Abstract

Abstract Background

The presence and progression of hepatic (liver) fibrosis into cirrhosis is a prognostic variable having impact on survival in people with alcoholic liver disease. Liver biopsy, although an invasive method, is the recommended 'reference standard' for diagnosis and staging of hepatic fibrosis in people with liver diseases. Transient elastography is a non‐invasive method for assessing and staging hepatic fibrosis.

To determine the diagnostic accuracy of transient elastography for diagnosis and staging hepatic fibrosis in people with alcoholic liver disease when compared with liver biopsy. To identify the optimal cut‐off values for differentiating the five stages of hepatic fibrosis.

The Cochrane Hepato‐Biliary Group Controlled and Diagnostic Test Accuracy Studies Registers, The Cochrane Library, MEDLINE (OvidSP), EMBASE (OvidSP), and the Science Citation Index Expanded (last search August 2014).

Diagnostic cohort and diagnostic case‐control study designs that assessed hepatic fibrosis in participants with alcoholic liver disease with transient elastography and liver biopsy, irrespective of language or publication status. The study participants could be of any sex and ethnic origin, above 16 years old, hospitalised or managed as outpatients. We excluded participants with viral hepatitis, autoimmunity, metabolic diseases, and toxins.

We followed the guidelines in the draft Cochrane Handbook for Systematic Reviews of Diagnostic Test Accuracy.

Five retrospective and nine prospective cohort studies with 834 participants provided data for the review analyses. Authors of seven of those studies sent us individual participant data. The risk of bias in the included studies was high in all but three studies. We could identify no serious concerns regarding the applicability of the studies in answering the main study question of our review, namely to use transient elastography to diagnose hepatic fibrosis. We could not identify the optimal cut‐off values for the fibrosis stages. The definition of the diagnosis of alcoholic liver disease was not provided in one study and was not clearly defined in two studies, but it was clear in the remaining 11 studies. The study authors used different liver stiffness cut‐off values of transient elastography for the hepatic fibrosis stages.

There was only one study (103 participants) with data on hepatic fibrosis stage F1 or worse, with a cut‐off of 5.9 kPa, and reporting sensitivity of 0.83 (95% confidence interval (CI) 0.74 to 0.90) and specificity of 0.88 (95% CI 0.47 to 1.00). The summary sensitivity and specificity of transient elastography for F2 or worse (seven studies with 338 participants and with cut‐offs around 7.5 kPa (range 7.00 to 7.8 kPa)) were 0.94 and 0.89 with LR+ 8.2 and LR‐ 0.07, which suggests that transient elastography could be useful to rule out the presence of significant hepatic fibrosis, thus avoiding liver biopsy.

Due to the wide range of cut‐off values (from 8.0 to 17.0 kPa) found in the 10 studies with 760 participants with hepatic fibrosis F3 or worse, we fitted a hierarchical summary receiver operating characteristic (HSROC) model and estimated a summary ROC (SROC) curve. The sensitivity of the 10 studies varied from 72% to 100% and the specificity from 59% to 89%. We performed an additional analysis by including the studies with a cut‐off value of around and equal to 9.5 kPa (range 8.0 to 11.0 kPa). The summary sensitivity and specificity of transient elastography (eight studies with 564 participants) were 0.92 and 0.70 with LR+ 3.1 and LR‐ 0.11, which suggests that transient elastography could also be useful to rule out the presence of severe hepatic fibrosis (F3 or worse), avoiding liver biopsy. We carried out a sensitivity analysis by considering only the studies with a cut‐off value equal to 9.5 kPa and the result did not differ.

We performed an HSROC analysis and reported an SROC curve for hepatic fibrosis stage F4 (cirrhosis). The HSROC analysis suggested that when the cut‐off value changes, there is a wide variation in specificity and a more limited variation in sensitivity. We performed an additional analysis with the studies with the most commonly used cut‐off value of 12.5 kPa. The summary sensitivity and specificity of transient elastography (seven studies with 330 participants) were 0.95 and 0.71 with LR+ 3.3 and LR‐ 0.07, which again suggests that transient elastography could be useful to rule out the presence of cirrhosis, avoiding liver biopsy.

