Serum fibrosis markers can detect large oesophageal varices with a high accuracy

OBJECTIVES: The aim of this study was to determine the value of serum fibrosis markers for the diagnosis of oesophageal varices in alcoholic patients. METHODS: Fifty-four sets of clinical and biochemical data, including serum markers of fibrosis, obtained from 146 heavy alcohol drinkers (106 men, 40 women; mean age 49.2+/-9.0 years) without any history of variceal bleeding were analysed. Gastroscopy and liver biopsy were performed in all patients. Multivariate analysis was performed to identify the markers best correlated with oesophageal varices. RESULTS: Fifty-nine patients (40.4%) had severe fibrosis (3+) and 48 (32.9%) had oesophageal varices (all grades considered together). In multivariate analysis, a prothrombin index below 60%, alkaline phosphatase activity over 110 IU/l, and hyaluronate over 100 g/l were the best markers for the prediction of oesophageal varices. The diagnostic accuracy for medium to large oesophageal varices using these three factors was 86%. Eight patients (16.7%) with oesophageal varices presented no or moderate fibrosis (F<3): one patient (12.5%) had an alkaline phosphatase level >110 IU/l. However, all eight of these patients had small oesophageal varices. CONCLUSIONS: These three non-invasive markers correctly predict the presence or absence of medium to large oesophageal varices in 86% of alcoholic patients.     

Prothrombin index is an indirect marker of severe liver fibrosis

OBJECTIVE: The non-invasive diagnosis of liver fibrosis is based mainly on biochemical markers. The main aim was to validate whether the prothrombin index is an indirect marker of the severity of liver fibrosis. PATIENTS AND METHODS: The predictive value of the prothrombin index for liver fibrosis was first assessed in 243 patients with chronic liver disease, then validated in 193 other patients with chronic liver disease. The reproducibility of measurement of the prothrombin index in different laboratories was evaluated in 82 other patients. RESULTS: In the first group, the prothrombin index was predicted accurately by serum hyaluronate (R(2)= 0.67 at the first step by multiple regression). The relationship between the prothrombin index and the area of fibrosis was not influenced significantly by non-fibrotic pathological lesions. The prothrombin index began to decrease when the Metavir fibrosis score was 2 versus 3 for albumin. In the second group, the prothrombin index and the histological fibrosis score were well correlated (r= -0.70, P< 10(-4)). Prothrombin index < or =80% or < or =70% diagnosed severe fibrosis or cirrhosis, respectively, and prothrombin index > or =105% or > or =100% excluded a diagnosis of severe fibrosis or cirrhosis, respectively, at the 95% probability level. The prothrombin indices measured in different laboratories were similar (78+/-18% v. 78+/-14%) and well correlated (r= 0.91, P< 10(-4)). CONCLUSIONS: The prothrombin index was well correlated with pathological liver fibrosis score, had a high diagnostic accuracy for severe fibrosis or cirrhosis especially due to alcohol, and was not influenced by other pathological lesions. The prothrombin index was reproducible. Thus, the prothrombin index expressed as a percentage is an accurate, reproducible, inexpensive and easily available marker of severe liver fibrosis.     

