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 propeptide of type III procollagen after cardiac transplantation and the effect of rejection

The present study examines serum concentrations of the aminoterminal propeptide of type III procollagen (S-PIIINP), a marker of type III collagen synthesis, after heart transplantation, and assesses changes induced by rejection. Fourteen transplant patients were included with 12 coronary artery bypass patients serving as controls. Mild to moderate rejection was found in 44 biopsies, and severe rejection in 6. Two severe rejection incidents occurred before postoperative day 10, the remainder at postoperative days 23 to 57. S-PIIINP was elevated in transplant patients at postoperative days 1 to 7 (p ≤ 0.01), with return to baseline at postoperative day 60 (p = 0.14, N = 6). S-PIIINP remained unchanged after mild to moderate rejection, but increased 1 to 2 weeks following severe rejection occurring after postoperative day 10. S-PIIINP was elevated in bypass patients from postoperative day 2 throughout the study period of 360 days (p ≤ 0.01). Thus, type III collagen turnover after heart transplant and coronary artery bypass grafting resembles wound healing. Collagen synthesis after severe rejection is reflected by SP-IIINP approximately 2 weeks after transplant. The findings may prove to be significant concerning the prognosis of heart transplant patients.     

充血性心力衰竭患者血清Ⅰ型前胶原羧基端肽及Ⅲ型前胶原氨基端肽的变化

目的 :研究充血性心力衰竭 (CHF)患者血清Ⅰ型前胶原羧基端肽 (PIP)和Ⅲ型前胶原氨基端肽 (PⅢP)含量变化及与反映左室结构和功能的参数间的关系。方法 :应用放射免疫法测定 2 0例正常人 (对照组 )和 6 1例CHF患者 (CHF组 )血清中PIP和PⅢP浓度 ,用M型超声心动图测算左室重量指数 (LVMI)和左室射血分数(LVEF) ,多普勒超声心动图测定二尖瓣口舒张早期和晚期最大血流速度 (VE和VA)。结果 :CHF组血清中PIP和PⅢP含量较对照组明显升高 ,并随着心功能等级的增加而有升高趋势 ,但与导致心力衰竭的基础病因无关。血清PⅢP和PIP水平与LVMI呈正相关 ,与VE/VA 呈负相关 ,并与同期测定的血浆血管紧张素Ⅱ和醛固酮含量有一定相关性。结论 :CHF患者血清PIP和PⅢP水平显著升高可以反映其左室重构过程中细胞外基质的代谢变化     

Serum levels of the aminoterminal propeptide of type III procollagen and hyaluronan during resolving and nonresolving posttransfusion non-A, non-B hepatitis

Serum levels of the aminoterminal propeptide of type III procollagen (PIIINP) and hyaluronan were analysed before and during the acute, recovery and chronic phases of non-A, non-B (NANB) posttransfusion hepatitis (PTH) in 13 patients. All patients were discovered during a prospective study on NANB PTH in patients undergoing open-heart surgery. 7/13 (54%) patients resolved their hepatitis within 6 months after onset, whereas 6/13 (46%) went on to chronic hepatitis. In 5 of these 6 patients a liver biopsy during the chronic phase of the hepatitis showed chronic active hepatitis in 2 and chronic persistent hepatitis in 3. During the acute NANB PTH phase the mean serum PIINP level rose significantly as compared to prehepatitis levels and to levels in a reference group not developing hepatitis. Neither PIIINP levels nor hyaluronan levels, however, could differentiate patients with resolving from patients with nonresolving hepatitis. These markers should, however, be further evaluated as potential markers for development of fibrosis/cirrhosis during chronic hepatitis.     

Aminoterminal propeptide of type III procollagen in serum in alcoholic liver disease

An assay of serum antigens related to the aminoterminal propeptide of type III procollagen has been suggested for monitoring fibrotic processes in the liver. These antigens were measured here in 61 alcoholics who were divided into four groups on the basis of liver histology: normal light microscopy, fatty liver, alcoholic cirrhosis with hepatitis, and inactive cirrhosis. All the subjects having alcoholic hepatitis with cirrhosis had elevated values in the assay, whereas some of those with either fatty liver or inactive cirrhosis still had normal values. It was, therefore, not possible on the basis of this method alone to distinguish fatty liver from cirrhosis or alcoholic hepatitis, although very high values were suggestive of alcoholic hepatitis. In a follow-up study, the aminopropeptide value decreased slowly during recovery from alcoholic hepatitis and increased rapidly after a new drinking bout. The antigens detected by the assay are heterogeneous in human serum. The proportions of the three main peptide forms varied during recovery from alcoholic hepatitis, the authentic propeptide being the main one at the acute stage, but almost disappearing later. The usefulness of the assay could probably be improved if distinct assays were available for the different antigen forms.     