We identified a small number of studies with a few participants and were unable to include several studies, which raises the risk of outcome reporting bias. With these caveats in mind, transient elastography may be used as a diagnostic method to rule out liver cirrhosis (F4) in people with alcoholic liver disease when the pre‐test probability is about 51% (range 15% to 79%). Transient elastography may also help in ruling out severe fibrosis (F3 or worse). Liver biopsy investigation remains an option if the certainty to rule in or rule out the stage of hepatic fibrosis or cirrhosis remains insufficient after a clinical follow‐up or any other non‐invasive test considered useful by the clinician.

The proposed cut‐off values for the different stages of hepatic fibrosis may be used in clinical practice, but caution is needed, as those values reported in this review are only the most common cut‐off values used by the study authors. The best cut‐off values for hepatic fibrosis in people with alcoholic liver disease could not be established yet.

In order to diagnose correctly the stage of hepatic fibrosis in people with alcoholic liver disease using transient elastography assessment, the studies should consider a single aetiology. Hepatic fibrosis should be diagnosed with both transient elastography and liver biopsy and in this sequence, and transient elastography cut‐off values should be pre‐specified and validated. The time interval between the two investigations should not exceed three months, which is the interval mainly valid for people without cirrhosis, and assessment of results should be properly blinded. Only studies with low risk of bias, fulfilling the Standards for Reporting of Diagnostic Accuracy may answer the review question.

Author(s)

Chavdar S Pavlov, Giovanni Casazza, Dimitrinka Nikolova, Emmanuel Tsochatzis, Andrew K Burroughs, Vladimir T Ivashkin, Christian Gluud

Abstract

Plain language summary

Transient elastography for measurement of liver fibrosis and cirrhosis in people with alcoholic liver disease

Background

Liver fibrosis is a change in the microscopic structure of the liver because of liver inflammation. After many years of excessive alcohol consumption, liver fibrosis progresses to cirrhosis. Abstaining from alcohol may stop the fibrosis from further progression into significant or severe fibrosis and cirrhosis. The latter lead to complications of underlying diseases, including cancer.

Measurement of the amount of fibrosis is called staging. There are five stages (F0: no scarring (no fibrosis); F1: minimal scarring; F2: scarring has occurred and extends outside the liver area (significant fibrosis); F3: fibrosis spreading and forming bridges with other fibrotic liver areas (severe fibrosis); F4: cirrhosis or advanced scarring). Cut‐off values may distinguish between the different stages of fibrosis, but in people with alcoholic liver disease, the best cut‐off values have not been determined yet.

Rationale

Liver biopsy is where a sample of tissue is taken from the liver using a small needle. It is the standard method of detecting and measuring fibrosis.

Transient elastography measures stiffening of the liver caused by progressive scarring, but it has not been validated in people with alcoholic liver disease.

Aims

To find out how well transient elastography may determine the presence or absence of fibrosis and if it can stage fibrosis in people with alcoholic liver disease when compared with liver biopsy.

Methods

Using Cochrane methods and searching the literature (August 2014), the review authors obtained results from 14 studies (834 participants), out of which only seven included people with only alcoholic liver disease. Participants underwent both transient elastography (the index test) and liver biopsy (the standard test).

Findings and conclusions

The number of studies and participants was small and the participants had different severity of liver fibrosis. Only four studies were judged good quality.

Transient elastography fibrosis stage F2 or worse (significant fibrosis)

There were seven studies with 338 participants: 81% of people had significant fibrosis. Out of 1000 people, 810 will have significant fibrosis. Of these 810 people, 49 people would be missed even though they had significant fibrosis. A clinical follow‐up could provide physicians with knowledge for the next diagnostic step. The remaining 190 people would not have significant fibrosis; 21 people would have unnecessary worries about their liver fibrosis stage.

