Liver Disease in Patients With Nonalcoholic Fatty Liver Disease Q14 Laurent Castera,1 Mireen ...

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Gastroenterology 2019;-:1–19

Noninvasive Assessment of Liver Disease in Patients With Nonalcoholic Fatty Liver Disease Q14

Laurent Castera,1 Mireen Friedrich-Rust,2 and Rohit Loomba3 1

Department of Hepatology, Hôpital Beaujon, Institut National de la Santé et de la Recherche Médicale Unité Mixte de Recherche 1149, University of Paris-VII, Clichy, France; 2Department of Internal Medicine 1, Division of Gastroenterology, Hepatology, Goethe University Hospital, Frankfurt, Germany; and 3Nonalcoholic Fatty Liver Disease Research Center, Division of Gastroenterology, Department of Medicine, University of California at San Diego, La Jolla, California Nonalcoholic fatty liver disease (NAFLD) is estimated to afﬂict approximately 1 billion individuals worldwide. In a subset of NAFLD patients, who have the progressive form of NAFLD termed nonalcoholic steatohepatitis (NASH), it can progress to advanced ﬁbrosis, cirrhosis, hepatocellular carcinoma, and liver-related morbidity and mortality. NASH is typically characterized by a speciﬁc pattern on liver histology, including steatosis, lobular inﬂammation, and ballooning with or without peri-sinusoidal ﬁbrosis. Thus, key issues in NAFLD patients are the differentiation of NASH from simple steatosis and identiﬁcation of advanced hepatic ﬁbrosis. Until now, liver biopsy has been the gold standard for identifying these 2 critical end points, but has well-known limitations, including invasiveness; rare but potentially life-threatening complications; poor acceptability; sampling variability; and cost. Furthermore, due to the epidemic proportion of individuals with NAFLD worldwide, liver biopsy evaluation is impractical, and noninvasive assessment for the diagnosis of NASH and ﬁbrosis is needed. Although much of the work remains to be done in establishing cost-effective strategies for screening for NASH, advanced ﬁbrosis, and cirrhosis, in this review, we summarize the current state of the noninvasive assessment of liver disease in NAFLD, and we provide an expert synthesis of how these noninvasive tools could be utilized in clinical practice. Finally, we also list the key areas of research priorities in this area to move forward clinical practice.

Keywords: NAFLD; Steatosis; NASH; Fibrosis; Noninvasive; VCTE; CAP; MRI-PDFF; MRE; Serum Biomarkers; ARFI; SWE.

N

onalcoholic fatty liver disease (NAFLD) affects around one-fourth of the general population worldwide.1 Nonalcoholic steatohepatitis (NASH), the active form of NAFLD, characterized by histological lobular inﬂammation and hepatocyte ballooning, is associated with faster ﬁbrosis progression and affects around 1.5%–6.5% of the general population.1 NAFLD is frequently associated with metabolic comorbidities, such as obesity (51%; 95% conﬁdence interval [CI], 41%–61%), type 2 diabetes (22%; 95% CI, 18%–28%), hyperlipidemia (69%; 95% CI, 50%– 83%), hypertension (39%; 95% CI, 33%–%46), and metabolic syndrome (42%; 95% CI, 30%–56%).1 Although the most common cause of death in patients with NAFLD is

cardiovascular disease, independent of other metabolic comorbidities, NAFLD is becoming a major cause of liver disease–related morbidity (eg, cirrhosis, end-stage liver disease, hepatocellular carcinoma, and liver transplantation), as well as mortality.2,3 NAFLD is expected in the next decade to become the leading indication for liver transplantation in the United States.4 It is estimated that liver-speciﬁc mortality and overall mortality among patients with NAFLD are 0.77 and 11.77 per 1000 person-years, whereas they are 15.44 and 25.56 per 1000 person-years among patients with NASH.1 The vast majority of NAFLD patients, however, will not progress, only a minority, namely those with NASH and advanced hepatic ﬁbrosis, are at greatest risk of developing complications of chronic liver disease.5 Indeed, advanced ﬁbrosis has been shown to be the major driver for long-term outcome and mortality.6–8 Thus, key issues in patients with NAFLD are the differentiation of NASH from simple steatosis and identiﬁcation of advanced hepatic ﬁbrosis. Given the huge number of at-risk patients, there is a substantial unmet need for efﬁcient and cost-effective means for risk stratiﬁcation of NAFLD patients for these 2 critical end points. Liver biopsy, the gold standard for identifying these 2 end points until now, appears unrealistic and unsuitable. In addition, it has well-known limitations, including invasiveness, poor acceptability, sampling variability, and cost. As a result, this has fueled the development of alternative noninvasive strategies, which have been an area of intensive research over the past decade.9 This review is aimed at discussing the performance, advantages, and limitations of noninvasive methods for the management of patients with NAFLD, including diagnosis Abbreviations: ALT, alanine transaminase; APRI, Aspartate Transaminaseto-Platelet Ratio Index; ARFI, acoustic radiation force imaging; AST, aspartate transaminase; AUROC, area under the receiver operating characteristic; BMI, body mass index; CAP, controlled attenuation parameter; CI, conﬁdence interval; CK, cytokeratin; 2D-SWE, 2dimensional shear wave elastography; ELF, Enhanced Liver Fibrosis; kPa, kilopascals; LSM, liver stiffness measurement; MRI, magnetic resonance imaging; MRS, magnetic resonance spectroscopy; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis MRE, magnetic resonance elastography; NAFLD, nonalcoholic fatty liver disease; NFS, nonalcoholic fatty liver disease ﬁbrosis score; PDFF, proton density fat fraction; pSWE, point shear wave elastography; RR, relative risk; SWE, shear wave elastography; TE, transient elastography. © 2019 by the AGA Institute 0016-5085/$36.00 https://doi.org/10.1053/j.gastro.2018.12.036

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REVIEWS AND PERSPECTIVES

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REVIEWS AND PERSPECTIVES

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and quantiﬁcation of steatosis, differentation of NASH from simple steatosis, and identiﬁcation of advanced hepatic ﬁbrosis.

Currently Available Noninvasive Methods and Their Limitations Noninvasive methods rely on 2 different approaches: a “biological” approach based on the quantiﬁcation of biomarkers in serum samples or a “physical” approach based on the measurement of liver stiffness, using either ultrasound- or magnetic resonance–based elastography techniques. Although these approaches are complementary, they are based on different rationales. Liver stiffness corresponds to a genuine and intrinsic physical property of liver parenchyma, whereas serum biomarkers indicate several, not strictly liver-speciﬁc, clinical and serum parameters that have been associated with NASH or ﬁbrosis stage, as assessed by liver biopsy.

Serum Biomarkers Current serum biomarkers (summarized in Table 1) include predictive models for diagnosing or grading steatosis (such as the Fatty Liver Index) or staging ﬁbrosis (eg, NAFLD Fibrosis Score), direct measures of hepatocellular damage (eg, circulating keratin 18 fragments) to differentiate patients with NASH from those with simple steatosis and direct measures of ﬁbrosis (eg, PIIINP or Pro-C3) to discriminate patients with advanced

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ﬁbrosis. Some are speciﬁc of NAFLD (eg, BARD and NAFLD ﬁbrosis scores) whereas some have been initially designed in hepatitis C (aspartate transaminase [AST]/alanine transaminase [ALT] ratio, Aspartate Transaminase-to-Platelet Ratio Index [APRI], FIB-4). A few are proprietary formulas (FibroTest, Fibrometer, Hepascore, and Enhanced Liver Fibrosis [ELF] score) but most are nonpatented. The practical advantages of analyzing serum biomarkers include their high applicability (>95%), their good interlaboratory reproducibility, and their potential widespread availability (nonpatented). However, none are liver-speciﬁc —their results can be inﬂuenced by comorbid conditions and they require critical interpretation of results.

Imaging Techniques Elastography There are 2 different but complementary approaches for measuring liver stiffness: ultrasound-based and magnetic resonance–based elastography techniques. The ﬁrst one uses ultrasound to detect the velocity of the microdisplacements (shear waves) induced in the liver tissue, whereas the latter uses the magnetic resonance scanner. The shear wave’s velocity is then converted into a liver stiffness measurement (LSM), expressed in kilopascals (kPa) or in meters per second. Vibration-controlled transient elastography (TE) has been the pioneer ultrasound-based

Table 1.Available Serum Biomarkers for Diagnosing Steatosis or for Staging Fibrosis in Patients With Nonalcoholic Fatty Liver Disease Index (ref)

Items, n Age Sex BMI Diabetes

Steatosis FLI14 HSI15 SteatoTest13

4 3 12

LAP16 ION17

3 3/4

X

X

X X X

Platelet AST ALT AST/ALT GGT TG count level level ratio level level

X

4

Fibrosis APRI161 FIB-4162 FibroTest163

2 4 8

X X

Fibrometer NAFLD164

7

X

ELF165

3

Hepacore166

6

X

X

BARD score167 NFS168

3 6

X

X

X

X

X X

X

X

X

X X X

X

X X

X X

NAFLD-LFS18

X

X X

X

X

X X

X

X

X X

X X

X

X X

Other components — Waist circumference — A2M, ApoA1, haptoglobin, T bilirubin, cholesterol, and glucose Waist circumference Waist-to-hip ratio (male yes; female no), and HOMA Metabolic syndrome and insulin — — — A2M, ApoA1, haptoglobin, and total bilirubin glucose, ferritin and body weight Hyaluronic acid, PIIINP and TIMP-1 A2M, hyaluronic acid and total bilirubin — Albumin

A2M, a2-macroglobulin; APOA1, apolipoprotein A1; FLI, fatty liver index; GGT, g-glutamyltransferase; HSI, Hepatic Steatosis Index; ION, Index of NASH; LAP, lipid accumulation product; NAFLD-LFS, NAFLD liver fat score; NFS, NAFLD ﬁbrosis score.

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Q10

181 182 183 184 185 186 187 188 189 190 191 192 193 194 195 196 197 198 199 200 201 202 203 204 205 206 207 208 209 210 211 212 213 214 215 216 217 218 219 220 221 222 223 224 225 226 227 228 229 230 231 232 233 234 235 236 237 238 239 240

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2D-SWE

3

Q1

301 302 303 304 305 306 307 308 309 310 311 312 313 314 315 316 317 318 319 320 321 322 323 324 325 326 327 328 329 330 331 332 333 334 335 336 337 338 339 340 341 342 343 344 345 346 347 348 349 350 351 352 353 354 355 356 357 358 359 360

REVIEWS AND PERSPECTIVES

IQR/M, interquartile range/median; QIBA, Quantitative Imaging Biomarkers Alliance. a MRE is reported as shear modulus, while ultrasound elastography techniques are reported in Young modulus. The Young modulus is 3 times the shear modulus.

No þ ? limited data þ ? limited data Similar to TE? limited data 13 ? Not well-deﬁned No kPa (2–150)

m/s (0.5–4.4) No

Radiologist or ultrasonographer Radiologist or ultrasonographer pSWE/ARFI

MRE

$$

No $$

n¼8 834 n¼2 447 þ ? limited data þ ? limited data Similar to TE? limited data

Congestion iron overload þ 0–2

2

$$$ No

Yes $

n ¼ 25 3862 n¼6 676 Congestion steatosis?

