Serum procollagen III peptide in chronic myeloproliferative disorders

Using a radioimmunoassay the serum concentration of the N-terminal propeptide of type III procollagen (P-III-P) was measured in 35 patients with chronic myeloproliferative disorders, including idiopathic myelofibrosis (n = 10), osteomyelosclerosis (n = 4), transitional myeloproliferative disorder (n = 5), polycythaemia vera (n = 10) and chronic myelogenous leukaemia (n = 6). The normal range in 35 healthy controls was 4.9-11.7 ng/ml. The serum concentration of P-III-P increased with increasing degrees of bone marrow reticulin fibrosis. By contrast, almost normal levels were detected in osteomyelosclerosis with an indolent clinical course, in which an excessive deposition of mature collagen fibres was found, representing mainly type I collagen. These observations indicate that the serum P-III-P level is positively correlated to the degree of bone marrow reticulin fibrosis, whereas levels are near normal in patients with osteomyelosclerosis and stable disease. Measurement of serum P-III-P may be a useful indicator of disease activity in myelofibrosing conditions.     

Serum type III procollagen peptide in alcoholic liver disease and idiopathic hemochromatosis: its relationship to hepatic fibrosis, activity of the disease and iron overload

To assess the value of type III procollagen peptide (sPIIIP) as a marker of hepatic fibrosis, sera from 73 patients with alcohol-related liver disease and 30 patients with idiopathic hemochromatosis (IHC) were studied by a specific radioimmunoassay. sPIIIP was increased in 87% of 30 patients with cirrhosis, in 16% of 32 with steatofibrosis but in none of 11 with steatosis. There was a significant correlation with histologic hepatocellular necroinflammation (r = 0.42, p less than 0.01), but not with hepatic fibrosis. sPIIP was increased in 33% of 30 patients with IHC, whether or not they had cirrhosis or fibrosis, and whatever the level of iron overload or the extent of the hepatic deterioration. IHC patients with increased levels of sPIIIP had a higher prevalence of superimposed hepatic damage than did those with normal procollagen levels (p less than 0.05). Our findings, therefore, weaken the diagnostic value of sPIIIP as an index of connective tissue deposition in the liver, and suggest that, at least in alcohol-related liver disease and IHC, hepatocellular necroinflammation influences the results.     

Serum type III procollagen peptide and laminin (Lam-P1) detect alcoholic hepatitis in chronic alcohol abusers

The diagnosis of alcoholic hepatitis is difficult to establish by conventional clinical and laboratory methods, and a firm diagnosis relies on liver histology. Since there are severe limitations in following patients with repeated liver biopsies, noninvasive procedures are needed to assess the presence of alcoholic hepatitis in chronic alcohol abusers. It has been suggested that serum Type III procollagen peptide levels correlates with the degree of inflammation in chronic liver disease. Since inflammation is a major histological finding in alcoholic hepatitis, we therefore studied the usefulness of measuring serum Type III procollagen peptide and laminin values in 45 consecutive chronic alcohol abusers, with or without cirrhosis, in detecting those with alcoholic hepatitis. The results showed that both Type III procollagen peptide and laminin values were elevated in all of the patients with established liver damage. However, the values were highest in those with liver cirrhosis plus alcoholic hepatitis (Type III procollagen peptide 50.4 +/- 36.4 ng per ml vs. 8.1 +/- 2.6 in controls, p less than 0.01; laminin 4.50 +/- 1.49 units per liter vs. 1.24 +/- 0.26 units per liter in controls, p less than 0.01), followed by subjects with alcoholic hepatitis alone (Type III procollagen peptide 23.5 +/- 17.6 ng per ml, p less than 0.01; laminin 2.60 +/- 1.09 units per liter, p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)     

Serum aminoterminal type III procollagen peptide in early rheumatoid arthritis: relation to disease activity and progression of joint damage

Serum levels of the aminoterminal type III procollagen peptide (S-PIIINP) have been used as markers of proliferative inflammation in rheumatoid arthritis (RA) and a prognostic significance has been suggested. To test this further we have measured S-PIIINP longitudinally for 2 years in 66 patients with definite RA and a disease duration of less than 2 years, and related the levels to clinical, biochemical, and radiographic findings. In this patient group the correlations between S-PIIINP and ESR and CRP, respectively, were higher than those obtained between S-PIIINP and articular indices, and markedly higher than in patients with RA of longer duration. Patients with normal mean levels of S-PIIINP during the study period had a significantly slower rate of radiographic progression than patients with elevated mean levels of S-PIIINP. ESR yielded in general higher correlations with the joint damage process than did S-PIIINP. The correlations between S-PIIINP and the joint damage scores increased with time. A multiple regression analysis showed that ESR explained most of the variance in joint damage progression over 2 years, but S-PIIINP added independent information. About one third of the variance could be explained by the two variables.     

