Markers of fibrogenesis and basement membrane formation in alcoholic liver disease. Relation to severity, presence of hepatitis, and alcohol intake.

This study investigated the relationships of the serum markers of fibrogenesis and basement membrane formation to the clinical and morphological severity of alcoholic liver disease and to the degree of alcohol abuse. The concentrations of the aminoterminal propeptide of type III collagen, type IV collagen, and laminin were measured from 87 samples representing a wide range of clinical and histological severities of the disease, which were assessed with indices that have been shown to correlate well with the risk of dying within 1 yr. Significant correlations (p less than 0.00001) were found between the markers of connective tissue metabolism and the Combined Clinical and Laboratory Index: (aminoterminal propeptide of type III collagen, rs = 0.82; type IV collagen, rs = 0.82; laminin, rs = 0.81), as well as between these markers and the Combined Morphological Index: (aminoterminal propeptide of type III collagen, rs = 0.70; type IV collagen, rs = 0.68; laminin, rs = 0.64). Whereas the patients with less than 8 mM of alcohol in their morning urine (mild or moderate drinkers) showed a significant (p less than 0.00001) decrease in these markers in a period of 27 +/- 1 wk, the patients with more than 8 mM of urinary alcohol (heavy drinkers) had no improvement. It is proposed that both fibrogenesis and basement membrane formation are associated with disease severity, degree of alcoholic hepatitis, and alcohol intake, which are important determinants of prognosis in alcoholic liver disease.     

Type III and type I procollagen markers in fibrosing alveolitis

Deposition of types I and III collagen is a typical feature in the development of pulmonary fibrosis. We assessed the propeptides of these procollagens as prognostic markers in 18 patients with fibrosing alveolitis. We analyzed the amino-terminal propeptide of type III procollagen (PIIINP) and the carboxy-terminal propeptide of type I procollagen (PICP) from samples of bronchoalveolar lavage fluid (BALF) and serum, and also estimated their concentrations in epithelial lining fluid (ELF) by the urea method. The level of PIIINP in serum (p < 0.05), BALF (p < 0.05), and ELF (p < 0.05), and the levels of PICP in BALF (p < 0.001) and ELF (p < 0.001) but not in serum, were significantly increased in the patients with fibrosing alveolitis as compared with 17 controls who had been investigated for minor respiratory symptoms. In the BALF and ELF of patients with fibrosing alveolitis, PICP but not PIIINP had significant negative correlations with the specific diffusion coefficient for carbon monoxide (DLCO/ VA). The amino-terminal propeptide of type III procollagen and the carboxy-terminal propeptide of type I procollagen in BALF correlated significantly with one another. During the follow-up period of 6 yr, seven of the 18 patients with fibrosing alveolitis died of the disease, 3 others died of malignancy, and one patient died from an unknown cause. DLCO (p < 0.05) differed significantly between the surviving patients and those who died of fibrosing alveolitis, and detectable PIIINP in BALF predicted death from fibrosing alveolitis (p = 0.05). In conclusion, these results show that PIIINP in BALF, ELF, and serum, and PICP in BALF and ELF, are increased in patients with fibrosing alveolitis. A high level of PICP in BALF, and especially in ELF, suggests a chronic process and increased synthesis of type I collagen in the lungs, whereas PIIINP in BALF and ELF suggests active disease and a poor prognosis.     

Serum carboxy terminal propeptide of type I procollagen to amino terminal propeptide of type III procollagen ratio is a better indicator than each single propeptide and 7S domain type IV collagen for progressive fibrogenesis in chronic viral liver diseases