A novel panel of blood markers to assess the degree of liver fibrosis

The objective was to develop new blood tests to characterize different fibrosis parameters in viral and alcoholic chronic liver diseases. Measurements included 51 blood markers and Fibrotest, Fibrospect, ELFG, APRI, and Forns scores. The clinically significant fibrosis was evaluated via Metavir staging (F2-F4), and image analysis was used to determine the area of fibrosis. In an exploratory step in 383 patients with viral hepatitis, the area under the receiving operator characteristic (AUROC) curve for stages F2-F4 in a test termed the "Fibrometer" test combining platelets, prothrombin index, aspartate aminotransferase, alpha2-macroglobulin (A2M), hyaluronate, urea, and age was 0.883 compared with 0.808 for the Fibrotest (P = .01), 0.820 for the Forns test (P = .005), and 0.794 for the APRI test (P < 10(-4)). The Fibrometer AUROC curve was 0.892 in the validating step in 120 patients. The AUROC curve for stages F2-F4 in a test combining prothrombin index, A2M, hyaluronate, and age was 0.962 in 95 patients with alcoholic liver diseases. The area of fibrosis was estimated in viral hepatitis by testing for hyaluronate, gamma-glutamyltransferase, bilirubin, platelets, and apolipoprotein A1 ((a)R(2) = 0.645), and in alcoholic liver diseases by testing for hyaluronate, prothrombin index, A2M, and platelets ((a)R(2) = 0.836). In conclusion, the pathological staging and area of liver fibrosis can be estimated using different combinations of blood markers in viral and alcoholic liver diseases. Whereas the Fibrometer has a high diagnostic accuracy for clinically significant fibrosis, blood tests for the area of liver fibrosis provide a quantitative estimation of the amount of fibrosis, which is especially useful in cirrhosis.     

Serum hyaluronate correlates with histological progression in alcoholic liver disease

OBJECTIVES: Chronic alcohol consumption may lead to the development of liver cirrhosis. Serum concentrations of hyaluronate were suggested as a predictor in chronic liver disease, but its power to distinguish between severity of fibrosis and inflammation had not been assessed. In order to evaluate hyaluronate as a marker to detect early stages of alcoholic liver disease and to establish a possible correlation with hepatic histology, serum concentrations were measured by radioimmunoassay in 87 patients with biopsy-proven fatty liver, fatty liver and mild fibrosis, fatty liver and inflammation, severe fibrosis and inflammation, and cirrhosis, and in 12 non-alcoholic control subjects. In addition, serum hyaluronate was determined in 40 non-cirrhotic alcoholic patients with either a normal serum aspartate aminotransferase (AST) or an AST elevated at least two-fold. RESULTS: Serum hyaluronate increased significantly with advanced stages of alcoholic liver disease, while levels in patients with fatty liver were elevated only slightly without reaching significance. Hyaluronate correlated well with histological stage and was highly sensitive for detecting fibrosis in general and perivenular fibrosis as an indicator of progression to cirrhosis. Hyaluronate levels were not influenced by AST levels. CONCLUSION: Serum hyaluronate is a good predictor of the presence of even moderate hepatic fibrosis in alcoholic liver disease, justifying its clinical use to assess morphological alterations of the liver in alcoholics.     

Chondrex (YKL-40), a potential new serum fibrosis marker in patients with alcoholic liver disease

OBJECTIVES: Chondrex (YKL-40) is a mammalian member of a protein family that includes bacterial chitinases. The pattern of its expression in certain tissues such as human liver or cartilage suggests a function in remodelling or degradation of extracellular matrix. The purpose of this study was to assess whether circulating YKL-40 might be a serum fibrosis marker in alcoholics. METHODS: Plasma YKL-40 was determined in 146 consecutive heavy drinkers (106 men, 40 women; mean age, 49.2 +/- 9.0 years). Liver biochemical parameters and serum fibrosis markers such as hyaluronate were also measured. Fibrosis and inflammation in liver biopsy were evaluated using a semi-quantitative scoring system. RESULTS: Plasma YKL-40 increased in parallel with the severity of fibrosis (P<0.00001). YKL-40 also increased in the presence of hepatic inflammation (P<0.01). Receiver operating characteristic curves of Chondrex revealed that a threshold of 330 microg/l gave a specificity of 88.5%; however, the sensitivity was only 50.8%. Only 11.5% of patients without severe fibrosis displayed a Chondrex plasma level above this threshold. A positive correlation was found between Chondrex and hyaluronate (r=0.40, P<0.0001), and a negative correlation was shown between Chondrex and the prothrombin index (r=-0.37, P<0.0001). CONCLUSIONS: The severity of liver fibrosis is associated with elevated circulating Chondrex levels. The overlap in YKL-40 values prevents use of Chondrex in a screening programme. High levels of Chondrex (above 330 microg/l) are predictive of severe liver fibrosis. Increased plasma YKL-40 may reflect the remodelling of liver fibrosis in alcoholics.     

