Limitations of liver biopsy and non-invasive diagnostic tests for the diagnosis of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis

It is estimated that 30%of the adult population in Japan is affected by nonalcoholic fatty liver disease(NAFLD).Fatty changes of the liver are generally diagnosed using imaging methods such as abdominal ultrasonography(US)and computed tomography(CT),but the sensitivity of these imaging techniques is low in cases of mild steatosis.Alanine aminotransferase levels may be normal in some of these patients,warranting the necessity to establish a set of parameters useful for detecting NAFLD,and the more severe form of the disease,nonalcoholic steatohepatitis(NASH).Although liver biopsy is currently the gold standard for diagnosing progressive NASH,it has many drawbacks,such as sampling error,cost,and risk of complications.Furthermore,it is not realistic to perform liver biopsies on all NAFLD patients.Diagnosis of NASH using various biomarkers,scoring systems and imaging methods,such as elastography,has recently been attempted.The NAFIC score,calculated from the levels of ferritin,fasting insulin,and typeⅣcollagen 7S,is useful for the diagnosis of NASH,while the NAFLD fibrosis score and the FIB-4 index are useful for excluding NASH in cases of advanced fibrosis.This article reviews the limitations and merits of liver biopsy and noninvasive diagnostic tests in the diagnosis of NAFLD/NASH.     

Radiologic evaluation of nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease (NAFLD) is a frequent cause of chronic liver diseases, ranging from simple steatosis to nonalcoholic steatohepatitis (NASH)-related liver cirrhosis. Although liver biopsy is still the gold standard for the diagnosis of NAFLD, especially for the diagnosis of NASH, imaging methods have been increasingly accepted as noninvasive alternatives to liver biopsy. Ultrasonography is a well-established and cost-effective imaging technique for the diagnosis of hepatic steatosis, especially for screening a large population at risk of NAFLD. Ultrasonography has a reasonable accuracy in detecting moderate-to-severe hepatic steatosis although it is less accurate for detecting mild hepatic steatosis, operator-dependent, and rather qualitative. Computed tomography is not appropriate for general population assessment of hepatic steatosis given its inaccuracy in detecting mild hepatic steatosis and potential radiation hazard. However, computed tomography may be effective in specific clinical situations, such as evaluation of donor candidates for hepatic transplantation. Magnetic resonance spectroscopy and magnetic resonance imaging are now regarded as the most accurate practical methods of measuring liver fat in clinical practice, especially for longitudinal follow-up of patients with NAFLD. Ultrasound elastography and magnetic resonance elastography are increasingly used to evaluate the degree of liver fibrosis in patients with NAFLD and to differentiate NASH from simple steatosis. This article will review current imaging methods used to evaluate hepatic steatosis, including the diagnostic accuracy, limitations, and practical applicability of each method. It will also briefly describe the potential role of elastography techniques in the evaluation of patients with NAFLD.     

Noninvasive imaging assessment of non-alcoholic fatty liver disease: Focus on liver scintigraphy

Noninvasive diagnoses of nonalcoholic fatty-liver disease (NAFLD) involve the use of serologic markers and imaging methods, such as conventional ultrasonography (US), computed tomography, and magnetic resonance imaging. Although these methods are reliable for the noninvasive detection of moderate to severe fatty changes in the liver, they are not reliable for detecting nonalcoholic steatohepatitis (NASH) and fibrosis. New imaging technologies, such as US-based transient elastography, acoustic radiation force impulse and magnetic resonance-based elastography, can reportedly be used to determine the severity of liver fibrosis associated with NASH. In this context, the field of nuclear medicine through liver scintigraphy has recently been proposed, and is being explored for use in the diagnosis of NASH. More importantly, nuclear medicine may contribute to the distinction between simple steatosis and NASH. For example, the enhanced release of cytokines and the decrease in the phagocytic activity of Kupffer cells play important roles in the pathogenesis of NASH. Removal of technetium-99m colloid from circulation by Kupffer cell phagocytosis therefore provides a valuable imaging technique. Thus, nuclear medicine is poised to provide useful tools for the evaluation of patients with NAFLD. However, the evidence is still scarce, and more studies with larger samples are needed to identify their role before they are used in clinical practice.     