Twenty chronic viral hepatitis patients, mainly with hepatitis B related with progression to liver cirrhosis were included for an assay of serum collagen markers: PICP (carboxy terminal propeptide of type I procollagen), PIIINP (amino terminal propeptide of type III procollagen), and 7S-IV (7S-domain type IV collagen). PICP is increased in 20% of chronic hepatitis patients with a mean of 190.3 ng/ml, which is not different from that of the follow-up concentration in liver cirrhosis, where 35% of cases were abnormal with a mean of 220.5 ng/ml. The serum level and percent of abnormality of PIIICP in chronic hepatitis and in liver cirrhosis are 23.5 ng/ml vs 14.8 ng/ml and 90% vs 100%, respectively (P>0.05). PICP/PIIINP is significantly higher during liver cirrhosis (15.11 vs 10.08,P<0.05). PICP during chronic hepatitis is not related to serum biochemical changes, while PICP during liver cirrhosis and PIIINP are correlated with hepatic enzymes. 7S-IV in chronic hepatitis and in liver cirrhosis is 14.0 ng/ml vs 10.9 ng/ml, respectively; both were positively correlated with hepatic enzymes. These results suggest that PICP/PIIINP is a better indicator of hepatic fibrogenesis than either PICP or PIIINP alone in viral hepatitis. A ratio of more than 12 is suggestive of liver cirrhosis.     

Influence of primary coronary intervention on myocardial collagen metabolism and left ventricle remodeling predicted by collagen metabolism markers

The aims of the present study were to analyze cardiac collagen metabolism changes in vivo during acute and nonacute phases of ST elevation myocardial infarction (STEMI) in patients who were treated with primary coronary intervention (PCI) only, and to determine the predictive significance of collagen I and III synthesis markers (PICP, PIIINP) as well as the collagen I degradation marker (ICTP) on left ventricular function and volume changes after STEMI. Serum levels of the carboxy-terminal propeptide of type I procollagen (PICP) and amino-terminal propeptide of type III procollagen (PIIINP) assessed on the 30th day and the carboxyterminal telopeptide located at the C end of collagen type I (ICTP) assessed on the 7th day after STEMI were significantly higher (P = 0.01, P = 0.019, P = 0.04, respectively) in the PCI unsuccessful group than in the PCI successful group. These findings support the theory that early and successful PCI not only limits the amount of muscle necrosis but also protects cardiac collagen from ischemia-related injury. PICP and PIIINP levels assessed on the fourth day after acute STEMI enables us to predict the development of left ventricular function (EF) and end-diastolic volume changes over the course of 6 months, irrespective of the initial EF or revascularization success.     

Dupuytren's disease in type I diabetic subjects: investigation of biochemical markers of type III and I collagen

OBJECTIVE: To clarify whether biochemical markers of collagen type III and I metabolism show alterations in type I diabetic subjects with Dupuytren's disease (DD) compared to those without DD. METHODS: DD was assessed in a total of 28 type I diabetic subjects, mean age 43.4 +/- 9.5 (SD) and duration of diabetes 25.2 +/- 9.7 years. Concentrations of aminoterminal propeptide of type III procollagen (PIIINP), carboxyterminal propeptide of type I procollagen (PICP) and carboxyterminal cross-linked telopeptide of type I collagen (ICTP) in serum and excretion of cross-linked N-telopeptides of type I collagen (NTX) and deoxypyridinoline crosslinks (DPyr) into urine were measured. RESULTS: The prevalence of DD was 32% (9 of 28 diabetic subjects). Average serum ICTP was 2.7 +/- 0.8 micrograms/l in subjects without DD and 3.6 +/- 1.2 micrograms/l with DD (p = 0.0276). No significant association between other collagen markers and DD was found. The reference intervals of PIIINP and ICTP were exceeded only in 1 and 2 subjects, respectively, and they both had DD. CONCLUSION: The degradation of type I collagen might be increased in diabetic subjects with DD. The overall implication was that synthesis or degradation of type III and I collagen in diabetic subjects with DD did not differ enough from those without DD to reflect changes in the biochemical markers of type III and I collagen.     

