| Abstract|| |
Assessment of fibrosis is important in chronic hepatitis B for a number of reasons including decision-making regarding treatment and predicting prognosis.Currently liver biopsy is considered the gold standard for assessing liver histology. However, since liver biopsy has significant limitations,the quest for a non-invasive alternative to assess hepatic fibrosis continues. A review of published literature reveals that extensive research has been carried out in this field, and several simple to complicated alternatives to liver biopsy for assessing hepatic fibrosis have been evaluated. A few have shown promise too, but we are still short of an ideal alternative to liver biopsy. Despite the fact that much has been done, we still have a long way to go before we can finally say farewell to liver biopsy.
Keywords: Chronic hepatitis B, hepatic fibrosis, liver biopsy, non-invasive alternative
|How to cite this article:|
Al-Mahtab M, Rahman S, Khan M. Non-invasive markers of hepatic fibrosis in chronic Hepatitis B: A review. Hep B Annual 2007;4:61-71
| Introduction|| |
Assessment of fibrosis is important in chronic hepatitis B for a number of reasons including decision-making regarding treatment and predicting prognosis. Currently liver biopsy is considered the gold standard for assessing liver histology.  However, liver biopsy has its limitations , and hence the quest continues for an non-invasive alternative to assess hepatic fibrosis. Liver biopsy is an invasive procedure, with non-negligible morbidity and negligible but possible mortality. It is at times not well accepted by patients, especially when repeated examinations are needed. There is a significant probability of sampling error, which may miss a cirrhosis diagnosis in up to 15-20% of cases and there is also a high intra-observer and inter-observer variability in the interpretation of biopsy samples.  More importantly, liver biopsy shows a 'snapshot in time' and fibrosis is assessed at a certain time-point, whereas fibrosis is a dynamic process evolving with time and at times regressing with successful therapy.
An ideal method to assess fibrosis which can replace biopsy must be easy to perform, inexpensive, safe and free of side effects. It must be acceptable to patients so as to be easily repeatable to permit repeated examinations. In addition, the results have to be specific, sensitive and reproducible. The test ideally should be independent of metabolic, biliary and renal changes and reflect fibrosis regardless of cause.
| AST-Platelet Ratio Index (APRI)|| |
It has been noted that advanced fibrosis is associated with opposing trend in AST level and platelets counts.  When the two are put in a ratio the results are very interesting. APRI has several advantages. Firstly, it is readily available, as AST and platelets counts are part of the routine tests in managing patients with chronic hepatitis. No additional blood tests or cost is necessary. Secondly, it is easy to compute, without the use of a complicated formula. In fact, clinicians could simply work out the value without use of a calculator. Thirdly, and more importantly, it is backed by sound pathogenesis. An advanced state of fibrosis is associated with lower level of megakaryocyte maturation and platelet production through lower production of thrombopoietin, portal hypertension and enhanced pooling and sequestration of platelets at the spleen. , APRI has been validated by various groups in patients with chronic hepatitis C.
However, we must be aware of the limitations of APRI. Firstly, APRI was originally derived in a group of patients with chronic hepatitis C. Its usefulness in other forms of chronic liver diseases including chronic hepatitis B remains uncertain. Two studies on patients with chronic hepatitis B showed a poor correlation between liver histology and APRI and a similar observation was also made by our group in Bangladesh. ,, Further, another study also showed poor correlation between APRI and hepatic fibrosis in patients with alcoholic liver disease.  Hence it seems that APRI is unlikely to be very useful in patients with liver diseases other than chronic hepatitis C. This may be due to the possibility that pathogenesis of fibrosis in chronic hepatitis C is different from that in chronic hepatitis B.
