Serum levels of YKL-40 and PIIINP as prognostic markers in patients with alcoholic liver disease

BACKGROUND/AIMS: YKL-40 (growth factor) and PIIINP (N-terminal propeptide of Type III procollagen) are potential markers of liver fibrosis. The aim was to evaluate the prognostic value of serum YKL-40 and PIIINP levels in patients with alcoholic liver disease. METHODS: Three hundred and seventy patients with alcoholic liver disease were studied in a trial of malotilate with a median follow-up period of 470 days; 75 patients died; 336 patients had a liver biopsy on entry. Serum levels of YKL-40 and PIIINP were determined by radioimmunoassay (RIA). RESULTS: Serum YKL-40 and PIIINP were elevated in the patients compared to controls. Patients with steatosis or no fibrosis had the lowest serum levels of YKL-40 and PIIINP, whereas patients with alcoholic hepatitis and/or cirrhosis had the highest levels. Serum YKL-40 was associated with the presence of fibrosis, and serum PIIINP was also associated with the different grades of fibrosis. Patients with elevated serum YKL-40 or PIIINP had shorter survival than patients with normal serum levels of YKL-40 (P<0.0001) or PIIINP (P=0.044). High degree of fibrosis predicted shorter survival (P=0.004). CONCLUSIONS: Serum levels of YKL-40 and PIIINP are elevated in alcoholic patients, related to the presence of liver fibrosis and may provide prognostic information.     

Comparison of assays for N-amino terminal propeptide of type III procollagen in chronic hepatitis C by using receiver operating characteristic analysis.

OBJECTIVE: During the process of liver fibrosis, type III procollagen is converted to type III collagen by cleavage of its amino terminal and carboxy terminal propeptides. Serum levels of amino terminal propeptide of type III procollagen (PIIINP) are a marker of collagen turnover in liver fibrosis. Two assays for PIIINP are available, one which measures both Col 1-3 (collagen synthesis) and Col 1 (collagen degradation) peptides, and one which measures Col 1-3 only. Using receiver operating characteristic analysis, the two PIIINP assays were compared with serum ALT as markers of liver disease in chronic hepatitis C. METHODS: Serum PIIINP was measured using both assays in 33 patients with chronic hepatitis C and five healthy controls. Liver biopsies in chronic hepatitis C patients were scored using a previously described grading and staging system. RESULTS: Serum PIIINP was significantly elevated in chronic hepatitis C compared to controls using both the combined Col 1-3 and Col 1 (median 0.61 vs 0.33 U/ml, P=0.001) and Col 1 assays (median 6.5 vs 3.5 microg/l, P=0.006). Serum PIIINP measured by the combined assay was significantly related to liver fibrosis, periportal necrosis and histological activity index (P<0.05). The area under the curve for specificity and sensitivity in detecting advanced liver disease was only significant for the combined assay (P=0.017). Serum PIIINP measured by the Col 1 assay was not related to these indices of disease severity while serum ALT was only related to portal inflammation. CONCLUSION: A serum PIIINP assay which measures both Col 1-3 and Col 1 peptides instead of Col 1-3 peptide alone is more predictive of severity of liver disease and should be used in preference as a non-invasive marker of liver injury in chronic hepatitis C.     

Increased serum procollagen III aminoterminal peptide in myelofibrosis

Myelofibrosis has been shown to involve an increase in type III collagen in the marrow. The aminoterminal procollagen III (PC III) peptide fragment is released during the production of PC III by fibroblasts and its serum level is therefore a marker for type III collagen synthesis. Using a recently developed sensitive radioimmunoassay, serum levels of PC III peptide were measured in 30 patients with myeloproliferative disease and 23 normal volunteers. Levels were found to be elevated above normal values in patients with polycythemia vera, even more elevated in patients with polycythemia and evidence of secondary myelofibrosis with myeloid metaplasia, and most strikingly elevated in patients with agnogenic myeloid metaplasia and severe marrow fibrosis. There was a significant association between serum levels of PC III peptide and the extent of reticulin fibrosis in bone marrow biopsies. Serum PC III level appears to be a quantitative marker for myelofibrosis.     

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.     

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.     