Serum type I collagen and N-terminal peptide of type III procollagen in chronic hepatitis. Relationship to liver histology and conventional liver tests.

The aim of this study was to compare serum N-terminal peptide of type III procollagen to aminotransferases and gamma-globulins as a marker for histological activity in patients with chronic hepatitis and to assess the role of type I collagen, a new serum marker, as a marker of fibrosis in these patients. Sixty patients with biopsy-proven chronic hepatitis were included in this study. Liver disease was virus B-related in 29, autoimmune in five, drug-induced in five, and of unknown etiology in 21. Each biopsy was independently assessed by two liver pathologists. Two histological scores, a score of activity and a score of fibrosis, were established. Serum N-terminal peptide of type III procollagen and type I collagen were assayed by liquid phase RIA. Significant correlations were noted between serum N-terminal peptide of type III procollagen and scores of activity (r = 0.70, p less than 10(-4)) and fibrosis (r = 0.45, p = 0.0005), and between serum type I collagen and scores of activity (r = 0.46, p = 0.0004) and fibrosis (r = 0.67, p less than 10(-4)). When the correlation between scores of activity and fibrosis (r = 0.52, p = 10(-4)) was considered by partial correlation, serum N-terminal peptide of type III procollagen was correlated with the score of activity (r = 0.63, p less than 10(-3)) but not with the score of fibrosis, and serum type I collagen was correlated with the score of fibrosis (r = 0.58, p less than 10(-3)), but not with the score of activity.(ABSTRACT TRUNCATED AT 250 WORDS)     

Serum type III procollagen N-terminal peptide in coal miners.

Health surveillance of workers exposed to fibrogenic agents ideally should identify individuals at risk or detect pulmonary fibrosis in preclinical stages. We investigated serum procollagen type III N-terminal peptide (PIIIP) in several groups of active miners and in a nondust-exposed control group. The purpose of this study was to determine the applicability of PIIIP as an early noninvasive marker of pulmonary fibrosis in workers exposed to coal mine dust. PIIIP levels were significantly elevated in miners without radiological signs of coal workers pneumoconiosis (CWP) as compared with the nonexposed controls. However, in coal miners with CWP beyond ILO classification 1/0, PIIIP levels were not significantly different from nondust-exposed controls. Trend analysis within the miners group indicated a decrease in PIIIP levels with progression of the fibrosis. Our data suggest that detection of early lung fibrosis by measuring serum PIIIP values may be more sensitive than radiological diagnosis of CWP. However, follow-up of the control miners with respect to serum PIIIP and chest radiography is essential to validate PIIIP as a biological marker for CWP.     

Serum aminoterminal procollagen type III peptide in acute viral hepatitis. A long-term follow-up study

The development of chronic viral liver disease is associated with increased deposition of connective tissue in the liver. The aminoterminal propeptide of procollagen type III (P-III-NP) is considered to reflect the metabolism of collagen type III, one of the major collagen types in liver fibrosis. The purpose of the present study was to elucidate, whether S-P-III-NP in patients with viral hepatitis was related to injury and repair processes in the liver. S-P-III-NP was determined in a prospective longitudinal study of 63 patients with acute viral hepatitis followed to healing or development of chronic liver disease. Two assays were applied. The P-III-NP Ria-gnost assay, which measures mainly the intact propeptide, and the P-III-NP Fab-assay, in which the antibody exhibits equal affinity to the intact propeptide as well as the degradation product col 1. At the onset of viral hepatitis, S-P-III-NP determined in either assay was equally elevated in the two groups. From the second month of follow-up, significantly higher levels in both assays were observed in patients developing chronic disease. During follow-up, the highest P-III-NP RIA-gnost values were seen in patients with chronic active hepatitis, and active cirrhosis. S-P-III-NP decreased towards normal levels during development of inactive cirrhosis. In the individual patient, S-P-III-NP Ria-gnost was positively related to transaminases. During follow-up of uncomplicated hepatitis a normalization of transaminases occurred before normalization of S-P-III-NP RIA-gnost. Considering, that S-P-III-NP, in contrast to the conventional laboratory variables, reflects the metabolism of type III collagen, it is assumed that determination of S-P-III-NP may provide new information on fibrogenesis in viral liver disease.     