New Doppler ultrasound signs improve the non-invasive diagnosis of cirrhosis or severe liver fibrosis

OBJECTIVES: To determine whether ultrasound and, particularly, new Doppler signs increased the diagnostic accuracy of the most accurate, currently available markers for the diagnosis of cirrhosis or severe fibrosis. METHODS: Thirty-two clinical (n = 4), biochemical (n = 11) and Doppler ultrasound (n = 17) variables were recorded in 106 patients with compensated chronic liver disease. Diagnostic accuracy was evaluated by discriminant analysis; first, globally, using all variables then by stepwise analysis. RESULTS: (A) Diagnosis of cirrhosis. Using Doppler ultrasound, diagnostic accuracy was 92% (95% confidence interval 81-98) globally, and 89% (76-95) with three variables (spleen length, hepatic vein spectrum and maximum portal vein velocity). Based upon clinical signs, diagnostic accuracy was 86% (77-92) globally, and 85% (76-91) with one variable (firm liver). Based upon biochemical parameters, diagnostic accuracy was 80% (70-88) globally, and 81% (72-88) with two variables (hyaluronate and platelet count). Based upon all parameters, diagnostic accuracy was 91% (79-96.5) globally, and 91% (79-96.5) with four variables (firm liver, hyaluronate, platelet and hepatic vein spectrum). On an intention to diagnose basis, Doppler ultrasound provided a lower independent contribution due to missing data. (B) In the diagnosis of severe fibrosis, diagnostic accuracy was 83% (69-92) globally, and 77% (62-87) with one variable. CONCLUSIONS: Cirrhosis can be correctly diagnosed in approximately 90% of patients with compensated chronic liver disease using a few Doppler ultrasound signs including a new sign, the hepatic vein spectrum. Doppler ultrasound could be used for the first line diagnosis and biochemical markers, such as hyaluronate, in patients with missing Doppler ultrasound data.     

Serum laminin and type IV collagen are accurate markers of histologically severe alcoholic hepatitis in patients with cirrhosis

BACKGROUND/AIMS: Severe alcoholic hepatitis occurs mainly in patients with cirrhosis, and has a high death rate. Corticosteroid therapy has been particularly advocated as reducing mortality in patients with severe histologic lesions. However, identification of these patients is difficult, requiring transvenous liver biopsy. Extracellular matrix serum markers have been proposed as non-invasive diagnostic tools in alcoholic liver disease. The aim of this study was to determine the accuracy of 5 extracellular matrix serum markers, i.e. laminin (Lam), N-terminal peptide of type III procollagen (PIIINP), type I (CI), type III (CIII) and type IV (CIV) collagens in identifying patients with severe histologic alcoholic hepatitis from among those with cirrhosis and suspected alcoholic hepatitis. METHODS: We studied 80 consecutive patients with alcoholic cirrhosis and clinical suspicion of alcoholic hepatitis referred for transvenous liver biopsy. Clinical severity of alcoholic hepatitis was assessed according to Maddrey's score. Histological severity was scored using the sum of the 3 following items: polynuclear infiltration (0-3); hepatocytes alterations (0-3); Mallory bodies (0-2). According to this score, patients were divided into 3 groups: mild (1-3), moderate (4-6), and severe (7-8) alcoholic hepatitis. Serum levels of the 5 extracellular matrix serum markers were measured at the time of biopsy using radioimmunoassays. Diagnostic value for histologically severe alcoholic hepatitis of the 5 extracellular matrix serum markers was assessed using receiver operating characteristic curves. RESULTS: Histological alcoholic hepatitis was present in 67 patients (mean alcoholic hepatitis score: 3.4+/-2.3). Maddrey's score was 66% sensitive and 69% specific for the diagnosis of severe histologic alcoholic hepatitis. The serum Lam and CIV concentrations were the most accurate in identifying correctly patients with severe histologic alcoholic hepatitis. At a cut-off of 4.1 UI/ml, Lam was 90% sensitive and 77% specific, whereas at a cut-off of 150 ng/ml, CIV was 89% sensitive and 77% specific. Combination of markers did not result in improved diagnostic value. CONCLUSION: In patients with cirrhosis, determination of serum Lam or CIV could represent a simple and accurate non-invasive method for identification of patients with histologically severe alcoholic hepatitis eligible for corticosteroid treatment.     

