Background and Aims
Porto‐sinusoidal vascular liver disease (PSVD) is a rare cause of portal hypertension. PSVD is still often misdiagnosed as cirrhosis, emphasizing the need to improve PSVD ...diagnosis strategies. Data on liver stiffness measurement using transient elastography (TE‐LSM) in PSVD are limited. The aim of this study was to evaluate the accuracy of TE‐LSM to discriminate PSVD from cirrhosis in patients with signs of portal hypertension.
Approach and Results
Retrospective multicenter study comparing TE‐LSM in patients with PSVD, according to Vascular Liver Disease Interest Group criteria, with patients with compensated biopsy‐proven cirrhosis associated with alcohol (n = 117), HCV infection (n = 110), or NAFLD (n = 46). All patients had at least one sign of portal hypertension among gastroesophageal varices, splenomegaly, portosystemic collaterals, history of ascites, or platelet count < 150 × 109/L. The 77 patients with PSVD included in the test cohort had lower median TE‐LSM (7.9 kPa) than the patients with alcohol‐associated, HCV‐related, and NAFLD‐related cirrhosis (33.8, 18.2, and 33.6 kPa, respectively; P < 0.001). When compared with cirrhosis, a cutoff value of 10 kPa had a specificity of 97% for the diagnosis of PSVD with a 85% positive predictive value. A cutoff value of 20 kPa had a sensitivity of 94% for ruling out PSVD with a 97% negative predictive value. Of the patients, 94% were well‐classified. Even better results were obtained in a validation cohort including 78 patients with PSVD.
Conclusions
This study including a total of 155 patients with PSVD and 273 patients with cirrhosis demonstrates that TE‐LSM < 10 kPa strongly suggests PSVD in patients with signs of portal hypertension. Conversely, when TE‐LSM is >20 kPa, PSVD is highly unlikely.
The activating natural cytotoxicity receptor NKp30 is critical for natural killer (NK) cell function and tumor immune surveillance. The natural cytotoxicity receptor‐3 (NCR3) gene is transcribed into ...several splice variants whose physiological relevance is still incompletely understood. In this study, we investigated the role of NKp30 and its major ligand B7 homolog 6 (B7‐H6) in patients with hepatocellular carcinoma (HCC). Peripheral blood NK cell phenotype was skewed toward a defective/exhausted immune profile with decreased frequencies of cells expressing NKp30 and natural killer group 2, member D and an increased proportion of cells expressing T‐cell immunoglobulin and mucin‐domain containing‐3. Moreover, NKp30‐positive NK cells had a reduced expression of NCR3 immunostimulatory splice variants and an increased expression of the inhibitory variant in patients with advanced tumor, resulting in deficient NKp30‐mediated functionality. Tumor‐infiltrating lymphocytes showed a prevalent inhibitory NKp30 isoform profile, consistent with decreased NKp30‐mediated function. Of note, there were significant differences in the cytokine milieu between the neoplastic and the surrounding non‐neoplastic tissue, which may have further influenced NKp30 function. Exposure of NK cells to B7‐H6‐expressing HCC cells significantly down‐modulated NKp30, that was prevented by small interfering RNA–mediated knockdown, suggesting a role for this ligand in inhibiting NKp30‐mediated responses. Interestingly, B7‐H6 expression was reduced in HCC tissue and simultaneously augmented as a soluble form in HCC patients, particularly those with advanced staging or larger nodule size. Conclusion: These findings provide evidence in support of a role of NKp30 and its major ligand in HCC development and evolution.