Does long-term losartan- vs atenolol-based antihypertensive treatment influence collagen markers differently in hypertensive patients? A LIFE substudy

BACKGROUND: The aim of this study was to investigate the effects of losartan- vs atenolol-based antihypertensive treatment on circulating collagen markers beyond the initial blood pressure (BP) reduction. METHODS: In 204 patients with hypertension and left ventricular (LV) hypertrophy we measured serum concentration of carboxy-terminal telopeptide of type I procollagen (ICTP), carboxy-terminal propeptide of type I procollagen (PICP), amino-terminal propeptide of type III procollagen (PIIINP), amino-terminal propeptide of type I procollagen (PINP) and LV mass by echocardiography at baseline and annually during 4 years of losartan- or atenolol-based antihypertensive treatment; 185 patients completed the study. RESULTS: Beyond the first year of treatment systolic and diastolic BP, LV mass index (LVMI) as well as collagen markers did not change significantly and were equal in the two treatment groups. Changes in PICP during first year of treatment were related to subsequent changes in LV mass index after 2 and 3 years of treatment (r=0.28 and r=0.29, both p<0.05) in patients randomized to losartan, but not atenolol. CONCLUSION: Long-term losartan- vs atenolol-based antihypertensive treatment did not influence collagen markers differently, making a BP-independent effect of losartan on collagen markers unlikely. However, initial reduction in circulating PICP may predict later regression of LV hypertrophy during losartan-based antihypertensive treatment.     

Plasma and tissue levels of collagen types I and III markers in patients with abdominal aortic aneurysms.

BACKGROUND: To study the levels of the aminoterminal propeptide of type III(PIIINP) and carboxyterminal propeptide of type I procollagen (PICP) in plasma and in the wall of abdominal aortic aneurysms in relation to their size and symptomatology. PIIINP serves as a marker of turnover and PICP as a marker of the synthesis of the corresponding collagens. METHODS: Experimental design: A prospective non-randomised study. Setting: University Hospital, Plzen, Czech Republic. Patients: Eighty-six patients who underwent resection of abdominal aortic aneurysms, average age 70.1 years (range 45 to 91 years), men to women ratio 5:1. The indication for resection was its symptomatology without relation to its diameter, and diameter over 5 cm in asymptomatic patients. Twenty patients (with similar age and gender distribution) scheduled for hernia repair or laparoscopic cholecystectomy were examined as a control group. Main outcome measures: The plasma and tissue PICP and PIIINP concentrations were evaluated using radioimmunoassay methods. The plasma samples were taken from the cubital vein without the use of a tourniquet. Full-thickness sections of the anterior abdominal aortic aneurysm wall at the site of the largest aneurysm diameter were taken at the time of operation. RESULTS: A significant difference between plasma PIIINP levels in patients with abdominal aortic aneurysms and the control group was observed (p<0.01). No correlation of PICP, PIIINP plasma levels with diameter and symptomatology of abdominal aortic aneurysms was found. The increase in PHIIINP tissue concentration was significant in patients with increasing diameter and positive symptomatology (p<0.01). No statistically significant correlation between plasma and tissue PICP and PIIINP concentrations was observed. CONCLUSIONS: The metabolism of type III collagen is increased in patients with abdominal aortic aneurysm, in contrast to type I collagen. The result is a degradation of collagen in the aneurysmal wall. The turnover of type III collagen increases with the enlargement of the aneurysm diameter and with the positive symptomatology. Degradation of type III collagen in the aneurysmal wall has therefore a fundamental significance for abdominal aortic aneurysm rupture. Because no correlation between plasma and tissue levels of PIIINP was found, the plasma levels of PIIINP cannot be used as the plasma markers of this process.     

Serum markers of bone metabolism in multiple myeloma: prognostic value of the carboxy-terminal telopeptide of type I collagen (ICTP)