Independent and additional prognostic value of aminoterminal propeptide of type III procollagen circulating levels in patients with chronic heart failure

BACKGROUND: In chronic heart failure (CHF), changes in the extracellular space contribute to cardiac dysfunction. We aimed to determine whether aminoterminal-propeptide of type III procollagen (PIIINP), a marker of extracellular matrix turnover, might provide prognostic information in CHF patients. METHODS AND RESULTS: A total of 101 consecutive CHF patients (mean age 61.7 +/- 8.7 years, 88% males) were followed up between 1999 and 2001. The combined endpoint of the study was death and hospitalization for heart failure. During follow-up there were 15 deaths and 11 hospitalizations for worsening heart failure. At the survival analysis, age (P = .02), New York Heart Association class (P = .014), s-creatinine (P = .014), plasma-PIIINP (p-PIIINP) levels (P = .005), left ventricular ejection fraction (LVEF) (P = .0002), and a restrictive mitral filling pattern (P = .0003) predicted event-free survival. At the multivariate analysis, p-PIIINP levels predicted outcome independently of other clinical variables, hormones, and echocardiographic and exercise testing variables (P < .05 in all models). In patients with LVEF <31%, the presence of p-PIIINP >4.7 microg/L levels was significantly associated with a higher risk of death and hospitalization as compared with the other patients (event-free survival rate at 12 months: 45% versus 95%; at 24 months: 27% versus 88%; at 36 months: 18% versus 85%, P < .0001). CONCLUSIONS: In patients with CHF, PIIINP levels predict outcome independently of clinical status, hemodynamics and hormonal activation. PIIINP levels provide additional prognostic information to that of left ventricular function alone, suggesting that it may reflect more than cardiac extracellular matrix turnover.     

Serum carboxyl-terminal propeptide of procollagen type I in exercise-induced left ventricular hypertrophy

BACKGROUND: Left ventricular hypertrophy (LVH) induced by exercise is considered to be a physiologic adaptive mechanism without fibrogenic hyperactivity, as occurs in pathologic hypertrophy. HYPOTHESIS: This study investigated serum markers of collagen synthesis and echo parameters of left ventricular diastolic function (LVdf) in 22 male athletes. METHODS: Twenty-two highly competitive male athletes (10 cyclists, 12 soccer players) were studied with full history, clinical examination, Doppler echocardiogram, and serum concentration of the carboxyl-terminal propeptide of collagen type I (PIP). They were divided into two groups: normal left ventricular mass (N) with left ventricular mass index (LVMI) < 125 g/m2 (14 athletes) and LVH with LVMI > 125 g/m2 (8 athletes). RESULTS: Age, body surface area, blood pressure, heart rate, and systolic function were not different between the groups. Serum concentration of PIP (N: 163 +/- 44.1 microg/l, LVH: 172.7 +/- 61.2 microg/l--NS) and LVdf (early to atrial peak mitral flow velocity ratio: [E/A] N: 1.77 +/- 0.47, LVH: 1.98 +/- 0.70--NS, and early to atrial peak mitral annulus velocity ratio: [Ea/Aa] N: 2.63 +/- 0.70, LVMI: 2.55 +/- 0.90 LV 1.61--NS) were similar in both groups. CONCLUSIONS: Normal serum concentration of PIP in athletes with LVH in association with normal LVdf indicates the possibility that in this type of physiologic hypertrophy there is mainly an increase of myocyte size without interstitial fibrosis.     

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.     

Serial determination of type III procollagen amino propeptide serum levels in patients with histologically progressive and non-progressive primary biliary cirrhosis.

We examined the value of serum procollagen III amino propeptide (PIIIP) for predicting the histological progression of primary biliary cirrhosis (PBC). Serial PIIIP measurements were obtained for nine patients with histologically progressive PBC and nine patients with histologically stable early disease, assessed by repeated liver biopsies and followed for up to 13 years. The means of the follow-up PIIIP concentrations were elevated in 39% of the cases; moreover, PIIIP levels were elevated at least once during follow-up in 72% of the cases. Mean follow-up PIIIP concentrations did not differ significantly between progressive and non-progressive patients. In addition, in the progressive group, histological progression was not reflected by PIIIP levels. No difference was found between the serum PIIIP levels corresponding to the histological stages I, II and III. The individual coefficients of the correlation between serum PIIIP and biochemical variables (bilirubin, alkaline phosphatase, ASAT, albumin) and histology showed a wide distribution without a consistent trend towards positive or negative. Treatment with cyclosporin A or cyclosporin A combined with prednisone did not influence serum PIIIP levels. Treatment with penicillamine combined with prednisone, however, resulted in a significant decrease in PIIIP concentrations (p less than 0.05). We conclude that serum PIIIP measurements are of no value for predicting the histological progression of PBC.     