Importance of imaging and recent developments in diagnosis of nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease (NAFLD) is one of the most common causes of chronic liver disease and is a major public health problem worldwide. It is a spectrum that includes simple steatosis, nonalcoholic steatohepatitis (NASH), fibrosis and cirrhosis. Recently, NAFLD prevalence in children and adolescents has increased too. The increasing prevalence has resulted in NASH-related chronic liver disease. Therefore, early diagnosis and treatment is quite important. Although liver biopsy is still the gold standard for diagnosis and staging of NAFLD, particularly for the diagnosis of NASH, imaging methods such as ultrasonography, computed tomography, magnetic resonance imaging with chemical shift imaging and especially magnetic resonance spectroscopy and elastography have been increasingly approved as noninvasive alternative methods. The aim of this review is to analyze the diagnostic accuracy and limitations of the imaging methods and recent developments in the diagnosis of NAFLD.     

非酒精性脂肪性肝病的无创性诊断方法

肝活组织检查（LB）是评估非酒精性脂肪性肝病（NAFLD）肝脏病理损伤程度的＂金标准＂,但因其有创性,未能广泛应用于临床。近年来非酒精性脂肪性肝炎（NASH）和进展期肝纤维化无创诊断方法研究进展较快,从临床及生物化学指标、生物标志物、影像学技术方面简述了诊断价值较高的部分无创诊断方法。目前认为NAFLD无创诊断方法尚不能取代LB,但联合应用血清细胞角蛋白18片段和NAFLD纤维化评分、瞬时弹性成像可初步诊断NASH及伴或不伴进展期肝纤维化,并进一步确定LB的使用。     

Prospective comparison of transient elastography,point shear wave elastography,APRI and FIB‐4 for staging liver fibrosis in chronic viral hepatitis

Ultrasound‐based elastography and serum indexes have been individually validated as noninvasive methods for staging liver fibrosis in chronic viral hepatitis. We aimed to compare the accuracy of transient elastography (TE), shear wave elastography (SWE), aspartate aminotransferase to platelet index (APRI) and Fibrosis‐4 index (FIB‐4) with the METAVIR liver fibrosis staging in viral hepatitis patients. We enrolled 121 treatment‐naïve chronic hepatitis B and C monoinfected patients. All underwent liver biopsy had biochemistry tests and liver stiffness measurements by TE using M and XL probes followed by point SWE performed on the same day. The accuracy of each method for predicting different fibrosis stages was demonstrated as an area under the receiver operating characteristic (AUROC) curves. The AUROCs of TE using M and XL probes, SWE, APRI and FIB‐4 were 0.771, 0.761, 0.700, 0.698 and 0.697, respectively, for significant fibrosis; 0.974, 0.973, 0.929, 0.738 and 0.859, respectively, for advanced fibrosis; and 0.954, 0.949, 0.962, 0.765 and 0.962, respectively, for cirrhosis. TE using the M probe was comparable to the XL probe in detecting all fibrosis stages. TE was superior to SWE for assessing significant fibrosis and advanced fibrosis. For cirrhosis, the performances of TE, SWE and FIB‐4 were similar. APRI was least accurate in liver fibrosis staging. To conclude, for patients with viral hepatitis, TE using either M or XL probe is an effective noninvasive test for assessing liver fibrosis, particularly advanced fibrosis and cirrhosis, while SWE and FIB‐4 possess an excellent accuracy in predicting cirrhosis.     

Transient elastography and other noninvasive tests to assess hepatic fibrosis in patients with viral hepatitis

Summary. The limitations of liver biopsy (invasive procedure, sampling errors, inter‐observer variability and nondynamic fibrosis evaluation) have stimulated the search for noninvasive approaches for the assessment of liver fibrosis in patients with viral hepatitis. A variety of methods including the measurement of liver stiffness, using transient elastography, and serum markers, ranging from routine laboratory tests to more complex algorithms or indices combining the results of panels of markers, have been proposed. Among serum indices, Fibrotest has been the most extensively studied and validated. Transient elastography appears as a promising method but has been mostly validated in chronic hepatitis C with performance equivalent to that of serum markers for the diagnosis of significant fibrosis. The combination of both approaches as first‐line assessment of liver fibrosis could avoid the performance of liver biopsy in the majority of patients with chronic hepatitis C, a strategy that deserves further evaluation in patients with hepatitis B or HIV‐HCV coinfection. Transient elastography also appears to be an excellent tool for early detection of cirrhosis and may have prognostic value in this setting. Guidelines are now awaited for the use of noninvasive methods in clinical practice.     

Can Nash Be Diagnosed,Graded, and Staged Noninvasively?

Nonalcoholic bland steatosis and nonalcoholic steatohepatitis (NASH) are stages in the spectrum of nonalcoholic fatty liver disease (NAFLD). NASH may progress to end-stage liver disease. Liver biopsy distinguishes between patients with NASH and no NASH and can stage fibrosis. Markers of hepatocyte apoptosis hold promise as noninvasive tests for NASH diagnosis. Several scoring systems that combine routine clinical and laboratory variables and some proprietary panels can assist in predicting fibrosis severity. Noninvasive imaging modalities are reasonably accurate available tools to determine severity of fibrosis in NAFLD, but none of them yet can replace liver biopsy.     

