Cross-Linked Multimeric Pro-Peptides of Type III Collagen (PC3X) in Hepatocellular Carcinoma - A Biomarker That Provides Additional Prognostic Value in AFP Positive Patients.

PURPOSE: Non-invasive biomarkers for diagnosing and prognosing hepatocellular carcinoma (HCC) are urgently needed. Cirrhosis is present in 80-90% of HCC patients. Cirrhosis is characterized by deposition and cross-linking of collagens that have crucial roles in HCC initiation and progression. We evaluated circulating cross-linked pro-peptides of type III collagen (PC3X) as a diagnostic and prognostic biomarker for HCC. PATIENTS AND METHODS: PC3X was measured by ELISA in plasma from patients with HCC (n=79), cirrhosis (n=86), non-cirrhotic hepatitis-B infection (n=74) and from healthy controls (n=44). PC3X was compared to the liver fibrosis marker PRO-C3 and the HCC tumor-cell derived marker alpha-fetoprotein (AFP). Diagnostic and prognostic potential was evaluated by AUROC and by calculating hazard ratios (HR) for progression-free survival (PFS) and overall survival (OS). RESULTS: PC3X, PRO-C3 and AFP were significantly elevated in patients with HCC compared to other liver diseases and healthy controls (p=0.0002, p<0.0001). In patients with normal AFP (<20 IU/mL), PC3X and PRO-C3 separated HCC from cirrhosis with an AUROC of 0.72 and 0.68, respectively. High PC3X and AFP predicted for poor PFS (HRPC3X=1.80, p=0.032; HRAFP=1.70, p=0.031) and OS (HRPC3X=2.12, p=0.024; HRAFP=2.55; p=0.003), whereas PRO-C3 did not (PFS: HR=1.19, p=0.059 and OS: HR=1.12, p=0.324). PC3X was independent of AFP (PFS: HR=1.74, p=0.045 and OS: HR=2.21, p=0.018) and combining the two improved prognostic value (PFS: HR=2.66, p=0.004 and OS: HR=5.86, p<0.0001). CONCLUSION: PC3X is associated with HCC independent of AFP and provides diagnostic and prognostic value for HCC patients. If validated, this suggests that PC3X has biomarker potential for HCC.

Endotrophin, a pro-peptide of Type VI collagen, is a biomarker of survival in cirrhotic patients with hepatocellular carcinoma.

AIM: Type VI collagen, is emerging as a signaling collagen originating from different types of fibroblasts. A specific fragment of Type VI collagen, the pro-peptide, is also known as the hormone endotrophin. We hypothesized that this fibroblast hormone would be of particular relevance in cancer types with a high amount of fibrosis activity, namely for outcome in hepatocellular carcinoma (HCC) cirrhotic patients. PATIENTS & METHODS: Plasma C6M, PRO-C6 and alphafeto-protein (AFP) were assessed in 309 patients with mixed etiologies (hepatitis C, hepatitis B, alcohol and nonalcoholic fatty liver) diagnosed as cirrhotics, cirrhotics with HCC, noncirrhotics and healthy controls. Progression-free survival and overall survival (OS) data were collected up to 6120 days after diagnosis. The ability of each marker to predict survival was investigated. RESULTS & CONCLUSION: The level of endotrophin assessed by PRO-C6 was able to separate healthy controls, noncirrhotics and cirrhotics from HCC (p < 0.05-0.0001). Both endotrophin and C6M provided value in the prediction of OS in cirrhotic patients with HCC. In the multivariate analysis for identifying HCC, in patients with high endotrophin (highest quartile) and that were positive for AFP (≥20 IU/ml), the hazard ratio for predicting OS was increased from 3.7 (p = 0.0006) to 14.4 (p = 0.0001) when comparing with AFP positive as a stand-alone marker. In conclusion, plasma levels for markers of Type VI collagen remodeling were associated with survival in cirrhotic patients with HCC. A combination of AFP with endotrophin improved the prognostic value compared with AFP alone for predicting OS in cirrhotic patients with HCC.

Prominent subcutaneous oedema as a masquerading symptom of an underlying inflammatory myopathy.

The inflammatory myopathies are a group of immune-mediated inflammatory muscle disorders that typically present with marked proximal muscle weakness. We report four cases of inflammatory myopathies with marked subcutaneous oedema as their main complaint. Three of the four patients had normal or low levels of creatine kinase, an enzyme often markedly elevated in these disorders. Magnetic resonance imaging of the muscles, followed by a muscle biopsy were used to make a definitive diagnosis.

Midkine Increases Diagnostic Yield in AFP Negative and NASH-Related Hepatocellular Carcinoma.