Phosphatase and tensin homolog (PTEN) is a regulator of phosphoinositide 3‐kinase signaling and an important tumor suppressor mutated/deleted in human cancers. PTEN deletion in the liver leads to ...insulin resistance, steatosis, inflammation, and cancer. We recently demonstrated that unsaturated fatty acids trigger steatosis by down‐regulating PTEN expression in hepatocytes via activation of a mammalian target of rapamycin (mTOR)/nuclear factor kappa B (NF‐κB) complex, but the molecular mechanisms implicated in this process are still unknown. Here, we investigated potential genetic and epigenetic mechanisms activated by fatty acids leading to PTEN down‐regulation. Our results indicate that unsaturated fatty acids down‐regulate PTEN messenger RNA expression in hepatocytes through mechanisms unrelated to methylation of the PTEN promoter, histone deacetylase activities, or repression of the PTEN promoter activity. In contrast, unsaturated fatty acids up‐regulate the expression of microRNA‐21, which binds to PTEN messenger RNA 3′‐untranslated region and induces its degradation. The promoter activity of microRNA‐21 was increased by mTOR/NF‐κB activation. Consistent with these data, microRNA‐21 expression was increased in the livers of rats fed high‐fat diets and in human liver biopsies of obese patients having diminished PTEN expression and steatosis. Conclusion: Unsaturated fatty acids inhibit PTEN expression in hepatocytes by up‐regulating microRNA‐21 synthesis via an mTOR/NF‐κB–dependent mechanism. Aberrant up‐regulation of microRNA‐21 expression by excessive circulating levels of fatty acids exemplify a novel regulatory mechanism by which fatty acids affect PTEN expression and trigger liver disorders. (HEPATOLOGY 2009.)
Proteomic analysis of tissues has advanced in recent years as instruments and methodologies have evolved. The ability to retrieve peptides from formalin‐fixed paraffin‐embedded tissues followed by ...shotgun or targeted proteomic analysis is offering new opportunities in biomedical research. In particular, access to large collections of clinically annotated samples should enable the detailed analysis of pathologically relevant tissues in a manner previously considered unfeasible. In this paper, we review the current status of proteomic analysis of formalin‐fixed paraffin‐embedded tissues with a particular focus on targeted approaches and the potential for this technique to be used in clinical research and clinical diagnosis. We also discuss the limitations and perspectives of the technique, particularly with regard to application in clinical diagnosis and drug discovery.
Liver failure is the major cause of death in alcoholic steatohepatitis (ASH). In experimental hepatitis, granulocyte‐colony stimulating factor (G‐CSF) mobilizes hematopoietic stem cells, induces ...liver regeneration, and improves survival. We studied the short‐term effects of G‐CSF on CD34+ stem cell mobilization, liver cell proliferation, and liver function in patients with ASH. Twenty‐four patients (mean age 54 years) with alcoholic cirrhosis Child‐Turcotte‐Pugh score 10 (7–12) and concomitant biopsy‐proven ASH Maddrey score 36 (21‐60) were randomized to standard care associated with 5 days of G‐CSF (10 μg/kg/day, group A, n = 13) or standard care alone (group B, n = 11). Serial measurement of CD34+ cells, liver tests, cytokines hepatocyte growth factor (HGF); tumor necrosis factor α; tumor necrosis factor‐R1; interleukin‐6; alfa‐fetoprotein, and 13C‐aminopyrine breath tests were performed. Proliferating hepatic progenitor cells HPC; double immunostaining (Ki67/cytokeratin 7), histology, and neutrophils were assessed on baseline and day 7 biopsies. Abstinent alcoholic patients with cirrhosis served as controls for immunohistochemistry. G‐CSF was well tolerated. At day 7, both CD34+ cells (+747% versus −6%, P < 0.003), and HGF (+212% versus −7%, P < 0.03) increased in group A but not in group B. Cytokines and aminopyrine breath test changes were similar between groups. On repeat biopsy, a >50% increase in proliferating HPC was more frequent in group A than in group B (11 versus 2, P < 0.003). Changes in Ki67+/cytokeratin 7+ cells correlated with changes in CD34+ cells (r = 0.65, P < 0.03). Neutrophils and histological changes were similar in both groups. Conclusion: G‐CSF mobilizes CD34+ cells, increases HGF, and induces HPC to proliferate within 7 days of administration. Larger trials would be required to determine whether these changes translate into improved liver function. (HEPATOLOGY 2008.)