| Breath Tests|| |
 C-breath tests for the study of liver function have been developed in order to non-invasively quantify residual liver function in patients with various degrees of liver fibrosis, from minimal stages up to liver cirrhosis. The maximum experience so far exists for the aminopyrine breath test. ,, Most hepatic breath tests measure the microsomal dealcylation of  C-labelled substrates and therefore the cytochrome P450 dependent enzymatic system. The cleaved methyl group is oxidized to formic acid and is finally exhaled as carbon dioxide. Due to its lack of toxicity in low doses, many groups nowadays prefer the use of methacetin. , In addition, the fast metabolism of  C-methacetin enables a more practical modification of the liver function test as a two-point-measurement with breath samples at baseline and 15 minutes after substrate ingestion. However, the hepatic metabolism of methacetin (also of phenacetin and erythromycin) depends on the hepatic blood flow, which might be altered in cirrhotic patients with portosystemic shunts.
Sequential studies performed over the years using various  C-breath test substrates show that increasing degrees of liver fibrosis are paralleled by concomitant modifications in  C-BT results.  Further studies should evaluate the diagnostic yield of  C-breath test in specific clinical situations. It has been seen that the  C-ABT results are progressively impaired as the severity of chronic hepatitis C increases.  Its role in chronic hepatitis B remains to be evaluated. Besides, although the initial results are promising, the presence of overlap in the  C breath test results between different degrees of chronic liver disease may represent a possible drawback of the test. It may be a useful tool to stage disease in patients who cannot, or do not want to, undergo liver biopsy.
| Ultrasound|| |
Ultrasound is unquestionably of great importance in the diagnosis of liver diseases. Indications for an ultrasound examination are the primary diagnosis of chronic liver disease and the screening for hepatocellular carcinoma.  Although ultrasonographic evaluation has proved to be reliable in differentiating cirrhosis from milder stages of fibrosis, its diagnostic value has not been definitely clarified, as documented by the wide range of sensitivity and specificity rates of ultrasonographic parameters.
Ultrasound evaluation of liver fibrosis in chronic liver disease has been performed by assessing various ultrasound factors such as liver size, bluntness of the liver edge, coarseness of the liver parenchyma, nodularity of liver surface, size of the lymph nodes around the hepatic artery, irregularity and narrowness of the inferior vena cava, portal vein velocity or spleen size.  Besides, it has been repeatedly demonstrated that gallbladder wall thickening is associated with periportal fibrosis in the absence of a calculous cholecystitis. 
Certain hemodynamic alterations in liver vessels are observed in chronic hepatic diseases. These alterations are generally the result rather than the cause of hepatic dysfunction and structural changes. Resistance and pulsatility indices, hepatic blood flow, waveforms in hepatic veins and blood velocity of the portal vein and hepatic arteries are parameters susceptible to pathologic and morphologic changes. These parameters can reliably be evaluated by Doppler sonography. The portal vein peak velocity (PVPV) decreases with the progression of chronic viral hepatitis and is closely correlated to histological fibrosis. Also PVPV is significantly different between chronic viral hepatitis and cirrhotic patients and it decreases with progression of the disease. 
The hepatic artery resistive index (HARI) increase in patients with chronic liver disease has been thought to be related to the architectural derangement that occurs within the liver with increasing severity of disease and increases with the rise in histological fibrosis scores. The HARI of patients with chronic viral hepatitis is significantly influenced by the degree of fibrous tissue deposits. HARI and hepatic artery pulsitivity index (HAPI) are significantly greater in patients with moderate or severe fibrosis than in those with mild fibrosis and in normal subjects. 
The hepatic vein waveform is triphasic in all healthy subjects. Abnormal waveforms of the hepatic vein correlate with fibrosis and steatosis in the surrounding parenchyma.  The ratio of HAPV to PVPV (A/P ratio) increases along with the severity or the degree of fibrosis. It has been observed that A/P ratio is an independent predictor of the degree of fibrosis. All patients with severe fibrosis have A/P ratio >3.5, whereas all patients with mild fibrosis have an A/P ratio <3.5. 
Splenic enlargement is a recognized secondary sign of a cirrhotic liver. Although it has been proposed that the spleen length could be an index to differentiate between mild, moderate or severe hepatitis when compared with the cirrhosis group, there is considerable overlap among the groups with no clear separation. 