Others Obesity

þþ XL-probe – þþ 3–27

Well-deﬁned IQR/M <30% Emerging QIBA consensus statement Not well-deﬁned Yes CAP Yes PDFF Hepatologist trained nurse kPa (2–75) or technician radiologist kPaa (2–11)

Conventional ultrasonography is the most commonly used imaging method for the diagnosis of hepatic steatosis because it is widely available, well established, well tolerated, and cheap. Typical ultrasonography features are hyperechogenicity as compared to the right kidney parenchyma, distal attenuation, and the presence of areas of focal sparing.24 The degree of steatosis can be subjectively scored as mild, moderate, and severe, or as reported in some studies by using ordinal ultrasonography scores.25,26 In a large meta-analysis24 (n ¼ 34 studies, 2815 patients with suspected or known liver diseases), pooled sensitivities and speciﬁcities of ultrasonography to distinguish moderate-tosevere fatty liver from the absence of steatosis, taking liver biopsy as the reference, were 85% (80%–89%) and 93% (87%–97%), respectively. However, in clinical practice,

TE

Ultrasonography

Performed by

Several steatosis scores have been proposed for the detection of steatosis, including the SteatoTest,13 Fatty Liver Index,14 Hepatic Steatosis Index,15 lipid accumulation product,16 the Index of NASH,17 and the NAFLD Liver Fat Score.18 Their diagnostic performances have been summarized in a recent review.19 Although SteatoTest, Fatty Liver Index NAFLD Liver Fat Score, lipid accumulation product, and Hepatic Steatosis Index have been validated independently,20–23 their diagnostic performances are difﬁcult to compare, as they have been designed and validated against different standards: liver biopsy, ultrasonography, or magnetic resonance spectroscopy. Nevertheless, when the Fatty Liver Index, NAFLD Liver Fat Score, and Hepatic Steatosis Index were retrospectively compared in the same cohort of 324 patients with suspected NAFLD and liver biopsy, their area under the receiver operating characteristic (AUROC) values for the diagnosis of steatosis (>5%) did not differ (0.83, 0.80, and 0.81, respectively).21 Further studies are needed, but it should be acknowledged that these scores have not gained much popularity, as they do not add much to the information provided by clinical, laboratory, and imaging studies done routinely in patients with suspected NAFLD.

Techniques

Serum Biomarkers

Confounders

Diagnosis and Grading of Steatosis

Steatosis Failure grading Quality criteria rate, % Inﬂammation

technique and is the most widely used worldwide, but newer elastography modalities like point shear wave elastography (pSWE), which includes acoustic radiation force impulse imaging (ARFI), or 2-dimensional shear wave elastography (2D-SWE), integrated in conventional ultrasound systems, are emerging.10–12 Their main characteristics, advantages, and limitations are summarized in Table 2. TE and magnetic resonance elastography (MRE) provide additional information in patients with NAFLD. The same machine can be used to determine whether steatosis is present: controlled attenuation parameter (CAP) for TE and calculation of the proton-density fat traction (PDFF) for MRE. Comprehensive technical details can be found in the Supplementary Material.

Evidence in NAFLD study Point of patients Cost care

Noninvasive Assessment of NAFLD

Units (range)

241 242 243 244 245 246 247 248 249 250 251 252 253 254 255 256 257 258 259 260 261 262 263 264 265 266 267 268 269 270 271 272 273 274 275 276 277 278 279 280 281 282 283 284 285 286 287 288 289 290 291 292 293 294 295 296 297 298 299 300

2019

Table 2.Respective Characteristics, Advantages, and Limitations of the 4 Available Elastography Techniques for Liver Fibrosis Staging

-

4

REVIEWS AND PERSPECTIVES

361 362 363 364 365 366 367 368 369 370 371 372 373 374 375 376 377 378 379 380 381 382 383 384 385 386 387 388 389 390 391 392 393 394 395 396 397 398 399 400 401 402 403 404 405 406 407 408 409 410 411 412 413 414 415 416 417 418 419 420

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mainly the presence or absence of steatosis is recorded and ultrasonography has the limitation that it can only detect steatosis with >2.5%–20% liver fat content27 and, therefore, a relevant number of patients with steatosis starting at 5% liver fat content can be missed.28 In addition, the accuracy of ultrasonography for diagnosis of liver steatosis is reduced in patients with obesity and coexistent renal disease.29,30 Recent studies obtained better results using quantitative ultrasound.28,31 Nevertheless, European guidelines for the management of NAFLD recommend using ultrasonography as ﬁrst-choice imaging in adults at risk for NAFLD.2

Controlled Attenuation Parameter

Q4 Q5 Q6

Q7

In the initial study assessing its performances in 115 patients with chronic liver diseases (15% with NAFLD only), CAP was able to accurately detect steatosis 11%, 33%, and 66% with AUROCs of 0.91, 0.95 and 0.89, respectively.32 Nevertheless, despite a good correlation with histological steatosis, overlapped results between different grades of steatosis suggest that CAP cannot differentiate adjacent grades of steatosis with good precision. A recent individual data meta-analysis33 based on 19 studies using the M-probe and having included 2735 patients (537 with NAFLD; 19.6%) has reported for steatosis 11%, 33%, and 66%, AUROCs of 0.82, 0.86, and 0.88, respectively, sensitivities of 0.69, 0.77, and 0.88 and speciﬁcities of 0.82, 0.81 and 0.78, respectively. The authors proposed optimal cutoffs of 248 dB/m (range, 237– 261 dB/m), 268 dB/m (range, 257–284 dB/m), and 280 dB/m (range, 268–294 dB/m), respectively. Interestingly, CAP values were inﬂuenced by several covariates, including NAFLD, diabetes, and body mass index (BMI). Other authors, using magnetic resonance imaging (MRI)PDFF as reference have recently suggested 288 dB/m as an optimal cutoff for detection of 5% fat in the liver.34 Table 3 summarizes the results of CAP in NAFLD patients.35–45 Several comments can be made: most studies have been conducted in small sample size (<100 patients) and heterogeneous populations with variable BMI and diabetes prevalence; this may be an explanation for the differences in proposed cutoffs. However, the cutoff associated with signiﬁcant steatosis (>33% of hepatocytes) is almost always >250 dB/m. Finally, most of these studies have been performed with the M-probe. In a recent US multicenter study, using the XL-probe, in 393 NAFLD patients, CAP had an AUROC of 0.76 for detecting steatosis >5% and a 96% positive predictive value at a cutoff of 263 dB/m.45 In contrast, the accuracy of CAP for separating steatosis 33% and 66% was suboptimal. Thus far only 2 studies36,46 compared head to head the performance of CAP with M- and XL-probes, using liver biopsy as reference, with conﬂicting results. In one study (236 Western patients with chronic liver disease with a mean BMI 24.4 ± 6.3 kg/m2), the performances and cutoff values were similar,46 whereas in another study (57 NAFLD Chinese patients with a mean BMI 30.2 ± 5.0 kg/m2), the performances were similar, but cutoff values were higher

-,

No.

-

with the XL-probe.36 Therefore, further studies are necessary before any ﬁrm conclusions can be drawn. Only 2 studies have performed a head-to head comparison of CAP with ultrasonography, taking liver biopsy as reference: 1 in 72 patients with chronic liver disease47 and the other 1 in 366 patients with chronic hepatitis B.48 Both studies showed that the performance of CAP for detecting and grading liver steatosis was higher than that of ultrasonography, however, the rate of overestimation was signiﬁcantly higher for CAP than for ultrasonography (30.5% vs 12.4%; P < .05).48 More studies are needed before any ﬁrm conclusion can be drawn. In the 3 studies39,43,44 comparing CAP and PDFF magnetic resonance spectroscopy (MRS) for grading steatosis, using liver biopsy as reference, CAP was outperformed by MRI-PDFF. In a study in 78 American patients with NAFLD,43 MRI-PDFF performed better than CAP for diagnosing all grades of steatosis (AUROC 0.99 vs 0.85, respectively; P ¼ .0091). Similarly, in a study in 127 Japanese patients with NAFLD,39 MRI-PDFF had better diagnostic accuracy than CAP, whatever the grade of steatosis. Finally, a study in 55 Dutch patients with NAFLD found similar results.44 Longitudinal studies are awaited. Recently, a study that followed up 4282 patients who had both a reliable LSM and 10 successful CAP measurements has shown that neither the presence nor the severity of hepatic steatosis predicted liver-related events, cancer, or cardiovascular events in the short term, while LSM and etiology independently predicted liver-related events.49 Subgroup analyses of viral hepatitis (hepatitis B: 37.0%; hepatitis C: 2.9%) and NAFLD patients (40.7% of the entire cohort) revealed similar results. In summary, CAP is a promising point-of-care technique for rapid and standardized steatosis quantiﬁcation, but needs to be better validated in patients with NAFLD with the XL-probe. CAP is outperformed by MRI-PDFF, but should to be compared to ultrasonography, which, despite its limitations, remains the most widely used tool for ﬁrst-line steatosis assessment.

Magnetic Resonance Imaging ProtonDensity Fat Traction Cross-Sectional Utility of Magnetic Resonance Imaging Proton-Density Fat Traction MRS has been employed in several large epidemiologic studies, and now with the development of MRI-PDFF, it has been more widely utilized in epidemiologic studies to classify presence of hepatic steatosis as well as to quantify the amount of liver fat.50–53

Longitudinal Comparison With Histology and Magnetic Resonance Spectroscopy A series of single-center studies suggested the utility of MRI-PDFF in the longitudinal assessment of changes in liver fat content with paired assessment with MRS and liver histology over a 24-week period.54–56 These studies suggested that MRI-PDFF was more sensitive than liver

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421 422 423 424 425 426 427 428 429 430 431 432 433 434 435 436 437 438 439 440 441 442 443 444 445 446 447 448 449 450 451 452 453 454 455 456 457 458 459 460 461 462 463 464 465 466 467 468 469 470 471 472 473 474 475 476 477 478 479 480

481 482 483 484 485 486 487 488 489 490 491 492 493 494 495 496 497 498 499 500 501 502 503 504 505 506 507 508 509 510 511 512 513 514 515 516 517 518 519 520 521 522 523 524 525 526 527 528 529 530 531 532 533 534 535 536 537 538 539 540 Steatosis Steatosis CAP Failure CAP cutoff, Male dB/m Se, % Sp, % Year d Design Patients, n sex, % Age, y Diabetes, % BMI, kg/m2 grading, % prevalence, % probe rate, % AUC 2012

P

57

53

45 ± 14

—

28.0 ± 5.5

Kumar41

2013

P

63

73

37a

—

25.1 ± 2.0

Chan35

2014

P

105

51

50 ± 11

52

29.4 ± 3.9

Karlas40

2014

P

50 (11 C)

50

55 ± 9

28

31.1 ± 4.2

de Ledinghen37

2016

R

261

59

56 ± 12

59

30.2 ± 5.1

Imajo39

2016

P

142 (10 C)

57

57 ± 15

50

28.1 ± 4.6

Park43

2017

P

104

43

51 ± 15

28

30.4 ± 5.2

Runge44

2017

P

55

73

52a

—

27.8a

Chan36

2017

R

57 (22 C)

49

50 ± 10

—

30.2 ± 5.0

Naveau42

2017

R

194

22

41 ± 01

18

44.0 ± 0.4

P

123

26

40 ± 01

22

44.0 ± 0.6

P

393

32

51 ± 11

43

34.4 ± 6.4

2018

33 66 33 66 5 33 66 5 33 66 >33 >66 5 >33 >66 5 >33 >66 5 >33 >66 5 >33 >66 5 >33 >66 5 >33 >66 5 >33 >66

74 46 59 11 97 64 14 100 62 24 72 32 83 58 17 91 43 15 91 47 16 98 76 26 85 59 39 81 58 37 95 57 27

M

19

M

—

M

4

M

8

M

24

M

11

M XL

— 6.7

M

0

M XL

6 2

XL

—

XL

—

M XL

5.0

0.78 0.72 0.79 0.77 0.97 0.86 0.75 0.93 0.94 0.82 0.80 0.66 0.88 0.73 0.70 0.85 0.70 0.73 0.77 0.78 0.78 0.94 0.80 0.69 0.85 0.59 0.39 0.81 0.58 0.37 0.76 0.70 0.58

245 301 258 283 263 281 283 233 268 301 310 311 236 270 302 261 305 312 260 296 334 260 266 267 308 335 341 298 303 326 285 311 306

97 76 78 71 92 97 100 93 97 82 79 87 82 78 64 72 63 64 90 92 78 91 91 100 68 65 74 78 90 83 80 77 80

67 68 73 68 94 68 53 87 81 76 71 47 91 80 74 86 69 70 60 55 76 87 87 47 69 79 74 83 69 71 77 57 40

C, controls; P, prospective; R, retrospective; Se, sensitivity; Sp, speciﬁcity. a Median.