Acoustic radiation force imaging sonoelastography for noninvasive staging of liver fibrosis

AIM: To investigate the diagnostic accuracy of acoustic radiation force impulse (ARFI) imaging as a noninvasive method for the assessment of liver fibrosis in chronic hepatitis C (CHC) patients.METHODS: We performed a prospective blind comparison of ARFI elastography, APRI index and FibroMax in a consecutive series of patients who underwent liver biopsy for CHC in University Hospital Bucharest. Histopathological staging of liver fibrosis according to the METAVIR scoring system served as the reference. A total of 74 patients underwent ARFI elastography, APRI index, FibroMax and successful liver biopsy.RESULTS: The noninvasive tests had a good correlation with the liver biopsy results. The most powerful test in predicting fibrosis was ARFI elastography. The diagnostic accuracy of ARFI elastography, expressed as area under receiver operating characteristic curve (AUROC) had a validity of 90.2% (95% CI AUROC =0.831-0.972, P < 0.001) for the diagnosis of significant fibrosis (F ≥ 2). ARFI sonoelastography predicted even better F3 or F4 fibrosis (AUROC = 0.993, 95% CI =0.979-1).CONCLUSION: ARFI elastography had very good accuracy for the assessment of liver fibrosis and was superior to other noninvasive methods (APRI Index,FibroMax) for staging liver fibrosis.     

Acoustic radiation force impulse imaging for non‐invasive assessment of liver fibrosis in chronic hepatitis B

Acoustic radiation force impulse (ARFI) imaging is a novel ultrasound‐based elastography method that is integrated in a conventional ultrasound machine. It might provide an alternative method to transient elastography for the noninvasive assessment of liver fibrosis. While previous studies have shown comparable diagnostic accuracy of ARFI to transient elastography in chronic hepatitis C, the aim of the present prospective multicenter study was to evaluate ARFI for the assessment of liver fibrosis in chronic hepatitis B. ARFI imaging involves the mechanical excitation of tissue using short‐duration acoustic pulses to generate localized displacements in tissue. The displacements result in shear‐wave propagation which is tracked using ultrasonic, correlation‐based methods and recorded in m/s. In the present international prospective study, patients infected with chronic hepatitis B received ARFI imaging, blood tests and if available transient elastography. The results were compared to liver biopsy as reference method analysed by a central pathologist. In 92 of 114 patients, a comparison of ARFI with transient elastography was possible. ARFI imaging and transient elastography correlated significantly with histological fibrosis stage. The diagnostic accuracy expressed as areas under ROC curves for ARFI imaging and transient elastography was 0.75 and 0.83 for the diagnosis of significant fibrosis (F ≥ 2), 0.93 and 0.94 for the diagnosis of severe fibrosis (F ≥ 3), and 0.97 and 0.93 for the diagnosis of liver cirrhosis, respectively. No significant difference was found between ARFI and transient elastography. ARFI imaging is a reliable ultrasound‐based method for the assessment of advanced stages of liver fibrosis in chronic hepatitis B.     

Non-invasive assessment of liver fibrosis in patients with chronic hepatitis B

In patients with chronic hepatitis B (CHB), liver fibrosis assessment is essential not only for determining prognosis but also for identifying patients who should receive treatment. Liver biopsy is limited by its invasiveness and sampling error. To explore effective non-invasive methods for liver fibrosis assessment, we reviewed international literature published over the past decade that focused on patients with CHB. Biomarker panels such as API, FIB-4, Forns Index, HepaScore, FibroMeter, FibroTest, Zeng Index and Hui Index detect advanced fibrosis and cirrhosis with fairly satisfactory accuracy with area under the receiver-operating characteristics curve higher than 0.85. However, most panels and the suggested cutoffs have not been independently validated. Transient elastography is accurate in detecting advanced fibrosis and cirrhosis, and the relative cutoffs have been defined. False-positive results may, however, occur in cases of active necroinflammation and cholestasis. Other promising imaging methods such as acoustic radiation force impulse and magnetic resonance elastography still require further validating studies. We conclude that transient elastography, FibroTest and API are the most widely validated. Transient elastography has been validated as the most useful non-invasive method for liver fibrosis assessment. To improve non-invasive performance of detecting liver fibrosis, a combined application of transient elastography and biomarkers may be the preferred course of action.     