Background & Aims:
Steatosis is a frequent histologic finding in chronic hepatitis C (CHC), but it is unclear whether steatosis is an independent predictor for liver fibrosis. We evaluated the ...association between steatosis and fibrosis and their common correlates in persons with CHC and in subgroup analyses according to hepatitis C virus (HCV) genotype and body mass index.
Methods:
We conducted a meta-analysis on individual data from 3068 patients with histologically confirmed CHC recruited from 10 clinical centers in Italy, Switzerland, France, Australia, and the United States.
Results:
Steatosis was present in 1561 patients (50.9%) and fibrosis in 2688 (87.6%). HCV genotype was 1 in 1694 cases (55.2%), 2 in 563 (18.4%), 3 in 669 (21.8%), and 4 in 142 (4.6%). By stepwise logistic regression, steatosis was associated independently with genotype 3, the presence of fibrosis, diabetes, hepatic inflammation, ongoing alcohol abuse, higher body mass index, and older age. Fibrosis was associated independently with inflammatory activity, steatosis, male sex, and older age, whereas HCV genotype 2 was associated with reduced fibrosis. In the subgroup analyses, the association between steatosis and fibrosis invariably was dependent on a simultaneous association between steatosis and hepatic inflammation.
Conclusions:
In this large and geographically different group of CHC patients, steatosis is confirmed as significantly and independently associated with fibrosis in CHC. Hepatic inflammation may mediate fibrogenesis in patients with liver steatosis. Control of metabolic factors (such as overweight, via lifestyle adjustments) appears important in the management of CHC.
In patients with idiopathic noncirrhotic portal hypertension (INCPH), data on morbidity and mortality of abdominal surgery are scarce. We retrospectively analyzed the charts of patients with INCPH ...undergoing abdominal surgery within the Vascular Liver Disease Interest Group network. Forty‐four patients with biopsy‐proven INCPH were included. Twenty‐five (57%) patients had one or more extrahepatic conditions related to INCPH, and 16 (36%) had a history of ascites. Forty‐five procedures were performed, including 30 that were minor and 15 major. Nine (20%) patients had one or more Dindo‐Clavien grade ≥ 3 complication within 1 month after surgery. Sixteen (33%) patients had one or more portal hypertension–related complication within 3 months after surgery. Extrahepatic conditions related to INCPH (P = 0.03) and history of ascites (P = 0.02) were associated with portal hypertension–related complications within 3 months after surgery. Splenectomy was associated with development of portal vein thrombosis after surgery (P = 0.01). Four (9%) patients died within 6 months after surgery. Six‐month cumulative risk of death was higher in patients with serum creatinine ≥ 100 μmol/L at surgery (33% versus 0%, P < 0.001). An unfavorable outcome (i.e., either liver or surgical complication or death) occurred in 22 (50%) patients and was associated with the presence of extrahepatic conditions related to INCPH, history of ascites, and serum creatinine ≥ 100 μmol/L: 5% of the patients with none of these features had an unfavorable outcome versus 32% and 64% when one or two or more features were present, respectively. Portal decompression procedures prior to surgery (n = 10) were not associated with postoperative outcome. Conclusion: Patients with INCPH are at high risk of major surgical and portal hypertension–related complications when they harbor extrahepatic conditions related to INCPH, history of ascites, or increased serum creatinine.
Sinusoidal obstruction syndrome Rubbia-Brandt, Laura
Clinics in liver disease,
11/2010, Letnik:
14, Številka:
4
Journal Article
Recenzirano
Sinusoidal obstruction syndrome (SOS), formerly named venoocclusive disease, is a well-known complication of hematopoietic stem cell transplantation and ingestion of food or drinks contaminated by ...pyrrolizidine alkaloids. Many other drugs and toxins have been associated with SOS, including several chemotherapeutic agents and immunosuppressors. SOS contributes to significant morbidity and mortality in all these settings. This review describes the histologic lesions of SOS, details its pathogenesis as it is understood today, specifies the recent data on its causes and how it may influence clinical management of colorectal liver metastases, and discusses the current knowledge on diagnosis and preventive options.
