Chitinase 3-like 1 is a profibrogenic factor overexpressed in the aging liver and in patients with liver cirrhosis

Older age at the time of infection with hepatitis viruses is associated with an increased risk of liver fibrosis progression. We hypothesized that the pace of fibrosis progression may reflect changes in gene expression within the aging liver. We compared gene expression in liver specimens from 54 adult donors without evidence of fibrosis, including 36 over 40 y old and 18 between 18 and 40 y old. Chitinase 3-like 1 (CHI3L1), which encodes chitinase-like protein YKL-40/CHI3L1, was identified as the gene with the greatest age-dependent increase in expression in liver tissue. We investigated the cellular source of CHI3L1 in the liver and its function using liver tissue specimens and in vitro models. CHI3L1 expression was significantly higher in livers of patients with cirrhosis of diverse etiologies compared with controls represented by patients who underwent liver resection for hemangioma. The highest intrahepatic CHI3L1 expression was observed in cirrhosis due to hepatitis D virus, followed by hepatitis C virus, hepatitis B virus, and alcohol-induced cirrhosis. In situ hybridization of CHI3L1 messenger RNA (mRNA) identified hepatocytes as the major producers of CHI3L1 in normal liver and in cirrhotic tissue, wherein hepatocytes adjacent to fibrous septa showed higher CHI3L1 expression than did those in more distal areas. In vitro studies showed that recombinant CHI3L1 promotes proliferation and activation of primary human hepatic stellate cells (HSCs), the major drivers of liver fibrosis. These findings collectively demonstrate that CHI3L1 promotes liver fibrogenesis through a direct effect on HSCs and support a role for CHI3L1 in the increased susceptibility of aging livers to fibrosis progression.

It is well-established that the incidence of severe liver disease with rapid liver fibrosis progression in humans is increased in the elderly, although the underlying mechanisms remain to be elucidated (1). The role of age has been particularly well documented in patients with hepatitis C virus (HCV) infection, where age at the onset of infection was found to be a major determinant for fibrosis progression and disease severity in immunocompetent subjects (2–6). Likewise, donor age was shown to have a major impact on graft outcome after liver transplantation for end-stage HCV disease: When the donors were younger than 40, the interval to cirrhosis was 10 y, whereas when the donors were 41 to 50 or older, the intervals were 6.7 and 2.7 y, respectively (7). Collectively, these data suggest that age-related changes in liver response to injury play a key role in determining the increased susceptibility of the aging liver to fibrosis (2, 4, 7).We hypothesized that the different rate of liver fibrosis progression in patients over 40 y of age could reflect changes in gene expression in aging livers. To test this hypothesis, we studied a large series of liver specimens from 54 well-characterized liver transplant donors by comparing gene expression between liver donors less than and over 40 y of age. We identified chitinase 3-like 1 (CHI3L1) as the gene with the greatest age-dependent increase in expression. CHI3L1, also known as YKL-40 in humans, is a secreted glycoprotein of ∼40 kDa (8), which has been shown to play a critical role in a variety of human diseases associated with inflammation, tissue remodeling, and injury (9–12). A correlation between serum levels of CHI3L1 with aging was previously documented in a large cohort of healthy individuals in Denmark (13). Elevated levels of CHI3L1 in serum have also been reported as a biomarker of liver fibrosis in patients with chronic liver disease of any etiology (9, 12, 14–18). However, the mechanisms underlying the correlation between increased circulating CHI3L1 levels and liver fibrosis have not yet been determined. There is very limited information on the expression of CHI3L1 in primary liver tissue, since in most previous studies serum was the sole clinical material analyzed. Thus, in this study, we investigated the source of CHI3L1 and the mechanisms linking CHI3L1 with liver fibrosis by using primary liver tissue and in vitro models.     

Phenotypic study in 40 patients with dysferlin gene mutations: high frequency of atypical phenotypes

OBJECTIVE: To describe the phenotypic spectrum of dysferlin (DYSF) gene mutations (which cause dysferlinopathies, autosomal recessive muscular dystrophies) in patients with a dysferlin protein deficiency. DESIGN: Clinical, biological, and pathological data from 40 patients were reviewed. The diagnosis of dysferlinopathy was based on the absence or strong reduction of dysferlin in muscle, and confirmed by mutational screening of the DYSF gene. SETTING: Two French neuromuscular diseases centers (in Paris and Marseilles). RESULTS: Two main dysferlinopathy phenotypes are well recognized: Miyoshi myopathy and limb-girdle muscular dystrophy type 2B. Typical Miyoshi myopathy and limb-girdle muscular dystrophy type 2B were found in 20 (50%) patients only. Unusual phenotypes included a mixed phenotype, referred to as "proximodistal," combining distal and proximal onset in 14 (35%) patients, pseudometabolic myopathy in 4 (10%), and asymptomatic hyperCKemia (an increased serum creatine kinase level) in 2 (5%). The disease may worsen rapidly, and 10 (25%) patients were initially misdiagnosed as having polymyositis. We suggest a relationship between proximodistal phenotype, inflammation, and severity. CONCLUSION: In addition to typical Miyoshi myopathy and limb-girdle muscular dystrophy type 2B, dysferlinopathies are a clinically heterogeneous group of disorders ranging from asymptomatism to severe functional disability.     

Paradoxical brain embolism caused by an arterial−venous fistula: a diagnostic pitfall

The transesophageal echocardiography (TEE) and contrast-enhanced transcranial Doppler/Duplex ultrasonography (ceTCD) are complementary methods for diagnosing a right to left shunt across a patent foramen ovale. We report on a case of paradoxical embolism across a subclavian arterial–venous fistula. This case underlines the necessity of performing the ceTCD, as in this condition the right to left shunt could be detected by means of ceTCD, whereas the TEE reveals regular findings.