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Wu LF, Xiang XX, Bai DS, Jin SJ, Zhang C, Zhou BH, Qian JJ, Jiang GQ. Novel noninvasive liver fibrotic markers to predict postoperative re-bleeding after laparoscopic splenectomy and azygoportal disconnection: a 1-year prospective study. Surg Endosc 2020; 35:6158-6165. [PMID: 33094827 DOI: 10.1007/s00464-020-08111-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2020] [Accepted: 10/16/2020] [Indexed: 12/15/2022]
Abstract
BACKGROUND Esophagogastric variceal re-bleeding (EGVR) is a common and potentially lethal complication after open or laparoscopic splenectomy and azygoportal disconnection (LSD) in patients with cirrhosis and portal hypertension. Currently, noninvasive biomarkers for predicting EGVR are lacking. This prospective study focused on developing a noninvasive and convenient clinical model for predicting postoperative EGVR. METHODS Between September 2014 and March 2017, we enrolled 164 patients with cirrhosis who successfully underwent LSD. Based on the absence or presence of EGVR, patients were divided into EGVR and non-EGVR groups. We used correlation analysis to determine significant candidate variables among the liver fibrotic markers procollagen type III (PC-III), hyaluronidase (HA), laminin (LN), and type IV collagen (C-IV). RESULTS Postoperative EGVR occurred in 22 (13.41%) patients. Correlation analyses showed that LN (r = 0.375; p < 0.001) and C-IV (r = 0.349; p < 0.001) were significantly positively associated with EGVR. The area under the receiver operating characteristic curve (AUC) of LN was 0.817 (95% confidence interval [CI] 0.722-0.913); that of C-IV was 0.795 (95% CI 0.710-0.881). In logistic multivariate regression, cutoff values LN ≥ 64 µg/L and of C-IV ≥ 65 µg/L were independent risk factors for EGVR. LN ≥ 64 µg/L combined with C-IV ≥ 65 µg/L was the best performing model, with AUC 0.867 (95% CI 0.768-0.967). CONCLUSION LN and C-IV are potential markers to predict EGVR. Combining the two markers showed satisfactory ability to predict EGVR in patients with cirrhosis and portal hypertension after LSD.
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Affiliation(s)
- Long-Fei Wu
- Department of Hepatobiliary Surgery, Clinical Medical College, Yangzhou University, Yangzhou, 225000, Jiangsu, China.,Department of Hepatobiliary Surgery, The First Clinical College, Dalian Medical University, Dalian, China
| | - Xiao-Xing Xiang
- Department of Digestive Diseases, Clinical Medical College, Yangzhou University, Yangzhou, China
| | - Dou-Sheng Bai
- Department of Hepatobiliary Surgery, Clinical Medical College, Yangzhou University, Yangzhou, 225000, Jiangsu, China
| | - Sheng-Jie Jin
- Department of Hepatobiliary Surgery, Clinical Medical College, Yangzhou University, Yangzhou, 225000, Jiangsu, China
| | - Chi Zhang
- Department of Hepatobiliary Surgery, Clinical Medical College, Yangzhou University, Yangzhou, 225000, Jiangsu, China
| | - Bao-Huan Zhou
- Department of Hepatobiliary Surgery, Clinical Medical College, Yangzhou University, Yangzhou, 225000, Jiangsu, China
| | - Jian-Jun Qian
- Department of Hepatobiliary Surgery, Clinical Medical College, Yangzhou University, Yangzhou, 225000, Jiangsu, China
| | - Guo-Qing Jiang
- Department of Hepatobiliary Surgery, Clinical Medical College, Yangzhou University, Yangzhou, 225000, Jiangsu, China.
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Chaudhuri D, Ghate NB, Panja S, Basu T, Shendge AK, Mandal N. Glycoside rich fraction from Spondias pinnata bark ameliorate iron overload induced oxidative stress and hepatic damage in Swiss albino mice. Altern Ther Health Med 2016; 16:262. [PMID: 27472924 DOI: 10.1186/s12906-016-1244-4] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2016] [Accepted: 07/23/2016] [Indexed: 11/10/2022]
Abstract
BACKGROUND Iron in the overloaded condition in liver promotes the overproduction of free radicals that lead to oxidative stress and ultimately hepatic damage. The present study was designed to evaluate the ameliorating potential from iron overloaded hepatotoxicity by the glycosidic fraction from Spondious pinnata bark (SPW1) along with its antioxidant property. METHODS The fraction was tested for its in vitro antioxidant, free radical scavenging property and iron chelation potential via standard biochemical assays. Iron overload condition was generated by the intraperitoneal administration of iron dextran in mice. The levels of serum enzymes, antioxidant enzymes in liver, markers of hepatic damage, liver iron, and ferritin content were measured in response to the oral treatment of SPW1. Histopathology of the liver sections was performed for visual confirmation of the amelioration potential of SPW1. RESULTS The fraction exhibited excellent in vitro antioxidant as well as free radical scavenging potential against both reactive oxygen species and reactive nitrogen species. Administration of SPW1 significantly normalized the disturbed levels of antioxidant enzymes, liver iron, lipid peroxidation, liver fibrosis, serum enzyme and ferritin better than standard desirox which were also supported by the morphological study of the liver sections. Phytochemical analysis as well as HPLC study, confirmed that the fraction mainly consisted of glycosidic phenolics and flavonoids that attributed to its biological activities. CONCLUSIONS The above results suggested that beneficial effects of SPW1 on iron overload induced hepatotoxicity that can be considered as a possible candidate against iron overload diseases.
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Chaudhuri D, Ghate NB, Panja S, Mandal N. Role of phenolics from Spondias pinnata bark in amelioration of iron overload induced hepatic damage in Swiss albino mice. BMC Pharmacol Toxicol 2016; 17:34. [PMID: 27459849 PMCID: PMC4962386 DOI: 10.1186/s40360-016-0077-6] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2016] [Accepted: 07/14/2016] [Indexed: 11/17/2022] Open
Abstract
Background Crude Spondias pinnata bark extract was previously assessed for its antioxidant, anticancer and iron chelating potentials. The isolated compounds gallic acid (GA) and methyl gallate (MG) were evaluated for their curative potential against iron overload-induced liver fibrosis and hepatocellular damage. Methods In vitro iron chelation property and in vivo ameliorating potential from iron overload induced liver toxicity of GA and MG was assessed by different biochemical assays and histopathological studies. Results MG and GA demonstrated excellent reducing power activities but iron chelation potential of MG is better than GA. Oral MG treatment in mice displayed excellent efficacy (better than GA) to significantly restore the levels of liver antioxidants, serum markers and cellular reactive oxygen species in a dose-dependent fashion. Apart from these, MG exceptionally prevented lipid peroxidation and protein oxidation whereas GA demonstrated better activity to reduce collagen content, thereby strengthening its position as an efficient drug against hepatic damage/fibrosis, which was further supported by histopathological studies. Alongside, MG efficiently eliminated the cause of liver damage, i.e., excess iron, by chelating free iron and reducing the ferritin-bound iron. Conclusions The present study confirmed the curative effect of GA and MG against iron overload hepatic damage via their potent antioxidant and iron-chelating potential. Electronic supplementary material The online version of this article (doi:10.1186/s40360-016-0077-6) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Dipankar Chaudhuri
- Division of Molecular Medicine, Bose Institute, P 1/12, C. I. T. Road, Scheme - VIIM, Kolkata, 700054, West Bengal, India
| | - Nikhil Baban Ghate
- Division of Molecular Medicine, Bose Institute, P 1/12, C. I. T. Road, Scheme - VIIM, Kolkata, 700054, West Bengal, India
| | - Sourav Panja
- Division of Molecular Medicine, Bose Institute, P 1/12, C. I. T. Road, Scheme - VIIM, Kolkata, 700054, West Bengal, India
| | - Nripendranath Mandal
- Division of Molecular Medicine, Bose Institute, P 1/12, C. I. T. Road, Scheme - VIIM, Kolkata, 700054, West Bengal, India.
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Keyte SV, Kenny PJ, Forcada Y, Church DB, Niessen SJM. Serum N-Terminal Type III Procollagen Propeptide: An Indicator of Growth Hormone Excess and Response to Treatment in Feline Hypersomatotropism. J Vet Intern Med 2016; 30:973-82. [PMID: 27425382 PMCID: PMC5108467 DOI: 10.1111/jvim.14373] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2015] [Revised: 04/25/2016] [Accepted: 06/11/2016] [Indexed: 01/03/2023] Open
Abstract
Background N‐terminal type III procollagen propeptide (PIIINP) is a biomarker of soft tissue proliferation. Hypersomatotropism (HS) is associated with soft tissue proliferation. Hypothesis Serum PIIINP is increased in cats with HS and decreases with effective treatment, and may be an additional tool in the diagnosis and treatment of feline HS. Animals Cats with uncomplicated diabetes mellitus (DM; n = 30) and with HS‐induced DM (HSDM; n = 30). Pre‐ and posttreatment samples were available from 5 cats undergoing radiotherapy (RT) and 16 cats undergoing hypophysectomy (HPX). Methods Retrospective and prospective cross‐sectional study. Analytical performance of a serum PIIINP ELISA was assessed and validated for use in cats. PIIINP and insulin‐like growth factor 1 (IGF‐1) radioimmunoassays (RIA) were performed pre‐ and post‐treatment in cats with DM and HSDM. PIIINP and IGF‐1 were compared between cats treated by RT and HPX. Results Serum PIIINP concentrations were significantly higher (P < .001) in HSDM cats (median, 19.6 ng/mL; range, 1.7–27.9) compared to DM cats (median, 5.0 ng/mL; range, 2.1–10.4). A cut‐off of 10.5 ng/mL allowed differentiation between DM and HSDM cats with 87% sensitivity and 100% specificity (area under the curve [AUC], 0.91; 95% confidence interval [CI], 0.82‐1). After RT, PIIINP increased significantly (P = .043) with no significant change in IGF‐1 concentrations. After HPX, serum PIIINP (P = .034) and IGF‐1 concentrations (P < .001) decreased significantly. Conclusion and clinical importance PIIINP concentrations are increased in cats with untreated HSDM compared to those with DM, demonstrating the effect of excess GH on soft tissue. PIIINP concentrations decreased after HPX in most HSDM cats.