UNLABELLED: Robust biomarkers for population-level hepatocellular carcinoma (HCC) surveillance are lacking. We compared serum midkine (MDK), dickkopf-1 (DKK1), osteopontin (OPN) and AFP for HCC diagnosis in 86 HCC patients matched to 86 cirrhotics, 86 with chronic liver disease (CLD) and 86 healthy controls (HC). Based on the performance of each biomarker, we assessed a separate longitudinal cohort of 28 HCC patients, at and before cancer diagnosis. Serum levels of MDK and OPN were higher in HCC patients compared to cirrhosis, CLD and HC groups. DKK1 was not different between cases and controls. More than half of HCC patients had normal AFP. In this AFP-negative HCC cohort, 59.18% (n = 29/49) had elevated MDK, applying the optimal cut-off of 0.44 ng/ml. Using AFP ≥ 20 IU/ml or MDK ≥ 0.44 ng/ml, a significantly greater number (76.7%; n = 66/86) of HCC cases were detected. The area under the receiver operating curve for MDK was superior to AFP and OPN in NASH-HCC diagnosis. In the longitudinal cohort, MDK was elevated in 15/28 (54%) of HCC patients at diagnosis, of whom 67% had elevated MDK 6 months prior. CONCLUSION: AFP and MDK have a complementary role in HCC detection. MDK increases the diagnostic yield in AFP-negative HCC and has greater diagnostic performance than AFP, OPN and DKK-1 in the diagnosis of NASH-HCC. Additionally, MDK has a promising role in the pre-clinical diagnosis of HCC.

Visceral adiposity in gastrointestinal and hepatic carcinogenesis.

There is emerging evidence that the association between obesity and cancer is mediated by visceral rather than generalised body fat. Visceral fat has been directly implicated in the risk and progression of several gastrointestinal cancers including colorectal, oesophageal, pancreatic and hepatocellular carcinomas. Excess visceral adipose tissue induces a state of chronic systemic inflammation and altered metabolic activity that promotes a pro-oncogenic environment. This review examines the evidence linking visceral fat in gastrointestinal and hepatic carcinogenesis and explores our current understanding of the mechanisms underlying this relationship.

Non-alcoholic fatty liver disease-related hepatocellular carcinoma: a sleeping tiger in the Asia Pacific.

The epidemiology of hepatocellular carcinoma (HCC) in the Asia Pacific will undergo significant change over the next few decades as the prevalence of viral hepatitis declines and the burden of metabolic diseases increases. As the Asia Pacific embraces continued affluence, obesity and diabetes rates are burgeoning, becoming increasingly important to the incidence of HCC. Obesity and diabetes are established risk factors for HCC, either as substrates for non-alcoholic fatty liver disease (NAFLD) or as independent carcinogens themselves. This review summarises the epidemiological data on changing HCC trends in the Asia Pacific, particularly as it pertains to the emerging problem of NAFLD-related HCC.

Visceral adiposity index is not a predictor of liver histology in patients with non-alcoholic fatty liver disease.

BACKGROUND & AIMS: Visceral adiposity is associated with hepatic steatosis, inflammation, and fibrosis in non-alcoholic fatty liver disease (NAFLD). The visceral adiposity index (VAI), a novel marker of visceral fat distribution and dysfunction, has been correlated with histology in hepatitis C. We assessed the ability of VAI to predict disease severity in NAFLD and hence its role as a non-invasive marker of liver damage. METHODS: We examined 190 adults with biopsy-proven NAFLD and 129 controls. All had anthropometric and metabolic profiling. VAI was calculated using waist circumference (WC), body mass index, triglycerides, and HDL-cholesterol. Abdominal fat was quantified by magnetic resonance imaging (MRI) in 38 patients. RESULTS: On multivariate analysis, NAFLD diagnosis and fasting glucose were independently associated with VAI (p <0.05). VAI increased across control, steatosis, and NASH groups (1.5, 2.3, and 3.2, respectively; p=0.000), however, this association was no stronger than the increase in WC across groups (r=0.452 vs. 0.540 respectively, p <0.001). VAI was not associated with steatosis, lobular inflammation or fibrosis, but WC was associated with fibrosis (p=0.01). VAI and WC correlated with an increasing number of metabolic syndrome components (r=0.623 vs. 0.614, p <0.001) and with metabolic syndrome diagnosis (r=0.559 vs. 0.509, p <0.001). VAI only modestly correlated with visceral fat on MRI (r=0.39, p <0.05) compared to WC (r=0.52, p <0.01). CONCLUSIONS: In NAFLD, VAI is not associated with steatosis, inflammation or fibrosis. VAI is no more powerful than WC in discriminating steatosis from steatohepatitis, reflecting limitations of the formula with what is known about the pathogenesis of NAFLD.