The fibrosis index (FI) is a new index obtained to differentiate cirrhosis from chronic hepatitis. The formula is as follows:
The FI is higher in cirrhotic patients than in chronic hepatitis; the value of 3.6 as a cut off is considered the optimal value in differentiating chronic hepatitis from cirrhosis with 96% accuracy. 
Although ultrasonographic evaluation has proved reliable in differentiating cirrhosis from milder stages of fibrosis, their diagnostic value has not been definitely clarified, as documented by the wide range of sensitivity and specificity rates. FI is considered the best measurement or index in differentiating chronic hepatitis from cirrhosis with 96% accuracy and may decrease the need for liver biopsy.
| Fibroscan|| |
Fibroscan or transient elastography for liver stiffness measurement (LSM)) is a non-invasive test that is based on the physics of transient elastography to assess liver fibrosis. A specialized ultrasound transducer placed over the liver transmits a mild amplitude, low frequency vibration. The vibration creates an elastic shear wave that moves through the underlying liver tissue. Its velocity is measured using pulse-echo ultrasound. Shear waves propagate more quickly in stiff tissue and liver stiffness increases with increased fibrosis. The machine validates that the measurement is through the liver and the procedure is performed by obtaining multiple validated measurements in each patient, reducing sampling errors. Fibroscan takes less than 5 minutes to perform, and produces immediate, operator-independent results, expressed in kilo-Pascal (kPa). 
The depth of measurement from the skin surface is between 25 mm and 65 mm, limiting its use in obese patients. Morbid obesity or narrow intercostal spaces prevent its use in 5 to 8% of patients. However, newer probes are being developed for obese patients or those who have narrow intercostal spaces. ,,
Several studies have evaluated the accuracy of Fibroscan, blood tests or combinations compared with liver biopsy. ,,,,,,, Most studies ,,,, have evaluated only HCV patients. Only one study  included patients with chronic liver disease of any origin, one included patients with biliary cirrhosis due to PBC or PSC  and one included only patients who were HIV and HCV co-infected.  The studies showed that Fibroscan results are reproducible across operators and time. , All these studies have reported that Fibroscan's diagnostic performance is good, with one study  indicating that it agrees perfectly with liver biopsy.
Studies have demonstrated that Fibroscan is able to discriminate degrees of fibrosis, as staged on the Metavir scale (F0 to F4 where F0 = no fibrosis and F4 = cirrhosis) with high accuracy. The AUROC (area under the receiver operating characteristic curve) values in different studies were F > 2 0.72 to 0.88; F > 3 0.90 to 0.91 and F = 4, 0.95 to 0.99. In a prospective multicenter study of 327 chronic HCV patients, the AUROCs for METAVIR stages F1 to F4 stages were 0.90, 0.88, 0.91 and 0.99.  This suggests that LSM is very accurate in identifying severe fibrosis or cirrhosis (F3-F4), but is less accurate in differentiating lesser degrees of fibrosis (F0-1 from F2).
Fibroscan is an evolving technology, which allows the non-invasive diagnosis of cirrhosis with high accuracy. It is free of side effects and easily repeatable. The ease of performing a Fibroscan also makes it suitable for repeated assessment of fibrosis and a suitable tool to monitor progression of liver disease or effects of therapy. However, no study is yet to addressed the optimal frequency of testing.
| Conclusion|| |
To conclude, the clinical-histological and functional evaluations of patients with chronic hepatitis B should not be considered to be mutually exclusive; rather their use should be optimized in order to provide the best information regarding the diagnosis, prognosis and follow up of patients so as to improve their care. Although liver biopsy remains the gold standard technique for the evaluation of patients with chronic liver disease, different non-invasive tests can be used in particular subsets of patients as a surrogate for liver biopsy.
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Assistant Professor of Hepatology, Bangabandhu Sheikh Mujib Medical University, Dhaka
Source of Support: None, Conflict of Interest: None