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Affiliation(s)
- S V Keyte
- Department of Clinical Science and Services, The Royal Veterinary College, University of London, Hatfield, Hertfordshire, UK
| | - P J Kenny
- Department of Clinical Science and Services, The Royal Veterinary College, University of London, Hatfield, Hertfordshire, UK
| | - Y Forcada
- Department of Clinical Science and Services, The Royal Veterinary College, University of London, Hatfield, Hertfordshire, UK
| | - D B Church
- Department of Clinical Science and Services, The Royal Veterinary College, University of London, Hatfield, Hertfordshire, UK
| | - S J M Niessen
- Department of Clinical Science and Services, The Royal Veterinary College, University of London, Hatfield, Hertfordshire, UK
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Nandeesha H, Rajappa M, Kadhiravan T, Srilatha K, Harichandrakumar KT, Thyagarajan D. Carbohydrate Deficient Transferrin and Interleukin-6 as Predictors of Fibrosis in Alcohol Cirrhosis. Indian J Clin Biochem 2015; 31:117-20. [PMID: 26855498 DOI: 10.1007/s12291-015-0534-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2015] [Accepted: 11/03/2015] [Indexed: 10/22/2022]
Abstract
The severity of alcoholic cirrhosis depends on the presence of liver inflammation and fibrogenesis. Previous studies have hypothesized that carbohydrate deficient transferrin can be used as marker of liver impairment in alcoholic liver disease patients. The present study was designed to assess whether carbohydrate deficient transferrin is associated with procollagen III peptide and predict fibrosis in alcohol cirrhosis patients. We enrolled 48 patients with alcoholic cirrhosis and 38 healthy controls. Serum carbohydrate deficient transferrin, procollagen III peptide and interleukin-6 levels were estimated in both groups. Serum carbohydrate deficient transferrin, procollagen III peptide and interleukin-6 were significantly increased in alcoholic cirrhosis patients compared to controls. Stepwise regression analysis showed that carbohydrate deficient transferrin (adjusted R(2) = 0.313, β = 0.362, p = 0.003) and interleukin-6 (adjusted R(2) = 0.194, β = 0.459, p = 0.001) were positively associated with procollagen III peptide when age, duration and amount of alcohol consumption were considered as covariates. We conclude that elevated carbohydrate deficient transferrin and interleukin-6 act as predictors of fibrosis in alcoholic cirrhosis.
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Affiliation(s)
- Hanumanthappa Nandeesha
- Department of Biochemistry, Jawaharlal Institute of Post Graduate Medical Education and Research, Puducherry, India
| | - Medha Rajappa
- Department of Biochemistry, Jawaharlal Institute of Post Graduate Medical Education and Research, Puducherry, India
| | - Tamilarasu Kadhiravan
- Department of Medicine, Jawaharlal Institute of Post Graduate Medical Education and Research, Puducherry, India
| | - Krishnamoorthy Srilatha
- Department of Biochemistry, Jawaharlal Institute of Post Graduate Medical Education and Research, Puducherry, India
| | - Kottyen Thazhath Harichandrakumar
- Department of Medical Biometrics and Informatics, Jawaharlal Institute of Post Graduate Medical Education and Research, Puducherry, India
| | - Durgadevi Thyagarajan
- Department of Biochemistry, Jawaharlal Institute of Post Graduate Medical Education and Research, Puducherry, India
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Diagnostic performance of collagen IV and laminin for the prediction of fibrosis and cirrhosis in chronic hepatitis C patients: a multicenter study. Eur J Gastroenterol Hepatol 2015; 27:378-85. [PMID: 25874509 DOI: 10.1097/meg.0000000000000298] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND/AIM To date, liver biopsy has been the gold standard used for the assessment of liver fibrosis in patients with chronic hepatitis C. Our aim was to evaluate the diagnostic performance of a panel of simple blood markers of liver fibrosis and the development a novel score to replace liver biopsy. PATIENTS AND METHODS Liver biochemical profile including transaminases, bilirubin, alkaline phosphatase, and albumin, in addition to platelet count, was evaluated using standard methods in 305 chronic hepatitis C patients. Serum type IV collagen and laminin were assayed using the ELISA technique. Liver biopsies were performed. Statistical analyses were carried out by logistic regression and receiver operating characteristic curves to assess and compare the diagnostic accuracy of blood markers. A stepwise combination algorithm was developed and validated in 317 additional patients. RESULTS The Fibrosis Discriminant Score (FDS) was developed combining collagen, laminin, aspartate aminotransferase/platelet ratio index, and albumin. FDS produced an area under receiver operating characteristic curve of 0.831 for significant fibrosis, 0.791 for advanced fibrosis, and 0.881 for cirrhosis. The FDS was correctly classified in 82% of patients with significant fibrosis with 79% sensitivity and 88% specificity at cut-off 0.66 or more. Similar results were obtained in a validation study in which, of 317 patients, liver biopsy could have been avoided in 81%. CONCLUSION A simple fibrosis index can be useful to select hepatitis C virus-infected patients with a very low risk of significant fibrosis in whom the protocol of liver biopsies may be avoided.
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Cequera A, García de León Méndez M. Biomarkers for liver fibrosis: Advances, advantages and disadvantages. REVISTA DE GASTROENTEROLOGÍA DE MÉXICO 2014. [DOI: 10.1016/j.rgmxen.2014.07.001] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
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[Biomarkers for liver fibrosis: advances, advantages and disadvantages]. REVISTA DE GASTROENTEROLOGÍA DE MÉXICO 2014; 79:187-99. [PMID: 24954541 DOI: 10.1016/j.rgmx.2014.05.003] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/15/2013] [Accepted: 05/21/2014] [Indexed: 12/17/2022]
Abstract
Liver cirrhosis in Mexico is one of the most important causes of death in persons between the ages of 25 and 50 years. One of the reasons for therapeutic failure is the lack of knowledge about the molecular mechanisms that cause liver disorder and make it irreversible. One of its prevalent anatomical characteristics is an excessive deposition of fibrous tissue that takes different forms depending on etiology and disease stage. Liver biopsy, traditionally regarded as the gold standard of fibrosis staging, has been brought into question over the past decade, resulting in the proposal for developing non-invasive technologies based on different, but complementary, approaches: a biological one that takes the serum levels of products arising from the fibrosis into account, and a more physical one that evaluates scarring of the liver by methods such as ultrasound and magnetic resonance elastography; some of the methods were originally studied and validated in patients with hepatitis C. There is great interest in determining non-invasive markers for the diagnosis of liver fibrosis, since at present there is no panel or parameter efficient and reliable enough for diagnostic use. In this paper, we describe the biomarkers that are currently being used for studying liver fibrosis in humans, their advantages and disadvantages, as well as the implementation of new-generation technologies and the evaluation of their possible use in the diagnosis of fibrosis.
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Mak TM, Huang YP, Zheng YP. Liver fibrosis assessment using transient elastography guided with real-time B-mode ultrasound imaging: a feasibility study. ULTRASOUND IN MEDICINE & BIOLOGY 2013; 39:956-966. [PMID: 23562022 DOI: 10.1016/j.ultrasmedbio.2013.01.009] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/27/2012] [Revised: 01/11/2013] [Accepted: 01/15/2013] [Indexed: 06/02/2023]
Abstract
Liver fibrosis is a kind of chronic damage of the liver and can lead to cirrhosis, one of the top 10 causes of death in the Western world. However, there is still a lack of noninvasive methods for diagnosing liver fibrosis. Fibroscan (Echosens, Paris, France), a device based on A-mode transient elastography, has shown promising results. In this study, a transient elastography system with real-time B-mode imaging for non-invasive liver fibrosis assessment, named Liverscan, was developed; its performance was tested and compared with that of the Fibroscan. A specific measurement probe was designed and fabricated with a B-mode ultrasound transducer fixed along the axis of a mechanical vibrator. It was integrated with the Liverscan to measure liver stiffness based on the shear wave propagation in liver tissues. The system was validated by mechanical indentation test using custom-made agar-gelatin phantoms with different stiffness. To further test its feasibility, in vivo measurements were conducted in 67 volunteers (age, 34 ± 3 years; body mass index, 21.3 ± 2.8 kg/m(2); Mean ± SD., 34 male and 33 female), including 20 patients with various liver diseases, and 28 (19 male and 9 female) being tested by both Liverscan and Fibroscan. A significant linear correlation between the stiffness measured by the mechanical indentation test and that by the Liverscan (r = 0.973; p < 0.001) was obtained. The in vivo liver stiffness measured by Liverscan was also correlated with that by Fibroscan significantly (r = 0.886; p < 0.001). There was a significant difference in liver stiffness between the 20 patients and the other healthy subjects (14.1 ± 3.4 kPa vs. 10.5 ± 2.1 kPa; p = 0.001). The intra- and inter-observer tests indicated that the measurements were repeatable with intra-class correlation coefficients being 0.987 (p < 0.001) and 0.988 (p < 0.001), respectively. This study demonstrated that Liverscan with a specifically designed probe was able to measure and differentiate liver of different stiffness using the established measurement protocol under the guidance of real-time B-mode ultrasound imaging.
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Affiliation(s)
- Tak-Man Mak
- Interdisciplinary Division of Biomedical Engineering, Faculty of Engineering, The Hong Kong Polytechnic University, Kowloon, Hong Kong, China
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Malik M, Segars J, Catherino WH. Integrin β1 regulates leiomyoma cytoskeletal integrity and growth. Matrix Biol 2012; 31:389-97. [PMID: 23023061 DOI: 10.1016/j.matbio.2012.09.005] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2012] [Revised: 09/14/2012] [Accepted: 09/18/2012] [Indexed: 11/17/2022]
Abstract
Uterine leiomyomas are characterized by an excessive extracellular matrix, increased mechanical stress, and increased active RhoA. Previously, we observed that mechanical signaling was attenuated in leiomyoma, but the mechanisms responsible remain unclear. Integrins, especially integrin β1, are transmembrane adhesion receptors that couple extracellular matrix stresses to the intracellular cytoskeleton to influence cell proliferation and differentiation. Here we characterized integrin and laminin to signaling in leiomyoma cells. We observed a 2.25±0.32 fold increased expression of integrin β1 in leiomyoma cells, compared to myometrial cells. Antibody-mediated inhibition of integrin β1 led to significant growth inhibition in leiomyoma cells and a loss of cytoskeletal integrity. Specifically, polymerization of actin filaments and formation of focal adhesions were reduced by inhibition of integrin β1. Inhibition of integrin β1 in leiomyoma cells led to 0.81±0.02 fold decrease in active RhoA, and resembled levels found in serum-starved cells. Likewise, inhibition of integrin β1 was accompanied by a decrease in phospho-ERK. Compared to myometrial cells, leiomyoma cells demonstrated increased expression of integrin α6 subunit to laminin receptor (1.91±0.11 fold), and increased expression of laminin 5α (1.52±0.02), laminin 5β (3.06±0.92), and laminin 5γ (1.66±0.06). Of note, leiomyoma cells grown on laminin matrix appear to realign themselves. Taken together, the findings reveal that the attenuated mechanical signaling in leiomyoma cells is accompanied by an increased expression and a dependence on integrin β1 signaling in leiomyoma cells, compared to myometrial cells.