Serum procollagen III peptide in alcoholic and other chronic liver diseases

Increased levels of serum procollagen III peptide (P-III-P) have been found in patients with alcoholic hepatitis and cirrhosis. Serum P-III-P was increased (greater than 15 micrograms/l) in 38 of 44 (86%) patients with alcoholic liver cirrhosis, in 6 of 20 (30%) with fatty liver, in 1 of 13 (8%) with non-alcoholic fatty liver, and in 3 of 14 (21%) with other chronic liver diseases. Median serum P-III-P was almost three times higher in alcoholic liver cirrhosis than in alcoholic fatty liver (p less than 0.001). Serum P-III-P was increased in three of six patients with alcoholic fatty liver and periportal fibrosis. In the total material (n = 91), a statistically significant negative correlation between serum P-III-P and albumin (r = -0.71, p less than 0.001) and Normotest (r = -0.63, p less than 0.001), respectively, and a positive correlation between serum P-III-P and bilirubin (r = 0.65, p less than 0.001) were found. The serum level of P-III-P had no prognostic value concerning the mortality in patients with alcoholic cirrhosis.     

Serum type III procollagen N-terminal peptide in patients with collagen diseases

The serum concentration of type III procollagen N-terminal peptide (P III P) level is known to reflect the activity of collagen biosynthesis. To analyze the correlation between the disease activity and serum P III P levels in collagen diseases, serum P III P levels in patients with rheumatoid arthritis (RA), progressive systemic sclerosis (PSS), and other collagen diseases were measured. In some patients serum levels of prolyl++-hydroxylase, which is an intra-cellular enzyme of collagen biosynthesis, were measured. Serum P III P levels were elevated in patients with PSS and MCTD/overlap syndrome, suggesting a high rate of collagen biosynthesis by fibroblasts. Patients with RA showed no significant elevation of serum P III P compared with normal control group. But the group of RA patients with elevated ESR and/or serum CRP values showed high levels of serum P III P. The correlation between the disease activity and serum P III P levels was observed in RA patients with positive rheumatoid factor (RF), but not patients without RF. In addition we measured P III P levels in synovial fluid of RA and osteoarthritis patients. The levels were one to three hundred times higher than serum levels, and they showed the positive correlation with serum levels, suggesting that serum P III P might be originated from synovial P III P.     

Serum aminoterminal type III procollagen peptide in inflammatory and degenerative rheumatic disorders

Summary Measurement of the aminoterminal type III procollagen peptide in serum has been suggested as a marker of the biosynthesis of collagen type III, a major connective tissue component in repair processes. In the present study the propeptide level correlated with the inflammatory synovial mass in rheumatoid arthritis and osteoarthritis. This implies that the propeptide level reflects the collagen type III synthesis occurring in the synovial repair processes, whether they were caused by inflammatory or degenerative rheumatic disorders. Physical activity did not enhance the transition of the propeptide from the synovial fluid or the inflamed synovial membrane to the blood. Normal serum propertide values were observed in most patients with ankylosing spondylitis and degenerative diseases of the spine. This may reflect the lower amount of inflammatory tissue in these diseases and hence the sensitivity of the assays.     

Serum amino-terminal type III procollagen peptide in rheumatoid arthritis. Relationship to disease activity, treatment, and development of joint erosions

Using 2 radioimmunoassays, increased serum levels of amino-terminal type III procollagen peptide and its degradation products were demonstrated in rheumatoid arthritis patients. Patients with active disease showed higher serum propeptide levels than did patients with inactive disease. Unlike D-penicillamine, azathioprine treatment suppressed the propeptide levels in patients with active disease. A 6-month prospective study showed significantly higher initial serum propeptide levels in patients with erosive progression. The propeptide level reflects disease activity and may be a valuable prognostic marker in rheumatoid arthritis.     

