Noninvasive Diagnosis Of Fibrosis Research Articles

Інвазивна та неінвазивна діагностика фіброзу підшлункової залози у хворих з ускладненими формами хронічного панкреатиту

The purpose of the study was to identify the patterns of changes in the state of the parenchyma of the pancreas in patients with complicated forms of chronic pancreatitis with evaluation of the diagnostic effectiveness of shear wave elastometry (graphy). Materials and methods. For the period from 2006 to 2018 58 patients with complicated forms of chronic pancreatitis were examined. The average age of patients is (47.1±3.2) years old. The medical history ranged from 3 to 15 years. The basis of morphological studies were biopsies of the pancreas obtained during surgery. Ultrasound elastometry and pancreatic parenchymal elastography were performed by transcutaneous shear wave approach in Shear Wave Elastography. Software consistency was assessed by the nature of the color mapping. Results and discussion. The morphometry of the volume parts of the structural components of the pancreas showed that with the development of complicated chronic pancreatitis there is an increase in the area of fibrous tissue and a decrease in the area of acinar components. The proof of this is the strong inverse relationship between the degree of fibrosis and the volume fraction of acinar tissue (r= -0.83; р <0.05), as well as the direct relationship between the degree of fibrosis and the volume fraction of connective tissue (r=0.61; р <0.05). If at a fibrosis of the III degree acinar tissue occupied (25.39±2.01)%, connective – (64.33±3.85)%, fatty – (6.42±4.48)%, at a fibrosis of the IV degree noted the following: the proportion of acinar tissue was only (2.86±0.76)%, connective – (74.11±4.17)%, and (20.14±4.29)% was adipose tissue. Such manifestations indicated severe irreversible changes in the external secretory function of the pancreas. When assessing changes in the stiffness of the pancreatic parenchyma with the deepening of fibrosis processes and data from transcutaneous shear wave elastography, it was found that the degree of fibrosis according to morphological data correlated with the degree of fibrosis according to shear wave elastography, r = 0.71; p <0.05. The following patterns were noted. Grade II pancreatic fibrosis was characterized by intralobular fibrosis, which covered 26-50% of the gland area, which corresponded to the shear wave elastography data in green-blue color (5.98-7.05 kPa). Grade III pancreatic fibrosis corresponded to intralobular fibrosis, which covered 51-75% of the gland area in shear wave elastography in green-yellow color (7.06-9.06 kPa). Grade IV pancreatic fibrosis was characterized by intralobular fibrosis, which covered 76-100% of the gland area, which corresponded to shear wave elastography data in yellow-red color (> 9.07 kPa). Conclusion. Thus, the objectification of shear wave elastography indicators of the pancreas based on the correlation of histological evaluation and morphometric indicators of structural changes in the pathological process allows to consider transcutaneous shear wave elastography as a promising and reliable method of non-invasive diagnosis of fibrosis in chronic pancreatitis

Noninvasive diagnosis of fibrosis in non-alcoholic fatty liver disease: diagnostic accuracy of different scores

Non-alcoholic fatty liver disease (NAFLD) is a spectrum of pathologies characterized by liver damage without history of excessive alcohol intake. Advanced fibrosis, generally detected by transient elastography (TE), is the most significant predictor of poor prognosis and mortality among these patients. This study aimed at assessing the accuracy of five noninvasive methods, compared to TE, for the evaluation of severity of liver fibrosis in patients with NAFLD. The cohort included 41 patients, in whom the result of TE was compared to AST/ALT ratio, BARD Score (Body Mass Index, AST/ALT ratio, diabetes), AST To Platelet Ratio Index (APRI), Fibrosis-4 Index (FIB-4 Index) and NAFLD Fibrosis Score (NFS). The severity of fibrosis, assessed by TE, was the following: F0 (absence of fibrosis): 17%, F1 (mild): 39%, F2 (moderate): 17%, F3 (advanced): 10%, F4 (cirrhosis): 17%. Performances of the diagnostic scores were: 49% for AST/ALT ratio, 68% for BARD Score, 73% for APRI, 59% and 71% for the lower and upper cut-off of FIB-4 Index, 61% and 76% for the lower and upper cut-off of NFS. Considering the scores compared to TE, AST/ALT ratio was not enough sensitive, while BARD Score had better diagnostic performance and APRI had a superior accuracy than the formers. However, FIB-4 and NFS were the most useful tests and their performance could be improved through the use of a single cut-off. These findings demonstrated that the most accurate scores, compared to TE, were NFS and FIB-4.

