transient elastography ( te ) by fibroscan ( echosens , paris , france ) is one of the most widely used and validated noninvasive methods for liver fibrosis staging . this method is painless , is not associated with potential complications , and is well accepted by patients , especially for repeated examinations . te is accurate for staging liver fibrosis   and can be used for prediction of mortality and severe outcome in patients with chronic liver diseases [ 3 , 4 ] . however , several points should be considered when using te for liver fibrosis staging to avoid misclassification of patients . some methodologic issues should be taken into account when interpreting studies that validate this method . liver stiffness can be influenced by nonfasting status , flare of transaminases , cardiac congestion , and extrahepatic cholestasis . in addition , the type and position of probe and operator experience can also impact on te results . a transducer probe transmits vibrations of mild amplitude and low frequency ( 50  hz ) inducing elastic shear waves that propagate through the liver tissue . propagation of shear waves is followed using a pulse - echo ultrasound acquisition measuring its velocity that is directly correlated with liver stiffness : the stiffer the tissue is , the faster the shear wave propagates . the examination is rapid ( less than 10  min ) and can easily be performed at the patient 's bedside . briefly , the probe is placed in an intercostal space at the intersection between the xyphoid and the median axillary line ( i.e. , on the right lobe of the liver , usually where liver biopsy would be performed ) . the operator , assisted by a time - motion ultrasound image , locates a liver portion free of large vascular structures and acquires the measurement (  shot  ) . the software determines whether the liver stiffness measure ( lsm ) is valid or not ; when a measure is invalid , it is automatically discharged . the result of the te represents the median of all valid acquisitions and ranges from 2.5 to 75.0  kpa . te should be considered reliable when all the following criteria are met : ( i ) 10 successful measurements ; ( ii ) an interquartile range lower than 30% of the median value ; and ( iii ) a success rate of more than 60% . in a study that evaluated more than 13,000 te examinations , unreliable results were independently associated with body mass index , lower operator experience , older age , female gender , and metabolic factors . currently , two probes are available for staging of liver fibrosis in adults : ( i ) m probe , the standard probe used in patients with normal weight , and ( ii ) xl probe , used in obese patients or when te results with m probe are unreliable . te results have been described as unreliable in around 20% of cases using the m probe   and in lower rates within the xl probe . in both probes liver stiffness is measured in volume such as a cylinder being 4  cm high and 1  cm wide ( 100 times higher than liver biopsy ) . technical differences between the m and xl probes include their central ultrasound frequency ( 3.5 versus 2.5  mhz ) , vibration amplitude ( 2 versus 3  mm ) , and the diameter of their tips ( 9 versus 12  mm ) . in addition , measures from xl probe are deeper compared to those performed by m probe . the  normal  values of te were defined in healthy individuals as around 5.5  kpa with the m probe , showing that liver stiffness was higher in males compared to females and in obese individuals compared to those with normal weight [ 10 , 11 ] . the standard expression of the effectiveness of a diagnostic test is represented by the area under the receiver operator characteristic curve ( auroc ) , which plots the sensitivity over 1specificity . te is an accurate tool for stage liver fibrosis with auroc ranging from 0.79 to 0.83 for significant fibrosis ( f  2 ) and from 0.95 to 0.97 cirrhosis ( f = 4 ) in patients with chronic liver diseases . in most studies auroc curves for te were calculated using liver biopsy as the gold standard . in this context , the result represents the probability that te will correctly rank random patients as  significant fibrosis or cirrhosis  or as  no fibrosis  based on liver fibrosis . this methodology leads to major issues : the assumption that liver biopsy is binary or dichotomy , whereas fibrosis staging uses a five - stage ordinal scale ( from f0 to f4 ) and the impact of diagnostic performance of noninvasive tests based on the spectrum bias . in addition , the diagnostic performance of te might be influenced by liver biopsy limitations . the spectrum bias and the impact of the prevalence of fibrosis stages in auroc estimation were demonstrated in a study that used a serum noninvasive method ( fibrotest ) . advanced fibrosis  was defined : the lowest auroc value was observed when only stage f2 was defined as advanced fibrosis and only stage f1 as nonadvanced fibrosis ( f1 versus f2 ) and the maximal value was observed when the authors evaluated f0 ( defined as nonadvanced fibrosis ) versus f4 ( advanced fibrosis ) . the adjustment of auroc values using the obuchowski method is an alternative to overcome the spectrum bias and the ordinal classification of liver biopsy . this methodology is a multinomial version of the auroc , with n = 5 ( i.e. , f0 , f1 , f2 , f3 , and f4 ) categories of liver biopsy . thus , the  weighted auroc  ( wauroc ) by the obuchowski method is a weighted average of the n(n  1)/2 different