This study was performed to evaluate the prognostic significance of serum markers of bone and collagen metabolism in multiple myeloma. Serum C-terminal telopeptide of type I collagen (ICTP) reflects degradation of bone, whereas serum osteocalcin, together with serum C-terminal propeptide of procollagen type I (PICP) and serum bone-specific alkaline phosphatase (bAP) reflect synthesis of bone matrix. The N-terminal propeptide of procollagen type III (PIIINP) in serum reflects synthesis of type III collagen. We analysed frozen sera from 109 patients with newly diagnosed multiple myeloma. Serum ICTP was elevated (>5.0μg/l) in most patients (median 6.6 μg/l, range 1.4–29.4 μg/l). Serum PIIINP was elevated (>4.2μg/l) in 46% (median 4.0 μg/l, range 1.4–20.1 μg/l). Serum PICP was generally within the reference limits, whereas serum osteocalcin and serum bAP were elevated in 19% and 37%, respectively. Serum ICTP correlated with serum PIIINP, serum β₂-microglobulin (β₂m), serum calcium, performance status, and stage. In univariate analysis, the test variables serum ICTP ( P =0.026) and serum osteocalcin ( P =0.036) were found to be of prognostic value, but PIIINP, PICP, or bAP in serum were not. Serum ICTP and serum β₂m had a similar prognostic value. In multivariate analysis, serum calcium showed the highest prognostic significance, and serum β₂m was the only other variable of independent prognostic value. However, in normocalcaemic patients, serum ICTP showed the highest prognostic significance, followed by serum osteocalcin. Thus, the serum levels of ICTP and osteocalcin seem related to bone turnover and calcium metabolism, and provide further information about myeloma activity, particularly in normocalcaemic patients.     

Biochemical markers of type III and I collagen: association with retinopathy and neuropathy in type 1 diabetic subjects.

AIMS: Connective tissue alterations may contribute to the development of diabetic long-term complications in eyes, kidneys and peripheral nerves. Collagen deposition may be increased in micro- and macrovascular disease in diabetic subjects. We tested whether biochemical markers of type III and I collagen metabolism are associated with retinopathy and neuropathy in Type 1 diabetes. METHODS: A total of 28 patients, mean age 43.4 +/- 9.5 (sd) and duration of diabetes 25.2 +/- 9.7 years, were studied. Stereoscopic colour fundus photographs were taken for assessment of retinopathy which was classified as no, background or proliferative. Concentrations of aminoterminal propeptide of type III procollagen (PIIINP), carboxyterminal propeptide of type I procollagen (PICP) and carboxyterminal cross-linked telopeptide of type I collagen (ICTP) in serum and urinary excretion of cross-linked N-telopeptides of type I collagen (NTX) and deoxypyridinoline crosslinks (DPyr) into urine were measured. RESULTS: Average serum PIIINP was higher in subjects with proliferative (3.2 +/- 1.1 microg/l) than without proliferative retinopathy (2.5 +/- 0.6 microg/l) (P = 0.03). Average serum PICP was higher in subjects without retinopathy (181.7 +/- 19.5 microg/l) than in subjects with background retinopathy (132.1 +/- 42.7 microg/l) (P = 0.02). Concentrations of other collagen markers were not different in subjects with or without retinopathy. No association between collagen markers and neuropathy was found. CONCLUSIONS: The increased synthesis of type III collagen, reflecting deposition of matrix and basement membrane connective tissue, may be involved in the pathogenesis of proliferative retinopathy in Type 1 diabetic subjects. On the other hand, we observed decreased synthesis of Type I collagen, which can result in weakened vascular integrity in subjects with retinopathy.     

Thrombolytic therapy with streptokinase stimulates collagen breakdown

BACKGROUND. Plasmin is capable of degrading extracellular matrix components such as collagen in vitro. To evaluate the significance of this for in vivo conditions, we set out to study the effect of streptokinase, which acts by converting plasminogen to plasmin, on the serum concentrations of the amino-terminal propeptide of type III procollagen (PIIINP) and the carboxy-terminal propeptide of type I procollagen (PICP). METHODS AND RESULTS. Twenty-three patients with suspected acute myocardial infarction were included in the study; 17 of them received thrombolytic therapy, and six were treated conservatively. PIIINP and PICP were assayed with radioimmunoassays. Kinetics of creatine kinase-MB release were determined to differentiate reperfusers from nonreperfusers. Composite curves of creatine kinase-MB release were constructed for different patient subgroups. During streptokinase infusion the serum concentrations of PIIINP increased rapidly, with a maximum mean increase of 50% (from 2.2 +/- 0.2 to 3.3 +/- 0.3 micrograms/l) in 45 minutes. A similar increase was also observed in two patients who received thrombolytic therapy but did not subsequently develop any myocardial infarction determined on the basis of enzyme release. The relative increase in PIIINP during streptokinase treatment was higher in those acute myocardial infarction patients with probable reperfusion than those with nonprobable reperfusion. Corresponding changes in PIIINP were not seen in the control group. Two days later there was a second increase in serum PIIINP for both patient groups. This change coincided with a similar increase in PICP. CONCLUSIONS. We conclude that streptokinase, probably by activation of plasminogen to plasmin, stimulates the breakdown of type III collagen during thrombolytic therapy. This phenomenon may decrease the risk of rethrombosis of the affected artery if the exposed collagen is responsible for thrombosis formation, but it could also be involved in the development of hemorrhagic complications during thrombolytic therapy. The second increase in PIIINP levels probably indicates type III collagen synthesis of the infarcted area. This investigation represents a pilot study, and more studies on the effects of various thrombolytic agents on interstitial collagen metabolism are obviously needed.     