Persistent elevation of the aminoterminal peptide of procollagen type III in serum of patients with acute viral hepatitis distinguishes chronic active hepatitis from resolving or chronic persistent hepatitis

We measured the serum concentration of the aminoterminal propeptide of collagen type III (PIIIP) in 22 patients with acute viral hepatitis (19 hepatitis B, 3 hepatitis non-A, non-B). Nine patients showed persistent biochemical remission, 13 patients developed chronic active hepatitis (CAH); 6 of those underwent therapy with methylprednisolone and azathioprine. Thirteen patients with chronic persistent viral hepatitis (CPH) and 38 healthy individuals were also investigated. In the control group, PIIIP values were 9.5 +/- 2.25 ng/ml (chi +/- SD; range 4-14 ng/ml). All patients with acute hepatitis showed elevated PIIIP values (range 20-125 ng/ml). In the 9 patients with biochemical resolution, PIIIP normalized after a maximum of 6.5 months (range 7.5-14 ng/ml). In CAH, PIIIP was persistently elevated on the day of the diagnostic biopsy (range 15.6-35.7 ng/ml). In comparison, the patients with chronic persistent hepatitis showed a range of 5.0-15.4 ng/ml. Differences between controls and CAH and CPH/CAH were statistically highly significant (P less than 0.001). Treatment of patients with CAH by immunosuppression resulted in normal PIIIP values in 3 and persistently elevated values in 3. One additional patient had normal PIIIP after treatment with an increased dose of methylprednisolone of 16 mg p.d. Serum concentrations of PIIIP offer a non-invasive index for the development of chronic active hepatitis from acute viral hepatitis. This blood test may also be useful for monitoring immunosuppressive treatment in CAH.     

Liver stellate cells and aminoterminal peptide of type III procollagen in chronic hepatitis C treated with interferon

BACKGROUND/AIMS: Fibrogenesis plays a crucial role in development of cirrhosis, and liver stellate cells, activated to myofibroblasts expressing alpha-smooth muscle actin, are responsible for deposition of fibrous matrix; aminoterminal peptide of type III procollagen is a serum marker of active fibrogenesis. Interferon can slow ongoing fibrogenesis in chronic viral hepatitis, but it remains unclear whether the drug acts by a direct effect on stellate cells or by inhibiting the necro-inflammatory process. The aim of this study was to evaluate, in selected cases of chronic hepatitis C, whether changes in stellate cell expression induced by interferon correlated with changes in serum levels of procollagen or with clinical response to the therapy, in order to further investigate the mechanism of interferon's effect on fibrogenesis. METHODOLOGY: We studied 30 patients with chronic hepatitis C, treated with interferon and followed for more than 6 months. Before and after-treatment evaluation included histological scores for portal activity, lobular activity and fibrosis; immunohistochemical scores for alpha-actin expression by activated stellate cells in liver biopsy; and radioimmunoassay for procollagen in serum. According to the clinical response to interferon, the patients were subdivided into sustained responders, delayed relapsers, early relapsers and non-responders. RESULTS: We found that alpha-actin scores, portal and lobular activity scores and procollagen levels were all significantly lower after the treatment in responder patients, whereas in non-responders the after-interferon values were not different from the basal values. Moreover we found that the patients who were still clinical responders at the time of after-therapy evaluation, but relapsed subsequently (delayed relap-sers), still showed a pattern of "low fibrogenesis", like the sustained responders. On the contrary, the patients who had already relapsed at the time of after-interferon evaluation (early relapsers) showed a pattern of "high fibrogenesis", like the non-responders. CONCLUSIONS: Since all the patients had received a similar treatment for a similar period, our results suggest that fibrogenesis activity in a defined time is related to the clinical response present in that time, and is influenced by short-term variations in necro-inflammatory activity induced by interferon, rather than by interferon itself.     