Features, diagnosis, and treatment of nonalcoholic fatty liver disease

As the global incidence of obesity has increased, nonalcoholic fatty liver disease (NAFLD) has become a worldwide health concern. NAFLD occurs in children and adults of all ethnicities and includes isolated fatty liver and nonalcoholic steatohepatitis (NASH). Patients with NASH are at risk for developing cirrhosis, hepatic decompensation, and hepatocellular carcinoma and have increased all-cause mortality. NAFLD is associated with a variety of clinical conditions and is an independent risk factor for hepatocellular carcinoma. The pathogenesis of NAFLD and the specific steps that lead to NASH and advanced fibrosis are not fully understood, although researchers have found that a combination of environmental, genetic, and metabolic factors lead to advanced disease. There have been improvements in noninvasive radiographic methods to diagnose NAFLD, especially for advanced disease. However, liver biopsy is still the standard method of diagnosis for NASH. There are many challenges to treating patients with NASH, and no therapies have been approved by the U.S. Food and Drug Administration; multimodal approaches are being developed and becoming the standard of care. We review pathogenesis and treatment approaches for the West's largest liver-related public health concern.     

Three-dimensional magnetic resonance imaging for stringent diagnosis of advanced fibrosis associated with nonalcoholic steatohepatitis

Background

The definitive diagnosis of nonalcoholic steatohepatitis (NASH) is currently based on histopathological assessment. This study aimed to elucidate the utility of a novel noninvasive method, three-dimensional magnetic resonance imaging (3D-MRI), for diagnosing advanced fibrosis in patients with NASH, using histopathological diagnosis as the reference standard.

Methods

This retrospective study included 30 consecutive patients who had been diagnosed with NASH by histopathology and had undergone 3D-MRI before biopsy. 3D-MRI provided a three-dimensional reconstruction of the liver from contrast-enhanced hepatobiliary phase MR images. In the present study, histopathological advanced fibrosis was defined as stage 3 and 4 NASH. Advanced fibrosis, diagnosed by 3D-MRI, was considered to be diffuse irregularity of the entire surface of the liver. The diagnostic features of 3D-MRI and the noninvasive evaluation systems (APRI, FIB-4 index, and BARD score) for identifying advanced and nonadvanced fibrosis of NASH were determined and compared.

Results

Nine (30 %) of the 30 study patients were diagnosed histopathologically with advanced fibrosis, and 11 (37 %) of 30 patients were diagnosed with advanced fibrosis using 3D-MRI. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of 3D-MRI for diagnosing advanced fibrosis were 100, 90, 82, and 100 %, respectively. The sensitivities of APRI, the FIB-4 index, and BARD score ranged from 78 to 89 %, the specificities from 71 to 90 %, the PPVs from 54 to 78 %, and the NPVs from 88 to 94 %.

Conclusion

Compared with the common noninvasive methods for diagnosing advanced fibrosis associated with NASH, 3D-MRI was more accurate.     

Noninvasive markers of fibrosis: key concepts for improving accuracy in daily clinical practice

Noninvasive markers of fibrosis have emerged as an alternative to the staging of fibrosis by means of liver biopsy. Apart from being noninvasive and thus lacking the adverse effects of liver biopsy, they offer some advantages such as reduced risk of sampling error, objectiveness in the interpretation of the result, appropriateness for repeated measurements and lower cost. Many studies have validated different panels of blood markers and imaging/transient elastography for the estimation of fibrosis with acceptable accuracy. Clinical scenarios leading to inacurate or failed estimation must be acknowledged, as well as the fact that performance of blood markers and transient elastography, and their diagnostic cut-off values vary among specific liver diseases. The combination of two blood markers or of a blood marker and transient elastography has been shown to increase accuracy of the estimation. Further, unlike liver biopsy the noninvasive markers of fibrosis are not associated with a ceiling effect after cirrhosis is identified, but can discriminate early from advanced stages of cirrhosis. Longitudinal studies have shown their utility as predictors of complications from portal hypertension and mortality, outperforming liver biopsy. In conclusion, noninvasive markers of fibrosis provide major advantages over liver biopsy. The reported performance of some of the available tests particularly when used in combination make them a reliable tool, very attractive for daily clinical practice.     