Noninvasive Assessment of NAFLD

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Friedrich-Rust38

Siddiqui45

2019

Authors

-

Table 3.Performances of Controlled Attenuation Parameter for the Diagnosis and Grading of Steatosis in Patients With Nonalcoholic Liver Disease, Taking Liver Biopsy as Reference

5

541 542 543 544 545 546 547 548 549 550 551 552 553 554 555 556 557 558 559 560 561 562 563 564 565 566 567 568 569 570 571 572 573 574 575 576 577 578 579 580 581 582 583 584 585 586 587 588 589 590 591 592 593 594 595 596 597 598 599 600

REVIEWS AND PERSPECTIVES

6

REVIEWS AND PERSPECTIVES

601 602 603 604 605 606 607 608 609 610 611 612 613 614 615 616 617 618 619 620 621 622 623 624 625 626 627 628 629 630 631 632 633 634 635 636 637 638 639 640 641 642 643 644 645 646 647 648 649 650 651 652 653 654 655 656 657 658 659 660

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histology in assessing changes in liver fat and has may be utilized in the setting of a clinical trial.57 These data have since been conﬁrmed in multicenter studies in both adult Q8 and pediatric populations.58 These studies have shown that longitudinal change in MRI-PDFF robust correlates with longitudinal change in MRS-PDFF (with correlation coefﬁcients ranging from 0.96 to 0.99), when both the MRI and MRS measurements at each time points are meticulously colocalized.55,57

Role of Magnetic Resonance Imaging ProtonDensity Fat Traction as an End Point in EarlyPhase Nonalcoholic Steatohepatitis Trial Several early phase trials in NASH have adopted MRIPDFF as an end point to examine efﬁcacy of various drugs to assess treatment response. Le et al54 followed by the MOZART (Magnetic Resonance Imaging and Elastography in Ezetimibe Versus Placebo for the Assessment of Response to Treatment in NASH) trial proposed the need for colocalization of regions of interests before and after treatment, as the liver fat is heterogeneously distributed.54,55,57 MRI-PDFF is unable to assess liver inﬂammation, ballooning, or resolution of NASH or improvement in ﬁbrosis.59

Clinical Utility of Amount of Decline in Liver Fat As the new trial data emerged, the experts started noticing a range of liver fat improvement in various trials. Using the paired MRI-PDFF and histology data from the MOZART trial, it appeared that, at a threshold of a relative 30% reduction in MRI-PDFF, one may start to appreciate signiﬁcantly higher odds of a 2-point improvement in NAFLD Activity Score on liver histology.60 These data require further validation, which is ongoing in the multicenter setting.61 Higher liver fat content at baseline in patients without ﬁbrosis has recently been shown to be associated with signiﬁcantly higher odds of ﬁbrosis progression than those patients who have lower liver fat content.62 These emerging data suggest that liver fat content may have prognostic signiﬁcance, especially early on the ﬁbrosis progression cascade, but need to be conﬁrmed. MRIPDFF estimation methods have been successfully implemented in the clinical setting as a tool for fat quantiﬁcation. They are Food and Drug Administration–approved and commercially available on the several MRI vendors, including GE Healthcare, Siemens, and Philips, and are now more readily available on newer scanners.63

Diagnosis of Nonalcoholic Steatohepatitis Serum Biomarkers Many serum biomarkers have been investigated for the diagnosis of NASH 64 but cytokeratin (CK)-18 is by far the one that has been the most widely investigated. CK-18 fragments come from apoptosis of hepatocytes accomplished by the enzyme caspase 3 and can be measured in

-,

No.

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serum by immunoassay. The M30 enzyme-linked immunosorbent assay measures the caspase-cleaved K18 fragments and detects apoptosis, which is a hallmark of steatohepatitis, whereas the M65 enzyme-linked immunosorbent assay detects total cell death. Since the initial study by Feldstein et al,65 reporting circulating serum levels of CK-18 to be predictive of NASH in patients with NAFLD (with AUROC of 0.83 and sensitivity of 0.75 and speciﬁcity of 0.81 for a CK18 value of about 250 U/L), many studies66–75 have conﬁrmed these results, though in rather small populations. In 2 subsequent meta-analyses,76,77 CK-18 had pooled AUROC of 0.82 (range, 0.76–0.88) to predict NASH with a Q9 median sensitivity of 66%–78% and speciﬁcity of 82%– 87%. There are however, several issues with CK-18: lack of a commercially available clinical test,78 limited sensitivity at the individual level79 and considerable variability in the suggested cutoffs and their respective diagnostic accuracy among studies, which makes choosing which threshold to use very difﬁcult.64 These limitations have resulted in limited clinical utility in practice so far. To increase CK-18 sensitivity, some authors have combined it with other biological parameters, such as sFas levels,80 uric acid,81 adiponectin and resistin (NASH diagnostics),74,82 or ALT and presence of metabolic syndrome (Nice Model).83 Other predictive models, combining clinical and laboratory parameters, have been proposed for the diagnosis of NASH, including HAIR (hypertension, increased ALT, and insulin resistance),84 Palekar score (age, sex, AST, BMI, AST/ALT ratio, and hyaluronic acid),85 Gholam score (AST and diabetes mellitus),86 oxNASH (13-hydroxyl-octadecadienoic acid/linoleic acid ratio, age, BMI, and AST),87 NAFIC score (ferritin, insulin and type IV collagen 7s),88 and NashTest (Biopredictive, Paris, France), a proprietary formula including 12 variables (age, sex, height, weight, serum levels of triglycerides, cholesterol, a2-macroglobulin, apolipoprotein A1, haptoglobin, g-glutamyltransferase, aminotransferases ALT, AST, and total bilirubin).89 In a meta-analysis from the developer, in 494 obese patients with a prevalence of NASH of 17.2%, the weighted AUROC of NashTest was 0.84.20 However, most of these models rely on small and highly selected populations (morbidly obese patients)83,90– 92 and have not been externally validated.93 The diagnostic performances of these different models have been recently reviewed and are therefore not detailed in the present review.78,94 Recently, several approaches using genetic biomarkers have been proposed, including single nucleotide polymorphisms located in PNPLA3, such as the NASH Score (PNPLA3 genotype, AST, and fasting insulin)95 and the NASH ClinLipMet Score (glutamate, isoleucine, glycine, lysophosphatidylcholine 16:0, phosphoethanolamine 40:6, AST, fasting insulin, and PNPLA3 genotype),96 but also expression of noncoding RNAs, speciﬁcally microRNAs, such as miR-122.97,98 However, the information yielded has had moderate clinical utility. In summary, none of the currently available serum marker are able to differentiate NASH from simple steatosis with high sensitivity and speciﬁcity, however, their diagnostic accuracy can be improved by combining different approaches.

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2019

Noninvasive Assessment of NAFLD

Imaging Techniques Studies on the ability of elastography to discriminate between isolated steatosis and NASH are limited to TE and MRE. The performances of MRE have been investigated in 5 studies39,43,99–101 and those of TE in 4.39,43,45,102 A wide range of AUROCS (0.35–0.93) and optimal cutoffs have been reported and likely depend on the prevalence of advanced ﬁbrosis in the study population.103 In the 2 studies39,43 with head-to-head comparison, there was no difference between TE and MRE. Currently, neither modality can reliably discriminate NASH from simple steatosis, although MRbased modalities are showing promise, as discussed in the Other Magnetic Resonance–Based Methods section.

Staging of Liver Fibrosis Serum Biomarkers The diagnostic performances of serum biomarkers have already been summarized in several reviews78,94,104 and, therefore, will not be detailed here. Brieﬂy, as for nonpatented tests, a recent meta-analysis (based on 64 studies in 13,046 NAFLD patients) comparing BARD, APRI, FIB-4, and NAFLD ﬁbrosis score (NFS) for diagnosing advanced ﬁbrosis reported summary AUROCS of 0.76, 0.77, 0.84, and 0.84, respectively.105 With an APRI threshold of 1.0 and 1.5, the sensitivities and speciﬁcities for advanced ﬁbrosis were 50.0% and 84.0% and 18.3% and 96.1%, respectively. With a FIB-4 threshold of 2.67 and 3.25, the sensitivities and speciﬁcities for advanced ﬁbrosis were 26.6% and 96.5% and 31.8% and 96.0%, respectively. The summary sensitivities and speciﬁcities of BARD score (threshold of 2), and NFS (threshold of 21.455) for advanced ﬁbrosis were 0.76 and 0.61, 0.72, and 0.70, respectively. Among the 4 biomarkers, FIB-4 and NFS are the most accurate with high negative predictive values (>90%) for ruling out advanced ﬁbrosis. They could therefore be used as ﬁrst-line tools in primary health care setting to identify patients without advanced ﬁbrosis who do not need further assessment. In that respect, FIB-4 may be more attractive to general practitioners, as it is based on widely available and simple parameters (age, transaminases, and platelets) and easier to calculate than NFS. There are, however, several limitations that should be acknowledged: ﬁrst, performances of FIB-4 and NFS to rule in advanced ﬁbrosis are rather inadequate, meaning that further assessment with another test is needed in case of positive results (Figure 1). Second, it is important to keep in mind that they have been mostly validated in liver clinics, where the prevalence of advanced ﬁbrosis is much higher than in primary health care settings. Third, when using FIB-4 or NFS, a signiﬁcant proportion of patients (around 30%) fall in the intermediate-risk category106 (Figure 1) and cannot be correctly classiﬁed. This may lead to unnecessary referral of these patients to liver clinics for further assessment. Finally, new age-adjusted cutoffs have been proposed recently to improve the diagnostic performance of NFS and FIB-4 for advanced ﬁbrosis.107 As for patented tests, no independent meta-analysis is available. A recent French study108 from the developer comparing Fibrometer to other patented (FibroTest and

7

Hepascore) and nonpatented (APRI, FIB-4, BARD, and NFS) serum biomarkers in 452 NAFLD patients, showed that Fibrometer (AUROC 0.82) outperformed all of the other tests for diagnosing advanced ﬁbrosis. These results require further independent conﬁrmation. Finally, novel markers, such as the PRO-C3, a commercially available assay that detects the synthesis of type III collagen, has been recently suggested to be superior to APRI, FIB-4, and NFS to identify patients with NAFLD and advanced ﬁbrosis when combined with age, platelet, and diabetes.109 These promising results require further validation. Finally, despite slight improvement in diagnostic accuracy over nonpatented biomarkers, the limited availability of patented tests and their cost might limit their wider application. In summary, among the different serum biomarkers studied, NFS and FIB-4 have been the most extensively studied and validated in different NAFLD populations and with consistent results. These tests perform best at excluding advanced ﬁbrosis (with negative predictive values >90%) and could therefore be used as a ﬁrst-line triage to identify patients at low risk of advanced ﬁbrosis in settings where more sophisticated tests are unavailable.9