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Affiliation(s)
- Minnie Malik
- Department of Obstetrics and Gynecology, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, United States
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García-Heredia A, Marsillach J, Aragonès G, Guardiola M, Rull A, Beltrán-Debón R, Folch A, Mackness B, Mackness M, Pedro-Botet J, Joven J, Camps J. Serum paraoxonase-3 concentration is associated with the severity of hepatic impairment in patients with chronic liver disease. Clin Biochem 2011; 44:1320-4. [DOI: 10.1016/j.clinbiochem.2011.08.003] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2011] [Revised: 07/29/2011] [Accepted: 08/02/2011] [Indexed: 12/20/2022]
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Rath T, Roderfeld M, Güler C, Wenzel C, Graf J, Beitinger F, Roeb E, Zachoval R. YKL-40 and transient elastography, a powerful team to assess hepatic fibrosis. Scand J Gastroenterol 2011; 46:1369-80. [PMID: 21905976 DOI: 10.3109/00365521.2011.613949] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVE Transient elastography (TE) is a non-invasive and accurate method for the diagnosis of severe hepatic fibrosis and cirrhosis (F = 3 and F = 4). However, the assessment of significant fibrosis (F = 2) by TE is impaired due to a high variation in the diagnostic accuracy. Within this study, we aim to compare the diagnostic value of TE and experimental biomarkers of liver fibrosis. MATERIAL AND METHODS A total of 55 patients with chronic liver disease of different etiologies were included in the study. Among them, patients with HCV infection represented the largest cohort (n = 25). Liver fibrosis was evaluated according to the Desmet/Scheuer score. All patients received TE. Serum concentrations of YKL-40, hyaluronic acid (HA), Laminin, C-terminal procollagen I peptide, MMP-9, TIMP-1, TIMP-2 and MMP-9/TIMP-1 complex were determined by ELISA. RESULTS In the total patient population, areas under the receiver operator characteristic curve (AUROC) for TE were 0.798 (F ≥ 2), 0.880 (F ≥ 3) and 1 (F = 4). Among the serum markers, highest diagnostic accuracies were calculated for YKL-40 for F ≥ 2 (0.792) and F ≥ 3 (0.914) and for YKL-40 and HA for F = 4 (both 0.936). In the subgroup of HCV patients, the following AUROCs for TE were calculated: 0.802 (F ≥ 2), 0.798 (F ≥ 3) and 0.998 (F = 4). YKL-40 exhibited the highest diagnostic accuracy of all biomarkers in the HCV population (0.880, 0.854 and 0.986, respectively). CONCLUSIONS YKL-40 is a powerful fibrosis marker with high diagnostic accuracy, in particular in HCV-associated liver disease. Its determination may confirm and improve the diagnostic accuracy of TE especially in early stages of liver fibrosis.
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Affiliation(s)
- Timo Rath
- Department of Internal Medicine, Division of Gastroenterology, Justus-Liebig-University Giessen, Giessen, Germany
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Pradere JP, Troeger JS, Dapito DH, Mencin AA, Schwabe RF. Toll-like receptor 4 and hepatic fibrogenesis. Semin Liver Dis 2010; 30:232-44. [PMID: 20665376 PMCID: PMC4099360 DOI: 10.1055/s-0030-1255353] [Citation(s) in RCA: 117] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Inflammation is strongly associated with chronic hepatic injury and the ensuing wound-healing process. Recent evidence from mouse models and human studies implicates Toll-like receptors (TLRs) as important regulators of the inflammatory response and a functional link between inflammation and fibrosis in the chronically injured liver. Here, we review mechanisms by which TLR4 and TLR4 ligands from the intestinal microbiota contribute to hepatic injury, inflammation, hepatic stellate cell activation, and fibrosis.
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Affiliation(s)
- Jean-Philippe Pradere
- Department of Medicine, Columbia University, College of Physicians and Surgeons, New York, NY
| | - Juliane S. Troeger
- Department of Medicine, Columbia University, College of Physicians and Surgeons, New York, NY
| | - Dianne H. Dapito
- The Institute of Human Nutrition, Columbia University, College of Physicians and Surgeons, New York, NY
| | - Ali A. Mencin
- Department of Medicine, Columbia University, College of Physicians and Surgeons, New York, NY
| | - Robert F. Schwabe
- Department of Medicine, Columbia University, College of Physicians and Surgeons, New York, NY,The Institute of Human Nutrition, Columbia University, College of Physicians and Surgeons, New York, NY
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Gressner OA, Beer N, Jodlowski A, Gressner AM. Impact of quality control accepted inter-laboratory variations on calculated Fibrotest/Actitest scores for the non-invasive biochemical assessment of liver fibrosis. Clin Chim Acta 2009; 409:90-5. [DOI: 10.1016/j.cca.2009.09.005] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2009] [Revised: 08/20/2009] [Accepted: 09/02/2009] [Indexed: 01/06/2023]
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Lee SK, Yi CH, Kim MH, Cheong JY, Cho SW, Yang SJ, Kwack K. Genetic association between functional haplotype of collagen type III alpha 1 and chronic hepatitis B and cirrhosis in Koreans. ACTA ACUST UNITED AC 2008; 72:539-48. [PMID: 19000145 DOI: 10.1111/j.1399-0039.2008.01144.x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Collagen type III alpha 1 (COL3A1) is one of the extracelluar matrix (ECM) proteins. The expression of COL3A1 is closely related to chronic liver diseases. In this study, we investigated whether single nucleotide polymorphisms (SNPs) of COL3A1 confer genetic susceptibility to patients with hepatitis B virus-infected liver diseases including chronic hepatitis B (CH), liver cirrhosis (CIR), and hepatocellular carcinoma (HCC). A total of 399 Korean (KOR) people, 111 patients with CH, 95 patients with CIR, 86 patients with HCC, and 107 spontaneously recovery, were genotyped for 16 SNPs of the COL3A1 gene. The 'A' allele of rs3106796 was highly associated with the CH [odds ratio (OR) = 1.62, P = 0.01], CIR (OR = 1.67, P = 0.01), and HCC (OR = 1.59, P = 0.03). There were six polymorphic SNPs that could be divided into two linkage disequilibrium (LD) blocks. The haplotype pattern of the KOR control seems to be similar to the patterns displayed in the Japanese, Chinese, and Caucasian populations sampled in the International HapMap project. Haplotype 3 (A-G-A) of the LD block 2 was significantly associated with CH (OR = 2.23, P = 0.02), CIR (OR = 2.24, P = 0.03), and HCC (OR = 2.27, P = 0.03). Moreover, diplotype analysis showed that they had increased relative risk for CH and CIR in the two diplotypes, dt3 (A-G-A/G-G-A; OR = 4.05, P = 0.01) and dt6 (A-A-A/A-G-A; OR = 7.42, P = 0.01 and OR = 5.84, P = 0.05) against dt1 (G-G-A/G-G-A), the most common diplotype in both KOR groups. In vitro reporter gene assays showed that the constructs containing the 'G' allele of rs3106796 appear to exert lower transcriptional activity of COL3A1 than the 'A' allele, depending on the promoter types.
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Affiliation(s)
- S K Lee
- Medical Genomics Laboratory, Graduate School of Life Science and Biotechnology, Pochon CHA University, Seongnam, Korea
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16
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Gressner OA, Weiskirchen R, Gressner AM. Biomarkers of hepatic fibrosis, fibrogenesis and genetic pre-disposition pending between fiction and reality. J Cell Mol Med 2008; 11:1031-51. [PMID: 17979881 PMCID: PMC4401271 DOI: 10.1111/j.1582-4934.2007.00092.x] [Citation(s) in RCA: 75] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Fibrosis is a frequent, life-threatening complication of most chronic liver diseases. Despite major achievements in the understanding of its pathogenesis, the translation of this knowledge into clinical practice is still limited. In particular, non-invasive and reliable (serum-) biomarkers indicating the activity of fibrogenesis are scarce. Class I biomarkers are defined as serum components having a direct relation to the mechanism of fibrogenesis, either as secreted matrix-related components of activated hepatic stellate cells and fibroblasts or as mediators of extracellular matrix (ECM) synthesis or turnover. They reflect primarily the activity of the fibrogenic process. Many of them, however, proved to be disappointing with regard to sensitivity and speci-ficity. Up to now hyaluronan turned out to be the relative best type I serum marker. Class II biomarkers comprise in general rather simple standard laboratory tests, which are grouped into panels. They fulfil most criteria for detection and staging of fibrosis and to a lesser extent grading of fibrogenic activity. More than 20 scores are currently available, among which Fibrotest™ is the most popular one. However, the diagnostic use of many of these scores is still limited and standardization of the assays is only partially realized. Combining of panel markers in sequential algorithms might increase their diagnostic validity. The translation of genetic pre-disposition biomarkers into clinical practice has not yet started, but some polymorphisms indicate a link to progression and outcome of fibrogenesis. Parallel to serum markers non-invasive physical techniques, for example, transient elastography, are developed, which can be combined with serum tests and profiling of serum proteins and glycans.
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Affiliation(s)
- O A Gressner
- Institute of Clinical Chemistry and Pathobiochemistry, Central Laboratory, RWTH-University Hospital, Aachen, Germany.
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17
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Kim MY, Baik SK, Jang YO, Suk KT, Kim JW, Kim HS, Cho MY, Choi SJ, Um SH, Han KH. Serum hyaluronic acid level: Correlation with quantitative measurement of hepatic fibrosis in a cirrhotic rat model. THE KOREAN JOURNAL OF HEPATOLOGY 2008; 14:159-67. [DOI: 10.3350/kjhep.2008.14.2.159] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Affiliation(s)
- Moon Young Kim
- Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - Soon Koo Baik
- Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - Yoon Ok Jang
- Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - Ki Tae Suk
- Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - Jae Woo Kim
- Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - Hyun Soo Kim
- Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - Mi Yun Cho
- Department of Pathology, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - Sun Joo Choi
- Department of Microbiology, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - Soon Ho Um
- Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| | - Kwang-Hyub Han
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
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18
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Attallah AM, Mosa TE, Omran MM, Abo-Zeid MM, El-Dosoky I, Shaker YM. Immunodetection of collagen types I, II, III, and IV for differentiation of liver fibrosis stages in patients with chronic HCV. J Immunoassay Immunochem 2007; 28:155-68. [PMID: 17424834 DOI: 10.1080/15321810701212088] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
The current study is aimed at evaluating serum collagens and other serum biochemical markers as useful, non-invasive markers of hepatic fibrosis associated with chronic hepatitis C virus (HCV). Collagen types I, II, III, and IV were detected in serum using ELISA and Western blot techniques. The ELISA levels of collagen I, II, III, and IV increased significantly with the progression of fibrosis staging. Based on receiver-operating characteristic (ROC) curve analysis, the collagen type III (70 kDa) and type IV (200 kDa) were more useful than other serum bio-markers for differentiating severe fibrosis from mild fibrosis. Multivariate discriminant analysis (MDA) selected a fibrosis discriminant score (FDS) = [2.345 + Collagen III (microg/mL) x 1.923 + Collagen IV (microg/mL) x 1.544 + ALT (U/mL) x 0.005] - [albumin(g/L) x 0.046]. The FDS correctly classified 87% of the severe fibrosis patients at a cut-off score = 2.2 (i.e., more than 2.2 indicated severe fibrotic liver and less than 2.2 indicated mild fibrotic liver) with specificity of 97%. In a validation study, the FDS was applied to the second cohort of patients and the results were reproduced without significant difference. In conclusion, the developed four-parameter based FDS is useful for identifying severe liver fibrosis in patients with chronic HCV infection.