Serum procollagen type III is an early and sensitive marker for veno- occlusive disease of the liver in children undergoing bone marrow transplantation

Veno-occlusive disease of the liver (VOD) is a life-threatening complication occurring in patients undergoing bone marrow transplantation (BMT). Although clinical signs and laboratory parameters such as elevation of serum bilirubin often suggest this condition, it would be useful to identify early biochemical markers for VOD. Fibrous alterations in the hepatic venules and small lobular veins occur during development of VOD; these changes are accompanied by the deposition of types I and III collagen in the liver tissue. Since the N- terminal propeptide of type III procollagen (PIIINP) is a sensitive marker of liver and lung fibrosis, we undertook a study to evaluate the usefulness of measurements of serum PIIINP in children with VOD. Seven of the 28 children who underwent BMT, both allogenic and autologous, developed VOD. All seven had an increase of more than 100 ng/mL in the serum PIIINP level, whereas only one of the remaining 21 children not affected by VOD had an increment of PIIINP more than 100 ng/mL (P = .0001). The levels of serum PIIINP were higher in the VOD group during the follow-up period of up to 91 days after BMT. The elevation of PIIINP also occurred at a stage of the disease usually preceding any other laboratory or clinical signs of VOD. Serum concentration of PIIINP thus seems to be of value as an early marker for VOD in children undergoing BMT.     

Monitoring of multiple myeloma and bone marrow fibrosis with aminoterminal propeptide of type III collagen (PIIINP)

Bone marrow fibrosis is known in myelomatosis and depends on the extent of plasma cell infiltration. The serum concentration of the aminoterminal propeptide of type III procollagen (PIIINP) has previously been reported to reflect fibrogenesis in the marrow in myelofibrosis. Here we followed 15 consecutive patients with newly diagnosed multiple myeloma with repeated PIIINP measurements during treatment with intermittent courses of melphalan and prednisolone. PIIINP was found to change with clinical behaviour of the disease, nonresponders and patients with recurrent disease having elevated values and the values in responders decreasing to the normal level or remaining there. Collagen fibres in plasma cell infiltrates of biopsies from bone marrow or skeletal tumours of these patients stained heavily with antibodies against PIIINP. Our results suggest that PIIINP works as a noninvasive indicator of bone marrow fibrogenesis. In multiple myeloma PIIINP is a sensitive, but not specific marker of disease course.     

Progression of fibrosis in hepatitis C with and without schistosomiasis: correlation with serum markers of fibrosis

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.     

Different effects of thyroid disease on serum levels of procollagen III N-peptide and hyaluronic acid

Serum levels of procollagen III N-peptide (PIIINP) and hyaluronic acid (HA) reflect secretion of procollagen III and HA from fibroblasts, a cell type sensitive to thyroid hormones. Serum PIIINP and HA concentrations were measured in different thyroid function states, the former by two different assays, one detecting intact and aggregated PIIINP (PIIINP assay) and another detecting low mol wt degradation products of PIIINP as well (Fab-PIIINP assay). Two thirds of 28 hyperthyroid patients had elevated serum PIIINP values (mean, 192% in the PIIINP assay and 243% in the Fab-PIIINP assay) compared to age- and sex-matched controls (P less than 0.001). Normalization was seen after medical treatment (n = 16). In contrast, serum HA levels increased from 49 +/- 30 to 68 +/- 37 ng/mL (P less than 0.01) when a euthyroid state was achieved. Hypothyroid patients (n = 23) had increased serum HA levels (mean, 162%; P less than 0.05), which normalized after L-T4 treatment (71 +/- 50 before and 41 +/- 20 ng/mL after treatment (n = 16; P less than 0.02). L-T4 treatment also increased serum PIIINP levels significantly. Subjects with familial dysalbuminemic hyperthyroxinemia (n = 8), representing a situation with elevated circulating levels of T4 due to enhanced protein binding, and patients with nontoxic goiter with serum TSH levels ranging from 3.6-0.05 mU/L had normal serum levels of PIIINP and HA. Our data suggest that the secretion of procollagen III and that of HA from fibroblasts are influenced differently by thyroid hormones, since the secretion of procollagen III seems enhanced by thyroid hormones, whereas the secretion of HA seems reduced. Neither euthyroidism with enhanced serum T4 levels (familial dysalbuminemic hyperthyroxinemia) nor euthyroidism with reduced serum TSH levels (nontoxic goiter) seems associated with alterations at the connective tissue level.     

Type III procollagen N-peptide correlates with β-2-microglobulin in myelomatosis

Summary The serum concentration of the N-terminal peptide of type III procollagen (PIIINP) was determined in 32 patients with myelomatosis (MM). Four subjects were studied at the time of diagnosis and the remaining patients at variable intervals from diagnosis. Serum concentration of beta-2-microglobulin (B2m) was measured in 31 patients. Serial measurements of both substances were performed in 20 patients. Serum PIIINP was increased in MM as compared with healthy control subjects (P < 0.001). Patients with active disease had significantly higher propeptide values (median 7.4; range 3.8–11.2) as compared to those with stable disease (median 4.3; range 2.2–9.6) (P < 0.009). A highly significant correlation existed between circulating PIIINP and B2m (P < 0.001). It is concluded that MM elicits a stromal reaction as reflected by parallel increases in serum PIIINP and serum B2m. In subsets of patients, e.g. those with non-secretory myeloma and in patients with smouldering disease, serum PIIINP may even be superior to B2m as an indicator of disease activity.     