Ultrasound-Based Elastography Transient Elastography Several meta-analysis, mostly performed in viral hepatitis patients, have reported good (88%–89%) and excellent (93%–96%), accuracies of TE for diagnosing advanced ﬁbrosis and cirrhosis, respectively.11 Two meta-analysis performed in NAFLD patients have conﬁrmed these results.76,105 The meta-analysis by Kwok, based on 9 studies (8 with the M-probe) including a total of 1047 NAFLD patients, reported summary sensitivities of 85% and 92% and speciﬁcities of 82% and 92% for diagnosing advanced ﬁbrosis and cirrhosis, respectively.76 Table 4 summarizes the results of the most recent studies (since 2015),39,43,108,110–113 as prior studies have been already summarized.104 These results deserve several comments: 1) these studies have included heterogeneous populations with a rather limited number of cirrhotic patients (<20%) and wide range or BMI (27–40 kg/m2); 2) the failure or unreliable results is lower when the XL-probe is used. Also, as shown in the most recent meta-analysis based on 19 studies (4 using the XL-probe) including a total of 2495 NAFLD patients from different ethnic backgrounds, summary AUROCs of TE did not differ between M- and XL-probes for diagnosing advanced ﬁbrosis (0.87 vs 0.86) and cirrhosis (0.92 vs 0.94), respectively105; 3) apart from the type of probe used, the uneven distribution of ﬁbrosis stages between studies may likely be an explanation for the observed differences between proposed cutoffs for a given end point, known as the spectrum bias.114,115 Finally, it should be stressed that all of these studies have been conducted in tertiary referral centers, where the proportion of patients with advanced ﬁbrosis is higher that in the general population, thus making it difﬁcult to extrapolate the performance of TE if used to detect cirrhosis in large populations. Overall, these results suggest that TE could be of interest to

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781 782 783 784 785 786 787 788 789 790 791 792 793 794 795 796 797 798 799 800 801 802 803 804 805 806 807 808 809 810 811 812 813 814 815 816 817 818 819 820 821 822 823 824 825 826 827 828 829 830 831 832 833 834 835 836 837 838 839 840

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print & web 4C=FPO

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Castera et al

Figure 1. A suggested algorithm for the use of noninvasive tests for risk stratiﬁcation of patients with suspected NAFLD in clinical practice. *Suspicion of NAFLD is based on the presence of steatosis on ultrasound or abnormal liver tests (transaminases/g-glutamyltransferase) in patients with risk factors (obesity, type 2 diabetes, or metabolic syndrome). Signiﬁcant alcohol consumption and secondary causes of steatosis should be excluded. The proposed algorithm is based on expert opinion. The choice of noninvasive tools should be sequential, guided by local availability and the context of use: in primary health care setting, simple inexpensive and widely available serum biomarkers, such as FIB-4 or NFS, with high negative predictive value (88%–95%) for ruling out advanced ﬁbrosis should be used as ﬁrst-line. Patients with low risk (FIB-4 <1.3 or NAFLD Fibrosis score < –1.455; 55 to 58% of cases) do not need further assessment. They should be offered lifestyle modiﬁcations and exercise. Those with intermediate (FIB-4 ¼ 1.3 to 3.25 or NFS ¼ –1.455 to 0.672; 30% of cases) and high risk (FIB-4 >3.25 or NFS >0.672; 12%–15% of cases, positive predictive value 75%–90%) of having advanced ﬁbrosis should be addressed to a referral center for LSM, using TE, in fasting condition, using M-probe for patients with skin–liver capsule distance <25 mm otherwise with the XL-probe. Patients at low risk of having advanced ﬁbrosis (LSM <8 kPa; NPV 94%– 100%) should be considered for a repeat evaluation within 1 year. Those with intermediate (LSM ¼ 8–10 kPa) or high risk (LSM 10 kPa, PPV 47%–70%) of having advanced ﬁbrosis should be considered for liver biopsy. However, confounders for liver stiffness should be carefully excluded to minimize the risk of false positive results. **Also patented serum biomarkers (FibroTest, Fibrometer, or ELF) could be considered in patients with intermediate risk according to local availability. In case of TE failure, alternative such as SWE/ARFI, MRE (particularly when BMI >35 kg/m2) may be considered according to local availability. In any case, all patients should be offered lifestyle modiﬁcations and exercise. As recommended by recent European Association for the Study of the Liver or American Association for the Study of Liver Diseases clinical practice guidelines, vitamin E (in non-diabetics) and pioglitazone may be considered in these patients. Also patients with cirrhosis should be screened for esophageal varices and hepatocellular carcinoma. In those with a liver biopsy, follow-up during treatment of LSM, using MRE, is the most promising noninvasive approach but requires further validation. NPV, negative predictive value; PPV, positive predictive value.

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901 902 903 904 905 906 907 908 909 910 911 912 913 914 915 916 917 918 919 920 921 922 923 924 925 926 927 928 929 930 931 932 933 934 935 936 937 938 939 940 941 942 943 944 945 946 947 948 949 950 951 952 953 954 955 956 957 958 959 960

961 962 963 964 965 966 967 968 969 970 971 972 973 974 975 976 977 978 979 980 981 982 983 984 985 986 987 988 989 990 991 992 993 994 995 996 997 998 999 1000 1001 1002 1003 1004 1005 1006 1007 1008 1009 1010 1011 1012 1013 1014 1015 1016 1017 1018 1019 1020 -

2019 Table 4.Performances of Transient Elastography for the Diagnosis of Advanced Fibrosis and Cirrhosis in Adult Patients With Nonalcoholic Fatty Liver Disease, Taking Liver Biopsy as Reference

Age, y

BMI, kg/m2

P

179 142 291

45 ± 13 44 ± 12 57 ± 12

29.3 ± 4.1 27.4 ± 3.7 32.1 ± 6.0

2016

P

164

51 ± 13

32.2a

Boursier108

2016

R

452

56 ± 12

31.1 ± 5.2

NASH-CRN

Imajo39

2016

P

57 ± 15

28.1 ± 4.6

Brunt

Petta169 Park43

2017 2017

R P

324 104

54 ± 13 51 ± 15

— 30.4 ± 5.2

Kleiner NASH-CRN

Chen111

2017

P

111

48a

Petta169 Siddiqui45

2017 2018

R P

761 393

59 ± 13 51 ± 11

Year

Design

Petta112

2015

R

Cassinotto110

2016

Tapper113

142 (10 C)

40.3 29.6 ± 4.9 34.4 ± 6.4

Kleiner NASH-CRN Brunt

Brunt Kleiner NASH-CRN

End point F3-F4 F3-F4 F3-F4 F4 F3-F4 F4 F3-F4 F4 F3-F4 F4 F3-F4 F3-F4 F4 F3-F4 F4 F3-F4 F3-F4 F4

Prevalence, % 23 20 43 17 18 NA 38 13 32 8 35 20 8 20 10 31 32 9

Cutoff, kPa

AUC

Se, %

Sp, %

Failure or unreliable, %

7.9/9.6 7.9/9.6 8.2/12.5 9.5/16.1 9.9

0.86 0.85 0.86 0.87 0.93

85 68 90/57 92/65 95

81 86 61/90 62/90 77

13.0 23.0 22.0

M M M

26.8

M

8.7 — 11.4 14.0 10.1 7.3 6.9 7.6 14.6 7.9/9.6 8.6 13.1

0.83 0.87 0.88 0.92 0.86 0.80 0.69 0.87 0.92 0.86 0.83 0.93

88 — 86 100 78 78 63 84 82 90/74 80 89

63 — 84 76 78 72 66 64 92 65/81 74 86

14.1

M

11.0

M

— — 6.7 — 18.7 — — 5.0

M M XL M XL M M XL

Probe

AUC, area under the curve; C, controls; NASH-CRN, nonalcoholic steatohepatitis clinical research network; P, prospective; R, retrospective; Se, sensitivity; Sp, speciﬁcity. a Median.

Noninvasive Assessment of NAFLD

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Scoring system

Patients, n

Authors

9

1021 1022 1023 1024 1025 1026 1027 1028 1029 1030 1031 1032 1033 1034 1035 1036 1037 1038 1039 1040 1041 1042 1043 1044 1045 1046 1047 1048 1049 1050 1051 1052 1053 1054 1055 1056 1057 1058 1059 1060 1061 1062 1063 1064 1065 1066 1067 1068 1069 1070 1071 1072 1073 1074 1075 1076 1077 1078 1079 1080

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Castera et al

Gastroenterology Vol.

exclude conﬁdently advanced ﬁbrosis and cirrhosis with high negative predictive value (around 90%) in these patients.9 For instance, at a cutoff <8 kPa, TE had a 94%– 100% negative predictive value.113,116 Finally, TE is recommended in the current guidelines on management of NAFLD.2,9

Acoustic Radiation Force Imaging Meta-analyses of pSWE using ARFI imaging in patients with chronic liver disease reported diagnostic accuracies of 89%–91% for advanced ﬁbrosis and 92%–93% for cirrhosis, with cutoffs ranging from 1.55–1.61 m/s for advanced ﬁbrosis and 1.80–1.87 m/s for cirrhosis, respectively.117,118 Other pSWE systems show comparable results to ARFI. However, different cutoffs are recommended for different systems.10,119 Only a few studies have evaluated pSWE using ARFI in patients with NAFLD with diagnostic accuracies of 84%–98% for advanced ﬁbrosis.38,110,120–124 A systematic review of 7 studies having included 723 NAFLD patients, reported a summary diagnostic accuracy, sensitivity and speciﬁcity of 90%, 80% and 85%, respectively, for the detection of signiﬁcant ﬁbrosis.125 However, signiﬁcant ﬁbrosis is not the most relevant end point and no data are available to date for advanced ﬁbrosis and cirrhosis. Similarly, no data are available for the follow-up of NAFLD patients using pSWE. Therefore, pSWE is not included in the current guidelines on management of NAFLD.

Shear Wave Elastography A retrospective meta-analysis, evaluating 2D-SWE in 1340 patients with chronic liver diseases from 13 centers worldwide, reported diagnostic accuracies of 91% and 95% for advanced ﬁbrosis and cirrhosis, and optimal cutoffs of 9.2, and 13.5 kPa, respectively.126 In the subgroup of 172 NAFLD patients, diagnostic accuracies were 93% and 92% for advanced ﬁbrosis and cirrhosis, respectively, with the same optimal cutoffs as for the overall group. When 2D-SWE was compared to TE in a subgroup of 91 NAFLD patients with reliable TE-values, 2D-SWE performed signiﬁcantly better for diagnosing advanced ﬁbrosis (AUROC difference of 12%; P ¼ .003). In another study in 291 NAFLD patients, 2D-SWE had diagnostic accuracies of 89% and 88% for detecting advanced ﬁbrosis and cirrhosis, respectively.110 The cutoff values with sensitivity >90% were 8.3 kPa and 10.5 kPa for advanced ﬁbrosis and cirrhosis, respectively. Interestingly, 2D-SWE outperformed TE and ARFI only for signiﬁcant ﬁbrosis. No data are available for the follow-up of NAFLD patients using 2D-SWE. Therefore, 2D-SWE is not included in the current guidelines on management of NAFLD.

Magnetic Resonance Elastography 2D-MRE has been shown in a prospective cohort of 117 patients with biopsy-proven NAFLD to have a high diagnostic accuracy for the detection of advanced ﬁbrosis.100 The AUROCs for the detection of any ﬁbrosis, advanced ﬁbrosis, and cirrhosis were 0.84, 0.92, and 0.89,

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respectively, with an optimal cutoff for advanced ﬁbrosis of 3.64 kPa. These results have been conﬁrmed in a metaanalysis based on 9 studies and 232 NAFLD patients.127 In another recent meta-analysis based on 5 studies and 628 NAFLD patients, the pooled AUROC of 2D-MRE for advanced ﬁbrosis was 0.96.105 In a head-to-head comparison between 3D-MRE vs 2DMRE, 3D-MRE at 40 Hz was superior to 2D-MRE at 60 Hz with an AUROC for the detection for advanced ﬁbrosis of 0.98 (3D-MRE) vs 0.92 (2D-MRE).101 However, processing of 3D-MRE takes a much longer time and has yet not been applied in multicenter studies. 3D-MRE appears to be an extremely promising tool for longitudinal changes in ﬁbrosis assessment. Further studies are needed to determine its role in ﬁbrosis assessment in routine clinical practice.