Staging of liver fibrosis in chronic hepatitis B patients with a composite predictive model:A comparative study

AIM:To evaluate the efficacy of 6 noninvasive liver fibrosis models and to identify the most valuable model for the prediction of liver fibrosis stage in chronic hepatitis B(CHB) patients.METHODS:Seventy-eight CHB patients were consecutively enrolled in this study.Liver biopsy was performed and blood serum was obtained at admission.Histological diagnosis was made according to the METAVIR system.Significant fibrosis was defined as stage score ≥ 2,severe fibrosis as stage score ≥ 3.The diagnostic accuracy of ...     

Serum hyaluronate in liver diseases: study by enzymoimmunological assay

It has been suggested that glycosaminoglycans are involved in the pathogenesis of liver fibrosis. Furthermore, recent studies have reported that one of them, hyaluronate, was mainly taken up and degraded by the liver. Using an enzymoimmunological assay, based on hyaluronate-hyaluronectin interaction, serum levels of hyaluronate were measured in 113 patients with various liver diseases. Patients were divided into six groups according to clinical, biological and histological data: Group 1-alcoholic cirrhosis (n = 47) including alcoholic cirrhosis with alcoholic hepatitis (n = 24); Group 2-primary biliary cirrhosis (n = 21); Group 3-cirrhosis related to viral hepatitis (n = 10); Group 4-idiopathic hemochromatosis (n = 17); Group 5-alcoholic fatty liver (n = 8); and Group 6-viral or drug acute hepatitis (n = 10). Ninety-four blood donors were studied as controls. Levels of hyaluronate were found to be strikingly elevated in Group 1 (1,225 +/- 1,137 micrograms per liter), Group 2 (792 +/- 739 micrograms per liter), Group 3 (649 +/- 373 micrograms per liter), and Group 4 (246 +/- 242 micrograms per liter), whereas patients in Group 5 (94 +/- 63 micrograms per liter) and Group 6 (73 +/- 57 micrograms per liter) had values close to controls (23 +/- 17 micrograms per liter). There was a significant correlation between serum hyaluronate and serum albumin, prothrombin time, factor V concentration and serum gamma-globulins. It is suggested that hyaluronate levels reflect both active fibrosis and hepatic failure and may be a quantitative marker of severity of hepatic injury.     

慢性乙型肝炎肝纤维化分期与血清肝纤维化标志物的相关性分析

目的 探讨血清透明质酸、Ⅲ型前胶原、层粘蛋白、Ⅳ型胶原等血清肝纤维化标志物与慢性肝炎肝组织炎症活动度及纤维化程度的相关性。方法 278例慢性肝炎患者经肝脏活栓后常规病理检查,肝活检前同时采血检测血清透明质酸、Ⅲ型前胶原、层粘蛋白、Ⅳ型胶原,结果应用x^2检验及t检验进行统计学处理。结果 肝组织纤维化程度与炎症活动度呈正相关关系,透明质酸可反映中度以上慢性肝炎炎症活动度及纤维化程度,且呈正相关;肝脏存在纤维化时层粘蛋白水平升高,与纤维化程度正相关;Ⅲ型前胶原、Ⅳ型胶原水平升高与炎症活动度有关。结论 血清透明质酸、Ⅲ型前胶原、层粘蛋白、Ⅳ型胶原可不同程度反映肝纤维纤维化程度,可作为血清肝纤维化检测指标,透明质酸更可反映肝硬化发展趋势。     

Serum markers for predicting advanced fibrosis in patients with chronic hepatitis B and nonalcoholic fatty liver disease

