Bone disease in patients with cirrhosis of different etiology and severity; are Klotho protein and osteoprotegerin potential biomarkers?

BACKGROUND AND AIMS: Cirrhosis is associated with increased risk for osteoporosis and osteopenia. This study aims to further investigate this relationship by examining if etiology and severity of cirrhosis are independent predictors of bone mineral density (BMD) loss. Furthermore we examined the serum levels of osteoprotegerin (OPG) and Klotho proteins that have been involved in bone metabolism. METHODS: Seventy-four patients with cirrhosis of different etiology and 25 matched healthy controls were included in this study. Bone mineral densitometry at both lumbar spine and femoral neck was measured. Serum total OPG, Klotho protein and vitamin D levels were also determined. Comparisons were performed according to etiology and severity of cirrhosis. RESULTS: Decreased bone density was observed in cirrhotic patients compared to healthy controls with T = -1.46 and T = -1.37 in lumbar spine and femoral bone respectively compared to T = -0.396 and T = -0.672 in the control group. In the cirrhotic group, osteopenia was observed in 46% in lumbar spine and 51% in femoral bone whereas osteoporosis was observed in 20% in lumbar spine and 9% in femoral bone. Decreased bone density was confirmed, regardless of cirrhosis etiology or stage of liver function. Patients were found to have higher levels of OPG than the control group (136 pg/ml vs. 67 pg/ml, p < 0.001), but lower levels of Klotho protein (1051 pg/ml vs. 1842 pg/ml, p < 0.001) regardless etiology and severity of cirrhosis. High OPG levels were found to be associated with low femoral bone density. CONCLUSIONS: BMD is lower in cirrhotic patients regardless etiology and severity of liver disease with osteopenia and osteoporosis be present in 50% and 20%, respectively. Higher levels of OPG and lower levels of Klotho protein were observed in cirrhotic patients regardless etiology and severity in comparison to matched healthy group.

Clinical presentation, diagnosis, and survival in cholangiocarcinoma: A prospective study.

BACKGROUND AND STUDY AIMS: The diagnosis of cholangiocarcinoma (CCA) is difficult. The present study aimed to assess the clinical features, diagnosis, and survival in CCA. PATIENTS AND METHODS: This is a prospective study on 46 patients with CCA who underwent endoscopic retrograde cholangiopancreatography (ERCP) or surgical resection and 20 controls with a clinical and ERCP suspicion for CCA in whom surgical biopsy and/or 4-year follow-up showed a benign biliary stricture. RESULTS: The median age at presentation was 71years (range 44-88). Thirty-four patients (73.9%) presented with painless jaundice. Median CA 19-9 value was 188IU/L (range 1-49,138), with a level of <100IU/L in 13 patients (28%). Total bilirubin was 11.9 (0.6-36.3)mg/dL. The tumour was intrahepatic in 3 (6.5%), hilar (Klatskin) in 25 (54.3%), and located in the lower third of the bile duct in 18 (39.1%) patients. The diagnosis was confirmed by positive cytology in 10 (21.7%), biopsy in 20 (43.5%), cholangioscopy in five (10.9%), and imaging and clinical grounds in 11 (23.9%) patients. Cytology was feasible in 36 patients; it was positive in 10 and "highly indicative" in two patients (33.3% sensitivity). Twenty-two patients (47.8%) were treated by surgical resection, and the rest were offered palliative biliary drainage. Mean estimated survival for the entire group of CCA patients was 21.5±3.3months. Survival was slightly longer in patients who underwent surgical resection than those who had palliative treatment; the estimated mean survival rates were 26.2±4.2 vs. 17.1±3.3months, respectively, but the difference was not statistically significant (p=0.115). CONCLUSION: The diagnosis of CCA is difficult and often delayed. The outcome is generally poor.

Soluble CD146, a novel endothelial marker, is related to the severity of liver disease.