Serum procollagen III peptide concentration in iron overload

Abstract: Patients with severe iron overload may develop hepatic fibrosis due to iron toxicity. Unfortunately, the follow-up of the fibrogenic activity during treatment by histological examination of tissue biopsies carries potential side effects, and may therefore not be justified ethically. Recently, the serum concentration of procollagen type III peptide (S-PIIINP) has been shown to be a valid serum marker of the activity of collagen metabolism in conditions with hepatic fibrosis unrelated to iron overload. In order to evaluate the potential usefulness of this test in patients with fibrosis due to iron overload, we investigated the relationship between the PIIINP serum concentration and the size of iron overload in 18 patients with hereditary haemochromatosis (HH) and in 14 patients with transfusional iron overload. A close correlation was found between S-ferritin and S-PIIINP (r=0.73, p<0.0001). Follow-up of 6 patients during iron depletion treatment revealed a normalization of the serum aminotransferase concentration before normalization of S-PIIINP was found. This may indicate that excess iron directly induces an increase in fibrogenesis rather than the increased fibrogenesis is secondary to hepatocellular injury caused by iron excess. Thus, serial measurements S-PIIINP may be useful in follow-up of the fibrogenic process due to iron overload.     

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.     

Serum aminoterminal type III procollagen peptide reflects repair after acute myocardial infarction

In 16 patients with acute myocardial infarction and in 15 controls, procollagen type III aminoterminal peptide in serum (PIIINP) was measured consecutively. Serum PIIINP was increased on the second to third postinfarction day (p less than 0.01) and remained elevated for more than 4 months. Peak values were observed on the third to seventh postinfarction day. The individual peak changes were correlated to infarction size calculated from serum CK-MB and serum lactate dehydrogenase (p = 0.60, p = 0.02). The changes in distribution of PIIINP-related antigens in serum after gel chromatography were similar to changes observed during wound healing in humans. PIIINP is cleaved off procollagen type III during the biosynthesis of type III collagen, which characterizes the early stages of repair and inflammation. Our findings suggest that serum PIIINP reflects the repair processes and scar formation following acute myocardial infarction. The serum PIIINP alterations in acute myocardial infarction differ essentially from the changes in myocardial enzymes reflecting myocardial injury. Serum PIIINP may therefore provide new and clinically relevant information on the healing of myocardial infarction.     

Serum concentrations of the carboxyterminal cross-linking domain of procollagen type IV (NC1) and the aminoterminal propeptide of procollagen type III (PIIIP) in chronic liver disease

Serum concentrations of both the carboxyterminal cross-linking domain (NC1) of procollagen type IV and the aminoterminal propeptide of procollagen type III (PIIIP) were measured by specific radioimmunoassays in 60 patients with chronic liver disease and 50 healthy controls. Compared with controls (5.3 +/- 1.3 ng/ml, mean +/- S.D.), NC1 concentrations were significantly elevated in patients with chronic active hepatitis (10.2 +/- 2.0 ng/ml) and liver cirrhosis (13.5 +/- 3.0 ng/ml), but not in chronic persistent hepatitis (6.0 +/- 0.9 ng/ml). The concentrations in patients with active liver cirrhosis were significantly higher than those in patients with inactive cirrhosis. Serum concentrations of PIIIP in controls, parients with chronic persistent hepatitis, chronic active hepatitis and cirrhosis were 5.8 (4.3-7.9), 5.3 (3.5-7.9), 17.5 (10.6-28.9), 16.7 (10.4-26.7) ng/ml, respectively (logarithmic mean and range of mean +/- S.D. after retransformation). Patients with liver cirrhosis had significantly higher concentrations of NC1 in serum than those with chronic active hepatitis, but there was no difference in serum PIIIP concentrations between the two groups. These data suggest an alteration of type IV collagen metabolism in chronic liver disease. In liver cirrhosis, the metabolism of collagen IV is apparently different from that of collagen type III; serum NC1 determinations may therefore provide additional information on chronic liver disease, particularly in patients with cirrhosis with a normal level of serum PIIIP. Further follow-up studies as well as investigations related to the basic mechanism of the elevation of these peptides in serum are needed in order to understand their clinical significance fully.     

Serum levels of aminoterminal type III procollagen peptide in normal subjects and hepatic fibrosis

Serum levels of aminoterminal type III procollagen peptide in normal subjects were determined by radioimmunoassay. The levels of the peptide markedly increase in infants and gradually decrease with age in childhood. The peptide increases again in prepubertal children and then decreases through adulthood. These findings suggest that increased levels of the peptide reflect accelerated collagen synthesis in the human body. Comparison of serum levels of the peptide with the degree of hepatic fibrosis revealed that the peptide increased in parallel with the progress of hepatic fibrosis.