Other Magnetic Resonance–Based Methods A novel method called LiverMultiScan (Perspectum Diagnostics) has been proposed recently as a noninvasive, imaging-based biomarker to measure liver fat and correlate it with liver iron content, ﬁbrosis, and inﬂammation. The 3 parameters included in the proprietary algorithm are liver fat assessment, T2*, and corrected T1 decay on advanced MRI.128 A pilot proof-of-concept study has shown promising data, and further larger validation of these parameters in patients with biopsy-proven NAFLD, and its utility in assessment of treatment response in NASH trials is being actively assessed.128 Recent novel data suggest that addition of damping ratio in addition to 2D-MRE and perhaps MRI-PDFF may help further advance the assessment of both inﬂammation and ﬁbrotic components of disease activity and severity of NAFLD.129 Further studies are needed to examine the exact utility and applicability of these approaches in assessment of NAFLD severity.

Comparison and Combination of Approaches Among clinical available modalities, MRE has the highest diagnostic accuracy in the detection of advanced ﬁbrosis in NAFLD,130 but the evidence is based on a limited number of selected patients (n < 700) in highly specialized tertiary centers. In a head-to-head comparison with 7 serum ﬁbrosis markers, including FIB-4, in 102 patients with NAFLD, 2DMRE performed better than all serum markers for the detection of advanced ﬁbrosis.131 When compared head to head with serum markers (FIB-4, NFS, APRI, BARD, Fibrometer, and FibroTest) in large cohorts of NAFLD patients (n ¼ 452 and n ¼ 761), TE outperformed all other serum markers,116 apart from Fibrometer.108 Some authors have proposed strategies combining TE with FIB-4 or NFS, either in a paired or in a serial fashion.112,116 Such serial strategy, however, increased the diagnostic performance with an accuracy around 70%, but at the price of an uncertainty area (around 20%) and a 10% rate of misclassiﬁed patients.116 MRE and TE have been compared head to head in patients with biopsy-proven NAFLD in 3 studies39,43,111 with conﬂicting results. Chen et al111 have shown in 111

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1141 1142 1143 1144 1145 1146 1147 1148 1149 1150 1151 1152 1153 1154 1155 1156 1157 1158 1159 1160 1161 1162 1163 1164 1165 1166 1167 1168 1169 1170 1171 1172 1173 1174 1175 1176 1177 1178 1179 1180 1181 1182 1183 1184 1185 1186 1187 1188 1189 1190 1191 1192 1193 1194 1195 1196 1197 1198 1199 1200

1201 1202 1203 1204 1205 1206 1207 1208 1209 1210 1211 1212 1213 1214 1215 1216 1217 1218 1219 1220 1221 1222 1223 1224 1225 1226 1227 1228 1229 1230 1231 1232 1233 1234 1235 1236 1237 1238 1239 1240 1241 1242 1243 1244 1245 1246 1247 1248 1249 1250 1251 1252 1253 1254 1255 1256 1257 1258 1259 1260

2019

Noninvasive Assessment of NAFLD

Table 5.Research Priorities and Unmet Needs in the Field Cut point for each modality with the context of use needs to be determined (eg, screening in primary care or screening in a diabetes clinic) Validation of quality criteria for each modality Cost-effectiveness of sequential use of clinical prediction rules (eg, FIB-4) followed by TE/SWE/ARFI followed by MRE Clinically meaningful increase/decrease in liver stiffness that is linked to a clinical outcome in NAFLD Clinically meaningful increase in liver stiffness that is associated with a 1-stage increase in liver ﬁbrosis Clinically meaningful decrease in liver stiffness that is associated with a 1-stage decrease in liver ﬁbrosis Cut point for liver stiffness for each modality that is associated with a need to treat varices in patients with NAFLD Clinically meaningful decrease in liver stiffness that is linked to a clinical outcome in NAFLD Does reduction in liver stiffness in cirrhosis is associated with reduction in the risk of liver decompensation despite no change in ﬁbrosis stage

patients with morbid obesity (mean BMI, 40.3 kg/m2) that MRE performed better than TE for detecting advanced ﬁbrosis in intention to diagnose, but not in per-protocol, analysis. In 2 other studies, 1 in 142 Japanese patients (mean BMI, 28.1 kg/m2), using only the M-probe39 and 1 in 104 American patients (mean BMI, 30.4 kg/m2), using both M and XL-probes,43 there was no statistical difference between MRE and TE for the detection of advanced ﬁbrosis. Differences in the studied populations might account for this discrepancy. Recent data suggest that, when staging ﬁbrosis taking liver biopsy as reference, BMI is signiﬁcantly associated with discordance of ﬁndings between MRE and TE, the degree of discordancy increasing with BMI.132 Finally, a recent individual patient meta-analysis (based on 230 patients) found that MRE had a statistically signiﬁcantly higher diagnostic accuracy than vibration-controlled TE in assessing each stage of ﬁbrosis in patients with biopsy-proven NAFLD.133 Therefore, further studies are needed before any ﬁrm conclusion can be drawn. As for comparison with pSWE using ARFI, 2D-MRE has been shown to be superior to pSWE for the detection of any ﬁbrosis, but not for advanced ﬁbrosis.120 In addition, pSWE underperformed in the setting of obesity and higher liver fat content. In summary, all of these modalities have a role in clinical practice and understanding the caveats associated with their utility (summarized in Table 2) are helpful in optimal clinical use of these tools.

Use in Clinical Practice In patients with suspected NAFLD (presence of steatosis on ultrasound or abnormal liver tests (transaminases/gglutamyltransferase in patients with risk factors such as obesity, type 2 diabetes, or metabolic syndrome), noninvasive tests can be used in clinical practice for risk stratiﬁcation. Whatever the approach, serum biomarkers or elastography, each modality is most reliable in excluding the

11

presence of advanced ﬁbrosis. As shown in Figure 1, the choice of noninvasive tools to be used should be guided by local availability and context of use. In primary health care setting, simple inexpensive and widely available serum biomarkers, such as FIB-4 or NAFLD ﬁbrosis scores, with high negative predictive value (>90%) for ruling out advanced ﬁbrosis should be used as ﬁrst-line. Patients with low risk (FIB-4 <1.3 or NAFLD Fibrosis score < –1.455; 55% to 58% of cases) of having advanced ﬁbrosis do not need further assessment. They should be offered lifestyle modiﬁcations and exercise. Those with intermediate (FIB4 ¼ 1.3 to 3.25 or NFS ¼ –1.455 to 0.672; 30% of cases) and high risk (FIB-4 >3.25 or NFS >0.672; 12% to 15% of cases, positive predictive value 75% to 90%) should be sent to a referral center for further assessment. Patented serum biomarkers (FibroTest, Fibrometer, or ELF) could be considered in patients with intermediate risk according to local availability. Otherwise TE, as the most widely available and best evaluated point-of-care technique, appears to be the tool of choice, although ARFI and SWE are becoming increasingly available. XL-probe should be used in patients with skin–liver capsule distance >25 mm in order to minimize the TE failure rate (<7%). Patients at low risk of having advanced ﬁbrosis (LSM <8 kPa; negative predictive value 94%–100%) should be offered lifestyle modiﬁcations and reevaluation after 1 year. For those with intermediate (LSM ¼ 8–10 kPa) or high risk (LSM 10 kPa, positive predictive value 47%–70%) of having advanced ﬁbrosis should be considered for liver biopsy. However, confounders should be carefully excluded to minimize the risk of false positive. In case of TE failure despite the use of XLprobe or high BMI (35 kg/m2), alternative techniques such as MRE or SWE/ARFI may be considered according to local availability. However, although SWE and ARFI seem to be as promising as TE, data are currently limited for these modalities regarding the determination of advanced ﬁbrosis in NAFLD. As for MRE, despite its high accuracy, cost and limited availability are limitations to its use in practice. Its role as a surrogate of ﬁbrosis improvement in therapeutic trials remains to be demonstrated. In any case, these patients should be offered lifestyle modiﬁcations and exercise and vitamin E (in nondiabetics) and pioglitazone may be considered, as recommended by recent European Association for the Study of the Liver or American Association for the Study of Liver Diseases clinical practice guidelines.2,3 Finally, patients identiﬁed as having advanced ﬁbrosis or cirrhosis should be screened for portal hypertension and liver cancer, given the increased risk of this disease in these individuals.

Special Populations and Controversies Patients with type 2 diabetes mellitus are known to be at increased risk for NAFLD and advanced ﬁbrosis. Noninvasive screening strategies for NAFLD, NASH, or advanced ﬁbrosis have been proposed in diabetic patients, including the use of routinely available clinical variables,134 TE,135,136 MRE,52 or combination of TE and ELF.137 It is noteworthy

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that most studies on noninvasive tests in NAFLD patients have not been stratiﬁed for the presence of diabetes. Several recent studies suggested that noninvasive tests, which were developed and validated in nondiabetic cohorts, underperformed when applied to diabetic patients.138–140 Thus, caution is requested when extrapolating results of noninvasive tests from nondiabetic populations to patients with diabetes. Also the role of ethnicity may be important to take into account,141,142 as most available studies have been done in Caucasians. Further studies are needed to address these issues.

Prognosis Several recent studies have shown the ability of liver stiffness, measured using TE,108 or serum biomarkers108,143,144 to predict clinical decompensation as well as survival in patients with NAFLD. A meta-analysis145 based on 17 studies in 7058 patients with chronic liver diseases (mainly related to viral hepatitis) has shown that baseline liver stiffness, measured using TE, was associated signiﬁcantly with risk of hepatic decompensation (6 studies; relative risk [RR], 1.07; 95% CI, 1.03–1.11), hepatocellular carcinoma (9 studies; RR, 1.11; 95% CI, 1.05–1.18), death (5 studies; RR, 1.22; 95% CI, 1.05–1.43), or a composite of these outcomes (7 studies; RR, 1.32; 95% CI, 1.16–1.51). In a nationwide study (National Health and Nutrition Examination Survey cohort)144 in 11,154 participants (34% with NAFLD) with a median follow-up of 14.5 years, those with a high probability of advanced ﬁbrosis using APRI (>1.5), NFS (>0.676), or FIB-4 (>2.67), had a 69% increase in mortality compared to subjects without ﬁbrosis (for NFS: hazard ratio, 1.69; 95% CI, 1.09–2.63; for APRI: hazard ratio, 1.85; 95% CI, 1.02>3.37; for FIB-4: hazard ratio, 1.66; 95% CI, 0.98>2.82) after adjustment for other known predictors of mortality.

Future Directions There is a wealth of data that are informing clinicians regarding the utility and limitations of each of the diagnostic modalities in the assessment of NAFLD. However, further advances are needed to reﬁne clinical management and more accurate identiﬁcation of patients at risk for ﬁbrosis progression and those who need to be treated in the setting of a clinical trial without subjecting them to a liver biopsy evaluation. The key research priorities in the ﬁeld are listed in Table 5. Addressing these gaps in knowledge would greatly impact the ﬁeld. Recently, efforts concentrating on “omics” approaches (lipidomics, proteomics, and metabolomics) using highthroughput technologies have shown promising results to identify novel biomarkers of NAFLD, NASH, and advanced ﬁbrosis.146 For instance, several studies based on lipidomics approaches have shown circulating oxidized fatty acids and products of arachidonic acid metabolism to be predictive of NASH.147–149 Similarly, proteomics have been used to identify NAFLD patients with active ﬁbrosis, by measuring extracellular matrix remodeling rates in tissue and blood.150

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Using a metabolomic approach,151 subtypes of NAFLD with speciﬁc serum metabolomic proﬁles that differentiate steatosis from NASH in each subtype could be identiﬁed and might be used to monitor disease progression and identify therapeutic targets for patients. Finally, omics technologies have been used for the proﬁling of gut microbiota and identiﬁcation of fecal-microbiome–derived metagenomic signatures associated with NASH and ﬁbrosis in several human studies.152,153 It should be stressed, however, that these ﬁndings rely on small cross-sectional studies with a lack of external validation. In addition, the complicated methodology involved in omics platforms as well as reproducibility between centers and stability of samples and high cost prevent far widespread application in clinical practice. Finally, given the high prevalence of NAFLD in the general population, noninvasive tests could be used as screening tools to identify patients with NAFLD at high risk of progression.154 Recently, several studies have screened systematically for liver ﬁbrosis, using either serum biomarkers155 or TE,156–158 the general population or at-risk populations,159 or diabetics or those with a family history of NAFLD cirrhosis.51,135 Their results suggest an alarmingly high prevalence of chronic liver diseases, mainly related to NAFLD, ranging between 5% and 8% in the general adult population and between 18% and 27% among individuals with risk factors.160 Thus, screening programs for liver ﬁbrosis in the general population, using TE for identifying patients with presymptomatic chronic liver diseases susceptible to interventions should be further assessed.