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19
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Plebani M, Basso D. Non-invasive assessment of chronic liver and gastric diseases. Clin Chim Acta 2007; 381:39-49. [PMID: 17374528 DOI: 10.1016/j.cca.2007.02.019] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2007] [Accepted: 02/13/2007] [Indexed: 02/06/2023]
Abstract
BACKGROUND In patients with both chronic liver diseases and dyspepsia there is the need for non-invasive, inexpensive and effective laboratory tests. These tests should not substitute but complement and integrate the information derived from invasive techniques such as liver biopsy and esofagogastroduodenoscopy. Natural history studies indicate that advanced fibrosis and cirrhosis develop in about 20%-40% of patients with chronic hepatitis B or C, and in a similar proportion of those with alcoholic or non-alcoholic steatohepatitis. In these patients, precise definition of the hepatic fibrosis stage is the most important parameter to assess the risk of disease progression and to decide for an immediate and appropriate antiviral therapy. METHODS Liver biopsy represents the gold standard for evaluating the presence, type and stage of liver fibrosis but a body of evidence has been accumulated to demonstrate the limitations of this technique, including inter- and intra-observer variations, sampling errors and variability. In recent years there has been an increasing interest in the possibility of identifying and describing liver fibrosis by using non-invasive, surrogate markers measurable in blood. Many studies have been dedicated to the evaluation of "direct" markers of fibrogenesis, while a second approach is based on the evaluation of single or combined biochemical parameters that reflect the stage of liver disease. Upper gastrointestinal symptoms are common in developed countries and this makes impossible the use of esofagogastroduodenoscopy in all patients with dyspepsia. The Maastricht 2-2000 Consensus meeting has suggested screening and treating Helicobacter pylori infection in dyspeptic patients in primary health care as the first line of therapy for newly onset dyspepsia. CONCLUSIONS Combination panels of biomarkers have been demonstrated to improve the accuracy of the single tests and with the use of algorithms based on sequential combination of non-invasive biomarkers a high diagnostic accuracy has been achieved for liver fibrosis. This, in turn, translates in a reduction by >50% in the need of taking liver biopsies. A biochemical panel which includes the measurement of serum pepsinogen I and II, gastrin G-17 and anti-H. pylori antibodies for patients with gastric disease, due to its high negative predictive value, appears to be a valuable approach to screen patients <55 years and with no alarm features, assuring safety and cost-effectiveness.
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Affiliation(s)
- Mario Plebani
- Department of Laboratory Medicine, University-Hospital of Padova, Italy.
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20
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Gressner AM, Arndt T. P. LEXIKON DER MEDIZINISCHEN LABORATORIUMSDIAGNOSTIK 2007. [PMCID: PMC7122100 DOI: 10.1007/978-3-540-49520-8_16] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
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21
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Parise ER, Oliveira AC, Figueiredo-Mendes C, Lanzoni V, Martins J, Nader H, Ferraz ML. Noninvasive serum markers in the diagnosis of structural liver damage in chronic hepatitis C virus infection. Liver Int 2006; 26:1095-9. [PMID: 17032410 DOI: 10.1111/j.1478-3231.2006.01356.x] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
AIM Several noninvasive markers are being used to assess the structural liver damage in patients with chronic hepatitis C (CHC). We evaluated the capacity of serum hyaluronic acid (HA), aspartate aminotransferase (AST)/ALT ratio, the AST to platelet ratio index (APRI) and gamma-glutamyltransferase (GGT) levels to predict the intensity of hepatic fibrosis in patients with CHC. PATIENTS AND METHODS In a total of 206 hepatitis C virus RNA-positive biopsied patients, AST, ALT, GGT levels, platelet count and serum HA concentration were determined. The APRI was calculated as the ratio of AST to platelets. RESULTS HA levels were best correlated with disease stage (r=-0.694; P<0.001). In the diagnosis of significant fibrosis (F2-F4), HA levels [AUC=0.879, 95% CI (0.832-0.927)] and APRI [AUC=0.824 (0.772-0.903)] were the markers with the best diagnostic accuracy. These parameters also best identified the presence of cirrhosis (F4), with an AUC of 0.908 (0.868-0.949) for HA and of 0.837 (0.772-0.903) for APRI. CONCLUSION Serum HA was the parameter that alone presented the best diagnostic accuracy in the assessment of hepatic fibrosis in CHC. The APRI showed a better diagnostic sensitivity than GGT levels or the AST/ALT ratio. Its simple determination and low cost make this index a valid alternative for the noninvasive staging of CHC.
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Affiliation(s)
- Edison R Parise
- Department of Gastroenterology, Federal University of São Paulo, São Paulo, Brazil.
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22
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Abstract
Development of liver fibrosis, which leads to cirrhosis, is the principal complication of all chronic liver diseases, regardless of their cause. Knowledge of the existence and severity of fibrosis is important from diagnostic and prognostic viewpoints. Its assessment plays an essential role in the treatment decision and makes it possible to assess the risk of progression to cirrhosis and the onset of its complications. Histologic examination of the liver remains the reference examination for assessing the extent of fibrosis during chronic liver disease. Nonetheless, the number of patients needing assessment, the risks of the punch-biopsy and the cost of this invasive examination have led many to propose other tools to assess fibrosis. Some standard indicators (transaminases, platelets, prothrombin time) have long been recognized as indirect markers of extensive fibrosis. More recently, progress in our knowledge of the mechanisms of liver fibrogenesis have made it possible to identify different peripheral blood components that may be of clinical interest. Thus serum assays of elements of the extracellular matrix, their decay products, or enzymes involved in their metabolism have been proposed as noninvasive indicators. Among these, hyaluronic acid appears the most interesting. For several years, scores have been calculated with algorithms that combine several indicators determined simultaneously to assess fibrosis in patients with hepatitis C and sometimes other chronic liver diseases. The Fibrotest is the best validated and most widely used of these. Finally, Fibroscan is a device for the diagnosis and quantification of hepatic fibrosis, based on the technique of transient elastography. The relative roles of these noninvasive markers and the value of their combinations must still be determined.
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Affiliation(s)
- Jérôme Guéchot
- Service de Biochimie A, AP-HP, Hôpital Saint-Antoine, Paris.
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23
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Ferré N, Marsillach J, Camps J, Mackness B, Mackness M, Riu F, Coll B, Tous M, Joven J. Paraoxonase-1 is associated with oxidative stress, fibrosis and FAS expression in chronic liver diseases. J Hepatol 2006; 45:51-9. [PMID: 16510204 DOI: 10.1016/j.jhep.2005.12.018] [Citation(s) in RCA: 76] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2005] [Revised: 12/02/2005] [Accepted: 12/05/2005] [Indexed: 12/04/2022]
Abstract
BACKGROUND/AIMS We previously reported that paraoxonase-1 activity measurement may be useful for the evaluation of liver diseases. Because oxidative stress plays a role in liver apoptosis, and lipid peroxides are hydrolyzed by paraoxonase-1, we have extended our studies to explore the relationships between this enzyme and oxidative stress, fibrosis and apoptosis. METHODS We measured paraoxonase-1 activity and concentration, soluble FAS concentration, serum fibrosis markers, and total peroxides in a group of patients with minimal hepatic changes (n=25), chronic hepatitis (n=51), or liver cirrhosis (n=17). We also measured the Knodell activity index in liver biopsies and performed FAS and PON1 immunostaining. RESULTS Patients with liver diseases showed an increase in soluble FAS, fibrosis markers and paraoxonase-1 concentrations, as well as a decrease in PON1 activity. Paroxonase-1 activity and concentration were correlated with soluble FAS (r=-0.43, P<0.001 and r=0.27, P=0.007, respectively). Paraoxonase-1 concentration showed a significant inverse association with FAS immunostaining (P=0.013) and a direct association with PON1 immunostaining (P<0.001). CONCLUSIONS These results suggest an active role of PON1 in the regulation of oxidative stress, fibrosis and hepatic cell apoptosis in chronic liver diseases.
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Affiliation(s)
- Natàlia Ferré
- DNA Unit, Centre de Diagnòstic Biomèdic, IDIBAPS, Hospital Clínic Universitari,C. Villarroel 170, 08036-Barcelona, Spain
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24
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Kamal SM, Turner B, He Q, Rasenack J, Bianchi L, Al Tawil A, Nooman A, Massoud M, Koziel MJ, Afdhal NH. Progression of fibrosis in hepatitis C with and without schistosomiasis: correlation with serum markers of fibrosis. Hepatology 2006; 43:771-9. [PMID: 16557547 DOI: 10.1002/hep.21117] [Citation(s) in RCA: 104] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Serial liver biopsies are the gold standard by which the progression of fibrosis is evaluated. This longitudinal cohort study assessed the different rates in the progression of fibrosis using serial liver biopsies and serum fibrosis markers YKL-40 and PIIINP and the cytokines, transforming growth factor beta (TGF-beta) and tumor necrosis factor alpha (TNuF-alpha). A 10-year cohort study was performed in patients with hepatitis C virus (HCV) alone or HCV and schistosomiasis. Patients were enrolled at the time of acute HCV infection and prospectively evaluated with two liver biopsies (at entry and end of follow-up), and true rates in the progression of fibrosis were calculated per year. Serum YKL-40, N-terminal propeptide of collagen III (PIIINP), TGF-beta, and TNF-alpha were measured, as well as the expression of TGF-beta, TNF-alpha, and YKL-40 mRNA in liver tissue. A significant increase in the progression rates of fibrosis occurred in the coinfected group (0.61 +/- 0.13) compared with the HCV monoinfection group (0.1 +/- 0.06; P < .001)). The progression of fibrosis rate/year had a direct linear correlation for YKL-40 (r = 0.892, P < .001) and for PIIINP (r = 0.577, P < .01). YKL-40 showed a linear correlation with TGF-beta (r = 0.897, P < .001). Hepatic mRNA levels of YKL-40 and TGF-beta correlated with the serum levels, confirming a hepatic source for the elevated serum levels. In conclusion, serial cytokine and fibrosis markers can accurately determine the rate at which fibrosis is progressing, identifying both those with rapid fibrosis and those with stable disease.
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Affiliation(s)
- Sanaa M Kamal
- Liver Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
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25
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Lebensztejn DM, Skiba E, Tobolczyk J, Sobaniec-Lotowska ME, Kaczmarski M. Diagnostic accuracy of serum biochemical fibrosis markers in children with chronic hepatitis B evaluated by receiver operating characteristics analysis. World J Gastroenterol 2006; 11:7192-6. [PMID: 16437671 PMCID: PMC4725072 DOI: 10.3748/wjg.v11.i45.7192] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the diagnostic accuracy of potent serum biochemical fibrosis markers in children with chronic hepatitis B evaluated by receiver operating characteristics (ROC) analysis. METHODS We determined the serum level of apolipoprotein A-I (APO A-I), haptoglobin (HPT) and a-2 macroglobulin (A2M) with an automatic nephelometer in 63 children (age range 4-17 years, mean 10 years) with biopsy-verified chronic HBeAg-positive hepatitis B. Fibrosis stage and inflammation grade were assessed in a blinded fashion according to Batts and Ludwig. We defined mild liver fibrosis as a score < or =2 and advanced fibrosis as a score equal to 3. ROC analysis was used to calculate the power of the assays to detect advanced liver fibrosis (AccuROC, Canada). RESULTS Serum concentrations of APO A-I, HPT and A2M were not significantly different in patients with chronic hepatitis B compared to controls. However, APO A-I level of 1.19 ng/L had a sensitivity of 85.7% and a specificity of 60.7% (AUC = 0.7117, P = 0.035) to predict advanced fibrosis. All other serum biochemical markers and their combination did not allow a useful prediction. None of these markers was a good predictor of histologic inflammation. CONCLUSION Apolipoprotein A-I may be a suitable serum marker to predict advanced liver fibrosis in children with chronic hepatitis B.
