ARFI elastography 之臨床應用

(1)

Clinical Applications of Acoustic Radiation Force Impulse (ARFI) Elastography (ARFI elastography 之臨床應用之臨床應用之臨床應用之臨床應用)

Effects of

hepatic necroinflammation

on

liver stiffness measurement

陳昇弘 Sheng-Hung Chen

中國醫藥大學臨床醫學研究所

中國醫藥大學附設醫院內科部消化系

Graduate Institute of Clinical Medical Science, China Medical University

Division of Hepatogastroenterology, China Medical University Hospital,

(2)

Mueller et al.

Hepatic Medicine-Evidence and Research 2012

(3)

(4)

Acuson S2000 with

a Siemens 4C1 curved array, 4.00 MHz for B-mode,

2.67 MHz for push pulses

and 3.08 MHz for detection pulses

(5)

(6)

Spectrum of

Clinical Applications of

ARFIE

Liver fibrosis staging

Noninvasive baseline evaluation and

chronological surveillance

Prognostication

Treatment decision making

Patient counseling

(7)

7

In the chronically injured liver, fibrogenesis is

the

complex dynamic interplay among various

hepatic cell types and mediators

in which the

process of

perpetuation follows initiation

.

With the clinical application of magnetic

resonance (MR) and ultrasound-based LSM,

studies using MR elastography (MRE),

FibroScan, and ARFI elastography have

demonstrated significant correlations

between liver stiffness and liver fibrosis.

However, liver stiffness and liver fibrosis are

not equivalent

…

Chen et al. BMC GE 2012 Effects of patient factors on noninvasive liver stiffness measurement

(8)

Mueller et al.

Hepatic Medicine-Evidence and Research 2012

Liver stiffness- a novel parameter for the diagnosis of liver disease

(9)

Among the various host factors that

affect LSM values,

necroinflammation

is

most common in clinical settings.

The

swelling of hepatocytes, interstitial

edema, and the infiltrates of

inflammatory cells

may increase LS in

patients with acute hepatitis…

(10)

The effects of

hepatic necroinflammatory

activity on liver stiffness

measurement (LSM)

have varied in previous studies.

Positive correlation (dominant to date)

Yoon et al.

Chen et al.

...

Insignificant correlation (only 2 reports)

Rizzo et al.

Colombo et al.

...

Negative correlation (only 1 report)

Harata et al.

(11)

Stiffness

Fibrosis stage

(12)

Coco et al. J Viral Hepatol 2007

Transient elastography-a new surrogate marker of liver fibrosis influenced by

(13)

Despite the variation among previous

investigations, several recent studies have

demonstrated the

necroinflammatory effects

on liver stiffness

by

evolving analyses

.

In a longitudinal study using FibroScan,

Sagir

et al. observed false positivity for cirrhosis

(cutoff > 12.5 kPa) in 15 of 20 non-cirrhotic

patients with acute liver damage of various

etiologies. In 6 patients, the LSMs

dropped

below 12.5 kPa with normalized ALT levels

during follow-up…

(14)

Sagir et al. Hepatology 2007

Transient elastography is unreliable

for detection of cirrhosis in patients with acute liver damage 15 cases > 12.5 kPa

(15)

Sagir et al. Hepatology 2007

Transient elastography is unreliable

for detection of cirrhosis in patients with acute liver damage

ALT Bil

(16)

Using a longitudinal analysis,

Arena

et al.

demonstrated significant correlations between

sequential serum ALT levels and LSM results at

different time points

.

Although these studies showed the need for caution

when analyzing LSM in patients with

necroinflammatory flares, they did not include

regression estimates…

(17)

Arena et al. Hepatology 2008

Acute viral hepatitis increased liver stiffness values measured by transient elastography

(18)

LS

(19)

(20)

Seo

et al. demonstrated that

peak ALT

levels

significantly explained

peak LSMs

in 31 patients in acute hepatitis A via

linear regressions adjusting for age and

sex…

(21)

Seo et al. Scand J Gastroenterol 2010 Dynamic changes in liver stiffness during the course of acute hepatitis A

LS

ALT BIL

n = 31, AHA

(22)

Seo et al. Scand J Gastroenterol 2010 Dynamic changes in liver stiffness during the course of acute hepatitis A

(23)

A cross-sectional study by

Lee

et al.

showed that LSM using FibroScan in

158 patients was independently

associated with

histological

necroinflammatory grading

, but

(24)

METHODS: We studied 158 patients with chronic liver disease who underwent transient elastography and liver biopsy sampling. Histologic findings on fibrosis and necroinflammatory activity in the biopsy specimens were evaluated

according to the Korean Society of Pathologists Scoring System. Routine biochemical tests were performed according to standard methods.

RESULTS: Liver stiffness was strongly correlated with liver fibrosis stage (Spearman coefficient=0.636, P<0.001), lobular activity (Spearman

coefficient=0.359, P<0.001), and portoperiportal activity grade (Spearman coefficient=0.448, P<0.001). Liver stiffness was significantly associated with serum levels of total bilirubin (P=0.025), direct bilirubin (P=0.049),

gamma-glutamyl transpeptidase (P=0.014), platelet count (P=0.004), albumin (P<0.001), and international normalized ratio (P<0.001). Multivariate analysis showed that fibrosis stage (B 3.50, P=0.009) and lobular activity grade (B 3.25, P=0.047)

were independently associated with liver stiffness.

Lee da M et al.

