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Cheng et al.                                                                                                                                                                                             Advances in liver fibrosis

           management in order to prevent further liver damage.   is obtained. Sampling error can be minimized by either
           This article focuses on the up-to-date approaches for   obtaining a specimen of sufficient size (at least 2 cm
           diagnosis, both invasive and non-invasive, and latest   in length) or from different lobes,  which  may not be
           development in treatments of liver fibrosis, particularly   feasible all the time. [14]  Well reported complications
           in NAFLD patients for whom a handful of clinical trials   from  liver biopsy examination include pain, [15]
           are currently ongoing.                             bleeding  such as wound  bleeding,  intraperitoneal
                                                              hemorrhage, hemobilia  or hemothorax, [15]  transient
           DIAGNOSIS OF LIVER FIBROSIS                        acute hypotension  or vasovagal syncope. [16]  Fatal
                                                              complications  like uncontrolled  bleeding,  bacteremia
           There are varieties of methods for making the diagnosis   and sepsis are rare but still possible. [17]  In patients with
           of liver fibrosis, which can be classified into invasive   HCC, liver biopsy also carries a risk of spreading the
           and non-invasive approaches.                       cancer cells. [18]

           Invasive approach - liver biopsy examination       Non-invasive approach
           For  invasive approach, it  refers to  liver biopsy   Radiological assessments are either ultrasonographic-
           examination,  which provides liver tissue for      based [e.g. transient elastography, acoustic radiation
           a histopathological  assessment of liver. Liver    force impulse  (ARFI) imaging  and shear wave
           biopsy  examination  can be done  percutaneously,   elastography  (SWE)]  or magnetic resonance  (MR)-
           transvenously (either transjugularly or transfemorally),   based [i.e. MR elastography (MRE)].
           or surgically  (open  or laparoscopic  operations). [6]
           Indications for liver biopsy are for diagnostic  and/or   Ultrasonographic based
           prognostic purposes, as well as for treatment planning. [7]  Transient elastography
                                                              Transient elastography (Fibroscan , Echosens, Paris,
                                                                                             ®
           Liver  biopsy  is still regarded as the gold  standard   France) assesses liver stiffness measurement (LSM)
           for  liver  fibrosis  assessment  in  various  chronic  liver   by transmitting shear wave followed by ultrasound wave
           diseases. [8,9]  Apart from general histological  staging,   through a probe putting on the skin overlying the liver
           liver biopsy can also provide  information  concerning   parenchyma. The velocity of the shear wave passing
           morphometry, which can provide additional information   through the liver parenchyma is calculated by Doppler
           on the distribution and the exact quantity of liver   technique. The higher the velocity, the stiffer the liver
           fibrosis. [10]  A recent quantitative tool called qFibrosis   parenchyma is. As mentioned by the manufacturer, for
           utilized 87 parameters aiming for combining the results   an examination to be considered as reliable, it requires
           of  collagen patterns,  collagen  architectural features   at least 10 successful  attempts and the ratio of
           and statistical analysis of features of respective   interquartile range to median of those measurements
           collagen patterns into a single index. This requires an   should be less than 0.3. [19]   LSM  reflects  the  degree
           unstained biopsy sample for  the  automated analysis   of  liver  fibrosis. [20]  It can even identify  those with no
           of liver fibrosis staging. [11]  All these evidences illustrate   or minimal fibrosis and differentiate them from those
           that liver biopsy plays an important role in the diagnosis   with severe fibrosis or cirrhosis. [21]  It has been proved
           of liver fibrosis.                                 useful across different liver disease entity (e.g. chronic
                                                              hepatitis B and C, autoimmune hepatitis). [22]  However,
           Apart from liver fibrosis staging, liver biopsy can provide   LSM by transient  elastography  is found  to be less
           different information important for the management   reliable in obese patients. [23,24]  It can be less accurate
           of the clinicians.  For example, in cases of NAFLD,   in certain situation, e.g. severe acute exacerbation of
           the  degree  of  necroinflammation  and  steatosis  can   hepatitis, [25]  post-treatment fibrosis stages in CHB [26]  or
           be  determined by liver  biopsy  so corresponding   chronic hepatitis C (CHC) patients. [27]
           management can be provided for  this potentially
           reversible situation. [12]  Liver biopsy is also helpful in   ARFI imaging
           diagnosing  adverse  drug  reaction  and  classification   ARFI is another technique for estimating liver fibrosis. It
           of liver tumors. [13]   Yet,  the most common reason for   is implemented in current ultrasound scanner, without
           conducting a liver biopsy is  for  assessing the liver   acquirement of external equipment. The conventional
           fibrosis  in  patients  with  chronic  viral  hepatitis  and   ultrasound probe automatically produces an acoustic
           NAFLD.                                             “push” pulse for generating shear-wave which passes
                                                              through the tissue.  The wave propagation  speed is
           Such a direct and useful method bears quite a few   assessed.  Again,  higher  the speed,  higher  the liver
           limitations. Sampling error is a major limitation for liver   stiffness measurement  is. [28,29]   There are several
           biopsy as only 1/50,000 of the whole liver parenchyma   advantages for ARFI. As it is a function of the ultrasound

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