Abnormal bone turnover in monoclonal gammopathy of undetermined significance: analyses of type I collagen telopeptide,osteocalcin, bone-specific alkaline phosphatase and propeptides of type I and type III procollagens

Abstract: The main difference between monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma (MM) is the presence of lytic bone destructions in the latter. About 20% of MGUS patients develop MM, and histomorphometric studies have shown disturbed bone turnover rates in some of these patients. This study was performed in order to evaluate whether serum analyses of the C-terminal telopeptide of type I collagen (ICTP), as a reflector of bone degradation, and of osteocalcin, bone-specific alkaline phosphatase (bAP) and the C-terminal propeptide of type I procollagen (PICP), as markers of bone formation, might give information on disturbancies of bone metabolism in MGUS. Furthermore, serum N-terminal propeptide of procollagen III (PIIINP) might give information on disturbances in collagen III metabolism in the bone marrow. In the 35 patients examined, serum ICTP was elevated in 12 patients (34%), serum PIIINP elevated in 6 patients (17%), serum osteocalcin elevated in 11 patients (31%), serum bAP elevated in 6 patients (17%), and serum PICP elevated in 4 patients (11%). Serum ICTP correlated significantly with PIIINP (r=0.72, p<0.001), and with serum osteocalcin (r=0.57, p<0.001) and serum bAP (r=0.51, p=0.002). These findings indicate disturbancies of bone turnover and affected collagen metabolism in some MGUS patients. Follow-up observation may reveal any prognostic value of these findings.     

Assessment of relationship between secretion of melatonin, activity of thyroid, adrenal cortex as well as testes and chosen markers of collagen metabolism in starved rats

In starved rats the mutual interrelations were studied between the secretion of melatonin (MEL), thyroid hormones (TT[_4], FT[_4], TT[_3], FT[_3], rT[_3]), corticosterone (B), testosterone (T) and some markers of collagen metabolism: serum concentrations of carboxyterminal propeptide of type I procollagen (PICP) and aminoterminal propeptide of type III procollagen (PIIINP) (determined by RIA method) as well as urine concentration of hydroxyproline (OH-Pr) (determined by colorimetric method). Starved rats were found to have significantly increased serum MEL, B, and rT[_3] concentrations while serum values of TT[_4], FT[_4], TT[_3], FT[_3], T and PICP as well as urinary OH-Pr were significantly decreased. The concentrations of PICP, PIIINP and OH-Pr correlated negatively with MEL and B values, but positively with TT[_4] and FT[_4]. It was concluded that starving may change the collagen metabolism in rats indirectly via a modulating effect of changes in MEL, thyroxine and corticosterone.     

Serum concentrations of aminoterminal propeptide of type III procollagen and propeptide of human type I procollagen in systemic lupus erythematosus

The purpose of this study was to assess the association between the serum levels of aminoterminal propeptide of type III procollagen (PIIINP) and carboxyterminal propeptide of type I procollagen (PICP) with disease activity and damage in systemic lupus erythematosus (SLE). Thirty-three patients with SLE were compared with 31 controls. The assessment in SLE included disease activity indices (SLEDAI, MEX-SLEDAI) and damage index (SLICC/ACR). PIIINP and PICP were measured by radioimmunoassay. Compared with controls, mean levels of PIIINP were higher in SLE (2.9±1.8 vs. 1.8±1.2, P=0.006). PICP was also increased in SLE versus controls (163±94 vs. 102±62, P=0.007). PIIINP was correlated with SLICC/ACR (r=0.33, P=0.048). No correlation was observed between PICP and PIIINP with other clinical or therapeutic variables. These preliminary data suggests a role of PIIINP as a marker for chronic damage. Follow-up studies are required to evaluate its utility in predicting future damage.     