Background & Aims
Our understanding of non‐alcoholic fatty liver disease (NAFLD) pathogenesis is improving, but there is still limited data on the function of resident liver macrophages in this ...context, especially when considering their contribution in dampening liver inflammation.
Methods
Liver macrophages were studied in mouse models of prolonged diet‐induced liver steatohepatitis and carbon tetrachloride‐induced liver injury. We assessed liver macrophages phenotype and costimulatory/inhibitory properties upon exposure to lipopolysaccharide or interleukin 4. We did phagocytosis and antigen presentation assays to investigate liver macrophages function as scavengers and immune response initiators. Using immunofluorescence staining, we further determined, in human liver tissue of patients with simple steatosis, non‐alcoholic steatohepatitis and chronic hepatitis B infection, the expression of the co‐inhibitory protein CD274 (Programmed‐death ligand 1) and major histocompatibility complex (MHC) class II.
Results
Both in humans and mice, within chronically inflamed fatty livers, liver macrophages acquired immunomodulatory properties by reducing the expression of MHC class II, and by enhancing co‐inhibitory signalling. Liver macrophages circumscribed endotoxin‐mediated inflammatory response by upregulating anti‐inflammatory genes arginase 1 and interleukin‐10. While hepatic macrophages isolated from mice with normal livers were capable of achieving endotoxin tolerance, our results indicated an impairment of this protective mechanism in the presence NASH‐like parenchymal abnormalities.
Conclusions
Liver macrophages can achieve endotoxin tolerance, but in the chronically inflamed fatty liver, while they acquire an immunomodulatory phenotype, liver macrophages fail to dampen immune‐mediated damage. Therefore, loss of tolerogenicity induced by ongoing liver insult may be a mechanism contributing to the worsening of NAFLD.
Rubbia‐Brandt L, Lauwers G Y, Wang H, Majno P E, Tanabe K, Zhu A X, Brezault C, Soubrane O, Abdalla E K, Vauthey J‐N, Mentha G & Terris B (2010) Histopathology56, 430–439 Sinusoidal obstruction ...syndrome and nodular regenerative hyperplasia are frequent oxaliplatin‐associated liver lesions and partially prevented by bevacizumab in patients with hepatic colorectal metastasis
Aims: Because of its efficacy, oxaliplatin (OX) is increasingly used as a chemotherapeutic agent in the treatment of colorectal liver metastases (CRLM). Oxaliplatin‐associated liver toxicity has been reported and can affect clinical practice, but studies on its prevalence and a full pathological description are lacking. The aims of this study were to fill this gap by providing, from a pathologist’s perspective, a detailed assessment of the spectrum of hepatic lesions associated with OX, to suggest a scoring system to quantify them, and to investigate the protective effect of bevacizumab against OX‐associated damage.
Methods and results: The spectrum of oxaliplatin‐associated liver lesions was investigated in a multi‐institutional series of surgically resected CRLM (n = 385). Among 274 patients treated by OX, 54% had moderate/severe sinusoidal obstruction syndrome (SOS). Peliosis, centrilobular perisinusoidal/venular fibrosis and nodular regenerative hyperplasia (NRH) developed in 10.6%, 47% and 24.5%, respectively. The 111 patients treated by surgery alone had no lesions. Hepatic lesions were less severe in patients treated with OX/bevacizumab (n = 70) compared with the group treated by OX alone (n = 204), with an incidence of moderate/severe SOS (31.4% versus 62.2%), peliosis (4.3% versus 14.6%), NRH (11.4% versus 28.9%, respectively) and centrilobular/venular fibrosis (31.4% versus 52%, respectively) (P < 0.001).
Conclusions: Pathologists should be aware of the distinctive lesions associated with OX and of their high prevalence. OX‐related lesions are less frequent in patients treated with bevacizumab, suggesting that this drug has a preventive effect. Uniform criteria for diagnosis and grading of OX‐associated lesions should help to include histological data in the optimal multidisciplinary management of CRLM.
PDF
