Novel serum and bile protein markers predict primary sclerosing cholangitis disease severity and prognosis.

BACKGROUND & AIMS: Prognostic biomarkers are lacking in primary sclerosing cholangitis, hampering patient care and the development of therapy. We aimed to identify novel protein biomarkers of disease severity and prognosis in primary sclerosing cholangitis (PSC). METHODS: Using a bead-based array targeting 63 proteins, we profiled a derivation panel of Norwegian endoscopic retrograde cholangiography bile samples (55 PSC, 20 disease controls) and a Finnish validation panel (34 PSC, 10 disease controls). Selected identified proteins were measured in serum from two Norwegian PSC cohorts (n=167 [1992-2006] and n=138 [2008-2012]), inflammatory bowel disease (n=96) and healthy controls (n=100). RESULTS: In the bile derivation panel, the levels of 14 proteins were different between PSC patients and controls (p<0.05); all were confirmed in the validation panel. Twenty-four proteins in the bile derivation panel were significantly (p<0.05) different between PSC patients with mild compared to severe cholangiographic changes (modified Amsterdam criteria); this was replicated for 18 proteins in the validation panel. Interleukin (IL)-8, matrix metallopeptidase (MMP)9/lipocalin (LCN)2-complex, S100A8/9, S100A12 and tryptophan hydroxylase (TPH)2 in the bile were associated with both a PSC diagnosis and grade of cholangiographic changes. Stratifying PSC patients according to tertiles of serum IL-8, but not MMP9/LCN2 and S100A12, provided excellent discrimination for transplant-free survival both in the serum derivation and validation cohort. Furthermore, IL-8 was associated with transplant-free survival in multivariable analyses in both serum panels independently of age and disease duration, indicating an independent influence on PSC progression. However, the Enhanced Liver Fibrosis (ELF®) test and Mayo risk score proved to be stronger predictors of transplant-free survival. CONCLUSIONS: Based on assaying of biliary proteins, we have identified novel biliary and serum biomarkers as indicators of severity and prognosis in PSC. LAY SUMMARY: Prognostic biomarkers are lacking in primary sclerosing cholangitis, hampering patient care and the development of therapy. We have identified inflammatory proteins including calprotectin and IL-8 as important indicators of disease severity and prognosis in bile and serum from patients with primary sclerosing cholangitis.

Mortality from non-malignant diseases among male Norwegian asphalt workers.

BACKGROUND: The possible associations between asphalt work and mortality from non-malignant diseases in a cohort of male Norwegian asphalt workers that formed part of the European asphalt worker mortality study are examined. METHODS: The mortality experience among 8,610 male workers ever employed in asphalt work was observed from 01.01.1970 until 12.31.1996, yielding 127,636 person years of observation. The cause-specific deaths observed in the study cohort were compared with the expected figures calculated from 5-year period- and age-specific national death rates. A study-specific job exposure matrix was used for individual-individual exposure estimates. RESULTS: Eight hundred and three workers died during the observation period (SMR = 0.92, 95% confidence intervals (CI) = 0.58, 1.40). The mortality from non-malignant respiratory diseases was elevated (SMR = 1.25, 95%CI = 0.97, 1.58) and was associated with years since first employment in the asphalt industry. Mortality from respiratory diseases was highest among the workers first employed in the 1960s. Among the different job types held by the workers the pavers and mastic asphalt workers had the highest mortality from respiratory diseases. A weak dose-response was found with cumulative exposure to PAH and bitumen fume and mortality from non-malignant respiratory diseases in analyses employing the job-exposure matrix. Overall mortality, the mortality from circulatory diseases (SMR = 0.93, 95%CI = 0.83, 1.03) and external causes (SMR = 0.90, 95%CI = 0.72, 1.11) was lower than expected. CONCLUSIONS: Mortality from respiratory diseases was found somewhat elevated among the asphalt workers. There was some evidence of exposure-response with both bitumen fume and PAH exposure. PAH from coal tar contributes to the PAH exposure.

Cancer incidence among male Norwegian asphalt workers.

BACKGROUND: The main objective of the present study was to investigate whether exposure to bitumen fumes could enhance the risk of cancer in asphalt workers. METHODS: A historical prospective cohort study was performed including 8,763 male asphalt workers from all main asphalt companies in Norway. Name, date of birth, and unique personal identification number, address, job type, and start and stop of employment in specific jobs was obtained for the workers. Information was complied from payroll and personnel records in the companies. The cohort was then linked to the Cancer Registry of Norway, which has complete records of individual cases of cancer in the Norwegian population since 1953. Follow-up was from 1 January 1970 to 31 December 1997. The 5-year age and period adjusted general male population in Norway served as reference population. RESULTS: Lung cancer was found elevated with standardized incidence ratio (SIR) = 1.3 (95% confidence intervals (CI) = 1.1, 1.7) in the overall analysis. Lung cancer was found more elevated in workers first exposed in the 1950s and 1960s and in mastic asphalt workers (SIR = 4.2, 95% CI = 1.2, 10, based on four cases) and pavers (SIR = 1.4, 95% CI = 1.0, 1.9). There was a deficiency in the incidence of malignant melanoma with 13 cases versus 26 expected. CONCLUSIONS: Risk of lung cancer was found enhanced among the asphalt workers. Some of the enhanced risk could probably be explained by the smoking habits of the workers. Exposure to coal tar may also have contributed to the enhanced risk.