Connective tissue components in serum in multiple myeloma: Analyses of propeptides of type I and type III procollagens,type I collagen telopeptide,and hyaluronan

The present study was performed to evaluate whether information concerning synthesis and degradation of type I collagen in multiple myeloma (MM) as obtained by serum analyses of C-terminal propeptide of type I procollagen (PICP) and the C-terminal telopeptide of type I collagen (ICTP) may be useful in evaluating the development of osteolytic bone destruction. Serum N-terminal propeptide of type III procollagen (PIIINP) may give information about marrow fibrosis in MM. No data are available about MM and serum hyaluronan, another important component of bone marrow stroma. We examined 15 consecutive patients before treatment and 15 sex- and age-matched controls. We found highly significant elevations in serum ICTP (median 6.2 vs. 2.4 μg/L; P < 0.01), PIIINP (median 5.2 vs. 2.9 μ/L; P < 0.01) and hyaluronan (median 122 vs. 45 μ/L; P < 0.01). ICTP in serum correlated closely to bone morbidity (r = 0.69; P < 0.01). Furthermore, serum ICTP correlated highly significantly to serum PIIINP (P < 0.01) and serum β₂-microglobulin (P < 0.01), whereas there was no correlation between hyaluronan and any of the collagen-derived peptides or β₂-microglobulin. The MM group was followed for 9–25 months and analysis of survival data suggested that serum ICTP may be of predictive value (P < 0.05). We conclude that important changes in connective tissue metabolism occur in MM. ICTP in serum seems to be a noninvasive marker of bone morbidity and may be of prognostic value. Furthermore, elevation of hyaluronan in serum is common in MM, the significance of which is unknown. © 1994 Wiley-Liss, Inc.     

Circulating collagen metabolites in systemic sclerosis. Differences between limited and diffuse form and relationship with pulmonary involvement

OBJECTIVE: To study collagen metabolites in systemic sclerosis (SSc) and their relationship with clinical manifestations of the disease. METHODS: Forty-eight SSc patients, 13 with a diffuse form (dcSSc), 23 with a limited form (lcSSc) and 12 with suspected SSc not fulfilling the ACR criteria, and 31 healthy controls were examined. Serum concentrations of aminoterminal type III procollagen peptide (PIIINP), aminoterminal and carboxyterminal type I procollagen peptides (PINP and PICP) and cross-linked carboxyterminal telopeptide of collagen I (ICTP) were determined by radioimmunoassay. RESULTS: Increased serum concentrations of ICTP were found in SSc patients compared with controls. Distinctly higher levels of ICTP were observed in dcSSc than in lcSSc. High serum ICTP was correlated with skin score and acute phase reactants, and with reduced pulmonary function. Serum PIIINP concentration was elevated in both lcSSc and dcSSc. CONCLUSION: Augmented collagen catabolism accompanies the increased collagen synthesis in SSc. Serum ICTP concentration is a marker of this feature and also reflects clinical severity.     

Changes in serum tissue inhibitor of matrix metalloproteinase-1 after interferon alpha treatment in chronic hepatitis C

BACKGROUND/AIMS: The aim of this study was to evaluate the effect of interferon alpha on the metabolism of hepatic fibrosis in chronic hepatitis C, monitoring serum tissue inhibitor of matrix metalloproteinase-1(TIMP-1) and N-terminal propeptide of type III procollagen (PIIINP) reflecting fibrolysis and fibrogenesis, respectively. METHODS: Serum levels of TIMP-1 and PIIINP were serially measured in 112 treated and 31 untreated patients with chronic hepatitis C during and after interferon alpha treatment. Furthermore, the relationships between these serum markers and the grades of hepatic fibrosis after interferon therapy were also investigated. RESULTS: Serum pretreatment levels of TIMP-1 and PIIINP in non-responders were significantly higher than those in sustained and transient responders, but these levels were not different in the latter two groups. Serum TIMP-1 levels decreased significantly during and after treatment in sustained responders, and decreased temporarily at the end of treatment in transient responders, although these levels were unchanged during and after treatment in non-responders and untreated patients. In contrast, serum PIIINP levels decreased significantly during and after treatment in all treated groups, but were unchanged in untreated patients. Histological examination 12 months after interferon was completed demonstrated that hepatic fibrosis improved in sustained responders and was unchanged in transient and non-responders, but progressed in untreated patients. CONCLUSION: These results suggest that interferon alpha treatment of chronic hepatitis C may improve hepatic fibrosis in sustained responders by the acceleration of fibrolysis as well as the inhibition of fibrogenesis, and that it may suppress the progression of hepatic fibrosis in non-sustained responders by the inhibition of fibrogenesis.     