Non-invasive diagnosis of fibrosis in patients with CHC and obesity

The aimof the study was to assess the possibilities of noninvasive diagnosis of liver fibrosis (FIB-4 and APRI indices) in patients with CHC and abdominal obesity.Materials and methods.52 men with CHC were examined. Genotype 1 was determined in 24 patients, genotype 3 in 19 patients and genotype 2 in 9 patients. According to the severity of fibrosis, patients with CHC were divided: without fibrosis (F0) - 12 patients, with weak fibrosis (F1) - 17 patients, with moderate fibrosis (F2) - 10 patients, with severe fibrosis (F3) - 8 patients, cirrhosis of the liver (F4) was detected in 5 patients. According to a liver biopsy, steatosis was found in 18 patients with CHC. Abdominal obesity was found in 34 patients with CHC. Non-invasive diagnosis of liver fibrosis was assessed using routine FIB-4 and APRI indices. The interval of values of FIB-4 and APRI, not related to the criteria for assessing the stage of fibrosis F3 and F4, we have conventionally designated as the «gray zone». The presence of insulin resistance was evaluated at HOMA-IR> 2.Results. Key values of the FIB-4 index in patients with CHC and abdominal obesity were found significantly more often than when calculating the APRI index. Insulin resistance in patients with CHC and abdominal obesity was statistically significantly more frequent than in patients with CHC and without abdominal obesity. At stages F3-F4 in patients with CHC, abdominal obesity and insulin resistance, APRI values were recorded more often in the «gray zone»than FIB-4 values.Conclusion.The FIB-4, APRI, HOMA-IR indices can be used in patients with CHC and abdominal obesity during the follow-up and dynamic monitoring of patients with CHC to highlight risk groups. FIB-4 was significantly more informative for determining the stage of fibrosis than APRI in patients with CHC and abdominal obesity with insulin resistance (HOMA-IR> 2).

Liver stiffness measurement in patients with nodular regenerative hyperplasia undergoing magnetic resonance elastography

Nodular regenerative hyperplasia (NRH) may mimic cirrhosis at imaging. We aim to investigate the effect of NRH on liver stiffness measurement (LSM) obtained with magnetic resonance elastography (MRE). This retrospective, Institutional Review Board-approved study included 37 subjects with NRH (Group 1) and no or minimal fibrosis (F0-F1), a control group (Group 2) made of 30 subjects with non-advanced fibrosis (F0-F2), and a control group (Group 3) made of 30 subjects with advanced fibrosis (F3-F4), all with available MRE. LSM was measured in each subject along with assessment of hepatic morphological features of cirrhosis and signs of portal hypertension. The significance of the difference in mean LSM between Group 1 and 2 and between Group 1 and 3 was evaluated using the Mann-Whitney U test. The difference in distribution of imaging features among groups was assessed using the Pearson χ2 or Fisher exact test. The mean ± SD LSM in Group 1 (3.56 ± 1.10kPa) was significantly higher compared to Group 2 (2.91 ± 0.52kPa, P = 0.019) and significantly lower compared to Group 3 (7.18 ± 2.08kPa, P < 0.001). Twelve (32%) patients with NRH had LSM ≥ 4.11kPa, and 6 (16%) patients had LSM ≥ 4.71kPa. Surface nodularity (P = 0.032) and caudate lobe hypertrophy (P = 0.004) were more commonly visualized in Group 1 than in Group 2. At least one feature of portal hypertension was observed in 16 (43%) NRH subjects. NRH may increase the LSM obtained with MRE and may represent a confounding factor when using liver stiffness for the non-invasive diagnosis of fibrosis.