OBJECTIVES: Angiogenesis and inflammation have been involved in the progression of fibrosis in patients with chronic liver disease (CLD). Soluble CD146 (sCD146), a biomarker that was recently characterized as a novel component of the endothelial junction is implicated in endothelial proliferation. Our study evaluates the performance of sCD146 in assessing liver fibrosis and cirrhosis, and determines if its levels are related to the severity of liver disease in patients with cirrhosis. MATERIAL AND METHODS: sCD146 levels were determined by a commercially available immunoenzymatic technique in 62 consecutive patients with cirrhosis, 43 patients with CLD and 27 healthy controls. RESULTS: Patients with cirrhosis compared to non-cirrhotics with CLD had a higher median sCD146 concentration (639 vs. 317 ng/ml). In receiver operating characteristic (ROC) curve analysis, the cut-off of 412 ng/ml showed a sensitivity of 78% and a specificity of 75% for diagnosis of cirrhosis, offering good diagnostic accuracy (area under the ROC curve [AUROC: 0.838]). Patients with compensated compared to those with decompensated cirrhosis had a lower median sCD146 concentration (399 vs. 848 ng/ml, respectively). A cut-off of 534 ng/ml offered a sensitivity of 83% and a specificity of 78% for differentiating compensated from decompensated cirrhosis (AUROC: 0.866). Furthermore, in cirrhotics, sCD146 correlated positively with AST, bilirubin levels and most importantly with international normalized ratio and model for end-stage liver disease (r = 0.648, p < 0.001 and r = 0.567, p < 0.001, respectively). CONCLUSION: sCD146 can be used as a surrogate, inexpensive biomarker for the diagnosis of cirrhosis. It is also well correlated with severity of liver disease in cirrhotic patients. Further studies are needed to define its role in clinical practice.

Presence of spur cells as a highly predictive factor of mortality in patients with cirrhosis.

BACKGROUND AND AIM: The presence of spur-cell anemia (SCA) is due to lipid disturbances of the erythrocyte membrane and may develop in patients with advanced liver cirrhosis. The accurate predicting value of SC for survival has not been clarified. The aim of this study was to evaluate SCA as a prognostic indicator in patients with cirrhosis. METHODS: We prospectively evaluated clinical, laboratory parameters, and survival in patients with cirrhosis, with or without SCA, during the period 2008-2011. Patients who had at admission renal failure, other causes of hemolytic anemia, hepatocellular carcinoma, sepsis, and/or active bleeding, were excluded. One hundred sixteen patients with cirrhosis were included. The presence of SCA (SC rate higher or equal to 5% [≥ 5%]) was diagnosed in 36 (31%) patients. RESULTS: Patients with SCA compared to those without had more advanced liver disease (higher Model for End-Stage Liver Disease [MELD], P < 0.001), higher total bilirubin (P < 0.001), and International Normalized Ratio (P < 0.001). Patients with SCA had worse survival (log rank P < 0.001). Survival of patients with SCA at the first, second, and third month of follow-up was 77%, 45%, and 33%, respectively. In multivariate Cox's regression analysis, the presence of SCA was an independent predictor of mortality (hazard ratio = 3.17 [95% CI 1.55-6.48]). CONCLUSIONS: The presence of spur-cell anemia is not uncommon in cirrhosis and seems to be strongly associated with mortality. SCA can be used in combination with MELD as an additional predictor of early mortality.

An extended fluorescence in situ hybridization approach for the cytogenetic study of cholangiocarcinoma on endoscopic retrograde cholangiopancreatography brushing cytology preparations.