To compare the diagnostic utility of serum markers in nonalcoholic fatty liver disease (NAFLD) patients with chronic hepatitis B (CHB).This study enrolled 118 consecutive biopsy-proven NAFLD patients with or without CHB. Fibrosis scores of each marker were compared against histological fibrosis staging. Receiver operating characteristic curve (ROC) analysis helped assess the accuracy of each marker.In patients with both diseases, 12.96% (7/54) had advanced fibrosis on biopsy and aspartate aminotransferase (AST) to platelet ratio index was the best performing marker for predicting advanced fibrosis. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and area under the ROC (95% confidence interval) for AST to platelet ratio index (APRI) were 0%, 93.62%, 0%, 86.27%, and 0.676 (0.524–0.828), respectively. The markers ranked as follows from highest to lowest with respect to their accuracy: APRI; BARD; fibrosis-4; and AST to ALT ratio. In patients without CHB, fibrosis-4 was the best performing marker for predicting advanced fibrosis. The sensitivity, specificity, PPV, NPV, and area under the ROC (95% confidence interval) for fibrosis-4 were 77.78%, 85.45%, 46.67%, 95.92%, and 0.862 (0.745–0.978), respectively.Serum markers are less reliable in predicting advanced fibrosis in NAFLD patients with CHB; APRI is the most accurate predictor of the absence of advanced fibrosis.     

Liver fibrosis markers in alcoholic liver disease

Alcohol is one of the main factors of liver damage. The evaluation of the degree of liver fibrosis is of great value for therapeutic decision making in patients with alcoholic liver disease (ALD). Staging of liver fibrosis is essential to define prognosis and management of the disease. Liver biopsy is a gold standard as it has high sensitivity and specificity in fibrosis diagnostics. Taking into account the limitations of liver biopsy, there is an exigency to introduce non-invasive serum markers for fibrosis that would be able to replace liver biopsy. Ideal serum markers should be specific for the liver, easy to perform and independent to inflammation and fibrosis in other organs. Serum markers of hepatic fibrosis are divided into direct and indirect. Indirect markers reflect alterations in hepatic function, direct markers reflect extracellular matrix turnover. These markers should correlate with dynamic changes in fibrogenesis and fibrosis resolution. The assessment of the degree of liver fibrosis in alcoholic liver disease has diagnostic and prognostic implications, therefore noninvasive assessment of fibrosis remains important. There are only a few studies evaluating the diagnostic and prognostic values of noninvasive biomarkers of fibrosis in patients with ALD. Several noninvasive laboratory tests have been used to assess liver fibrosis in patients with alcoholic liver disease, including the hyaluronic acid, FibroTest, FibrometerA, Hepascore, Forns and APRI indexes, FIB4, an algorithm combining Prothrombin index (PI), α-2 macroglobulin and hyaluronic acid. Among these tests, Fibrotest, FibrometerA and Hepascore demonstrated excellent diagnostic accuracy in identifying advanced fibrosis and cirrhosis, and additionally, Fibrotest was independently associated with survival. Therefore, the use of biomarkers may reduce the need for liver biopsy and permit an earlier treatment of alcoholic patients.     

Biological diagnosis of the type of liver disease in alcoholic patients with abnormal liver function tests

OBJECTIVES: The histological diagnosis of the different stages of alcoholic liver disease is not systematic. The aim of this study was to assess whether common biological features were useful in identifying the different stages. METHODS: One thousand twenty six alcoholic patients with liver histology and without any associated diseases or infections likely to alter serum liver tests were studied. Diagnostic analyses were performed using stepwise discriminant analysis in the entire population and in asymptomatic patients. RESULTS: a) Serum ASAT activity levels were only normal in 39% of the patients with normal histological liver and in 14% of the patients with steatosis; b) liver failure was already present in patients with fibrosis without cirrhosis; c) betagamma block was the only biochemical parameter which confirmed the diagnosis of cirrhosis without biopsy; d) the diagnostic accuracy of common tests was weak for the diagnosis of alcoholic liver disease without cirrhosis but prothrombin time could be useful in excluding the diagnosis of cirrhosis with and without acute alcoholic hepatitis when liver biopsy is not available. CONCLUSION: Only a prothrombin time of 80% with a negative predictive value of 94% and the presence of beta-gamma [corrected] block with a positive predictive value of 98% were useful for assessing the diagnosis of cirrhosis in all patients with alcoholic liver disease.     