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Affiliation(s)
- Dariusz Marek Lebensztejn
- 3 rd Department of Pediatrics, Medical University of Bialystok, 17 Waszyngtona Str., 15-274 Bialystok, Poland. dariuszmar.
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26
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Affiliation(s)
- Raz Jelinek
- Department of Chemistry and Staedler Minerva Center for Mesoscopic Macromolecular Engineering, Ben Gurion University of the Negev, Beersheva 84105, Israel.
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27
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Kakizaki I, Kojima K, Takagaki K, Endo M, Kannagi R, Ito M, Maruo Y, Sato H, Yasuda T, Mita S, Kimata K, Itano N. A novel mechanism for the inhibition of hyaluronan biosynthesis by 4-methylumbelliferone. J Biol Chem 2004; 279:33281-9. [PMID: 15190064 DOI: 10.1074/jbc.m405918200] [Citation(s) in RCA: 221] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Specific inhibitors of hyaluronan (HA) biosynthesis can be valuable therapeutic agents to prevent cancer invasion and metastasis. We have found previously that 4-methylumbelliferone (MU) inhibits HA synthesis in human skin fibroblasts and in group C Streptococcus. In this paper, the inhibition mechanism in mammalian cells was investigated using rat 3Y1 fibroblasts stably expressing HA synthase (HAS) 2. Exposure of the transfectants to the inhibitor resulted in significant reduction of HA biosynthesis and matrix formation. The evaluation of HAS transcripts and analysis of cell-free HA synthesis demonstrated the post-transcriptional suppression of HAS activity by MU. Most interesting, the post-transcriptional suppression of HAS activity was also observed using p-nitrophenol, a well known substrate for UDP-glucuronyltransferases (UGT). We investigated whether the inhibition was exerted by the glucuronidation of MU using both high pressure liquid chromatography and TLC analyses. The production of MU-glucuronic acid (GlcUA) was consistent with the inhibition of HA synthesis in HAS transfectants. MU-GlcUA was also detected at a similar level in control cells, suggesting that the glucuronidation was mediated by an endogenous UGT. Elevated levels of UGT significantly enhanced the inhibitory effects of MU. In contrast, the inhibition by MU was diminished to the control level when an excess of UDP-GlcUA was added to the cell-free HA synthesis system. We propose a novel mechanism for the MU-mediated inhibition of HA synthesis involving the glucuronidation of MU by endogenous UGT resulting in a depletion of UDP-GlcUA.
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Affiliation(s)
- Ikuko Kakizaki
- Department of Biochemistry, Hirosaki University School of Medicine, 5 Zaifu-cho, Hirosaki 036-8562, Japan
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28
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Soliman KM, Abdel Aziz M, Nassar YH, Abdel-Sattar S, El-Ansary A. Effects of carnosine on bilharzial infestation in hamsters: biochemical and histochemical studies. Comp Biochem Physiol B Biochem Mol Biol 2002; 131:535-42. [PMID: 11959036 DOI: 10.1016/s1096-4959(02)00031-3] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
We tested the ability of carnosine to improve some liver disorders induced by Schistosoma mansoni parasite in hamsters (Mesocricetus auratus). Results indicate that parasitic infestation induced elevation in serum alkaline phosphatase, gamma-glutamyl transferase, aspartate aminotransferase and procollagen III peptide as a marker of liver fibrosis. Administration of carnosine (10 mg/day) for 15 days either concurrent with infection, 2 and 4 weeks post-infestation was effective in reducing differential worm burden. It was also effective in renormalizing blood glucose level depending on the time course. The most evident effect of carnosine was on serum procollagen III peptide level, which was lowered in infested groups treated with carnosine. Histopathological studies confirmed the potential use of carnosine for intervention in schistosomiasis.
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Affiliation(s)
- Kawther M Soliman
- Department of Biochemistry, Faculty of Medicine, Cairo University, Cairo, Egypt.
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29
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Basso D, Belluco C, Mazza S, Greco E, Della Rocca F, Pauletto P, Nitti D, Lise M, Plebani M. Colorectal cancer metastatic phenotype stimulates production by fibroblasts of N-terminal peptide of type III collagen: clinical implications for prognosis. Clin Chim Acta 2001; 312:135-42. [PMID: 11580919 DOI: 10.1016/s0009-8981(01)00621-0] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
In this study we assessed whether the serum levels of the N-terminal peptide of type III collagen (PIIIP), an index of type III collagen synthesis, are influenced by colorectal cancer stage, and whether "in vitro" fibroblast growth and PIIIP production could be altered by tumor tissues obtained from metastatic and nonmetastatic colorectal cancer. 208 colorectal cancer patients (115 colon and 93 rectum) were studied; 54 were stage I, 62 stage II, 37 stage III and 55 stage IV. PIIIP serum levels were significantly higher in stage IV as compared to all other patient groups. The 5-year survival of stage I, stage II, stage III and stage IV patients were 87%, 88%, 32% and 20%, respectively. In the subgroup of stage I and stage II patients considered together, PIIIP (> 0.5 U/ml), but not CEA (> 5 microg/l) serum levels, were predictive for survival. Fibroblast growth was significantly inhibited, while PIIIP production was significantly enhanced, when these cells were conditioned with colorectal cancer homogenates obtained from patients with distant metastases, than from those without distant metastases. In conclusion, colorectal tumors, when metastatic, stimulate fibroblasts' PIIIP synthesis and the serum levels of this peptide might predict patients' outcome after radical surgery.
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Affiliation(s)
- D Basso
- Department of Laboratory Medicine, University Hospital, University of Padova, Via Giustiniani 2, 35128, Padua, Italy
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30
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Wick G, Kalischnig G, Maurer H, Mayerl C, Müller PU. Really old-palaeoimmunology: immunohistochemical analysis of extracellular matrix proteins in historic and pre-historic material. Exp Gerontol 2001; 36:1565-79. [PMID: 11525878 DOI: 10.1016/s0531-5565(01)00141-3] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
In this review, we summarize data concerning the respective preservation and deterioration of antigenic determinants of various collagenous and non-collagenous extracellular matrix (ECM) proteins in palaeontologic material of different ages. ECM proteins are the major quantitative constituents of mammalian organisms and were, therefore, selected as important representative proteins for these analyses. The specimens, studied by immunofluorescence and immunohistochemical techniques, included the skin of 500-1500 year-old human mummies from Peru, skin and striated muscle from the 5300-year-old glacier mummy ("Iceman") from Tyrol, Austria, and a 50-million-year-old bat with preserved soft body parts from the fossil excavation site of Messel, Germany. In frozen sections of the former two sources, epitopes recognized by specific antibodies for triple-helical antigenic determinants of different types of collagen resistant against conventional proteases were preserved, while non-helical domains, as well as the non-collagenous ECM proteins, could no longer be demonstrated. The fossil bat, although showing evidence of fibrous, collagen-like structures in conventional histology, revealed no collagenous or non-collagenous ECM proteins by any technique. It later turned out that this was due to the replacement of the original soft parts in these fossils by lawns of bacteria. These studies introduced immunological techniques into palaeontology and opened new approaches for studying physiologically- and pathologically-altered structures in tissues of animals and humans of considerable historical age.
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Affiliation(s)
- G Wick
- Institute of Pathophysiology, University of Innsbruck, Medical School, Fritz-Pregl-Str. 3/IV, 6020 Innsbruck, Austria.
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31
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Fortunato G, Castaldo G, Oriani G, Cerini R, Intrieri M, Molinaro E, Gentile I, Borgia G, Piazza M, Salvatore F, Sacchetti L. Multivariate Discriminant Function Based on Six Biochemical Markers in Blood Can Predict the Cirrhotic Evolution of Chronic Hepatitis. Clin Chem 2001. [DOI: 10.1093/clinchem/47.9.1696] [Citation(s) in RCA: 42] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
Abstract
Background: Serologic markers have been proposed for monitoring hepatic fibrosis in chronic active liver disease. Because none of these markers, when used singly, is totally satisfactory, we developed and evaluated a multivariate approach.
Methods: We studied two cohorts of chronic hepatitis (54 patients) and cirrhosis patients (49 patients) to identify a panel of biochemical markers that discriminates between the two diseases. Using multivariate discriminant analysis, we selected a function, based on the concentrations of six biochemical markers (fibronectin, prothrombin, pseudocholinesterase, alanine aminotransferase, manganese superoxide dismutase, and N-acetyl-β-glucosaminidase). We then prospectively validated this function on a second temporal cohort of patients.
Results: Multivariate discriminant analysis correctly classified 93.7% of patients (94.3% of chronic hepatitis and 92.9% of cirrhosis patients) in the first cohort and 85% of patients (89.5% of chronic hepatitis patients and 81% of cirrhosis patients) in the second cohort.
Conclusions: Discriminant analysis of results of six inexpensive biochemical markers provides a high predictive value for differentiation between liver cirrhosis and chronic hepatitis. Consequently, these biochemical markers condensed into a multivariate discriminant analysis value for each patient provide information that can be contributory for subsequent options during the evolution of the natural history of chronic hepatitis.
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Affiliation(s)
- Giuliana Fortunato
- Dipartimento di Biochimica e Biotecnologie Mediche and CEINGE scarl, and
| | - Giuseppe Castaldo
- Dipartimento di Biochimica e Biotecnologie Mediche and CEINGE scarl, and
- Facoltà di Scienze Matematiche, Fisiche e Naturali, and
| | - Giovannangelo Oriani
- Dipartimento di Biochimica e Biotecnologie Mediche and CEINGE scarl, and
- Dipartimento “SAVA”, Università del Molise, 86170 Isernia, Italy
| | - Raimondo Cerini
- Dipartimento di Medicina Pubblica e della Sicurezza Sociale-Sezione di Malattie Infettive, Università di Napoli “Federico II”, I-80131 Naples, Italy
| | | | - Eugenia Molinaro
- Dipartimento di Biochimica e Biotecnologie Mediche and CEINGE scarl, and
| | - Ivan Gentile
- Dipartimento di Medicina Pubblica e della Sicurezza Sociale-Sezione di Malattie Infettive, Università di Napoli “Federico II”, I-80131 Naples, Italy
| | - Guglielmo Borgia
- Dipartimento di Medicina Pubblica e della Sicurezza Sociale-Sezione di Malattie Infettive, Università di Napoli “Federico II”, I-80131 Naples, Italy
| | - Marcello Piazza
- Dipartimento di Medicina Pubblica e della Sicurezza Sociale-Sezione di Malattie Infettive, Università di Napoli “Federico II”, I-80131 Naples, Italy
| | | | - Lucia Sacchetti
- Dipartimento di Biochimica e Biotecnologie Mediche and CEINGE scarl, and
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Kobayashi H, Horikoshi K, Yamataka A, Yamataka T, Okazaki T, Lane GJ, Miyano T. Hyaluronic acid: a specific prognostic indicator of hepatic damage in biliary atresia. J Pediatr Surg 1999; 34:1791-4. [PMID: 10626856 DOI: 10.1016/s0022-3468(99)90314-7] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND/PURPOSE Hepatic fibrosis can progress in biliary atresia (BA) and is associated with capillarization of hepatic sinusoids. The significance of serum hyaluronic acid (HA) as a noninvasive indicator of histological sinusoidal endothelial cell (SEC) damage and hepatic fibrosis in BA, is investigated. METHODS A total of 28 postoperative BA patients (mean age, 11.0+/-3.7 years) and 20 normal controls (mean age, 10.5+/-2.8 years) were studied. BA patients were divided into group I, good liver function (n = 8); group II, moderate liver dysfunction (n = 10); and group III, severe liver dysfunction (n = 10). Serum HA was determined using a one-step sandwich enzyme immunoassay, and liver histological damage was confirmed immunohistochemically using an antibody against factor VIII-related antigen (FVIIIRAg), which is specific for detecting damaged SEC. RESULTS Serum HA was significantly higher (P < .0001) in group III (84.6+/-36.5 ng/mL) than in group I (15.9+/-6.9 ng/mL) or group 11 (28.7+/-10.7 ng/mL). Although immunoreactive products of FVIIIRAg were abundant in group III, they were not detected in SEC from group II. CONCLUSION Serum HA may be of value for monitoring postoperative BA patients as a noninvasive indicator of SEC damage and progressive hepatic fibrosis.