FRI-413 - Noninvasive diagnosis of fibrosis in the patients with hepatitis C virus infection treated with direct-acting antivirals

FRI-413 - Noninvasive diagnosis of fibrosis in the patients with hepatitis C virus infection treated with direct-acting antivirals

Putting it all together: Noninvasive diagnosis of fibrosis in nonalcoholic fatty liver disease in adults and children.

Putting it all together: Noninvasive diagnosis of fibrosis in nonalcoholic fatty liver disease in adults and children.

Covering the Cover

In a nationwide, population-based study, exposure to endoscopy during pregnancy was associated with a minor increased risk of preterm birth or small for gestational age, but not congenital malformations or stillbirth. Each year in the United States, an estimated 19,000 women undergo an endoscopy during pregnancy. However, understanding of the implications of endoscopy on fetal outcomes is poor. In aggregate, prior studies reporting pregnancy outcomes after endoscopy encompass only about 400 women. Thus, not surprisingly, published guidelines are quite restrictive, generally discouraging endoscopy during pregnancy and, if absolutely necessary, recommending that procedures occur during the second trimester. This reluctance to perform endoscopy during pregnancy may lead to greater harm if withholding a clinically indicated procedure causes a delay in diagnosis or treatment of a condition that negatively impacts maternal or fetal wellbeing. In this issue of Gastroenterology (with an editorial by Mitchell Cappell), Ludvigsson et al report the results of a Swedish nationwide population-based cohort study examining the outcomes of 3052 pregnancies exposed to endoscopy (esophagogastroduodenoscopy, colonoscopy, sigmoidoscopy, or endoscopic cholangiopancreatographies) compared with 1,589,173 pregnancies that were not exposed to endoscopy. Compared with women who were not exposed, women who underwent endoscopy during pregnancy experienced adjusted relative risks of 1.54 (95% confidence interval [CI], 1.36-1.75) for preterm birth and 1.30 (95% CI, 1.07-1.57) for small for gestational age. These associations did not seem to differ according to the trimester of pregnancy. Importantly, there was no association of endoscopy with risk of either congenital malformations or stillbirths. Based on the results of several sensitivity analyses, the excess risk of preterm birth and small for gestational age appeared primarily due to underlying disease activity. Interpretation of these findings is limited by a lack of information about endoscopy characteristics (eg, clinical indication, duration, type of sedation) and disease activity. Nonetheless, this study, the largest of its kind, should provide substantial reassurance that endoscopy is rarely associated with adverse fetal outcomes. See page 554; editorial on page 475. In a cross-sectional, single-center study of 104 adults undergoing liver biopsy for nonalcoholic steatohepatitis, magnetic resonance elastography with proton density fat fractionation was more accurate in detecting any fibrosis and steatosis than ultrasound-based transient elastography with controlled attenuation parameter. Nonalcoholic fatty liver disease encompasses a broad spectrum of severity ranging from benign hepatic steatosis to nonalcoholic steatohepatitis, which can progress to cirrhosis and cancer. At present, the current gold standard for diagnosis of nonalcoholic steatohepatitis is liver biopsy. However, this invasive method is limited by sampling error, variability in agreement in pathologic interpretation, and the risk of procedural complications. In this issue of Gastroenterology, Park et al (with an editorial by Thomas Karlas et al) report a cross-sectional study of 104 consecutive adults in a single US tertiary care center who underwent magnetic resonance elastography and ultrasound-based transient elastography (Fibroscan M and XL probe) before liver biopsy for suspected nonalcoholic fatty liver disease. They found that magnetic resonance elastography, with an area under the receiver operating curve of 0.82 (95% CI, 0.74-0.91), was significantly more accurate for diagnosis of any fibrosis (stage 1-4) compared with transient elastography, with an area under the receiver operating curve of 0.67 (95% CI, 0.56-0.87; P for difference = .0116; Figure 1). In addition, assessment of magnetic resonance-based proton density fat fraction, with an area under the receiver operating curve of 0.99 (95% CI, 0.98-1.00), was significantly more accurate for diagnosis of any steatosis (grades 1-3) compared with transient elastography-based controlled attenuation parameter, with an area under the receiver operating curve of 0.85 (95% CI, 0.75-0.96; P for difference = .009). Although limited by its cross-sectional, single-center design, these findings corroborate results reported in Japanese cohorts and suggest that magnetic resonance-based techniques are superior