代偿性肝硬化无创性诊断指标的筛选及评价

目的：比较肝纤维化血清标志物对慢性乙型肝炎（CHB）代偿性肝硬化的诊断评价，筛选可行的无创性诊断标志物。方法：350例CHB患者经皮肝脏穿刺活检术行病理组织学检查，B型超声波检查肝硬化图像，检测血清透明质酸（HA）、Ⅲ型前胶原肽（PCⅢ）、层黏连蛋白（LN）及Ⅳ型胶原（CⅣ）等肝纤维化标志物。用临床流行病学方法确定诊断截断值，并对各项指标作诊断评价分析，比较不同标志物的诊断评价指标。结果：85例CHB患者经肝脏活检术确认为代偿性肝硬化，81例经B型超声波检查有肝硬化图像，ROC曲线下面积以HA最高；血清HA、PCⅢ、LN及CⅣ对代偿期肝硬化的诊断截断值分别为154．35μg/L、198．44μg/L，137．58μg/L和100．80μg/L，对其应诊断灵敏度分别为82．4％，63．5％，57．3％及70．6％，特异度为79．3％，54．0％，56．8％及68．3％，准确度为80．0％，56．3％，56．9％及68．9％，并联试验诊断虽可提高灵敏度，但相应降低特异度及准确度，与其他无创性诊断方法比较，HA有较高水平的诊断评价指标（u≥1．814，P＜0．05），血清HA诊断代偿性肝硬化的截断值以119．17μg/L较恰当，其相应诊断灵敏度，特异性度，准确度，阳性预告值及阴性预选值分别为87．1％、67．6％、72．3％、46．25％，94．7％。结论：在现有肝脏纤维化血清标志物及超声波检查等无创性诊断指标中，血清HA是代偿性肝硬化最好的诊断标志物。     

Stepwise combination algorithms of non-invasive markers to diagnose significant fibrosis in chronic hepatitis C

BACKGROUND/AIMS: In chronic hepatitis C, biopsy is the gold standard for assessment of liver fibrosis. Non-invasive markers have been proposed but their use is limited by diagnostic accuracy. Our aim was to increase the diagnostic performance of non-invasive markers of liver fibrosis by combining them in sequential algorithms. METHODS: One hundred and ninety patients with chronic hepatitis C were evaluated for AST to platelets ratio (APRI), Forns' index and Fibrotest at the time of liver biopsy and stepwise combination algorithms were developed and validated prospectively in 100 additional patients. RESULTS: Three algorithms were developed: (1) significant fibrosis (F>or=2 by METAVIR) was identified with high diagnostic performance (>94% accuracy) using APRI as screening test, followed by Fibrotest in APRI non-classified cases and restricting liver biopsy to patients classified F0-F1 by non-invasive tests. (2) A slightly modified algorithm had similar performance when applied to hepatitis C carriers with normal ALT. (3) Identification of cirrhosis (95% accuracy) was achieved using a dedicated algorithm with different cut-off, reducing by 60-70% the liver biopsies needed. CONCLUSIONS: Stepwise combination of non-invasive markers of liver fibrosis improves the diagnostic performance in chronic hepatitis C. Need for liver biopsy is reduced by 50-70% but cannot be completely avoided.     