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Affiliation(s)
- H Kobayashi
- Department of Pediatric Surgery, Juntendo University School of Medicine, Tokyo, Japan
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Murawaki Y, Ikuta Y, Okamoto K, Koda M, Kawasaki H. Serum matrix metalloproteinase-3 (stromelysin-1) concentration in patients with chronic liver disease. J Hepatol 1999; 31:474-81. [PMID: 10488707 DOI: 10.1016/s0168-8278(99)80040-3] [Citation(s) in RCA: 23] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND/AIMS Matrix metalloproteinase (MMP)-3 plays an important role in extracellular matrix degradation, because of its broad substrate specificity and its activation of other proMMPs. Our aims in the present study were to determine whether the measurement of serum MMP-3 is clinically useful for assessing ongoing liver fibrolysis in patients with chronic liver disease. METHODS We measured the serum MMP-3 concentrations with a sandwich enzyme immunoassay in 58 patients with chronic hepatitis, 22 patients with liver cirrhosis, 45 patients with hepatocellular carcinoma and 124 healthy individuals. The liver MMP-3 content was also measured in autopsied livers. RESULTS Among the healthy controls, the serum levels of MMP-3 were about 2-fold higher in the males than in the females. In this study, the serum MMP-3 results of mainly the male group were analyzed because of the large number of male subjects. Compared to the control level, the mean serum MMP-3 concentration was 55% lower in chronic hepatitis, 53% lower in liver cirrhosis and 46% lower in hepatocellular carcinoma. There was no significant difference in the serum MMP-3 levels among the chronic hepatitis, liver cirrhosis and hepatocellular carcinoma groups. The serum MMP-3 levels were not related to the histological degree of necroinflammation or of liver fibrosis in the patients with chronic hepatitis. No significant difference in serum MMP-3 levels was observed among three Child's subgroups in the group of cirrhotic patients. In the group of patients with hepatocellular carcinoma, the serum MMP-3 levels were not related to the severity of liver function, the HCC tumor size, or the histological differentiation. The serum MMP-3 level was not correlated with serum markers for connective tissue turnover, i.e. procollagen type III peptide, 7S fragment of type IV collagen, hyaluronan and tissue inhibitor of metalloproteinase-1 in the patients with chronic liver disease or hepatocellular carcinoma. CONCLUSIONS The measurement of serum MMP-3 is of little use for assessing fibrolysis in chronically diseased livers.
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Affiliation(s)
- Y Murawaki
- Second Department of Internal Medicine, Tottori University School of Medicine, Yonago, Japan
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Ogata T, Okuda K, Ueno T, Saito N, Aoyagi S. Serum hyaluronan as a predictor of hepatic regeneration after hepatectomy in humans. Eur J Clin Invest 1999; 29:780-5. [PMID: 10469166 DOI: 10.1046/j.1365-2362.1999.00513.x] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
BACKGROUND The capacity for hepatic regeneration after hepatectomy is important for allowing surgeons to determine the appropriate extent of resection. However, conventional preoperative liver function tests are unsatisfactory for estimating the post-operative regenerative capacity of the remnant liver. The aim of this study was to evaluate the relationship between preoperative serum hyaluronan and hepatic regeneration. METHODS Preoperative serum hyaluronan levels and the hepatic regeneration rate were estimated in 49 patients using computerized tomographic volumetry. The hepatic fibrotic rate was calculated with non-tumorous tissues stained with Azan-Mallory. Immunolocalization of factor VIII-related antigen (FVIIIAg) was examined as a marker for hepatic sinusoidal capillarization. RESULTS The serum hyaluronan level was significantly correlated with the hepatic regeneration rate (P < 0. 001). Patients with serum hyaluronan levels below 200 ng mL-1 exhibited a significant correlation between the hepatic regeneration rate and the hepatic fibrotic rate. However, patients with serum hyaluronan levels above 200 ng mL-1 did not demonstrate a distinct correlation. The hepatic regeneration rate of patients with FVIIIAg in the liver and serum hyaluronan levels above 200 ng mL-1 were very low compared with those without FVIIIAg (P < 0.001). Multiple regression analysis revealed that serum hyaluronan was a significant predictor of post-operative hepatic regeneration among several clinical variables (r = 0.857, R2 = 0.735). CONCLUSION It has been suggested that hepatic regeneration is closely related to both hepatic fibrosis and hepatic sinusoidal capillarization. The serum hyaluronan level is regarded as a useful predictor for hepatic regeneration after hepatectomy.
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Affiliation(s)
- T Ogata
- Kurume University School of Medicine, Kurume, Japan
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Kardorff R, Mugashe C, Gabone RM, Mahlert C, Doehring E. Diagnostic value of connective tissue metabolites in Schistosoma mansoni related liver disease. Acta Trop 1999; 73:153-64. [PMID: 10465055 DOI: 10.1016/s0001-706x(99)00022-4] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
Reliable non-invasive markers of hepatosplenic involvement in schistosomiasis are needed for determination of morbidity levels in endemic populations and for diagnosis and follow-up of affected individuals. Serum levels of connective tissue metabolites have been investigated as fibrosis markers in various hepatic disorders, but their accuracy in the detection of hepatosplenic schistosomiasis under endemic conditions has not been fully elucidated. 206 adult inhabitants of a Tanzanian village highly endemic for schistosomiasis mansoni (prevalence 88%) underwent clinical, parasitological and sonographic work-up; sera were tested for aminoterminal procollagen III-peptide (PIIIP), carboxyterminal procollagen IV peptide (NC1) and laminin. Connective tissue marker levels did not correlate with the presence or intensity of infection. NC1 levels were significantly correlated with periportal liver fibrosis (P < 0.001), splenomegaly (P < 0.002), portal vein dilatation (P < 0.004) and the presence of portosystemic collaterals (P < 0.001); for PIIIP and laminin, none of the respective relationships was significant. Due to wide overlap of NC1 levels between individuals with normal sonography findings and those with advanced periportal fibrosis and portal hypertension, the sensitivity and positive predictive value of this markers to detect these individuals were low (< 40%), although specificity and overall accuracy in the given setting were good (80-90%). It is concluded that PIIIP and laminin are not useful as diagnostic serum markers of hepatosplenic schistosomiasis at the community level; NC1 was significantly related to various indices of hepatosplenic involvement, but its low sensitivity precludes its use as a screening tool under endemic conditions.
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Affiliation(s)
- R Kardorff
- Department of Paediatrics II, Hannover Medical School, Hannover, Germany.
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George DK, Ramm GA, Walker NI, Powell LW, Crawford DH. Elevated serum type IV collagen: a sensitive indicator of the presence of cirrhosis in haemochromatosis. J Hepatol 1999; 31:47-52. [PMID: 10424282 DOI: 10.1016/s0168-8278(99)80162-7] [Citation(s) in RCA: 46] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
BACKGROUND/AIM Hereditary haemochromatosis can now be diagnosed by genetic testing, although determining the presence or absence of cirrhosis remains crucial to patient management. While many studies have investigated the utility of various serum markers of cirrhosis in chronic liver diseases, few have examined specifically patients with hereditary haemochromatosis. The aim of this study was to assess the utility of serum type IV collagen and serum laminin in diagnosing hepatic fibrosis and cirrhosis in patients with hereditary haemochromatosis. METHODS The study group consisted of 42 patients with hereditary haemochromatosis and 19 Caucasian controls. Serum type IV collagen, laminin, matrix metalloproteinase-2 (MMP-2) and tissue inhibitor of metalloproteinase (TIMP-1) concentrations were measured by enzyme-linked immunosorbant assay in serum from patients with haemochromatosis and control subjects. Liver biopsies from patients with haemochromatosis were graded for fibrosis and correlated with serum markers of hepatic fibrosis. RESULTS Serum type IV collagen concentration was significantly increased in haemochromatosis patients compared to controls (130+/-79 ng/ml vs 81 +/- 17 ng/ml, p<0.05) and was significantly correlated with both the grade of histological fibrosis (r=0.67, p<0.0001) and serum MMP-2 levels (r=0.42, p<0.05). A serum type IV collagen concentration > 115 ng/ml (mean+2 SD of controls) was 100% sensitive and 69% specific in detecting severe (grade 3) fibrosis and cirrhosis. The sensitivity results of serum laminin and TIMP-1 were 11% and 56% respectively. CONCLUSIONS Elevated serum type IV collagen is a sensitive indicator of the presence of severe fibrosis and cirrhosis in patients with haemochromatosis. Useful markers of hepatic fibrosis in other chronic liver diseases may not be applicable to haemochromatosis.