to transient elastography for the accurate, noninvasive assessment of fibrosis and steatosis in nonalcoholic fatty liver disease. Further studies are needed to compare the longitudinal predictive value and cost-effectiveness of these modalities before clinical recommendations can be offered. See page 598; editorial on page 479. PGE2, via EP4 receptor mediated CREB activation, increases YAP transcription which then increases both COX-2 and EP4 expression, amplifying PGE2 signaling. These processes contribute to resolution of mucosal integrity, but also promote tumorigenesis. Arachidonic acid is a polyunsaturated phospholipid released from cell membranes by phospholipase A2 and metabolized to prostaglandins, prostacyclin, and thromboxanes by cyclooxygenases-1 and -2. In the intestine, prostaglandin E2 (PGE2) maintains mucosal homeostasis and contributes to epithelial regenerative processes after injury. However, this reparative capability is a 2-edged sword because PGE2 also promotes colonic tumorigenesis. Given the prominent role of arachidonic acid metabolism and PGE2 in tumorigenesis, this axis has been an attractive therapeutic target in colon cancer. However, more recently discovered roles for prostaglandins in mucosal repair processes raise the possibility of untoward side effects after inhibition of this pathway. An improved understanding of downstream processes influenced by PGE2 may improve our abilities to manipulate this axis in a therapeutically beneficial fashion. In this issue of Gastroenterology, Kim et al identify Hippo pathway constituent Yes-Associated Protein (YAP) as a PGE2 downstream target important in preserving intestinal integrity after injury. PGE2 activates the prostaglandin E2 receptor-4 (EP4) G-protein–coupled receptor resulting in CREB phosphorylation, leading to increased YAP transcription and Hippo pathway activation. YAP/TEAD, the transcriptionally active complex, enhanced transcription of the EP4 receptor and cyclooxygenase-2, thus augmenting PGE2 production. Increased levels of both the ligand and receptor amplified PGE2-mediated activation of Hippo signaling. Thus, the authors identified a feed-forward circuit, hypothesized to rapidly maximize signaling tone on pathway activation (Figure 2A and B). Swift activation would be beneficial in the setting of intestinal injury. Not surprisingly, the authors also determined that PGE2-mediated YAP signaling also contributed to intestinal tumorigenesis. The present study focused on understanding the biologic effects of a subset of known YAP targets; it remains to be determined what contributions other YAP/TEAD targets have on intestinal wound responses and tumorigenesis. Understanding the relationship between prostaglandin signaling and YAP activation could lead to therapies targeting both pathways designed to inhibit this positive feedback loop in colon cancer prevention. See page 616. miRNA dysfunction induced by inflammatory cytokines contributes to the pathogenesis of colitis-associated carcinoma in mice. Mechanisms contributing to the pathogenesis of colon cancer in the setting of chronic inflammation are incompletely understood. MicroRNAs (miRNA) are approximately 22-nucleotide noncoding RNAs that suppress the expression of complementary RNA targets. RNA polymerase II transcription of noncoding regions generates primary miRNAs, which then require further processing by Drosha and Dicer RNA polymerase IIIs prior to loading onto the RNA-induced silencing complex. The target suppression effects of miRNA's depends on a specific target’s function and the cellular context of its repression. Thus, miRNAs can function as tumor suppressors or promoters. Furthermore, there is evidence suggesting that, in cancer, inflammation globally reduces miRNA levels and function. In this issue of Gastroenterology, Yoshikawa et al build on earlier observations demonstrating that Dicer haploinsufficiency augmented tumorigenesis in mouse models, suggesting that the global reduction in miRNA species observed in human cancer may contribute to colorectal cancer. They reasoned that inflammatory cytokines, commonly increased in inflammatory carcinogenesis, may suppress miRNA function and promote tumorigenesis. Treating a panel of colorectal cancer cell lines with tumor necrosis factor, interleukin (IL)-1A, or IL-1B interfered with miRNA-mediated repression of known targets. To generate an in vivo readout of miRNA function, they developed a transgenic green fluorescent protein miRNA target reporter mouse in which colitis-associated carcinoma was induced using a single injection of azoxymethane intraperitoneal followed by repeated cycles of dextran sodium sulfate in the drinking water. This model is known to generate robust increases in tumor necrosis factor, IL-1A and IL-1B in the colonic mucosa, and the authors observed increased green fluorescent protein reporter activity, indicating that inflammatory stimuli