Conclusions Signiﬁcant progress has been made regarding the noninvasive assessment of liver disease in patients with NAFLD. Use of noninvasive tests should be tailored according to the setting (primary heath care, tertiary referral center, trial) and clinical needs (screening, staging of ﬁbrosis, follow-up). Regarding detection and grading of steatosis, MRI-PDFF is the most accurate method but appears better suited for assessment and follow-up of selected patients in clinical trials, whereas conventional ultrasound, and if no steatosis is shown, CAP, as a point of care technique, could be used as triage in large unselected populations. Regarding NASH, no highly sensitive and speciﬁc blood tests are available to differentiate NASH from simple steatosis. Neither imaging modality can reliably discriminate NASH from simple steatosis, although MR-based modalities are showing promise. As for the identiﬁcation of advanced ﬁbrosis, MRE, TE, as well as FIB-4 and NFS are the most accurate and validated methods. FIB-4 and NFS are best suited as ﬁrst-line tools in primary health care setting to conﬁdently exclude advanced ﬁbrosis, whereas TE and MRE are more suited for referral centers to select the patients who require a liver biopsy. Finally, there is increasing evidence that serum markers and liver stiffness, measured using TE, accurately identify the subgroup of patients with NAFLD at a higher risk to reach the outcome of liver-related complications and death/liver transplantation.

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Supplementary Material Note: To access the supplementary material accompanying this article, visit the online version of Gastroenterology at www.gastrojournal.org, and at https://doi.org/10.1053/ j.gastro.2018.12.036.

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steatosis in patients with nonalcoholic fatty liver disease. Liver Int 2006;26:151–156. 86. Gholam PM, Flancbaum L, Machan JT, et al. Nonalcoholic fatty liver disease in severely obese subjects. Am J Gastroenterol 2007;102:399–408. 87. Feldstein AE, Lopez R, Tamimi TA, et al. Mass spectrometric proﬁling of oxidized lipid products in human nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. J Lipid Res 2010;51:3046–3054. 88. Sumida Y, Yoneda M, Hyogo H, et al. A simple clinical scoring system using ferritin, fasting insulin, and type IV collagen 7S for predicting steatohepatitis in nonalcoholic fatty liver disease. J Gastroenterol 2011; 46:257–268. 89. Poynard T, Ratziu V, Charlotte F, et al. Diagnostic value of biochemical markers (NashTest) for the prediction of non alcoholo steato hepatitis in patients with non-alcoholic fatty liver disease. BMC Gastroenterol 2006;6:34. 90. Campos GM, Bambha K, Vittinghoff E, et al. A clinical scoring system for predicting nonalcoholic steatohepatitis in morbidly obese patients. Hepatology 2008; 47:1916–1923. 91. Ulitsky A, Ananthakrishnan AN, Komorowski R, et al. A noninvasive clinical scoring model predicts risk of nonalcoholic steatohepatitis in morbidly obese patients. Obes Surg 2010;20:685–691. 92. Lassailly G, Caiazzo R, Hollebecque A, et al. Validation of noninvasive biomarkers (FibroTest, SteatoTest, and NashTest) for prediction of liver injury in patients with morbid obesity. Eur J Gastroenterol Hepatol 2011; 23:499–506. 93. Machado MV, Cortez-Pinto H. Non-invasive diagnosis of non-alcoholic fatty liver disease. A critical appraisal. J Hepatol 2013;58:1007–1019. 94. Vilar-Gomez E, Chalasani N. Non-invasive assessment of non-alcoholic fatty liver disease: clinical prediction rules and blood-based biomarkers. J Hepatol 2018; 68:305–315. 95. Hyysalo J, Mannisto VT, Zhou Y, et al. A populationbased study on the prevalence of NASH using scores validated against liver histology. J Hepatol 2014; 60:839–846. 96. Zhou Y, Oresic M, Leivonen M, et al. Noninvasive detection of nonalcoholic steatohepatitis using clinical markers and circulating levels of lipids and metabolites. Clin Gastroenterol Hepatol 2016;14:1463–1472 e6. 97. Becker PP, Rau M, Schmitt J, et al. Performance of Serum microRNAs -122, -192 and -21 as biomarkers in patients with non-alcoholic steatohepatitis. PLoS One 2015;10:e0142661. 98. Pirola CJ, Fernandez Gianotti T, Castano GO, et al. Circulating microRNA signature in non-alcoholic fatty liver disease: from serum non-coding RNAs to liver histology and disease pathogenesis. Gut 2015;64:800–812. 99. Chen J, Talwalkar JA, Yin M, et al. Early detection of nonalcoholic steatohepatitis in patients with nonalcoholic fatty liver disease by using MR elastography. Radiology 2011;259:749–756. 100. Loomba R, Wolfson T, Ang B, et al. Magnetic resonance elastography predicts advanced ﬁbrosis in patients with

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nonalcoholic fatty liver disease: a prospective study. Hepatology 2014;60:1920–1928. 101. Loomba R, Cui J, Wolfson T, et al. Novel 3D magnetic resonance elastography for the noninvasive diagnosis of advanced ﬁbrosis in NAFLD: a prospective study. Am J Gastroenterol 2016;111:986–894. 102. Lee CM, Jeong WK, Lim S, et al. Diagnosis of clinically signiﬁcant portal hypertension in patients with cirrhosis: splenic arterial resistive index versus liver stiffness measurement. Ultrasound Med Biol 2016; 42:1312–1320. 103. Ajmera V, Loomba R. Can elastography differentiate isolated fatty liver from nonalcoholic steatohepatitis? Semin Liver Dis 2018;38:14–20. 104. Castera L. Noninvasive evaluation of nonalcoholic fatty liver disease. Semin Liver Dis 2015;35:291–303. 105. Xiao G, Zhu S, Xiao X, et al. Comparison of laboratory tests, ultrasound, or magnetic resonance elastography to detect ﬁbrosis in patients with nonalcoholic fatty liver disease: a meta-analysis. Hepatology 2017; 66:1486–1501. 106. Alexander M, Loomis AK, Fairburn-Beech J, et al. Realworld data reveal a diagnostic gap in non-alcoholic fatty liver disease. BMC Med 2018;16:130. 107. McPherson S, Hardy T, Dufour JF, et al. Age as a confounding factor for the accurate non-invasive diagnosis of advanced NAFLD ﬁbrosis. Am J Gastroenterol 2017; 112:740–751. 108. Boursier J, Vergniol J, Guillet A, et al. Diagnostic accuracy and prognostic signiﬁcance of blood ﬁbrosis tests and liver stiffness measurement by FibroScan in nonalcoholic fatty liver disease. J Hepatol 2016;65:570–578. 109. Daniels SJ, Leeming DJ, Eslam M, et al. ADAPT: an algorithm incorporating PRO-C3 accurately identiﬁes patients with NAFLD and advanced ﬁbrosis. Hepatology 2018 Jul 16. https://doi.org/10.1002/hep.30163. [Epub ahead of print]. 110. Cassinotto C, Boursier J, de Lédinghen V, et al. Liver stiffness in nonalcoholic fatty liver disease: a comparison of supersonic shear imaging, FibroScan, and ARFI with liver biopsy. Hepatology 2016;63:1817–1827. 111. Chen J, Yin M, Talwalkar JA, et al. Diagnostic performance of MR elastography and vibration-controlled transient elastography in the detection of hepatic ﬁbrosis in patients with severe to morbid obesity. Radiology 2017;283:418–428. 112. Petta S, Vanni E, Bugianesi E, et al. The combination of liver stiffness measurement and NAFLD ﬁbrosis score improves the noninvasive diagnostic accuracy for severe liver ﬁbrosis in patients with nonalcoholic fatty liver disease. Liver Int 2015;35:1566–1573. 113. Tapper EB, Challies T, Nasser I, et al. The performance of vibration controlled transient elastography in a us cohort of patients with nonalcoholic fatty liver disease. Am J Gastroenterol 2016;111:677–684. 114. Ransohoff DF, Feinstein AR. Problems of spectrum and bias in evaluating the efﬁcacy of diagnostic tests. N Engl J Med 1978;299:926–930. 115. Poynard T, Halfon P, Castera L, et al. Standardization of ROC curve areas for diagnostic evaluation of liver

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ﬁbrosis markers based on prevalences of ﬁbrosis stages. Clin Chem 2007;53:1615–1622. 116. Petta S, Wong VW, Camma C, et al. Serial combination of non-invasive tools improves the diagnostic accuracy of severe liver ﬁbrosis in patients with NAFLD. Aliment Pharmacol Ther 2017;46:617–627. 117. Friedrich-Rust M, Nierhoff J, Lupsor M, et al. Performance of acoustic radiation force impulse imaging for the staging of liver ﬁbrosis: a pooled meta-analysis. J Viral Hepat 2012;19:e212–e219. 118. Nierhoff J, Chavez Ortiz AA, Herrmann E, et al. The efﬁciency of acoustic radiation force impulse imaging for the staging of liver ﬁbrosis: a meta-analysis. Eur Radiol 2013;23:3040–3053. 119. Sporea I, Bota S, Gradinaru-Tascau O, et al. Comparative study between two point shear wave elastographic techniques: acoustic radiation force impulse (ARFI) elastography and ElastPQ. Med Ultrason 2014;16:309– 314. 120. Cui J, Heba E, Hernandez C, et al. Magnetic resonance elastography is superior to acoustic radiation force impulse for the diagnosis of ﬁbrosis in patients with biopsyproven nonalcoholic fatty liver disease: a prospective study. Hepatology 2016;63:453–461. 121. Fierbinteanu Braticevici C, Sporea I, Panaitescu E, et al. Value of acoustic radiation force impulse imaging elastography for non-invasive evaluation of patients with nonalcoholic fatty liver disease. Ultrasound Med Biol 2013;39:1942–1950. 122. Guzman-Aroca F, Frutos-Bernal MD, Bas A, et al. Detection of non-alcoholic steatohepatitis in patients with morbid obesity before bariatric surgery: preliminary evaluation with acoustic radiation force impulse imaging. Eur Radiol 2012;22:2525–2532. 123. Palmeri ML, Wang MH, Rouze NC, et al. Noninvasive evaluation of hepatic ﬁbrosis using acoustic radiation force-based shear stiffness in patients with nonalcoholic fatty liver disease. J Hepatol 2011;55:666–672. 124. Yoneda M, Suzuki K, Kato S, et al. Nonalcoholic fatty liver disease: US-based acoustic radiation force impulse elastography. Radiology 2010;256:640–647. 125. Liu H, Fu J, Hong R, et al. Acoustic radiation force impulse elastography for the non-invasive evaluation of hepatic ﬁbrosis in non-alcoholic fatty liver disease patients: a systematic review & meta-analysis. PLoS One 2015;10:e0127782–e0127782. 126. Herrmann E, de Lédinghen V, Cassinotto C, et al. Assessment of biopsy-proven liver ﬁbrosis by twodimensional shear wave elastography: an individual patient data-based meta-analysis. Hepatology 2018; 67:260–272. 127. Singh S, Venkatesh SK, Wang Z, et al. Diagnostic performance of magnetic resonance elastography in staging liver ﬁbrosis: a systematic review and meta-analysis of individual participant data. Clin Gastroenterol Hepatol 2015;13:440–451 e6. 128. Pavlides M, Banerjee R, Tunnicliffe EM, et al. Multiparametric magnetic resonance imaging for the assessment of non-alcoholic fatty liver disease severity. Liver Int 2017;37:1065–1073.