Transient elastography fibrosis stage F3 or worse (severe fibrosis)

There were eight studies with 564 participants: 61% of people had severe fibrosis. Out of 1000 people, 610 would have severe fibrosis. Of these 610 people, 49 people would be missed even though they had severe fibrosis. A clinical follow‐up could provide physicians with knowledge for the next diagnostic step. The remaining 390 people would not have severe fibrosis; 117 people would have unnecessary worries about their liver fibrosis stage.

Transient elastography fibrosis stage F4 (cirrhosis)

There were seven studies with 330 participants: 51% of people had cirrhosis. Out of 1000 people, 510 will have cirrhosis. Of these 510 people, 26 people would be missed even though they had cirrhosis. A clinical follow‐up could provide physicians with knowledge for the next diagnostic step. The remaining 490 people would not have cirrhosis; 143 people would have unnecessary worries about their liver fibrosis stage.

Transient elastography may be used as a diagnostic tool to rule out liver cirrhosis and may also help in ruling out severe fibrosis in people with alcoholic liver disease. Liver biopsy investigation still remains an option if the certainty to rule in or rule out the stage of hepatic fibrosis or cirrhosis remains insufficient after a clinical follow‐up or any other non‐invasive test considered useful by the clinician.

The best cut‐off values for differentiating between the five liver fibrosis stages could still not be established.

Future studies should include only people with alcoholic liver disease. Hepatic fibrosis should be diagnosed with transient elastography followed by liver biopsy and the transient elastography cut‐off values of liver stiffness for the different stages of liver fibrosis should be decided before the test occurs. The time interval between the two tests should not exceed three months, an interval that is mainly valid for people without cirrhosis. Assessors of results should be unaware of the treatment given.

Author(s)

Chavdar S Pavlov, Giovanni Casazza, Dimitrinka Nikolova, Emmanuel Tsochatzis, Andrew K Burroughs, Vladimir T Ivashkin, Christian Gluud

Reviewer's Conclusions

Authors' conclusions

Implications for practice

We identified a small number of studies with a few participants each and were unable to include several studies, which raises the risk of outcome reporting bias. With these caveats in mind, transient elastography may be used as a diagnostic method to rule out liver cirrhosis (F4) in people with alcoholic liver disease when the pre‐test probability is 51% (range 15% to 79%). Transient elastography may also help in ruling out severe fibrosis (F3 or worse). The use of transient elastography for severe fibrosis and cirrhosis may lead to a reduced need for liver biopsy. Liver biopsy investigation still remains an option if the certainty to rule in or rule out the stage of hepatic fibrosis or cirrhosis remains insufficient after a clinical follow‐up or any other non‐invasive test considered useful by the clinician.

The proposed cut‐off values for the different stages of hepatic fibrosis may be used in clinical practice, but one should be very cautious, as those reported in this review were only the most common cut‐off values used by the study authors. The best cut‐off values for hepatic fibrosis in people with alcoholic liver disease could not be established yet.

Implications for research

In order to obtain precise and reliable accuracy results of transient elastography, used for diagnosing hepatic fibrosis in people with alcoholic liver disease, prospective studies of adequate sample size, enrolling only participants with alcoholic liver disease, need to be performed. Hepatic fibrosis should be diagnosed with both transient elastography and liver biopsy (the reference standard) and in this sequence, and the optimal cut‐off values of transient elastography should be identified and validated for hepatic fibrosis in people with alcoholic liver disease. The time interval between transient elastography and liver biopsy investigations in people without cirrhosis should not exceed three months, and assessment of results should be properly blinded, as only studies with low risk of bias, fulfilling the Standards for Reporting of Diagnostic Accuracy (The STARD statement) may answer the review questions.