globally repress miRNA function in vivo. Next, turning to define the mechanism of this effect, the authors demonstrated that inflammatory cytokines decreased miRNA loading into RISCs under inflammatory stimuli via reducing A3G levels, which was also observed in ulcerative colitis samples. Last, augmenting miRNA function using the ROCK inhibitor fasudil reduced tumorigenesis in both azoxymethane/dextran sodium sulfate and IL-10-/- models without affecting inflammation. These observations implicate global miRNA dysfunction in the pathogenesis of colitis-associated carcinoma. Further work is required to fully understand the clinical significance of these observations and, as the authors note, their findings raise therapeutic possibilities for ROCK inhibitor-mediated restoration of miRNA function in patients at risk for developing inflammatory carcinogenesis. See page 631. Outcomes of Pregnancies for Women Undergoing Endoscopy While They Were Pregnant: A Nationwide Cohort StudyGastroenterologyVol. 152Issue 3PreviewEndoscopy is an integral part of the investigation and management of gastrointestinal disease. We aimed to examine outcomes of pregnancies for women who underwent endoscopy during their pregnancy. Full-Text PDF Prostaglandin E2 Activates YAP and a Positive-Signaling Loop to Promote Colon Regeneration After Colitis but Also Carcinogenesis in MiceGastroenterologyVol. 152Issue 3PreviewProstaglandin E2 (PGE2) is mediator of inflammation that regulates tissue regeneration, but its continual activation has been associated with carcinogenesis. Little is known about factors in the PGE2 signaling pathway that contribute to tumor formation. We investigated whether yes-associated protein 1 (YAP1), a transcriptional co-activator in the Hippo signaling pathway, mediates PGE2 function. Full-Text PDF Repression of MicroRNA Function Mediates Inflammation-associated Colon TumorigenesisGastroenterologyVol. 152Issue 3PreviewLittle is known about the mechanisms by which chronic inflammation contributes to carcinogenesis, such as the development of colon tumors in patients with inflammatory bowel diseases. Specific microRNA (miRNAs) can function as suppressors or oncogenes, and widespread alterations in miRNA expression have been associated with tumorigenesis. We studied whether alterations in miRNA function contribute to inflammation-associated colon carcinogenesis. Full-Text PDF Collaboration, Not Competition: The Role of Magnetic Resonance, Transient Elastography, and Liver Biopsy in the Diagnosis of Nonalcoholic Fatty Liver DiseaseGastroenterologyVol. 152Issue 3PreviewThe global obesity pandemic necessitates characterization of nonalcoholic fatty liver disease (NAFLD) in an extremely large and growing number of patients. This disease subsumes hepatic fat, inflammation, and fibrosis. Fibrosis is of particular interest, being the strongest predictor of mortality,1,2 and noninvasive techniques for assessing its severity are becoming part of routine care, at least in Asia and Europe.3 As we endeavor to understand NAFLD more fully, steatosis quantification has become increasingly successful, although we are still struggling to understand its clinical implications. Full-Text PDF Evaluating the Safety of Endoscopy During Pregnancy: The Robust Statistical Power vs Limitations of a National Registry StudyGastroenterologyVol. 152Issue 3PreviewFrom 1957 to 1962, an epidemic of about 4000 cases of phocomelia, a severe, congenital malformation of deformed or rudimentary limbs, occurred from in utero fetal exposure to thalidomide1 after its administration to pregnant mothers to treat nausea and vomiting or anxiety during the first trimester of pregnancy, even though thalidomide had been shown to be safe and efficacious in both nonpregnant laboratory animals and nonpregnant subjects enrolled in clinical trials.2 The medical community therefore codified through the United States Food and Drug Administration Drug Regulation Act of 1962 that the safety of drugs during pregnancy cannot be extrapolated from clinical studies in nonpregnant patients, but must be demonstrated directly by clinical studies in pregnant patients. Full-Text PDF Magnetic Resonance Elastography vs Transient Elastography in Detection of Fibrosis and Noninvasive Measurement of Steatosis in Patients With Biopsy-Proven Nonalcoholic Fatty Liver DiseaseGastroenterologyVol. 152Issue 3PreviewMagnetic resonance imaging (MRI) techniques and ultrasound-based transient elastography (TE) can be used in noninvasive diagnosis of fibrosis and steatosis in patients with nonalcoholic fatty liver disease (NAFLD). We performed a prospective study to compare the performance of magnetic resonance elastography (MRE) vs TE for diagnosis of fibrosis, and MRI-based proton density fat fraction (MRI-PDFF) analysis vs TE-based controlled attenuation parameter (CAP) for diagnosis of steatosis in patients undergoing biopsy to assess NAFLD. Full-Text PDF