Assessment of liver fibrosis by a noninvasive method of transient elastography and biochemical markers

AIM: To assess the correlation between the fibrotic area (FA) as calculated by a digital image analysis (DIA), and to compare the diagnostic accuracy of FibroScan to the other existing Liver fibrosis (LF) markers using the receiver operating curve analysis. METHODS: We recruited 30 patients who underwent a liver resection for three different etiologies including normal liver, hepatitis B, and hepatitis C. Liver stiffness was measured by using a FibroScan. The FA was then calculated by DIA to evaluate LF in order to avoid any sampling bias. RESULTS: The FA negatively correlated with Prothrombin time (PT), platelet count, lecithin-cholesterol acyltransferase (LCAT), and pre-albumin (ALB). On the other hand, the findings of FibroScan correlated with similar markers. The FA positively correlated with FibroScan, serum hyaluronate level, and type IV collagen level, and aspartate transaminase to platelet ratio index (APRI). The area under the receiver operating curve for FibroScan was higher than that for the other markers, even though the statistical significance was minimal. CONCLUSION: Our findings suggest that FibroScan can initially be used to assess LF as an alternative to a liver biopsy (LB) and serum diagnosis, because it is a safe method with comparable diagnostic accuracy regarding the existing LF markers.     

Evaluation of a panel of non-invasive serum markers to differentiate mild from moderate-to-advanced liver fibrosis in chronic hepatitis C patients

BACKGROUND/AIMS: In chronic hepatitis C (CHC) infection, a liver biopsy provides important information that guides treatment decisions, but is invasive, expensive and associated with possible complications. Extracellular matrix remodeling proteins may be useful non-invasive markers of fibrosis. The aim of this study was to evaluate the diagnostic accuracy of a panel of these markers in CHC patients, develop a predictive algorithm that differentiates no/mild (METAVIR F0-F1) from moderate/severe (F2-F4) fibrosis, and validate the model in external cohorts. METHODS: A combination of matrix markers were initially evaluated and optimized in 294 CHC patients from a single center, and validated in an external cohort of 402 patients. RESULTS: Hyaluronic acid, TIMP-1 and alpha2-macroglobulin were selected as having the best predictive accuracy for F2-F4 fibrosis (combined AUROC = 0.831). At an index cut-off >0.36 and prevalence for F2-F4 of 52%, results in all 696 patients indicated positive and negative predictive values of 74.3 and 75.8% with an accuracy of 75%. CONCLUSIONS: The three-marker panel may reliably differentiate CHC patients with moderate/severe fibrosis from those with no/mild fibrosis, although accurate delineation between stages was not possible. Prospective studies are required to determine the potential utility of the marker panel in guiding treatment decisions and following disease progression.     

Urinary assays for desmosine and hydroxylysylpyridinoline in the detection of cirrhosis

Background/Aims: Non-invasive markers of liver fibrosis have great potential for both the diagnosis and therapy of liver disease and cirrhosis. The aim of this study was to evaluate the potential of urinary amino acids desmosine (DES) and isodesmosine (IDES) derived from the breakdown of elastin and hydroxylysylpyridinoline (HP) and lysylpyridinoline (LP) derived from fibrillar collagen in diagnosing chronic liver disease.Methods: We studied 48 patients with chronic liver disease who had varying degrees of liver fibrosis, grade 0–6 using a modified Knodell score, and 20 control subjects without liver disease. Urinary DES (μg/g creatinine) and HP (mmol/mmol creatinine) were measured by an isotope dilution, high performance liquid chromatography method. For liver disease patients, aminoterminal propeptide of type III procollagen (PIIINP) and alanine aminotransferase were determined. The urine and serum markers were correlated to degree of fibrosis and inflammation on liver biopsies. Differences between groups were analyzed by ANOVA and multiple linear regression was applied to determine independence of variables. Sensitivity, specificity and receiver operating curves were derived for each marker.Results: In the 17 patients with liver fibrosis score of 5–6, mean urinary DES, IDES, HP and LP were all significantly greater than in the control group (p<0.05). Urinary DES and IDES correlated best with fibrosis score, r=0.61 for both markers. The correlation coefficient between serum PIIINP and fibrosis score was 0.47. Urinary DES and HP each had an overall diagnostic accuracy of 77% for fibrosis. Combining markers improved accuracy to over 80%. No correlation was seen between the urinary markers and inflammation scores.Conclusions: Urinary DES and HP are potentially useful clinical markers for liver fibrosis, especially when used in combination or in association with PIIINP.     