curves corresponding to all pairwise comparisons between 2  2 of the n categories . each pairwise comparison is weighted according to the distance between fibrosis stages with a penalty function proportional to the difference in metavir classes between stages . this penalty function was defined as 0.25 per difference among fibrosis stages . when the differences between metavir classes are one ( i.e. , f0 to f1 ) , two ( f0 versus f2 ) , three ( f0 versus f3 ) , or four stages ( f0 versus f4 ) , the penalty is 0.25 , 0.50 , 0.75 , or 1.00 , respectively . the impact of the spectrum bias and the fact that liver biopsy is not dichotomy were validated in a study using te for stage fibrosis in patients with chronic hepatitis c ( chc ) and healthy volunteers ( controls ) . analyzing only patients , this study showed lower auroc ( 95% ci ) values between adjacent stages [ f1 versus f2 : auroc = 0.613 ( 0.5730.650 ) ] than between aggregated stages [ auroc = 0.745 ( 0.7160.771 ) for f0f1 versus f2f3f4 and auroc = 0.852 ( 0.8230.877 ) and f0f1f2f3 versus f4 , resp . ] . in addition , auroc values for diagnosis of fibrosis stage 2 were higher when analyzing all individuals ( patients and controls ) compared to the analysis of chc patients without controls [ auroc = 0.830 ( 0.8100.848 ) versus 0.761 ( 0.7340.785 ) , p < 0.001 ] . this difference might be explained by the fact that authors changed the prevalence of fibrosis stages in the sample , increasing the proportion of individuals with f0 stage , by adding the controls . however , wauroc ( 95% ci ) were similar in these two analyses [ wauroc = 0.894 ( 0.8870.901 ) versus 0.883 ( 0.8740.892 ) ; p = ns ] when analyzing chc patients and controls versus chc patients showing that the obuchowski method is not influenced by this bias . the diagnostic performance [ auroc ( 95% ci ) ] of te with and without the obuchowski method was recently reported in a study with a prevalence of fibrosis stages of 54% , 30% , 9% , and 7% for f0f1 , f2 , f3 , and f4 , respectively . auroc values were 0.874 ( 0.8110.937 ) for f  2 and 0.942 ( 0.8900.993 ) for f = 4 . the wauroc was 0.89 ( 0.860.93 ) when the obuchowski method was used to adjust the diagnostic performance of the noninvasive test . in addition , similar te diagnostic performance was reported in meta - analyses in patients with chronic hepatitis b [ wauroc = 0.89 ( 0.830.96 ) ]   and chronic hepatitis c [ 0.88 ( 0.870.89 ) ]   adjusted by the obuchowski method . preliminary studies reported that severe necroinflammatory activity , such as alanine transaminases ( alt ) greater than 10 times the upper limit of normal ( uln ) , might lead to an increase in liver stiffness and an overestimation of fibrosis estimation . more recent studies showed that even in lesser grades of activity liver stiffness might be overestimated . in patients with chronic hepatitis b having the same fibrosis stage by liver biopsy , those with alt levels 2 times uln had higher te results compared to those with normal transaminases ( 9.5 versus 4.7  kpa , p > 0.001 ) . this hypothesis was validated by analyzing a significant decrease in liver stiffness values after a 3-month antiviral treatment in chronic hepatitis b compared to pretreatment levels ( 7.9 versus 6.4  kpa ; p < 0.001 ) . patients had elevated transaminases that normalized after 3-month antiviral treatment and the time between first and second measures was a very short delay to consider regression of liver fibrosis . similar results were reported in chronic hepatitis c : considering patients with fibrosis stages f3 identified by liver biopsy , those with important necroinflammatory activity ( a2a3a4 ) had higher liver stiffness measurements compared to those without activity ( a0a1 ) [ 14.6 versus 6.2  kpa ; p < 0.05 ] . studies reported that liver stiffness highly correlates with total bilirubin levels ( spearman 's correlation r = 0.67 and 0.69 ) and decreases after successful biliary drainage ( from 10.8 to 7.1  kpa and 7.6 to 5.4  kpa in both studies ) [ 24 , 25 ] . the reasons underlying the high stiffness in cholestasis are unknown but could be related to tissue swelling , inflammation , edema , and increased intracellular pressure due to impaired bile flow . in addition , the increased hydrostatic pressure alone seems to contribute to increased liver stiffness during extrahepatic cholestasis . hepatic congestion might increase liver stiffness measurements leading to an overestimation of fibrosis and a misclassification of cirrhosis . in a case - report , authors showed a significant decrease of liver stiffness after a cardiac transplant ( 44.3 versus 3.8  kpa ; p < this hypothesis was validated in few studies that evaluated te in patients with cardiac dysfunction and controls . liver stiffness measurements were significantly higher in patients with heart failure than in controls and decreased during hospitalization after control of cardiac disease . in addition , liver stiffness was increased in patients with right - sided heart failure compared to healthy controls [ 9.7 ( iqr 5.010.8 )  kpa versus 4.4 ( 3.65.1 )  kpa , p < 0.001 ] . these findings can be explained by worsening cardiac dysfunction increasing hepatic vein pressure leading to intrahepatic blood stasis and higher liver stiffness . liver stiffness measurement significantly increased immediately after food intake ( 6.0  2.1 versus 4.9  2.1  kpa ; p < 0.001 ) in patients with no fibrosis and moderate fibrosis ( 8.2  2.3 versus 7.2  1.3  kpa ; p = 0.008 ) . the impact of nonfasting status on liver stiffness was validated in patients with chc : an increase in liver stiffness was observed 15 to 45 minutes after the onset of the meal with return to baseline premeal levels within 120 minutes . these results reinforce that te should be performed in 120 to 180  min fasting status . liver stiffness values were significantly higher in subjects with severe steatosis ( 66% at liver biopsy ) compared to those without ( f0-f1 6.9 versus 5.8  kpa , p   =  0.04 ; f0f2 7.4 versus 6.0  kpa , p   =  0.001 ) in a study with biopsy - proven patients with nonalcoholic fatty liver disease . in addition , a higher rate of false - positive te results was observed in patients with steatosis 66% compared to those without ( f0-f1 23.6% versus 14.9% , f0f2 33.3% versus 13.2% ) . similar results were observed in patients with chc : amongst patients within the same fibrosis stages ( f0f2 and f3-f4 ; f0f3 and f4 ) , mean liver stiffness values were significantly higher in subjects with moderate - severe steatosis ( 20% at liver biopsy ) compared to those without . the experience of the operator was independently associated with unreliability of this method in a study that analyzed more than 13,000 examinations . an operator effect in te was validated in a study that used fibrotest as the reference : the diagnostic performance of te was significantly better when examinations performed by the nonexperimented operator were excluded ( auroc = 0.80 versus 0.70 ; p = 0.009 ) . the performance of at least 100 examinations should be considered to define an experienced operator . the first study reported a high intraclass correlation coefficient [ icc = 0.990 ( 95% ci 0.9770.987 ) ] . besides the description of similar results , other authors showed 25% of discordance of at least one stage of liver fibrosis by te performed by experienced operators . this relatively high rate of classification of fibrosis stages was reported in more recent studies [ 32 , 3537 ] . both examinations were performed by an experienced operator , were well correlated , and presented high icc values . however , these studies reported a rate from 20 to 30% discrepancy of at least one stage of fibrosis . we are aware that it is very difficult , even with liver biopsy , to distinguish between intermediate adjacent fibrosis stages ( i.e. ; f2 versus f3 ) . however , this variability of at least one stage of fibrosis might impact on the management of patients with chronic liver disease . the correct classification of fibrosis stage might impact on access to new direct - acting antiviral ( daa ) treatment for patients with chc or duration of treatment . this variability might be associated with the choice of intercostal space or probe position   or might be related to the te technique itself and a few factors that can not be controlled during examination . te results performed in a longitudinal follow - up ( repeated measurements ) might be more accurate than a single measure and interobserver variability might be minimized when te measures are performed by the same experienced operator during follow - up . patients with cholestatic liver diseases , such as primary biliary cirrhosis and primary sclerosing cholangitis , seem to have higher stiffness than those with viral hepatitis . therefore , for each stage of fibrosis , cutoffs are higher than in chronic viral hepatitis either because of the nature of the liver disease or because of cholestasis . liver stiffness might be influenced by nonfasting status , flare of transaminases , heart failure , extrahepatic cholestasis , and presence of severe steatosis leading to an overestimation of liver fibrosis . in addition , a not negligible interobserver variability can also impact on management of patients with chronic liver diseases . the prevalence of fibrosis stages and the fact that liver biopsy is not dichotomy might have impacted on the diagnostic performance of the test . transient elastography should be performed by an experienced operator ( > 100 exams ) , in a fasting status , and its results should be handled by specialist clinicians that are aware of limitations of this method .
transient elastography ( te ) based on liver stiffness measurement ( lsm ) is one of the most validated noninvasive methods for liver fibrosis staging in patients with chronic liver diseases . 
 this method is painless , has no potential complications , is rapid ( < 10  min ) , and can be performed at the patient 's bedside . 
 however , several points should be considered when interpreting te results . 
 this review aims to discuss the critical points that might influence liver stiffness and te results . 
 spectrum bias and the impact of the prevalence of fibrosis stages should be taken into account when interpreting the studies that validated this method using liver biopsy as a gold - standard . 
 lsm might be influenced by nonfasting status , flare of transaminases , heart failure , extrahepatic cholestasis , presence of steatosis , aetiology of liver disease , type and position of probe , and operator 's experience . 
 in addition , interobserver variability can impact on the management of patients with chronic liver diseases . 
 te should be performed by an experienced operator ( > 100 exams ) , in a 3-hour fasting status , and its results should be handled by specialist clinicians that are aware of the limitations of this method .