Korean J Hepatol 2009

Factors associated with liver stiffness in chronic liver disease

(25)

Fung

et al reported

a poor PPV (as low

as 10%)

for LSM by using FibroScan to

diagnose true cirrhosis in 102

HBV-infected patients (median ALT: 89,

range: 46-501 IU/L), among whom 32

patients had an LS value greater than

11.0 kPa...

(26)

Fung et l. AJG 2010

Correlation of liver stiffness and histological features in healthy persons and in patients with

(27)

Multiple logistic regressions by

Myers

et

al. showed that serum

ALT

levels

greater than the optimal cutoff value

60 IU/L

from ROC analysis were

significantly correlated with the

discordance (at least 2 stages between

FibroScan and biopsy

)...

(28)

Myers et al. Liver Int 2010

Prevalence, risk factors and causes of discordance in fibrosis staging

by transient elastography and liver biopsy

n = 251, CLD

(29)

Myers et al. Liver Int 2010

Prevalence, risk factors and causes of discordance in fibrosis staging

(30)

Algorithms using

distinct sets of cutoff

values

stratified by reference and

elevated serum ALT levels have been

developed, …

(31)

Chan et al. J Viral Hepat 2009

Alanine aminotransferase-based algorithms of liver stiffness measurement

by transient elastography (Fibroscan) for liver fibrosis in chronic hepatitis B

PPV: 82% (48–97) NPV: 38% (95% CI 10–74) n = 161, CHB F 4 F 3 4 F 2 3 4 F 1 2 3 4

(32)

32

Chan et al. J Viral Hepat 2009

Alanine aminotransferase-based algorithms of liver stiffness measurement

by transient elastography (Fibroscan)

13 (1–53)

(33)

Kim et al. Liver Int 2010

A novel liver stiffness measurement-based prediction model for cirrhosis in hepatitis B patients

(34)

(35)

(36)

(37)

…but

ALT specific cutoff

values

did not

significantly enhance the diagnostic

performances in a study of 202

HBV-infected patients using FibroScan…

(38)

Cardoso et al. LI 2012

Direct comparison of diagnostic performance of TE

in patients with chronic hepatitis B and chronic hepatitis C n = 202, HBV; n = 363, HCV

(39)

Cardoso et al. LI 2012

Direct comparison of diagnostic performance of TE

in patients with chronic hepatitis B and chronic hepatitis C HBV

(40)

Tapper

et al. further delineated the

positive necroinflammatory effects on

LSM using FibroScan through linear

regressions in

684 HCV patients

with

METAVIR F0, F1 and F2

.

Logistic regressions also showed that

false positivity of liver fibrosis staging

was associated with both histological

and serum hepatic necroinflammatory

activity…

(41)

Tapper Clin Gastroenterol Hepatol 2012

Levels of Alanine Aminotransferase Confound Use of Transient Elastography

to Diagnose Fibrosis in Patients with CHC

(42)

(43)

(44)

Yoon

et al. used ARFI elastography to

demonstrate a significant correlation

(Pearson's r = 0.431, P < .05) between

LSM values and serum ALT levels, and

a marked positive effect of histological

necroinflammatory activity on LSM.

However, this study did not adjust for

(45)

Yoon Dig Dis Sci 2012

Liver Stiffness Measurement

Using Acoustic Radiation Force Impulse (ARFI) Elastography and Effect of Necroinflammation

(46)

Yoon Dig Dis Sci 2012

Liver Stiffness Measurement

Using Acoustic Radiation Force Impulse (ARFI) Elastography and Effect of Necroinflammation

(47)

47

(48)

48

(49)

Conclusion

Although necroinflammation exhibits

positive

effects on LS after adjusting for liver fibrosis

stages,

It exhibited

negative

effects on liver fibrosis

staging after adjusting for LS

Nonetheless, patients with higher ALT levels

have been shown to be at increased risk of

advanced liver fibrosis without adjusting for

LS

stiffness fibrosis stage

(50)

50

(51)

In contrast to results indicating positive

necroinflammatory effects on liver

stiffness,

Harata

et al. identified a

negative

correlation between serum

ALT levels and liver stiffness in patients

with cholestasis.

Cholestasis is a condition in which the

release of hydrostatic pressure with

synchronous necroinflammatory activity

can, paradoxically, reduce the values of

LSM using FibroScan…

(52)

Harata Hepatol Res 2011

Liver stiffness in extrahepatic cholestasis correlates positively with bilirubin and negatively with alanine aminotransferase

(53)

53

Harata Hepatol Res 2011

Liver stiffness in extrahepatic cholestasis correlates positively with bilirubin and

(54)

(55)

We are currently developing a study design that will allow the analysis of the dynamic effects of

necroinflammation on LSM over a short timeframe, during which changes in the fibrosis stage are not significant.

Cutoff variability among previous studies on the LSM-based assessment of fibrosis may have resulted from the diverse etiologies of hepatitis, ethnicity, variable patient profiles, and prolonged intervals between liver biopsy and the acquisition of LSM. Any significant time lag between a biopsy and an ultrasound-based

assessment of stiffness can affect LSM because of changes in fibrosis characteristics

.

Direct tissue and gene markers will also be employed.

A larger sample will allow the randomization of

training and validation cohort assignments, as well as the external validation of the

(56)

LSM

Submission under review: regarding the noninvasive diagnostic tool – ARFIE in CHB patients

Diagnostic index for advanced liver fibrosis in Asian chronic hepatitis B patients based on necroinflammation and liver stiffness measurement

Validity

Compared with competing tests

Cutoffs

Associated (host) factors