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.     

Serum osteocalcin and carboxyterminal propeptide of type I procollagen in rheumatoid arthritis.

OBJECTIVES--Previous reports indicate that serum osteocalcin (serum bone GLA protein (S-BGP)) and carboxyterminal propeptide of type I procollagen (PICP) can be used as indicators of bone formation and turnover. The purpose of this study was to assess the activity of bone formation in patients with rheumatoid arthritis (RA) using S-BGP and S-PICP. The biochemical data were compared with data obtained from bone histomorphometry. METHODS--Concentrations of S-BGP and S-PICP were measured in 119 women with RA aged 30-66 years and 47 healthy female controls matched for age. Bone histomorphometry of iliac crest samples was performed in 107 patients with RA. RESULTS--Weak to moderate correlations between the serum markers and histological bone formation parameters were found. Concentrations of S-BGP and S-PICP were significantly decreased in patients with RA compared with the controls (S-BGP 7.2 (2.3) v 8.7 (2.1) micrograms/l; S-PICP 105 (32) v 117 (38) micrograms/l. The lowest values were found in patients with recent onset RA. CONCLUSIONS--These findings suggest that bone formation and bone remodelling are generally reduced in patients with RA.     

Serum levels of type I and III procollagen fragments in Paget's disease of bone

Patients with Paget's disease of bone were found to have elevated serum levels of type I procollagen carboxyterminal peptide (pColl-I-C) which correlated with other measurements of disease activity. The elevated levels of pColl-I-C decreased within hours after the injection of salmon calcitonin and within weeks after oral dichloromethylene diphosphonate treatment. The decrease in serum pColl-I-C after a single injection of salmon calcitonin was associated with a decrease in urinary hydroxyproline excretion, both of which rose toward pretreatment values within 7 h. The pColl-I-C levels remained normal for months after dichloromethylene diphosphonate therapy was discontinued. Using a RIA for the type III procollagen amino-terminal peptide (pColl-III-N), it was found that serum levels were also elevated in patients with Paget's disease. The levels of pColl-III-N also decreased after the injection of salmon calcitonin, but not to the same extent as those of pColl-I-C. After chronic therapy with dichloromethylene diphosphonate, serum levels of pColl-III-N decreased, but not into the normal range. We postulate that whereas pColl-I-C is derived from synthesis of mineralized bone collagen, pColl-III-N is derived from the loose fibrous stroma replacing marrow in areas closely associated with active Pagetic bone disease.     

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.     

Increased levels of amino terminal propeptide of type III procollagen are an unfavourable predictor of survival in systemic sclerosis

OBJECTIVE: Investigation of the impact on survival of inflammatory parameters (C-reactive protein, ESR), markers of immune activation (serum soluble IL-2 receptor, soluble CD30), and N-terminal propeptide of type III procollagen levels (PIIINP) in systemic sclerosis (SSc). METHODS: In a prospective follow up study, clinical and laboratory data of 80 patients with SSc were evaluated. Kaplan-Meier survival curves and Cox proportional hazards model were used. Eighty cases with SSc were evaluated. Female/male ratio was 8/72. The mean (+/-SD) age was 49.3 (+/-12.3) years, 16 patients died during our mean follow up of 58.1 months. RESULTS: In the univariate analysis, the presence of a C-reactive protein level above 20 mg/l was an unfavourable prognostic sign (p<0.001). Increased level of PIIINP level also caused an unfavourable outcome of disease (p<0.001). Conversely, increased ESR, soluble IL-2 receptor, soluble CD30 levels, presence of anaemia, did not influence the prognosis. Male gender (p<0.005), diffuse cutaneous SSc, clinically significant lung involvement (p<0.001), kidney (p<0.0001), cardiac (p<0.05) manifestations including pericarditis (p<0.02) were unfavourable prognostic signs by univariate Kaplan-Meier method. Multivariate analysis by Cox proportional hazards model showed that the increased level of PIIINP (RR: 6.98), and presence of diffuse cutaneous SSc (RR: 5.14) were independent unfavourable prognostic signs. CONCLUSIONS: An increased collagen metabolism unfavourably influences the outcome of SSc. This parameter may also be a potential candidate as a disease activity marker.     

Is measurement of type III procollagen amino propeptide useful in primary biliary cirrhosis?