Value of fibrosis markers for staging liver fibrosis in patients with precirrhotic alcoholic liver disease

Background: Our aim was to identify markers predictive of fibrosis in alcoholic liver disease (ALD). Percutaneous liver biopsy is the recommended standard for histologic assessment of liver fibrosis. Seven serum markers (tissue inhibitor of matrix metalloproteinase 1 {TIMP1}, tenascin, collagen VI, amino‐terminal propeptide of type III collagen {PIIINP}, matrix metalloproteinases {MMP2}, laminin, and hyaluronic acid {HA}) representing various aspects of collagen and extracellular matrix deposition and degradation, have been proposed as noninvasive surrogates for liver biopsy. Moreover, a diagnostic algorithm including 3 serum markers (TIMP1, PIIINP, HA) and age has been proposed to accurately detect fibrosis with acceptable levels of sensitivity/specificity in a chronic hepatitis C subgroup. Methods: To determine variability of these markers in liver fibrosis with different etiologies, we conducted an evaluation of their correlative properties in a subgroup of patients (n = 247) with biopsy confirmed liver fibrosis resulting from long‐term heavy alcohol consumption. Patients were participants in a recently completed VA multicenter clinical trial followed over 2 years with liver biopsy at baseline and 24 months, and with markers assessed every 3 months. Results: Among the markers measured in this alcoholic subgroup all except collagen VI displayed significant correlation with degrees of fibrosis. Three markers, TIMP1, PIIINP and HA adjusted for age, emerged as the most promising predictors of the degree of fibrosis in a population of alcoholics. However, there was little change over time as related to change in fibrosis. The lower than expected accuracy of these markers based on receiver operating curves (ROC) also showed their limited use in this etiologic subgroup. Conclusion: In alcoholic patients, various markers have limited value in predicting and diagnosing the stages of fibrosis compared to liver biopsy. Thus, further prospective studies are required to better define the usefulness of each marker or their combination which are possibly affected by alcohol metabolism.     

慢性乙型肝炎肝纤维化无创性诊断模型的建立

目的建立由临床及血清指标组成的综合诊断模型，以无创性的评估慢性乙型肝炎肝纤维化。方法慢性乙型肝炎患者270例，随机分成模型组（195例）和验证组（75例），均行肝活组织检查及病理分期，并按纤维化程度设定不同判别终点（≥S2，≥S3，S4），同时检测、记录26项临床和实验室常用指标，包括年龄、性别、血常规、生化、凝血酶原时间、病毒载量及血清纤维化四项标志物等参数。在模型组，对指标依次行单因素分析和多因素Logistic回归分析，筛选出与研究终点相关的独立预测因子，在此基础上构建诊断肝纤维化的指数模型，最后在独立的验证组中检验模型的诊断效率。结果在模型组，建立了一个由年龄、血小板计数、γ-谷氨酰转肽酶和透明质酸四项指标构成的判别肝纤维化程度的指数模型（FibroIndex）。受试者工作特征曲线（ROC）分析显示，FibroIndex判别≥s3的ROC曲线下面积（AUC）为0．889，以积分3．0为界值，诊断的敏感性90．2％，特异性76．1％，准确性82．0％，且其积分与肝纤维化分期呈良好的正向线性相关（r=0．731，p〈0．01）I该指数判别≥s2和s4的界值分别为2．2、5．4，诊断的AUC分别为0．873．0．872，敏感性、特异性分别为79％、82％和83％、75％。将FibroIndex以同样标准应用于验证组，其与模型组AUC比较差异无统计学意义，两组的诊断效率总体上相近。结论运用无创诊断模型评价慢性肝炎肝纤维化严重程度具有敏感、准确和可重复性，并有望在一定程度上替代肝活组织检查来监测慢性乙型肝炎肝纤维化的动态变化。