Magnetic Resonance Elastography vs Transient Elastography in Detection of Fibrosis and Noninvasive Measurement of Steatosis in Patients With Biopsy-Proven Nonalcoholic Fatty Liver Disease

Magnetic resonance imaging (MRI) techniques and ultrasound-based transient elastography (TE) can be used in noninvasive diagnosis of fibrosis and steatosis in patients with nonalcoholic fatty liver disease (NAFLD). We performed a prospective study to compare the performance of magnetic resonance elastography (MRE) vs TE for diagnosis of fibrosis, and MRI-based proton density fat fraction (MRI-PDFF) analysis vs TE-based controlled attenuation parameter (CAP) for diagnosis of steatosis in patients undergoing biopsy to assess NAFLD. We performed a cross-sectional study of 104 consecutive adults (56.7% female) who underwent MRE, TE, and liver biopsy analysis (using the histologic scoring system for NAFLD from the Nonalcoholic Steatohepatitis Clinical Research Network Scoring System) from October 2011 through May 2016 at a tertiary medical center. All patients received a standard clinical evaluation, including collection of history, anthropometric examination, and biochemical tests. The primary outcomes were fibrosis and steatosis. Secondary outcomes included dichotomized stages of fibrosis and nonalcoholic steatohepatitis vs no nonalcoholic steatohepatitis. Receiver operating characteristic curve analyses were used to compare performances of MRE vs TE in diagnosis of fibrosis (stages 1-4 vs 0) and MRI-PDFF vs CAP for diagnosis of steatosis (grades 1-3 vs 0) with respect to findings from biopsy analysis. MRE detected any fibrosis (stage 1 or more) with an area under the receiver operating characteristic curve (AUROC) of 0.82 (95% confidence interval [CI], 0.74-0.91), which was significantly higher than that of TE (AUROC, 0.67; 95% CI, 0.56-0.78). MRI-PDFF detected any steatosis with an AUROC of 0.99 (95% CI, 0.98-1.00), which was significantly higher than that of CAP (AUROC, 0.85; 95% CI, 0.75-0.96). MRE detected fibrosis of stages 2, 3, or 4 with AUROC values of 0.89 (95% CI, 0.83-0.96), 0.87 (95% CI, 0.78-0.96), and 0.87 (95% CI, 0.71-1.00); TE detected fibrosis of stages 2, 3, or 4 with AUROC values of 0.86 (95% CI, 0.77-0.95), 0.80 (95% CI, 0.67-0.93), and 0.69 (95% CI, 0.45-0.94). MRI-PDFF identified steatosis of grades 2 or 3 with AUROC values of 0.90 (95% CI, 0.82-0.97) and 0.92 (95% CI, 0.84-0.99); CAP identified steatosis of grades 2 or 3 with AUROC values of 0.70 (95% CI, 0.58-0.82) and 0.73 (95% CI, 0.58-0.89). In a prospective, cross-sectional study of more than 100 patients, we found MRE to be more accurate than TE in identification of liver fibrosis (stage 1 or more), using biopsy analysis as the standard. MRI-PDFF is more accurate than CAP in detecting all grades of steatosis in patients with NAFLD.

