FibroMeter scores are predictive noninvasive markers of advanced and significant liver fibrosis in patients with chronic viral hepatitis or metabolic dysfunction-associated steatotic liver disease.

Background: FibroMeter and FibroMeter vibration-controlled transient elastography (FibroMeter VCTE) were assessed in a Greek cohort of patients with chronic viral hepatitis (CVH) B and C or metabolic dysfunction-associated steatotic liver disease (MASLD) to evaluate their accuracy in predicting advanced liver fibrosis against other well-validated noninvasive markers. Methods: Group 1: n=83 CVH and group 2: n=38 MASLD patients underwent liver biopsy and transient elastography (TE) on the same day as sera collection. FibroMeter scores APRI and FIB-4 were calculated in all 121 patients, while MASLD fibrosis score (MFS) was also calculated in group 2. Results: In CVH, FibroMeter VCTE performed equivalently to TE and better than the other markers in predicting advanced (≥F3) and significant (≥F2) fibrosis (area under the receiver operating characteristic curve [AUC] 0.887, P<0.001 for F3; AUC 0.766 P<0.001 for F2). FibroMeter Virus (cutoff 0.61) had lower sensitivity (20%) but performed equivalently to APRI and FIB-4. In MASLD, all markers but APRI performed equivalently in predicting advanced fibrosis. FibroMeter VCTE >0.2154 had the same sensitivity (100%) and specificity (81%) as TE (cutoff >7.1 kPa). FibroMeter MASLD >0.25 performed equivalently to MFS and FIB4, but with higher specificity (100%). Both FibroMeter and FibroMeter VCTE correlated with liver histology but not with liver enzymes. Conclusions: FibroMeter VCTE predicts accurately advanced fibrosis in CVH and MASLD, irrespectively of transaminase levels. FibroMeter Virus can be applied only as an alternative marker in CVH, while FibroMeter MASLD performs equally to TE and calculated scores (MFS, FIB-4) in predicting advanced fibrosis in MASLD patients.

Investigation of Clinically Significant Molecular Aberrations in Patients with Prostate Cancer: Implications for Personalized Treatment, Prognosis and Genetic Testing.

The data on tumor molecular profiling of European patients with prostate cancer is limited. Our aim was to evaluate the prevalence and prognostic and predictive values of gene alterations in unselected patients with prostate cancer. The presence of gene alterations was assessed in patients with histologically confirmed prostate cancer using the ForeSENTIA® Prostate panel (Medicover Genetics), targeting 36 clinically relevant genes and microsatellite instability testing. The primary endpoint was the prevalence of gene alterations in homologous recombination repair (HRR) genes. Overall, 196 patients with prostate cancer were evaluated (median age 72.2 years, metastatic disease in 141 (71.9%) patients). Gene alterations were identified in 120 (61%) patients, while alteration in HRR genes were identified in 34 (17.3%) patients. The most commonly mutated HRR genes were ATM (17, 8.7%), BRCA2 (9, 4.6%) and BRCA1 (4, 2%). The presence of HRR gene alterations was not associated with advanced stage (p = 0.21), age at diagnosis (p = 0.28), Gleason score (p = 0.17) or overall survival (HR 0.72; 95% CI: 0.41-1.26; p = 0.251). We identified clinically relevant somatic gene alterations in European patients with prostate cancer. These molecular alterations have prognostic significance and therapeutic implications and/or may trigger genetic testing in selected patients. In the era of precision medicine, prospective research on the predictive role of these alterations for innovative treatments or their combinations is warranted.

Hemophagocytic lymphohistiocytosis diagnosed by bone marrow trephine biopsy in living post-COVID-19 patients: case report and mini-review.

Hemophagocytic lymphohistiocytosis (HLH) constitutes a life-threatening inflammatory syndrome. Postmortem histological findings of bone marrow (BM) from COVID-19 patients showed histiocytosis and hemophagocytosis and supported the hypothesis that secondary HLH (sHLH) may be triggered by SARS-CoV-2 infection. However, there are a limited number of sHLH cases in which trephine has been performed in living post-COVID-19 patients. Here we present a recent case and a mini-review of sHLH diagnosed by trephine biopsy in living patients after COVID-19. An 81-year-old man with a past medical history of hypertension, diabetes, ischemic stroke, was referred to the hospital to evaluate leukocytosis, pyuria, and elevation of inflammatory markers four weeks after recovering from COVID-19. Computed tomography of the abdomen did not reveal focal signs of infection or hepatosplenomegaly. The patient received intravenous meropenem and two packed red blood cell units. Leukocytes and C-reactive protein were gradually decreased. A BM biopsy was performed and the patient was discharged on cefixime. BM smear revealed severe anemia, lymphopenia, and dysplastic morphologic findings of erythroblasts, neutrophils, and megakaryocytes. Trephine biopsy revealed hypercellular marrow dyserythropoiesis, plasmacytosis, lymphocytosis, histiocytosis, hemophagocytosis, and the absence of granulomas or carcinoma. Immunohistochemistry documented a mixed population of T lymphocytes (CD3+) and B lymphocytes (CD20+). Strong positivity for CD68 confirmed histiocytosis. CD138 κ, λ staining proved polyclonal plasmacytosis. Perl's staining showed excess hemosiderin deposits. Based on our findings, we document sHLH in trephine BM biopsy of a living post-COVID-19 patient and persistent leukocytosis, underscoring the diagnostic value of trephine biopsy in preventing life-threatening conditions such as COVID-19.

Altered DNA methylation pattern characterizes the peripheral immune cells of patients with autoimmune hepatitis.