Serum Type I Collagen Propeptide and Severity of Alcoholic Liver Disease

We assessed the relationship of serum type I collagen propeptide concentrations with various severity indices of alcoholic liver disease, including clinical and morphological severity, the amount of alcohol consumption, and the serum levels of other components of connective tissue. The serum concentration of the carboxyterminal propeptide of type I procollagen (PICP) was measured with a new radioimmunoassay that is devoid of a crossreaction caused by type III procollagen-derived fragments. A significant correlation was found between serum PICP and the Combined Clinical and Laboratory Index (CCLI) (rs = 0.58, p < 0.001) and the Combined Morphological Index (CMI) (rs = 0.57, p < 0.01). However, PICP was elevated less frequently than serum type III collagen propeptide (PIIINP), type IV collagen or laminin, and the correlations with the latter three parameter with both the CCLI (PIIINP: rs = 0.80, type IV collagen: rs = 0.80; and laminin: rs = 0.81) or CMI (PIIINP: rs = 0.75, type IV collagen: rs = 0.72; and laminin rs = 0.61) were all stronger than that of PICP. Furthermore, although during a follow-up period of 6 months, the mild or moderately drinking patients had a significant decrease in PIIINP and the heavily drinking patients had no improvement. PICP was, however, found to improve in both the mild and heavy drinkers. These results point to differences in handling of type I and type III collagen propeptides in alcoholic liver disease. The latter appears to be a more sensitive indicator of disease severity, presence of alcoholic hepatitis, and the amount of alcohol intake.     

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 levels of aminoterminal type III procollagen peptide and hyaluronan predict mortality in systemic sclerosis.

Systemic sclerosis (SSc) is characterized by an excessive accumulation of collagen in skin and internal organs and increased serum concentrations of different connective tissue metabolites have been reported. In this study of 82 patients with SSc, serum concentrations of aminoterminal type III procollagen peptide (PIIINP), smaller PIIINP-related antigens (Fab PIIINP) and hyaluronan (HA) were increased as compared to healthy controls matched for age and sex. Patients with a shorter disease duration (less than 3 years) had higher serum levels of PIIINP and Fab PIIINP than patients with a longer disease duration. The highest serum concentrations of PIIINP and HA were seen in seven patients who died within 2 years.     

ROC curves in evaluation of serum fibrosis indices for hepatic fibrosis

AIM:Use Receiver operating characteristic(ROC) curves to find out the relationship between serum level of hyaluronic acid(HA),typeⅢ procollagen (PCⅢ）,N-terminal procollagen Ⅲ peptied(PⅢNP),iaminin(LN),type Ⅳ collagen(C-Ⅳ）and hepatic fibrosis,as well as to determined their value in clinical practice.     

Evaluation of procollagen III peptide as a marker of tissue hyperthyroidism in long-term treated women with TSH suppressive doses of thyroxine.

Increased serum concentrations of the aminoterminal propeptide of collagen III (PIIINP) are found in overt hyperthyroidism. Thus, measurement of serum PIIINP might be useful as an early marker of tissue hyperthyroidism in patients with TSH suppressive thyroxine treatment. In a prospective study we evaluated female patients followed in the thyroid outpatient clinic. Serum PIIINP concentrations were analysed in three groups: patients with TSH suppressive thyroxine treatment for more than 6 months (n = 33, TSH < 0.1 mU/l), patients with thyroxine substitution for hypothyroidism for more than 6 months (n = 20, TSH 0.2-4.0 mU/l) and spontaneous hyperthyroid patients (n = 8, TSH < 0.03 mU/l, increased freeT4 and/or T3). Beside TSH, thyroid hormones and serum PIIINP we measured serum SHBG and a clinical score. Hyperthyroid patients had clearly elevated serum PIIINP and SHBG values and a higher clinical score when compared with other study groups (p < 0.001). Patients with TSH suppressive thyroxine treatment had higher fT4 and T3 concentrations than the thyroxine substitution group (fT4 22 +/- 4.8 pmol/l vs. 17 +/- 2.6 pmol/l, T3 2.2 +/- 0.4 nmol/l vs. 1.8 +/- 0.3 nmol/l, p < 0.001) and also elevated serum SHBG values (77.6 +/- 27.5 nmol/l vs. 58.4 +/- 18 nmol/l, p < 0.01). However, serum PIIINP concentrations and the clinical score were very similar in both thyroxine treated groups (PIIINP in TSH suppression group 3.0 +/- 0.67 microg/l vs. 2.8 +/- 0.65 microg/l in the substitution group, clinical score 2 +/- 1.8 pts. vs. 1.7 +/- 1.5 pts. p = n.s.). In conclusion, serum PIIINP is not a reliable early marker for detection of tissue hyperthyroidism in long-term thyroxine treated women with suppressed TSH.     

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.