Non invasive diagnosis of fibrosis in HCV infection: Role in the treatment indication, follow-up, and the assessment of the prognosis

Non invasive diagnosis of fibrosis in HCV infection: Role in the treatment indication, follow-up, and the assessment of the prognosis

Non-invasive Diagnosis of Fibrosis in Non-alcoholic Fatty Liver Disease

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in developed as well as in developing countries. Its prevalence continues to rise currently affecting approximately 20-30% of adults and 10% of children in the United States. Non-alcoholic fatty liver disease represents a wide spectrum of conditions ranging from fatty liver, which in general follows a benign non-progressive clinical course, to non-alcoholic steatohepatitis (NASH), a more serious form of NAFLD that may progress to cirrhosis and end-stage liver disease. Liver biopsy remains the gold standard for evaluating the degree of hepatic necroinflammation and fibrosis; however, several non-invasive investigations, such as serum biomarkers, have been developed to establish the diagnosis and also to evaluate treatment response. There has been a substantial development of non-invasive risk scores, biomarker panels, and radiological modalities to identify at risk patients with NAFLD without recourse to liver biopsy on a routine basis. Examples include combination of serum markers like NAFLD fibrosis score (NFS), BARD score, fibrometer, FIB4, and non-invasive tools like fibroscan which assess fibrosis in patients with NAFLD. Other markers of fibrosis that have been evaluated include high-sensitivity C-reactive protein, plasma pentraxin 3, interleukin-6, and cytokeratin-18. This review focuses on the methods currently available in daily clinical practice in hepatology and touches briefly on the potential future markers under investigation.

How to assess liver fibrosis in chronic hepatitis C: serum markers or transient elastography vs. liver biopsy?

The assessment of liver fibrosis is a major issue in the management of patients with chronic hepatitis C. Liver biopsy has traditionally been considered the gold standard for the evaluation of tissue damage, including fibrosis. In addition, it detects associated lesions such as steatosis, steatohepatitis or iron overload, which provide useful information for patient management and prognosis. Liver biopsy is, however, an invasive procedure, with a risk of rare but potentially life-threatening complications and it is prone to sampling errors. These limitations have led to the development of non-invasive methods. Currently available tests rely on two different but complementary approaches: (i) a 'biological' approach based on the dosage of serum biomarkers of fibrosis; (ii) a 'physical' approach based on the measurement of liver stiffness, using transient elastography. Although significant progress has been made in the non-invasive diagnosis of fibrosis, it is increasingly clear that these methods will not completely replace liver biopsy. Instead, non-invasive methods and liver biopsy should be used in an integrated approach for more efficient and convenient management of patients with chronic hepatitis C. The aim of this review is to discuss the advantages and limitations of liver biopsy and non-invasive methods and the perspectives for their use in clinical practice.

Serum hyaluronic acid: A promising marker of hepatic fibrosis in chronic hepatitis B