We have examined the value of serum type III procollagen amino propeptide (PIIINP) measurement both in evaluation of disease activity and in estimation of prognosis in primary biliary cirrhosis (PBC). 55 paired sera from 32 PBC patients not receiving treatment known to affect PIIINP levels not with non-hepatic inflammatory conditions were used to estimate serum PIIINP by radioimmunoassay. Significant correlations were found between serum PIIINP and serum albumin (P less than 0.001), bilirubin (P less than 0.002) and aspartate transaminase (P = 0.01). The mean serum PIIINP level rose with advancing histological stage (P less than 0.001). In 18 patients in whom more than 1 serum was assayed (mean follow-up 42 months) PIIINP often fell, particularly in patients with established cirrhosis and advanced disease. The independent prognostic value of PIIINP was examined using Cox's proportional hazards model with three other prognostic co-variables (bilirubin, albumin, patient age). Stepwise regression analysis selected albumin (P less than 0.001) and bilirubin (P = 0.002) as the most important prognostic factors. PIIINP did not give independent prognostic information. We conclude that PIIINP is another marker of disease activity in PBC which confers no benefit over existing conventional measurements in routine management of this disease.     

Serum levels of carboxy-terminal propeptide of human type I procollagen are an indicator for the progression of diabetic nephropathy in patients with type 2 diabetes mellitus

The finding that glomerular mesangial cells produce human type I collagen suggests that the serum levels of carboxy-terminal propeptide of human type I procollagen (P1CP) may reflect the severity of diabetic nephropathy. We therefore investigated the relationship between serum P1CP levels and the extent of diabetic complications in 100 patients (46 males and 54 females) with Type 2 diabetes and in 64 healthy subjects. Serum P1CP was determined by radioimmunoassay. In diabetes, we defined P1CP levels less than 142 ng/ml as a normal P1CP group (group A), whereas we defined them as equal to or greater than 142 ng/ml as a high P1CP group (group B). The diabetic patients had significantly elevated serum P1CP levels compared with the controls. The prevalence of hypertension, proliferative diabetic retinopathy or macroalbuminuria was significantly higher in group B than in group A. Serum P1CP levels showed a significant positive correlation with urinary albumin excretion, but not with fasting blood glucose, glycosylated hemoglobin A(1c) or serum osteocalcin. Macroalbuminuric patients showed significantly higher P1CP levels than the normoalbuminuric patients. In patients in the absence of diabetic nephropathy, no significant differences of P1CP levels were found among the severity of diabetic retinopathy. The present results suggest that serum P1CP levels reflect the progression of diabetic nephropathy in patients with Type 2 diabetes.     

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.     

Is the aminoterminal propeptide of type III procollagen degraded in the liver? A study of type III procollagen peptide in serum during liver transplantation in pigs

The aminoterminal propeptide of type III collagen was monitored in serum during liver transplantation in nine pigs. The aim was to investigate whether removal of the liver causes any changes in the serum concentration of the propeptide. Another connective tissue component, hyaluronan, a glycosaminoglycan known to be degraded in the liver endothelial cells, was also measured. Removal of the liver caused a significant increase in the concentration of the intact propeptide as well as of hyaluronan. Gel filtration confirmed the increase in the amount of intact propeptide. However, another large propeptide-related antigen, eluted near the void volume, appeared in the antigen profile during the anhepatic phase. This peak probably represents the propeptide still attached to the collagen molecule (pN collagen). The findings indicate that the liver is involved in the degradation of the propeptide and of larger propeptide-holding proteins.     

Serum concentrations of N-terminal propeptide of type III procollagen and laminin in the outflow of fibrotic livers compared with liver-distal regions

The immunoreactive serum concentrations of the basement membrane glycoprotein laminin, including its split product (pepsin-resistant fragment P1), and of the aminoterminal propeptide of type III procollagen, were measured in liver outflow (hepatic vein) and in liver-distal venous (renal vein) and arterial (femoral artery) regions in liver cirrhotic and fibrotic patients (n = 40). In the majority of patients with liver fibrosis and cirrhosis (0.52 to 0.69) the relatively highest concentrations of laminin (2.09 U/ml, p less than 0.05) and of procollagen propeptide (28.5 ng/ml, p less than 0.001) were found in the hepatic vein. No significant correlations were observed between the concentrations of the two biomatrix proteins in either region of the circulation, but a highly positive statistical correlation (r = 0.9425) was found between the level of laminin in the hepatic vein of cirrhotic subjects and portal venous pressure. The respective correlations were lower for laminin measured in the renal vein and the femoral artery. The concentration of procollagen propeptide was statistically not related to the portal venous pressure.