The cytological diagnosis of cholangiocarcinoma has been significantly aided by applying a 4-probe fluorescence in situ hybridization system on endoscopic retrograde cholangiopancreatography brushing smears, aiming mainly at the detection of hyperdiploidy. However, this approach adds little to our understanding of the genetic background of the disease. With the prospect of obtaining additional data on chromosomal aberrations, we have extended the fluorescence in situ hybridization study, with the application of 4 independent 2-probe systems in 35 patients with documented cholangiocarcinoma. Fluorescence in situ hybridization assays were performed on endoscopic retrograde cholangiopancreatography brushing smears, with probes for the 7q31, 11q13 (CCND1), 17p53 (TP53), and 9p21 (INK4 locus) bands, together with the respective centromeric probe. Hyperdiploidy, involving at least 2 of the 4 chromosomes targeted, was found in 31 patients. 17p13 deletion was detected in 3, and 9p21 deletion, in 5 of the hyperdiploid cases, with the 2 aberrations concurrent in 1. CCND1 amplification was found in 1 case as the sole abnormality and in another together with hyperdiploidy, but in apparently unrelated clones. This work indicates that interphase fluorescence in situ hybridization is a practical and useful tool for the cytogenetic study of cholangiocarcinoma on endoscopic retrograde cholangiopancreatography brushing smears, which is often the only available tissue specimen of the tumor. Apart from hyperdiploidy, it provides additional data on the genetic profile of cholangiocarcinoma, especially regarding structural chromosomal aberrations and clonal diversity. This line of investigation may prove useful in the delineation of oncogenesis and the interpretation of the diverse clinical features of the disease.

Sarcoid-like granulomatosis in patients treated with anti-TNFα factors. A case report and review of the literature.

This report describes a 56-year-old woman who developed granulomatous lesions consistent with sarcoidosis during adalimumab therapy for rheumatoid arthritis. Cervical and axillary lymphadenopathy developed approximately 21 months after adalimumab administration. Non-caseating epithelioid cell granulomas consistent with sarcoidosis were detected both in an axillary lymph node specimen and in the bone marrow. Diseases showing similar histologic changes, especially tuberculosis, were excluded, and a diagnosis of sarcoidosis was made. Adalimumab was discontinued, and recovery was observed. The current case is, to our knowledge, the first to describe adalimumab-induced non-caseating granulomas in lymph nodes and bone marrow without pulmonary involvement in a patient treated for rheumatoid arthritis.

A case of liver sarcoidosis mimicking cirrhosis.

Although autopsy series report liver granulomas in up to 70% of patients, computed tomography detection of hepatic and splenic lesions is described in 5% and 15% of sarcoidosis cases, respectively. A rather rare case of liver sarcoidosis mimicking macronodular cirrhosis is presented by this current article. Imaging findings in our patient were in compliance with the diagnosis of liver cirrhosis, although liver biopsy findings eventually revealed sarcoid granulomas located in the portal and lobular areas without fibrotic lesions. Histological and imaging modalities in liver sarcoidosis are discussed.

Hepatotoxicity induced by cyproterone acetate: a report of three cases.

Cyproterone acetate (CPA) is a steroidal synthetic progestagen and anti-androgenic compound widely administered in prostate cancer which has been evidentially correlated with a severe hepatotoxic potency. Three male patients aged 78-83 years are presented, in whom severe hepatotoxic reactions emerged after CPA administration. Patients were treated with CPA at the doses of 200-300 mg/d for malignant prostate disease for 3-12 mo prior to the acute manifestation of the hepatic disease. Clinical features compatible with mixed hepatocellular and cholestatic liver disease including jaundice, white stools and dark urine, manifested in all three cases whereas encephalopathy and ascites were present in two of the patients. Other primary causes of hepatotoxicity (alcohol consumption and viral hepatitis) were also verified in two cases, and in those patients biopsy findings revealed the presence of cirrhotic lesions in liver parenchyma. Discontinuation of the therapeutic agent led to the amelioration of the clinical profile in all the patients whereas a patient died 40 d after hospital admission due to sepsis, despite acute liver disease improvement. The current article highlights the hepatotoxic potency of a widely administered therapeutic agent and illustrates the importance of clinical surveillance especially in patients with previous hepatic diseases. Three relevant cases are reported and a review of the published literature is made.