Biochemical markers of types I and III collagen and limited joint mobility in type 1 diabetic patients

Abstract. Limited joint mobility (LJM), a long-term complication of diabetes, has been shown to be associated with microvascular complications of diabetes. Connective tissue alterations may contribute to the development of LJM and other diabetic complications. We tested whether biochemical markers of types I and III collagen metabolism are associated with LJM in type 1 diabetes. We studied 28 male patients of mean age 43.4 years (SD=9.5) and with a duration of diabetes of 25.2 years (SD=9.7) years. LJM assessment included goniometric measurements of the joints and classification by Rosenblooms method. We measured serum concentrations of aminoterminal propeptide of type III procollagen (PIIINP), carboxyterminal propeptide of type I procollagen (PICP) and carboxyterminal crosslinked telopeptide of type I collagen (ICTP); urinary excretion of crosslinked N-telopeptides of type I collagen (NTX) and deoxypyridinoline crosslinks (DPyr) was also measured. Although average serum PIIINP tended to be higher in subjects with moderatesevere LJM (3.1±1.3 µg/l) than in subjects with mild LJM (2.5±0.7 µg/l) or without LJM (2.6±0.4 µg/l), no significant association was found (p<0.27). Concentrations of the other collagen markers were not different in subjects with or without LJM. We conclude that synthesis and degradation of types I and III collagen in diabetic subjects with LJM did not differ from those without LJM to reflect changes in the biochemical markers of these proteins.     

Serum basement membrane and type III procollagen-related antigens in primary biliary cirrhosis

A characteristic histological lesion in early primary biliary cirrhosis (PBC) is disruption of the basement membrane around small bile ducts, which at later stages of the disease is followed by fibrosis. To assess the significance of serum basement membrane- and type III procollagen-related antigens in reflecting such processes, we have measured radioimmunologically the concentrations of serum laminin, type IV collagen and the aminoterminal propeptide of type III procollagen in 22 patients with PBC, classified into four stages according to liver histology. The mean laminin concentration in PBC patients was twice that of the healthy control subjects. Increased concentrations were observed in all patients with stage III or IV of the disease and also in 60% (6/10) of the patients, with early stages (I or II). Elevated serum type IV collagen concentrations were found only in four patients, all in the late, fibrotic stages of the disease. The basement membrane protein changes in serum were in accordance with immunohistochemical findings obtained with the antibodies against these proteins. Neither of these serum parameters emerged, however, as a significant predictive factor for survival. The changes in serum aminoterminal propeptide of type III procollagen resembled those in laminin P1. Moreover, the propeptide was also significant as a predictive factor for survival.     

Collagen metabolites in the peripheral and splanchnic circulation of patients with Crohn disease.

BACKGROUND: Fragments of collagen arising during synthesis and breakdown have been suggested as markers of fibrous tissue remodelling in Crohn disease. We compared serum concentrations of the C-terminal propeptide of collagen I (PICP), the N-terminal propeptide of collagen III (PIIINP) and the C-terminal telopeptide of type I collagen (ICTP) in the splanchnic and systemic circulation in Crohn disease requiring segmental intestinal resection. METHOD: 15 consecutive patients undergoing surgery due to strictures or continuous inflammation. Male:female ratio was 6:9. Blood was drawn from a peripheral vein prior to surgery. Immediately before intestinal resection, additional samples were drawn from the antecubital vein and from a mesenteric vein draining the affected intestinal segment. PIIINP, PICP and ICTP were measured with radioimmunoassays. RESULTS: Pre-surgery S-ICTP (median 5.5 microg/L; range 3.2-17.2 microg/L) was significantly increased in peripheral blood compared with healthy controls (median 2.6 microg/L; range 0.6-5.7 microg/L), P < or = 0.05. By contrast, S-PICP (median 98 microg/L; range 62-137 microg/L) and S-PIIINP (median 2.5 microg/L; range 1.2-7.4 microg/L) were significantly lower than S-PICP (median 133 microg/L; range 66-284 microg/L) and S-PIIINP (median 3.4 microg/L; range 1.0-7.1 microg/L) in healthy controls, P < or = 0.05. During surgery. no difference in S-PICP and S-PIIINP was documented between peripheral blood and splanchnic blood. In contrast, S-ICTP was increased in splanchnic blood (median 6.2 microg/L; range 2.7-17.4) compared to peripheral blood (median 5.0 microg/L; range 3.1-13.4) (P=0.05). CONCLUSION: The present study provides further evidence that the altered intestinal collagen metabolism in Crohn disease is reflected in the local and systemic circulation.     