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Affiliation(s)
- D K George
- Joint Clinical Sciences Program, University of Queensland Department of Medicine and Queensland Institute of Medical Research, Brisbane, Australia
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Murawaki Y, Yamada S, Ikuta Y, Kawasaki H. Clinical usefulness of serum matrix metalloproteinase-2 concentration in patients with chronic viral liver disease. J Hepatol 1999; 30:1090-8. [PMID: 10406188 DOI: 10.1016/s0168-8278(99)80264-5] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND/AIMS The production of matrix metalloproteinase (MMP)-2 was reported to be increased in chronically diseased livers. Our aims in the present study were to elucidate the clinical usefulness of the serum MMP-2 concentration in chronic viral liver disease. METHODS We measured serum MMP-2 concentrations with a sandwich enzyme immunoassay in 62 patients with chronic hepatitis, 35 patients with liver cirrhosis, 55 patients with hepatocellular carcinoma and 24 healthy individuals. The assay detects proMMP-2 and proMMP-2 complexed with tissue inhibitor of metalloproteinase-2, but not active forms of MMP-2. The liver MMP-2 content was also measured in autopsied cirrhotic and non-cirrhotic livers. Gelatin zymography and gel filtration chromatography were carried out using the serum. RESULTS The serum MMP-2 concentration was significantly increased in the liver cirrhosis and hepatocellular carcinoma patients, but not in the patients with chronic hepatitis. There was no significant difference in the serum MMP-2 level between the liver cirrhosis and hepatocellular carcinoma groups. In the patients with chronic viral liver disease, serum MMP-2 concentration showed the best correlation with the degree of liver fibrosis and with serum hyaluronate level. The zymography of serum showed the majority of MMP-2 in serum exists as a proMMP-2. The chromatography of serum revealed a single peak at the position of about 90 kDa corresponding to an MMP-2 complexed with tissue inhibitor of metalloproteinases-2. The liver MMP-2 content was markedly increased in the cirrhotic livers compared with the non-cirrhotic livers, and was positively correlated with the liver collagen content. When investigating the utility of the serum MMP-2 test for differentiating liver cirrhosis from chronic hepatitis, the utility of serum MMP-2 was equal to that of serum hyaluronate, which is known as the best current test for diagnosing liver cirrhosis. CONCLUSIONS The serum MMP-2 concentration reflects mainly the amount of proMMP-2 complexed with tissue inhibitor of metalloproteinase-2. The serum MMP-2 level was markedly increased in cirrhotic patients, and may be explained by an overproduction in the cirrhotic liver. In the clinical state, the measurement of serum MMP-2 was as useful a test for diagnosing liver cirrhosis as is the serum hyaluronate level.
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Affiliation(s)
- Y Murawaki
- Second Department of Internal Medicine, Tottori University School of Medicine, Yonago, Japan
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Schuppan D, Cho JJ, Jia JD, Hahn EG. Interplay of matrix and myofibroblasts during hepatic fibrogenesis. CURRENT TOPICS IN PATHOLOGY. ERGEBNISSE DER PATHOLOGIE 1999; 93:205-18. [PMID: 10339913 DOI: 10.1007/978-3-642-58456-5_21] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Affiliation(s)
- D Schuppan
- Department of Medicine I, University of Erlangen-Nürnberg, Germany
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Kardorff R, Klotz M, Melter M, Rodeck B, Hoyer PF. Prediction of survival in extrahepatic biliary atresia by hepatic duplex sonography. J Pediatr Gastroenterol Nutr 1999; 28:411-7. [PMID: 10204506 DOI: 10.1097/00005176-199904000-00012] [Citation(s) in RCA: 19] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Abstract
BACKGROUND The clinical course of biliary atresia patients is extremely variable. To optimize conservative treatment and correctly schedule liver transplantation, noninvasive investigations that are predictive of individual survival and that can be performed regularly are needed. In this study, the prognostic value of Doppler sonography was investigated in these patients. METHODS Thirty biliary atresia patients (age range, 1 month to 15.2 years; mean, 4.0 years) and 38 control subjects underwent standardized Doppler sonography of liver and spleen. Biochemical tests of liver function and of fibrogenesis were performed in parallel. Individual clinical outcome was registered 1 and 2 years later. RESULTS In control subjects, maximum portal flow velocity (Vmax) was more than 16 cm/sec, and the hepatic vein flow pattern was triphasic. Among children with biliary atresia, those with diminished portal Vmax, a flattened hepatic vein flow curve, or a hepatic artery resistance index of 0.8 or more had significantly lower indices of hepatic protein synthesis (albumin, cholinesterase), higher bilirubin levels, and higher concentrations of markers of connective tissue turnover (procollagen peptides, laminin P1) than did those with normal Doppler sonography measurements. The rate of survival without transplantation during the following 2 years was significantly lower in children with abnormal Doppler findings. From portal and hepatic vein flow measurements, patient survival 2 years later could be predicted with an accuracy of 93%. CONCLUSIONS In children with extrahepatic biliary atresia, Doppler sonography of the hepatic blood flow is a noninvasive indicator of disease severity. Moreover, it allows a highly accurate prediction of patient survival for the following 2 years.
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Affiliation(s)
- R Kardorff
- Department of Pediatric Nephrology and Metabolic Disorders, Medical School Hannover, Children's Hospital, Germany
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40
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Murawaki Y, Ikuta Y, Idobe Y, Kawasaki H. Serum matrix metalloproteinase-1 in patients with chronic viral hepatitis. J Gastroenterol Hepatol 1999; 14:138-45. [PMID: 10029294 DOI: 10.1046/j.1440-1746.1999.01821.x] [Citation(s) in RCA: 47] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
BACKGROUND AND AIMS Previously we found that serum matrix metalloproteinase (MMP)-1 activity decreased with progression of chronic liver disease. Our objectives in the present study were to observe the change in the serum MMP-1 protein concentration using recently developed specific enzyme immunoassays for MMP-1 and MMP-1 complexed with tissue inhibitor of metalloproteinases (TIMP)-1 and to elucidate the clinical usefulness of the serum MMP-1 test in chronic viral hepatitis. We measured the serum concentrations of MMP-1 and MMP-1/TIMP-1 complex using these immunoassays in 64 patients with histologically characterized chronic viral hepatitis. RESULTS Serum MMP-1 concentration was inversely related to the histological severity of chronic hepatitis (P< 0.0001). It was closely associated with the histological degree of periportal necrosis (P< 0.0001), intralobular necrosis (P< 0.005), portal inflammation (P<0.0001) and liver fibrosis (P< 0.05). The serum concentration of MMP-1/TIMP-1 complex was also related to the histological severity of chronic hepatitis (P< 0.0001). It was associated with the degree of portal inflammation (P< 0.05), but not with the degree of periportal necrosis, intralobular necrosis or liver fibrosis. As serum MMP-1 level was closely associated with the histological degree of necroinflammation, we examined the ability of the serum MMP-1 test to differentiate active and inactive forms of hepatitis with a receiver operating curve. The results were compared with those of serum procollagen type III N-peptide (PIIINP) test. We found that the serum MMP-1 test was superior to the serum PIIINP test in assessing liver necroinflammation. CONCLUSIONS In addition to the previously reported changes in enzyme activity, MMP-1 proteins in serum decreased during histological progression of chronic hepatitis. The serum MMP-1 test may be useful clinically to differentiate active and inactive types of hepatitis in patients with chronic viral hepatitis.
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Affiliation(s)
- Y Murawaki
- Second Department of Internal Medicine, Tottori University School of Medicine, Yonago, Japan
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Miller GR, Smith CA, Stauber WT. Determination of fibrosis from cryostat sections using high performance liquid chromatography: skeletal muscle. THE HISTOCHEMICAL JOURNAL 1999; 31:89-94. [PMID: 10416680 DOI: 10.1023/a:1003592710740] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
Analysis of hydroxyproline (collagen) and pyridinoline (collagen cross-links) in biopsies prepared for routine histological evaluation with OCT compound was performed. Frozen sections (250 microm-thick) were cut from cardiac muscle, diaphragm, liver, and soleus muscle from the rat. After removal of OCT compound by rinsing, the samples were dried, weighed and hydrolyzed in 6 N HCl. A portion of the hydrolysate was analyzed for hydroxyproline using high performance liquid chromatography with collagen type I as the standard. Collagen concentrations ranged from 6.6 microg/mg dry weight (liver) to 74.7 microg/mg dry weight (diaphragm). From the remainder of the hydrolyzate, pyridinoline cross-links of collagen were separated and analyzed similarly by high performance liquid chromatography. The concentration of pyridinoline ranged from 2.6 ng/mg dry weight (liver) to 35.6 ng/mg dry weight (diaphragm). These techniques were adequate to analyze both collagen and pyridinoline (i.e. collagen cross-links) in small biopsy samples (< 1 mg dry weight) routinely used in clinical pathology. The method proved useful in the quantitation of focal fibrosis in a partially denervated rat soleus. Denervation was confirmed using fast myosin immunohistochemistry which revealed large areas of small myofibres containing fast myosin. Collagen concentration increased by five-fold and collagen cross-links by more than 7-fold consistent with fibrotic changes known to occur with denervation.
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Affiliation(s)
- G R Miller
- Department of Physiology, West Virginia University, Morgantown 26506, USA
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Esterre P, Raobelison A, Ramarokoto CE, Ravaoalimalala VE, Boisier P, Roux J. Serum concentrations of sICAM-1, sE-, sP- and sL-selectins in patients with Schistosoma mansoni infection and association with disease severity. Parasite Immunol 1998; 20:369-76. [PMID: 9767602 DOI: 10.1046/j.1365-3024.1998.00168.x] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
Increased serum concentrations of soluble intercellular adhesion molecule-1 (sICAM-1, CD54) and of soluble E- (CD62E), but not soluble P- (CD62P) and L- (CD62 L) selectins, were detected in Malagasy patients living in an hyperendemic focus of Schistosoma mansoni. Levels of sICAM-1 remained elevated for several months after treatment with praziquantel. Serum levels of ICAM-1, but not of other markers, were significantly correlated with the disease severity, as indicated by ultrasonographical data, and with some circulating fibrosis markers (at least hyaluronic acid). sICAM-1 level may reflect endothelial inflammatory reactions, probably harmful, in the liver and may be useful for monitoring morbidity evolution in schistosomiasis mansoni.
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Affiliation(s)
- P Esterre
- ImmunoParasitology & Epidemiology Units, Institut Pasteur de Madagascar, BP 1274, Antananarivo 101, Madagascar
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Wong VS, Hughes V, Trull A, Wight DG, Petrik J, Alexander GJ. Serum hyaluronic acid is a useful marker of liver fibrosis in chronic hepatitis C virus infection. J Viral Hepat 1998; 5:187-92. [PMID: 9658372 DOI: 10.1046/j.1365-2893.1998.00100.x] [Citation(s) in RCA: 101] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Patients with chronic hepatitis C virus (HCV) infection are often asymptomatic with few clinical signs of liver disease. Recognition of the presence of fibrosis or cirrhosis is difficult without liver biopsy, but with the availability of effective treatments, such as interferon, and the potential for progression to hepatoma in some cases, an accurate measure of the stage of disease is important. Serum hyaluronic acid (HA) has been identified as a potential marker of fibrosis or cirrhosis in other settings. In a prospective study in 130 chronic HCV carriers therefore, serum HA concentrations were compared with conventional liver function tests (including alanine aminotransferase (ALT), a-glutathione-S transferase (GST) and serum HCV RNA in order to determine which identified the stage of liver fibrosis as assessed by liver biopsy most accurately. The median HA concentrations according to the stage of fibrosis 0, 1 & 2, 3 and 4 & 5 were 17 g l-1 (range 5-37), 17 g l-1 (5-80), 30 g l-1 (10-105) and 350 g l-1 (20-800) respectively. The median HA concentration in stage 4 & 5 was significantly greater than in stages 0, 1 & 2 or 3. Serum HA concentration rose with age, but even when adjusted for age the median HA at stage 4 & 5 was greater than all other groups (95% CI of difference between the medians exceeded 0). Thus, serum HA gave a sensitivity and specificity for stage 4 & 5 fibrosis of 85% and 88% respectively, exceeding those for ALT or GST. In contrast, serum ALT or GST levels were not correlated with the stage of fibrosis although ALT was significantly greater in the cirrhotic group when compared to the group with no fibrosis (stage 0). There was no correlation between serum HA and either the grade of inflammatory changes or serum HCV RNA. These results suggest that serum hyaluronic acid is a useful marker of liver fibrosis in patients with chronic HCV infection. It could therefore be used to monitor patients at risk of progressive fibrosis, in controlled clinical trials, as a measure of response to antifibrotic therapy and in those in whom liver biopsy is difficult or contraindicated.