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129. Yin M, Glaser KJ, Manduca A, et al. Distinguishing between hepatic inﬂammation and ﬁbrosis with MR elastography. Radiology 2017;284:694–705. 130. Dulai PS, Sirlin CB, Loomba R. MRI and MRE for noninvasive quantitative assessment of hepatic steatosis and ﬁbrosis in NAFLD and NASH: clinical trials to clinical practice. J Hepatol 2016;65:1006–1016. 131. Cui J, Ang B, Haufe W, et al. Comparative diagnostic accuracy of magnetic resonance elastography vs. eight clinical prediction rules for non-invasive diagnosis of advanced ﬁbrosis in biopsy-proven non-alcoholic fatty liver disease: a prospective study. Aliment Pharmacol Ther 2015;41:1271–1280. 132. Caussy C, Chen J, Alquiraish MH, et al. Association between obesity and discordance in ﬁbrosis stage determination by magnetic resonance vs transient elastography in patients with nonalcoholic liver disease. Clin Gastroenterol Hepatol 2018;16:1974–1982.e7. 133. Hsu C, Caussy C, Imajo K, et al. Magnetic resonance vs transient elastography analysis of patients with nonalcoholic fatty liver disease: a systematic review and pooled analysis of individual participants. Clin Gastroenterol Hepatol 2019;17:630–637.e8. 134. Bazick J, Donithan M, Neuschwander-Tetri BA, et al. Clinical model for NASH and advanced ﬁbrosis in adult patients with diabetes and NAFLD: guidelines for referral in NAFLD. Diabetes Care 2015;38: 1347–1355. 135. Kwok R, Choi KC, Wong GL, et al. Screening diabetic patients for non-alcoholic fatty liver disease with controlled attenuation parameter and liver stiffness measurements: a prospective cohort study. Gut 2016; 65:1359–1368. 136. Roulot D, Roudot-Thoraval F, G NK, et al. Concomitant screening for liver ﬁbrosis and steatosis in French type 2 diabetic patients using Fibroscan. Liver Int 2017; 37:1897–1906. 137. Patel P, Hossain F, Horsfall LU, et al. A pragmatic approach identiﬁes a high rate of nonalcoholic fatty liver disease with advanced ﬁbrosis in diabetes clinics and atrisk populations in primary care. Hepatol Commun 2018; 2:893–905. 138. Bril F, McPhaul MJ, Caulﬁeld MP, et al. Performance of the SteatoTest, ActiTest, NashTest and FibroTest in a multiethnic cohort of patients with type 2 diabetes mellitus. J Investig Med 2019;67:303–311. 139. Bril F, Millan L, Kalavalapalli S, et al. Use of a metabolomic approach to non-invasively diagnose non-alcoholic fatty liver disease in patients with type 2 diabetes mellitus. Diabetes Obes Metab 2018;20:1702–1709. 140. Chang YH, Lin HC, Hwu DW, et al. Elevated serum cytokeratin-18 concentration in patients with type 2 diabetes mellitus and non-alcoholic fatty liver disease. Ann Clin Biochem 2018:4563218796259. 141. Bril F, Portillo-Sanchez P, Liu IC, et al. Clinical and histologic characterization of nonalcoholic steatohepatitis in African American patients. Diabetes Care 2018; 41:187–192. 142. Xia MF, Yki-Jarvinen H, Bian H, et al. Inﬂuence of ethnicity on the accuracy of non-invasive scores

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predicting non-alcoholic fatty liver disease. PLoS One 2016;11:e0160526. 143. Angulo P, Bugianesi E, Bjornsson ES, et al. Simple noninvasive systems predict long-term outcomes of patients with nonalcoholic fatty liver disease. Gastroenterology 2013;145:782–789 e4. 144. Kim D, Kim WR, Kim HJ, et al. Association between noninvasive ﬁbrosis markers and mortality among adults with nonalcoholic fatty liver disease in the United States. Hepatology 2013;57:1357–1365. 145. Singh S, Fujii LL, Murad MH, et al. Liver stiffness is associated with risk of decompensation, liver cancer, and death in patients with chronic liver diseases: a systematic review and meta-analysis. Clin Gastroenterol Hepatol 2013;11:1573–1584 e1–e2; quiz e88–e89. 146. Pirola CJ, Sookoian S. Multiomics biomarkers for the prediction of nonalcoholic fatty liver disease severity. World J Gastroenterol 2018;24:1601–1615. 147. Gorden DL, Myers DS, Ivanova PT, et al. Biomarkers of NAFLD progression: a lipidomics approach to an epidemic. J Lipid Res 2015;56:722–736. 148. Loomba R, Quehenberger O, Armando A, et al. Polyunsaturated fatty acid metabolites as novel lipidomic biomarkers for noninvasive diagnosis of nonalcoholic steatohepatitis. J Lipid Res 2015;56:185–192. 149. Puri P, Wiest MM, Cheung O, et al. The plasma lipidomic signature of nonalcoholic steatohepatitis. Hepatology 2009;50:1827–1838. 150. Decaris ML, Li KW, Emson CL, et al. Identifying nonalcoholic fatty liver disease patients with active ﬁbrosis by measuring extracellular matrix remodeling rates in tissue and blood. Hepatology 2017;65:78–88. 151. Alonso C, Fernandez-Ramos D, Varela-Rey M, et al. Metabolomic identiﬁcation of subtypes of nonalcoholic steatohepatitis. Gastroenterology 2017;152:1449–1461 e7. 152. Boursier J, Mueller O, Barret M, et al. The severity of nonalcoholic fatty liver disease is associated with gut dysbiosis and shift in the metabolic function of the gut microbiota. Hepatology 2016;63:764–775. 153. Loomba R, Seguritan V, Li W, et al. Gut Microbiomebased metagenomic signature for non-invasive detection of advanced ﬁbrosis in human nonalcoholic fatty liver disease. Cell Metab 2017;25:1054–1062 e5. 154. Castera L. Diagnosis of non-alcoholic fatty liver disease/ non-alcoholic steatohepatitis: non-invasive tests are enough. Liver Int 2018;38(Suppl 1):67–70. 155. Poynard T, Lebray P, Ingiliz P, et al. Prevalence of liver ﬁbrosis and risk factors in a general population using non-invasive biomarkers (FibroTest). BMC Gastroenterol 2010;10:40. 156. Koehler EM, Plompen EP, Schouten JN, et al. Presence of diabetes mellitus and steatosis is associated with liver stiffness in a general population: the Rotterdam study. Hepatology 2016;63:138–147. 157. Roulot D, Costes JL, Buyck JF, et al. Transient elastography as a screening tool for liver ﬁbrosis and cirrhosis in a community-based population aged over 45 years. Gut 2011;60:977–984.

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158. Wong VW, Chu WC, Wong GL, et al. Prevalence of nonalcoholic fatty liver disease and advanced ﬁbrosis in Hong Kong Chinese: a population study using protonmagnetic resonance spectroscopy and transient elastography. Gut 2012;61:409–415. 159. Harman DJ, Ryder SD, James MW, et al. Direct targeting of risk factors signiﬁcantly increases the detection of liver cirrhosis in primary care: a cross-sectional diagnostic study utilising transient elastography. BMJ Open 2015;5:e007516. 160. Gines P, Graupera I, Lammert F, et al. Screening for liver ﬁbrosis in the general population: a call for action. Lancet Gastroenterol Hepatol 2016;1:256–260. 161. Wai CT, Greenson JK, Fontana RJ, et al. A simple noninvasive index can predict both signiﬁcant ﬁbrosis and cirrhosis in patients with chronic hepatitis C. Hepatology 2003;38:518–526. 162. Sterling RK, Lissen E, Clumeck N, et al. Development of a simple noninvasive index to predict signiﬁcant ﬁbrosis in patients with HIV/HCV coinfection. Hepatology 2006; 43:1317–1325. 163. Imbert-Bismut F, Ratziu V, Pieroni L, et al. Biochemical markers of liver ﬁbrosis in patients with hepatitis C virus infection: a prospective study. Lancet 2001;357:1069– 1075. 164. Cales P, Laine F, Boursier J, et al. Comparison of blood tests for liver ﬁbrosis speciﬁc or not to NAFLD. J Hepatol 2009;50:165–173. 165. Rosenberg WM, Voelker M, Thiel R, et al. Serum markers detect the presence of liver ﬁbrosis: a cohort study. Gastroenterology 2004;127:17041713. 166. Adams LA, George J, Bugianesi E, et al. Complex noninvasive ﬁbrosis models are more accurate than simple models in non-alcoholic fatty liver disease. J Gastroenterol Hepatol 2011;26:1536–1543. 167. Ratziu V, Giral P, Charlotte F, et al. Liver ﬁbrosis in overweight patients. Gastroenterology 2000;118: 1117–1123. 168. Angulo P, Hui JM, Marchesini G, et al. The NAFLD ﬁbrosis score: a noninvasive system that identiﬁes liver ﬁbrosis in patients with NAFLD. Hepatology 2007;45:846–854. 169. Petta S, Wong VW-S, Cammà C, et al. Improved noninvasive prediction of liver ﬁbrosis by liver stiffness measurement in patients with nonalcoholic fatty liver disease accounting for controlled attenuation parameter values. Hepatology 2017;65:1145–1155.

Received June 7, 2018. Accepted December 24, 2018. Reprint requests Address requests for reprints to: Laurent Castera, MD, PhD, Service d’Hépatologie, Hôpital Beaujon, Assistance Publique-Hôpitaux de Paris, 100 boulevard du General Leclerc, 92110 Clichy, France. e-mail: Q2 [email protected]. Acknowledgments Author contributions: Laurent Castera contributed to drafting and writing of the manuscript and to critical revision for important intellectual content. Mireen Friedrich-Rust contributed to drafting and writing of the manuscript and to critical revision for important intellectual content. Rohit Loomba contributed to drafting and writing of the manuscript and to critical revision for important intellectual content.

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Conﬂicts of interest The authors disclose the following: Laurent Castera: speaker bureau of AbbVie, Echosens, Intercept, Gilead, and Sirtex. Advisory boards for Allergan, Gilead, MSD, Pﬁzer, and Servier. Mireen Friedrich-Rust: speaker honorarium from Echosens, Siemens. Advisory board for Toshiba. Research support for Echosens, Supersonic, and Siemens. Rohit Loomba: grants from Allergan, BMS, Boehringer Ingleheim, Eli Lily, Galectin, Galmed, GE, Genﬁt, Gilead, Intercept, Janssen, Madrigal, NGM, Prometheus, Siemens, Shire, Pﬁzer, advisory committees for Arrowhead Research, Conatus, Galmed, Gemphire, Gilead, Intercept, NGM, and Cirius. Consultant for Bird Rock Bio, BMS, Coh

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Bar, Celgene, Civi Bio, Conatus, Enanta, Gilead, GRI Bio, Ionis, Metacrine, NGM, Receptos, Sanoﬁ, Salix, Kowa, and Median technologies. Co-founder of Liponexus Inc. Funding Rohit Loomba is supported in part by grant R01-DK106419-01 from the National Institute of Diabetes and Digestive and Kidney Diseases National Institute of Health. Research reported in this publication was supported by the National Institute of Environmental Health Sciences of the National Q13 Institute of Health under Award P42ES010337.