Serum laminin and portal pressure in alcoholic cirrhosis. A study of 39 patients

A correlation between serum laminin, a glycoprotein found in basement membranes, and hepatic wedge pressure has previously been reported in a small number of patients with various liver diseases. To study this relationship in patients with alcoholic cirrhosis, we measured the wedge hepatic pressure and venous gradient, in comparison with serum concentrations of laminin and collagen metabolism products: N-terminal peptide of type III procollagen, collagen type I, and collagen type III in 39 patients. A statistically significant correlation was observed between serum laminin and wedged hepatic pressure (r = 0.529; p less than 10(-3] or hepatic venous gradient (r = 0.482; p = 0.002). By contrast, no statistically significant correlation was found between hemodynamic parameters and serum concentrations of N-terminal peptide of type III procollagen, collagen type I or collagen type III. These results suggest that, in patients with alcoholic cirrhosis, portal pressure may be estimated by serum concentration of laminin, and that perisinusoidal fibrosis, especially basement membrane thickening, may play an important role in the pathogenesis of portal hypertension in these patients.     

Markers of collagen and basement membrane metabolism in sera of patients with progressive systemic sclerosis.

The concentrations of the amino terminal propeptide of type III procollagen, the 7S domain of type IV collagen, and the fragment P1 of laminin (PIIINP, 7S, and P1 respectively) and the activity of galactosylhydroxylysyl glucosyltransferase (GGT) in serum were evaluated as indicators of disease activity in a cross sectional study of 84 patients with progressive systemic sclerosis. The mean values of PIIINP, P1, and GGT were raised in progressive systemic sclerosis, 19-32% of patients having abnormal values of the various tests. PIIINP, measured with two different assays, and P1 were associated with active, acute, or subacute disease. GGT also correlated positively with some acute phase proteins in the whole group, without a clear association with the course of the disease. Arthritis was associated with increased PIIINP concentrations as well as with an increased activity of GGT. Kidney disease led to raised concentrations of the degradation products of PIIINP. Raynaud's phenomenon in the hands was related to increased PIIINP concentrations.     

An update on biomarkers of heart failure in hypertensive patients

Biomarkers should have high sensitivity, specificity, reproducibility, be cost-effective, and provide incremental predictive or diagnostic utility over standard risk factors or tests. Despite numerous studies investigating biomarkers in heart failure (HF), there are only a few that predict HF in hypertensive patients. This article summarizes data from numerous studies concerning possible biomarkers of HF in hypertensive patients such as: serum uric acid (SUA), interleukins, monocyte chemoattractant protein one (MCP-1), cardiotrophin-1 (CT-1), carboxy-terminal propeptide of procollagen type I (PICP), type I collagen telopeptide (CITP) and N-terminal propeptide of type III procollagen (PIIINP), metalloproteinases (MMPs), B-type natriuretic peptide (BNP) and its derivatives, glycoprotein CA125 and cystatin C. Early detection of patients of increased risk of hypertensive heart disease may result in early implementation of effective preventive strategies. Therefore, there is need to identify newer biomarkers, if they can improve risk prediction, identifying patients, in which earlier or more aggressive intervention will improve clinical outcomes.     

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

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