Noninvasive evaluation of nonalcoholic fatty liver disease: Current evidence and practice

With the increasing number of individuals with diabetes and obesity,nonalcoholic fatty liver disease(NAFLD) is becoming increasingly prevalent,affecting one-quarter of adults worldwide. The spectrum of NAFLD ranges from simple steatosis or nonalcoholic fatty liver(NAFL) to nonalcoholic steatohepatitis(NASH). NAFLD, especially NASH, may progress to fibrosis, leading to cirrhosis and hepatocellular carcinoma. NAFLD can impose a severe economic burden,and patients with NAFLD-related terminal or deteriorative liver diseases have become one of the main groups receiving liver transplantation. The increasing prevalence of NAFLD and the severe outcomes of NASH make it necessary to use effective methods to identify NAFLD. Although recognized as the gold standard, biopsy is limited by its sampling bias, poor acceptability, and severe complications, such as mortality, bleeding, and pain. Therefore, noninvasive methods are urgently needed to avoid biopsy for diagnosing NAFLD. This review discusses the current noninvasive methods for assessing NAFLD,including steatosis, NASH, and NAFLD-related fibrosis, and explores the advantages and disadvantages of measurement tools. In addition, we analyze potential noninvasive biomarkers for tracking disease processes and monitoring treatment effects, and explore effective algorithms consisting of imaging and nonimaging biomarkers for diagnosing advanced fibrosis and reducing unnecessary biopsies in clinical practice.     

Nonalcoholic fatty liver in Asia: Firmly entrenched and rapidly gaining ground

Nonalcoholic fatty liver disease (NAFLD) is becoming an important chronic liver disorder in Asia. Prevalence figures show regional variations but at least 10% of the general population in Asia have fatty liver. Fatty liver can develop with relatively small changes in weight (2-3?kg), often with increasing central adiposity. The metabolic syndrome may precede or follow NAFLD. Overt diabetes is present in one-third of cases but when oral glucose tolerance tests are performed, a further third of individuals have impaired glucose tolerance or diabetes. Natural history data are still scarce but cases of advanced hepatic fibrosis and hepatocellular carcinoma are now regularly reported. Many cases of cryptogenic cirrhosis are also attributable to NAFLD. Histological progression has been demonstrated for patients with NASH as well as for those with hepatic steatosis alone. Genetic factors may in part contribute to the rise in NAFLD. Polymorphisms within apolipoprotein C3 (APOC3) gene have been linked to NAFLD in lean Indian men. Although a number of other polymorphisms involving genes controlling adipose distribution, insulin signalling, adipokine responses and hepatic fibrosis have been reported, these studies have been underpowered. Transient elastography could help in detecting and monitoring hepatic fibrosis but further refinements in technique are necessary for obese individuals. Of the biomarkers, hyaluronic acid and cytokeratin-18 fragment testing show promise as markers of hepatic fibrosis and NASH, respectively. Lifestyle alterations including dietary changes and increased physical activity remain the cornerstone of management. Attention should be paid to prevention through public education of campaigns addressing the increase in both adult and childhood obesity.     

Noninvasive Markers of Fibrosis and Inflammation in Nonalcoholic Fatty Liver Disease

The prevalence of nonalcoholic fatty liver disease (NAFLD) is increasing worldwide. Nonalcoholic steatohepatitis (NASH) and fibrosis are associated with elevated morbidity and mortality, and a means of differentiating these diseases from simple steatosis (SS) is needed. Liver biopsy in all patients with NAFLD is not feasible, thus necessitating a noninvasive method for discerning the presence of inflammation and fibrosis. Of the various serum markers, cytokeratin-18 seems to best predict NASH, the NAFLD Fibrosis Score is most closely correlated with fibrosis, and transient elastography can be used for diagnosis of cirrhosis, or to exclude cirrhosis, although its utility is limited by obesity.     

Noninvasive investigations for non alcoholic fatty liver disease and liver fibrosis

Non-alcoholic fatty liver disease (NAFLD) includes a spectrum of diseases that have insulin resistance in common and are associated with metabolic conditions such as obesity, type 2 diabetes mellitus, and dyslipidemia. NAFLD ranges from simple liver steatosis, which follows a benign course, to nonalcoholic steatohepatitis (NASH), a more severe entity, with necroinflmmation and f ibrosis, which can progress to cryptogenic cirrhosis and end-stage liver disease. Liver biopsy remains the gold standard for evalu...     

Noninvasive diagnosis of cirrhosis: A review of different imaging modalities

Progressive hepatic fibrosis can lead to cirrhosis, so its early detection is fundamental. Staging fibrosis is also critical for prognosis and management. The gold standard for these aims is liver biopsy, but it has several drawbacks, as it is invasive, expensive, has poor acceptance, is prone to inter observer variability and sampling errors, has poor repeatability, and has a risk of complications and mortality. Therefore, non-invasive imaging tests have been developed. This review mainly focuses on the role of transient elastography, acoustic radiation force impulse imaging, and magnetic resonance-based methods for the noninvasive diagnosis of cirrhosis.