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Supplementary Material Ultrasound-Based Elastography Transient Elastography TE was the ﬁrst commercially available ultrasoundbased elastography technique developed for the measurement of liver stiffness using a dedicated device (FibroScan, Echosens, Paris, France).1 TE measures the velocity of a low-frequency (50 Hz) elastic shear wave propagating through the liver. This velocity is directly related to tissue stiffness, called the elastic modulus, expressed as E ¼ 3rv2, where v is the shear velocity, and r is the density of tissue, assumed to be constant: the stiffer the tissue, the faster the shear wave propagates. The examination is performed on the right lobe of the liver through the intercostal space. The measurement depth is between 25 and 65 mm using the Mprobe (standard probe) and between 35 and 75 mm using the XL-probe. As suggested by the manufacturer, 10 successful acquisitions should be performed on each patient. The median of these measurements is displayed and used for interpretation. Results are expressed in kPa, and range from 2 to 75 kPa with a normal value around 5 kPa.2 Advantages of TE include a short procedure time (<5 minutes), immediate results, good reproducibility, and the ability to perform the test at the bedside or in an outpatient clinic—it is not a difﬁcult procedure to learn. Therefore, TE can be considered as a point-of-care technique (Table 2). However, accurate results require careful interpretation of data, based on at least 10 validated measurements, a success rate (the ratio of valid measurements to the total number of measurement) >60%, and an interquartile range (IQR; reﬂects variations among measurements) of <30% of the median value (IQR/LSM 30%).3 It has been suggested that an even lower IQR should be used, especially in nonAsian patients with advanced ﬁbrosis, but these criteria have not been independently validated.4 The major challenge for the use of TE in NAFLD patients in clinical practice is the high rate of failure (no valid shot) or unreliable results (not meeting manufacturer’s recommendations: ie, valid shots <10, success rate <60%, or IQR/LSM >30%) in these patients, ranging from 11% to 26.8% using M-probe (Table 4). Such a wide range may be explained by the differences in the deﬁnitions used (failure vs unreliable results), as well as in the BMI of the studied populations (higher rates in the populations with higher BMI). In the largest series to date, on more than 13,000 examinations in 7261 European patients with chronic liver disease seen during a 5-year period, failure to obtain any measurement was observed in 3% of cases and unreliable results (not meeting manufacturer’s recommendations) in 16%,5 mostly due to patient obesity or limited operator experience. The XL-probe has been proposed by the manufacturer to overcome these limitations for overweight and obese patients.6 The software of the system controls the choice of the probe based on the skin-to-liver capsule distance. Generally, the XL-probe is chosen when this distance is >25 mm. In a recent multicenter US study, based on 1696 examinations in 992 NAFLD patients (BMI 33.6 ± 6.5 kg/m2) in whom both M- and XL-probes were

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used, the failure and unreliable results rate were 3.2% and 3.9%, respectively.7 Importantly the liver stiffness cutoffs are lower with the XL-probe than with the M-probe by around 1.5 kPa and need to be adapted.8 The risk of overestimating liver stiffness values has been reported with other confounding factors, including ALT ﬂares9–11; extrahepatic cholestasis12; congestive heart failure13; and, more recently, food intake.14–16 Therefore, TE should be performed in patients fasting for at least 2 hours.17 The inﬂuence of steatosis in NAFLD patients is still a matter of debate, with conﬂicting results: some studies suggest that steatosis is associated with an increase in liver stiffness,18,19 whereas others do not.20–22

Controlled Attenuation Parameter Recently, a novel parameter, the CAP has been proposed for the noninvasive grading of hepatic steatosis using TE (FibroScan 502 Touch; Echosens, Paris, France). CAP measures the degree of ultrasound attenuation by hepatic fat at the same time, on the same volume, and on the same signal as liver stiffness is measured at the center frequency of the FibroScan M-probe (3.5 MHz).23 Results are expressed as decibels per meter (dB/m) and range from 100 to 400 dB/ m. CAP has been initially only available with the M-probe, but has recently become available also with the XL-probe.24 CAP has been shown to have good inter-observer reproducibility with concordance between observers ranging from 0.82 (95% CI, 0.78–0.85)25 to 0.84 (95% CI, 0.77–0.88).26 However, the agreement between raters decreased for BMI >30 kg/m2 (0.65) and for CAP values <240 dB/m (0.44).25 Intra-observer reproducibility remains to be studied. The inﬂuence of food intake on CAP results has been examined by 2 studies with conﬂicting results: one27 showed an increase in CAP values by 10%, whereas another28 observed a signiﬁcant decrease. Additional data are needed before any ﬁrm conclusion can be drawn. Failure rate of obtaining any CAP measurement in patients with NAFLD, using the M-probe, ranges from 0% to 24% (Table 3). Interestingly, in a large study29 based on 5323 examinations performed with M-probe in 4451 patients with chronic liver disease, failure ranged from 0.5% in young males with no sign of the metabolic syndrome to 33% in elderly females with diabetes and hypertension. Failure was signiﬁcantly associated with older age, BMI, presence of metabolic syndrome, and with female sex, a ﬁnding consistent with what has been reported for LSM.5 However, when using the XL-probe, the failure rate was lower at 3.2%.7 In the absence of speciﬁc quality criteria provided by the manufacturer, investigators have used those recommended for LSM. Recently, an international multicenter study, including 754 consecutive patients, in whom CAP was measured by the M-probe before liver biopsy, has shown that the accuracy of CAP declined when its IQR was >40 dB/m with AUROC for fatty liver of 0.77 vs 0.90, in patients with IQR <40 dB/m (P ¼ .004).30 The authors suggested that an IQR <40 dB/m could be used as a quality criterion. Other authors suggested IQR <30 dB/m for a valid CAP.31 These ﬁndings require further external validation before any recommendation can be made.

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In summary, recent guidelines recommend that TE should be performed using a standardized protocol in fasting patients with critical interpretation of results taking confounding factors into account.17,32,33

Point Shear Wave Elastography pSWE, which includes ARFI, is based on the measurement of shear waves and has the advantage over TE that it is integrated in conventional ultrasound systems34 (Table 2). This enables pSWE in addition to abdominal ultrasound scan with the same system, which is of special interest in countries where the same operator can perform conventional ultrasound and pSWE. At present, most large ultrasound companies offer an additional elastography method integrated in their ultrasound systems. Region of interest (ROI) localization can be chosen under B-mode visualization. A single acoustic impulse is used to induce a shear wave within a small ROI (approximately 1.0 0.5 cm) and the velocity of shear waves is measured in meter/s or kPa. The technique for shear wave induction, the frequencies used, as well as the size of ROI differ between companies and need be taken into account when interpreting the results.17,32,33 Measurement should be performed 1–3 cm below the liver capsule. A median of 10 measurements should be used for clinical interpretation. Improved quality is obtained by pSWE estimation algorithms, which warn the user if measurement is not adequate. In addition, quality criteria, such as an IQR/median 30% and SD 30% have been reported to improve accuracy.32 pSWE can be performed in patients with obesity and ascites. A disadvantage is the smaller size of ROI compared to TE and the less-evaluated quality criteria. Like TE, pSWE values increase after meal intake. Elastography should therefore be performed after fasting for at least 2 hours.32

2-Dimensional Shear Wave Elastography 2D-SWE is the most novel ultrasound-based elastography method.34 Like pSWE, it is integrated in conventional ultrasonography systems, enabling the additional performance of elastography with the same probes as abdominal ultrasound (Table 2). Multiple shear waves are induced using acoustic impulses. The size of the ROI of interest can be increased to approximately 2 2 cm and shown as either single image or in real-time. Velocity of stiffness can then be measured at varying locations within this ROI and statistical quantities, such as the mean, SD, minimum and maximum values of the 2D-SWE or Young’s modulus in kPa are calculated and displayed. The measurement box should be placed at least 10 mm below the liver capsule. At least 3 measurements should be obtained and the report should include median and IQR. The technique for shear wave induction, as well as the frequencies used, differ between companies and should be taken into account when interpreting the results. All 2D-SWE systems have some kind of quality indicators of the shear wave speed estimate. However, quality criteria for clinical interpretation remain poorly evaluated.17,32,33 It can be performed in patients with obesity and ascites. Like TE, 2D-SWE values increase

19.e2

after meal intake. Elastography should therefore be performed after fasting for at least 2 hours.32

Magnetic Resonance-Based Imaging Over the last 2 decades, the utility of MRI-based methods have evolved to their current state and positioned themselves as one of the most accurate methods to noninvasively quantify liver fat, liver iron, and liver ﬁbrosis (Table 2). Two key quantitative biomarkers that will be discussed in more details include MRI-PDFF and MRE.35,36 Magnitude-based gradient-recalled-echo technique estimates PDFF, an MRI-based biomarker of liver fat content37–39 using low ﬂip angle to minimize T1 bias38,40,41 and 6 gradient-recalled echoes to calculate and correct for T2* signal decay.38,40–42 Parametric liver PDFF maps are computed pixel-by-pixel from source images using customdeveloped software that models observed signal as a function of echo time (TE), taking into account the multiple frequency components of triglyceride.40,41,43–45 PDFF values are obtained by placing ROIs in representative portions of the maps. The rationale for using MRE to assess NASH and ﬁbrosis is that extracellular matrix alterations associated with these conditions harden the liver and change its mechanical properties.46,47 Currently, 2D-MRE is available clinically. In this section, both MRI-PDFF and 2D-MRE will be discussed as the lead MRI biomarkers and we will brieﬂy discuss some of the emerging MRI based biomarkers as well.

Magnetic Resonance Imaging Proton Density Fat Fraction MRI-PDFF is an emerging accurate, reproducible, quantitative imaging-based biomarkers that has the ability to estimate the quantify liver fat in its entire dynamic range.36 MRI-PDFF improves upon previous methods for fat quantiﬁcation as it corrects for T1 decay and T2* and is unaffected by the age, sex, body mass index, iron content, inﬂammation, and ﬁbrosis.31 MRI-PDFF of the liver is deﬁned as the ratio of the density of mobile protons from triglycerides in the liver and the total density of protons from mobile triglycerides and mobile water.48 There are 2 methods to estimate MRI-PDFF, including the magnitude MRI-PDFF or ideal MRI-PDFF, which have a high degree of correlation between them and either method can be used to assess liver fat.48 Both methods provide rapid assessment of liver fat in all the 9 segments of the liver within a short breath hold (approximately 20 seconds).31 Reproducibility of PDFF measurements might be affected by food intake,49 but more data are needed before any ﬁrm conclusion can be drawn. Among all methods for detection of liver fat and quantiﬁcation of liver fat MRS-PDFF and MRI-PDFF have emerged as the gold standard. MRI-PDFF has been validated in numerous studies comparing against MRS, phantom studies, ex vivo human liver tissue, as well as liver histology, in patients with and without NAFLD.50,51

Magnetic Resonance Elastography MRE is an imaging technique that measures the stiffness of the liver by introducing shear waves and imaging their

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Gastroenterology Vol.

propagation using MREs.52 MRE (Resoundant, Rochester, MN) requires a special adaptation and proprietary hardware and software installment over conventional MRI scanners. During an MRE, shear waves at 60 Hz are mechanically generated by a circular device that is attached to the right side of the chest wall anterior to the liver. These shear waves and their propagation are then visualized via a 2D gradient-recalled echo pulse sequence. Wave images are interpreted by generating shear wave elastograms by the software. The mean LSM is a summary of the average perpixel stiffness measurements from the regions of interest. MRE has a low failure rate typically 1%–2%. It is not affected by ascites and etiology of liver disease.36 However, when massive, ascites has been recently suggested to be associated with MRE failure in a large retrospective study.53 There is conﬂicting evidence on the effect of BMI on MRE measurements: a recent study found that BMI was not a contributing factor in failure,54 but found waist circumference to be a signiﬁcant factor of failure whereas another study found that BMI was associated with MRE failure.53 It should be stressed, however, that BMI has an impact for ﬁtting into an MRI scanner not for getting an MRE. Finally, MRE can be affected by iron overload, but this can be assessed during an MRI using R2* as an estimate of iron content in the liver.

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Noninvasive Assessment of Liver Disease in Patients With Nonalcoholic Fatty Liver Disease

Noninvasive Assessment of Liver Disease in Patients With Nonalcoholic Fatty Liver Disease

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