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Affiliation(s)
- V S Wong
- Department of Medicine, Cambridge University School of Clinical Medicine, Addenbrooke's NHS Trust, UK
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Pilette C, Rousselet MC, Bedossa P, Chappard D, Oberti F, Rifflet H, Maïga MY, Gallois Y, Calès P. Histopathological evaluation of liver fibrosis: quantitative image analysis vs semi-quantitative scores. Comparison with serum markers. J Hepatol 1998; 28:439-46. [PMID: 9551682 DOI: 10.1016/s0168-8278(98)80318-8] [Citation(s) in RCA: 147] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND/AIMS Liver fibrosis is mainly evaluated by qualitative histological examination. Although histological semi-quantitative scores and quantitative determination with image analysis are now possible, these methods have not been fully validated and compared. Therefore, we evaluated these two methods prospectively in 243 patients with chronic liver disease. METHODS The semi-quantitative fibrosis score was evaluated by two independent pathologists, using the Knodell fibrosis score and a 6-grade score derived from the Metavir score; the area of fibrosis was measured by image analysis. The serum levels of hyaluronate, N-terminal peptide of procollagen III, laminin, transforming growth factor-beta1, alpha2-macroglobulin, apolipoprotein A1, PGA score and prothrombin index were measured. RESULTS There was a good correlation between the semi-quantitative fibrosis score and the area of fibrosis (r=0.84, p<10(-4)). Using multiple regression analysis, the semi-quantitative score was predicted by the 8 serum markers with R2=0.69 (R2=0.59 for hyaluronate at the 1st step) while the area of fibrosis was predicted with R2=0.79 (R2=0.76 for hyaluronate at the 1st step), and the Knodell fibrosis score was predicted with R2=0.65 (R2=0.31 for hyaluronate at the 1st step). CONCLUSIONS The area of fibrosis, as determined by image analysis, and the semi-quantitative score are well correlated. However, for serum markers the correlation is higher with the area of fibrosis than with the semi-quantitative score. Other characteristics such as reproducibility, rapidity, simplicity, adaptability, and exhaustiveness also favor image analysis.
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Affiliation(s)
- C Pilette
- Service d'Hépato-Gastroentérologie, CHU, Angers, France
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Osmers RG, Schütz E, Diedrich F, Wehry B, Krauss T, Oellerich M, Kuhn W. Increased serum levels of hyaluronic acid in pregnancies complicated by preeclampsia or hemolysis, elevated liver enzymes, and low platelets syndrome. Am J Obstet Gynecol 1998; 178:341-5. [PMID: 9500497 DOI: 10.1016/s0002-9378(98)80023-9] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
OBJECTIVE Fifteen percent of patients who later have hemolysis, elevated liver enzymes, and low platelets syndrome develop initially have nonspecific symptoms. Early diagnosis could ensure adequate obstetric management; however, prognostic biochemical tests are lacking. We hypothesized that elevated hyaluronic acid serum levels might be an early indicator of hemolysis, elevated liver enzymes, and low platelets syndrome because it is known to be a sensitive marker of liver cell function. STUDY DESIGN Hyaluronic acid in serum was measured in patients with normal pregnancies (n = 109) and in those patients with pregnancies complicated by preeclampsia (n = 14) or hemolysis, elevated liver enzymes, and low platelets syndrome (n = 11). RESULTS A significant increase in hyaluronic acid serum concentrations was observed in patients with hemolysis, elevated liver enzymes, and low platelets syndrome or with preeclampsia (p < 0.05). The extent of hyaluronic acid serum levels in hemolysis, elevated liver enzymes, and low platelets syndrome correlated with the clinical severity of the individual course of disease as measured by intensive care unit time (r = 0.72; p < 0.02). CONCLUSIONS Serum levels of hyaluronic acid in preeclampsia and hemolysis, elevated liver enzymes, and low platelets syndrome are significantly elevated and might play an important diagnostic and prognostic role in patients with hemolysis, elevated liver enzymes, and low platelets syndrome.
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Affiliation(s)
- R G Osmers
- Department of Obstetrics and Gynecology, University of Goettingen, Germany
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Afdhal NH, Keaveny AP, Cohen SB, Nunes DP, Maldonado N, O'Brien M, Stone PJ. Urinary assays for desmosine and hydroxylysylpyridinoline in the detection of cirrhosis. J Hepatol 1997; 27:993-1002. [PMID: 9453424 DOI: 10.1016/s0168-8278(97)80142-0] [Citation(s) in RCA: 19] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
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, graded 0-6 using a modified Knodell score, and 20 control subjects without liver disease. Urinary DES (microg/g creatinine) and HP (nmol/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.
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Affiliation(s)
- N H Afdhal
- Evans Department of Medicine, Boston Medical Center and Boston University School of Medicine, 02118, USA
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Plebani M, Basso D, Roveroni G, De Paoli M, Galeotti F, Corsini A. N-terminal peptide of type III procollagen: a possible predictor of colorectal carcinoma recurrence. Cancer 1997; 79:1299-303. [PMID: 9083150 DOI: 10.1002/(sici)1097-0142(19970401)79:7<1299::aid-cncr5>3.0.co;2-c] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
BACKGROUND The first step of colorectal carcinoma spread depends on the ability of the tumor cells to degrade and invade the extracellular matrix (ECM). The objectives of the current study were to evaluate the serum pattern of laminin, C-terminal peptide of Type I (PIP), and N-terminal peptide of Type III (PIIIP) procollagens, markers of ECM synthesis, in the follow-up of patients after resection for colorectal carcinoma and to evaluate their role in predicting local recurrence or metastases. METHODS A total of 32 patients who had undergone resection for colorectal carcinoma were followed for a median period of 24 months (range, 6-36 months). Every 3 months, laminin, PIP, and PIIIP were measured in the sera together with the tumor markers carcinoembryonic antigen (CEA), CA 19-9, and tissue plasminogen activator (TPA). Twenty-one patients (Group 1) had no signs of recurrence, whereas the remaining 11 (Group 2) developed hepatic (n = 7) or pulmonary (n = 4) metastases. RESULTS No variations were observed in either group for laminin, CEA, CA 19-9, or TPA, whereas significant increases in PIP and PIIIP were observed in both groups 3 months after surgery. The increase in PIP and PIIIP at the 3-month follow-up was significantly greater in Group 1 than in Group 2. The difference between values at 3 months and basal values enabled a discrimination between Group 1 and Group 2, with a sensitivity of 36% and 91% and a specificity of 71% and 71% for PIP and PIIIP, respectively. CONCLUSIONS The authors believe PIIIP is useful as an early prognostic indicator of recurrence in the follow-up of patients who have undergone radical resection for colorectal carcinoma.
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Affiliation(s)
- M Plebani
- Dipartimento di Medicina di Laboratorio, Azienda Ospedaliera, Padova, Italy
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Fabris C, Falleti E, Federico E, Toniutto P, Pirisi M. A comparison of four serum markers of fibrosis in the diagnosis of cirrhosis. Ann Clin Biochem 1997; 34 ( Pt 2):151-5. [PMID: 9133247 DOI: 10.1177/000456329703400203] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
C-terminal peptide of procollagen I, N-terminal peptide of procollagen III, collagen IV and serum prolyl hydroxylase were measured in 100 patients with cirrhosis and 71 patients with noncirrhotic chronic liver disease. Patients with cirrhosis had significantly higher mean values of prolyl hydroxylase, collagen IV, N-terminal peptide of procollagen III and C-terminal peptide of procollagen I as compared to noncirrhotic patients. This difference was maintained for collagen products even after stratification for alcohol intake, although all markers of fibrosis were higher in alcoholics. Stepwise logistic regression analysis showed that collagen IV, and N-terminal peptide of procollagen III were independently associated with cirrhosis. Receiver-operating characteristic (ROC) curves showed that collagen IV and N-terminal peptide of procollagen III perform more efficiently than C-terminal peptide of procollagen I and prolyl hydroxylase in identifying cirrhosis.
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Affiliation(s)
- C Fabris
- Department of Clinical and Experimental Pathology and Medicine, University of Udine, Italy
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Murawaki Y, Ikuta Y, Nishimura Y, Koda M, Kawasaki H. Serum markers for fibrosis and plasma transforming growth factor-beta 1 in patients with hepatocellular carcinoma in comparison with patients with liver cirrhosis. J Gastroenterol Hepatol 1996; 11:443-50. [PMID: 8743916 DOI: 10.1111/j.1440-1746.1996.tb00289.x] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
In order to elucidate collagen metabolism in hepatocellular carcinoma (HCC) tissue, we compared levels of different potential markers of collagen metabolism and plasma transforming growth factor-beta 1 in patients with HCC and in patients with liver cirrhosis. Serum levels of prolyl hydroxylase and the tissue inhibitor of metalloproteinase-1 in patients with HCC were significantly higher than those in patients with liver cirrhosis and increased with the size of the HCC tumour, whereas the serum levels of procollagen type III propeptide and type IV collagen 7S domain were similar in the two groups. In HCC, the increased plasma transforming growth factor-beta 1 levels were closely correlated with serum levels of prolyl hydroxylase and the tissue inhibitor of metalloproteinase-1. These findings suggest that, in HCC tissue, the intracellular biosynthesis of collagen is enhanced, whereas the secretion of procollagen is disturbed and the degradation of collagen is suppressed by the excess production of the tissue inhibitor of metalloproteinase-1. The results also suggest that plasma transforming growth factor-beta 1 plays an important role in the altered metabolism of collagen in HCC.
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Affiliation(s)
- Y Murawaki
- Second Department of Internal Medicine, Tottori University School of Medicine, Yonago, Japan
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Stauber WT, Knack KK, Miller GR, Grimmett JG. Fibrosis and intercellular collagen connections from four weeks of muscle strains. Muscle Nerve 1996; 19:423-30. [PMID: 8622719 DOI: 10.1002/mus.880190402] [Citation(s) in RCA: 53] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
The effect of repeated cycles of muscle strain was studied in the soleus muscle of female rats. Muscle strains were repeated 3X/week for 1 month using two different strain protocols. Striking changes, including marked variability in fiber size, evidence of degradation and regeneration, and an expanded extracellular matrix were pronounced in the fast-stretched muscles but not in the slow-stretched muscles. However, the slow-stretched muscles did contain struts of connective tissue joining adjacent myofibers. Therefore, repeated muscle strains at high strain rates produced morphological changes similar to many myopathies, including fibrosis, whereas adaptation occurred in response to the same number of strains at slow strain rates. Such diverse tissue responses have relevance to the understanding of the mechanisms of skeletal muscle dysfunction in cumulative trauma disorders and in the design of preventive actions and treatments.
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Affiliation(s)
- W T Stauber
- Department of Physiology, West Virginia University, Morgantown, West Virginia, USA
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