The chronic hepatitis B (CHB) virus affects 350 million individuals worldwide. The infection that is caused by the virus is accompanied by a progressive deposit of hepatic fibrosis, which in turn may lead to cirrhosis.[1,2] Liver biopsy is the gold standard for the assessment of the fibrosis, but it is hampered by several disadvantages such as poor patient compliance, sampling error, and poor intra- and inter-observation concordance.[3] Noninvasive evaluation of liver fibrosis is thus a subject of great clinical interest. Many parameters for noninvasive diagnosis of liver fibrosis were studied extensively in the past.[4–8] These parameters include routine laboratory tests, serum markers of fibrosis and inflammation, ultrasonography and radiological imaging studies.[9] However, at present, none of these tests or markers alone is accurate or reliable in predicting hepatic fibrosis, either in CHB or other related diseases like chronic hepatitis C (CHC). Ideally, a marker of hepatic fibrosis should be liver specific. It should also be able to measure the activity of the matrix deposition, reflect the underlying fibrosis, irrespective of the cause, should be easy to perform and yet sensitive enough to distinguish between the different stages of fibrosis. In the liver, hyaluronic acid (HA) is mostly synthesized by the hepatic stellate cells and degraded by the sinusoidal endothelial cells.[10] It has been shown that serum HA levels increase in chronic liver diseases and that progressive liver damage can be identified early by serum HA assessment.[11,12] In patients with chronic liver diseases of various etiologies, increases in serum HA levels occur together with the development of liver fibrosis. In alcoholic liver disease, Tran et al., found that HA was the best marker for the prediction of severe fibrosis, where HA had a diagnostic accuracy of 91.1%.[13] Prior to that, Oberti et al. had observed that HA and prothrombin index were the best predictive factors.[14] There are many studies about serum HA as a fibrosis marker in CHC.[9,15–18] One of these studies has suggested cut-off values of HA to discriminate the different stages of liver fibrosis, but it was limited by the number of cirrhotic patients included amounting to only 5% of the study group.[17] In literature, there are few studies about the noninvasive diagnosis of fibrosis in CHB.[3,19–21] The results obtained in patients with CHB appear relevant since HCV and HBV infection may differ significantly in terms of fibrosis progression and the presence of related markers.[22,23] This was elegantly demonstrated in a recent study that enrolled both CHB and CHC patients who underwent liver biopsy and had FibroScan performed on the same day. The study concluded that the efficacy of liver stiffness as measured by FibroScan was superior in detecting fibrosis in patients with CHC than in patients with CHB.[24] Therefore, it appears that data pertaining to CHC cannot be routinely applied to CHB. This adds to the importance of the work done by Geramizadeh et al., in this issue of the Saudi Journal of Gastroenterology, who tried to validate the value of HA as a simple laboratory test to discriminate between patients with and without significant fibrosis in CHB.[25] This study included 93 patients with CHB, who had liver biopsy. Interestingly, any biopsy specimen of less than 2 cm was excluded, which is a very important factor in increasing the accuracy of liver biopsy reports. Also, examining liver pathology specimens by two independent experts, blinded to the clinical and laboratory data, certainly minimized the interobserver differences. This is crucial in studies evaluating noninvasive fibrosis markers, wherein the ‘gold standard’ of liver biopsy should ideally find a replacement in real ‘gold’. This was not the case in similar studies,[19] where the biopsy size was 10 mm only and all biopsies were reviewed by a single pathologist whose experience was not reported. In the study of Geramizadeh et al., a cut-off value of HA 113 ng/ml was chosen for identifying the absence or presence of mild fibrosis and another value of HA 181.9 ng/ml was chosen for identifying the absence or presence of severe fibrosis and cirrhosis. This is different from the study of Montazeri et al., where a cut-off value of 126.4 ng/ml could discriminate mild fibrosis from extensive fibrosis.[19] It should be noted that in both the studies, the number of patients with severe fibrosis and cirrhosis was small (16 and 17%, respectively) and there was no distinction between incomplete and established cirrhosis, which is potentially important in clinical practice in relation to decision making for treatment and prognosis issues. Moreover, the present study lacked data about alanine transaminase (ALT) and aspartate transaminase (AST) activities, HBV DNA level and HBeAg status. This is an important limitation, as these biochemical and virological parameters may affect the stage of fibrosis in CHB. This was previously demonstrated in the study by Zeng et al., where their model of noninvasive diagnosis of liver fibrosis in CHB was applied only to patients with HBeAg positive status and elevated transaminases activity, and was not applied to patients with negative HBV DNA, normal or minimally elevated ALT activity, or HBeAg negative patients.[26] Therefore, future studies concerning the evaluation of HA or other noninvasive markers for the diagnosis of fibrosis of CHB should routinely include these biochemical and virological data. This will not only allow for proper interpretation of fibrosis markers in different phases of CHB, but may also help in comparison of the results of studies including different CHB populations. Besides, a large cohort of cirrhotic patients is needed for the proper evaluation of HA and other noninvasive markers in the diagnosis of cirrhosis. Further large scale studies may allow a more precise cut-off value of HA between each stage of fibrosis, rather than a mere distinction between mild and severe fibrosis. Finally, combining HA level with other serum markers or Fibroscan for assessing hepatic fibrosis should be considered. In conclusion, this study shows that serum HA is a promising marker of hepatic fibrosis in CHB, but it should be validated in well-designed controlled studies that avoid the limitations of the previous work and consider combination with other simple non-invasive markers of liver fibrosis.