BACKGROUND AND AIMS: Little is known about the impact of DNA methylation modifications on autoimmune hepatitis (AIH) pathogenesis and therapeutic response. We investigated the potential alterations of DNA methylation in AIH peripheral lymphocytes at diagnosis and remission. METHODS: Ten AIH patients at diagnosis (time-point 1; AIH-tp1), 8/10 following biochemical response (time-point 2; AIH-tp2), 9 primary biliary cholangitis (PBC) and 10 healthy controls (HC) were investigated. Peripheral CD19(+) and CD4(+) cells were isolated. Global DNA methylation (5m C)/hydroxymethylation (5hm C) was studied by ELISAs. mRNA of DNA methylation (DNMT1/3A/3B) and their counteracting hydroxymethylation enzymes (TET1/2/3) was determined by quantitative RT-PCR. Epigenome wide association study (EWAS) was performed in CD4(+) cells (Illumina HumanMethylation 850 K array) in AIH and HC. Total 5m C/5hm C was also assessed by immunohistochemistry (IHC) on paraffin-embedded liver sections. RESULTS: Reduced TET1 and increased DNMT3A mRNA levels characterized CD19(+) and CD4(+)-lymphocytes from AIH-tp1 compared to HC and PBC, respectively, without affecting global DNA 5m C/5hm C. In AIH-tp1, CD4(+) DNMT3A expression was negatively correlated with serum IgG (P = .03). In remission, DNMT3A decreased in both CD19(+) and CD4(+) cells compared to AIH-tp1 (P = .02, P = .03 respectively). EWAS in CD4(+) cells from AIH patients confirmed important modifications in genes implicated in immune responses (HLA-DP, TNF, lnRNAs and CD86). IHC showed increased 5hm C staining of periportal infiltrating lymphocytes in AIH-tp1 compared to HC and PBC. CONCLUSION: Altered TET1 and DNMT3A expressions, characterize peripheral lymphocytes in AIH. DNMT3A was associated with disease activity and decreased following remission. Gene DNA methylation modifications affect immunological pathways that may play an important role in AIH pathogenesis.

Patient with prostatic adenocarcinoma with plasmacytoid features and an aberrant immunohistochemical phenotype diagnosed by biopsy and a mini-review of plasmacytoid features in the genitourinary system: A case report.

Prostate cancer is one of the most commonly diagnosed malignancies in men. Most of these tumors are adenocarcinomas. Plasmacytoid is a rare variant of adenocarcinoma described by previous studies in the genitourinary system and is characterized by the plasmacytoid appearance of tumor cells with abundant cytoplasm and abnormally placed hyperchromatic nuclei. However, to the best of our knowledge, plasmacytoid adenocarcinoma has rarely been described in the prostate. This report describes a new case of plasmacytoid adenocarcinoma of the prostate diagnosed by biopsy and summarizes the known literature on plasmacytoid features in the genitourinary system. A 62-year-old male patient presented to the hospital with urinary retention, hematuria, weakness and weight loss. The digital rectal examination revealed an irregular enlargement. Laboratory findings showed elevated levels of prostate specific antigen (PSA; 43.6 ng/ml). Transrectal ultrasound showed invasion of the right seminal vesicle. Prostate tumor core biopsies were collected and sent for diagnosis. Histological examination revealed a high-grade prostatic adenocarcinoma Gleason score of 5+5 (total score 10). The tumor cells had a plasmacytoid appearance with abundant cytoplasm and abnormally placed hyperchromatic nuclei. The immunohistochemical phenotype was characterized by abundant positivity for cytokeratin (CK)AE1/AE3 and PSA. By contrast, tumor cells were negative for p63, CK 34BE12 and GATA binding protein 3 (urothelial markers), synaptophysin (neuroendocrine marker). Tumor cells were also negative for E-cadherin, which is particularly indicative of CDH1 alterations. To the best of our knowledge, this is the first description of a plasmacytoid adenocarcinoma of the prostate diagnosed by biopsy, showing an irregular immunophenotype that may indicate somatic CDH1 alterations. The presentation of a novel rare variant of prostatic carcinoma that differs from other neoplasms of the genitourinary system may contribute to an improved understanding of this uncommonly found histological pattern that may also be mandatory due to the clinical and prognostic implications of this diagnosis.

Bursitis of the coccyx in an adult with rheumatoid arthritis mimicking a sacrococcygeal meningocele.

BACKGROUND: Bursitis is a chronic inflammatory condition characterized by the deposition of cholesterol, macrophage infiltration, and bursal wall calcification. Bursitis is, however, rarely found in the sacrococcygeal region where it may present as a space-occupying mass. CASE DESCRIPTION: A 64-year-old male with rheumatoid arthritis presented with 3 years' duration of difficulty sitting and walking due to a soft-tissue mass involving the coccyx region. Once the patient's MR demonstrated a cystic lesion with erosion of the coccyx, the patient underwent gross total resection of the lesion that proved to be pathologically consistent with bursitis. Postoperatively, the patient's complaints fully resolved. CONCLUSION: Bursitis may present as a soft-tissue tumor-like lesion in the coccyx that favorably responds to gross total surgical excision.

Promyelocytic Leukemia Antigen Expression: a Histological Marker for Primary Biliary Cholangitis Diagnosis?

BACKGROUND AND OBJECTIVES: Distinguishing primary biliary cholangitis (PBC) from other cholestatic diseases at the histological level could be assisted by new methods, such as immunohistochemical staining of specific antigens. METHODS: We evaluated whether the detection of promyelocytic leukemia protein (PML) can serve as a specific and sensitive marker for PBC diagnosis. Liver biopsies from 26 PBC patients, 20 primary sclerosing cholangitis (PSC), 37 viral hepatitis, 11 non-alcoholic steatohepatitis (NASH) and 5 normal patients were investigated after immunostaining with the anti-PML monoclonal PG-M3, IgG1 antibody. RESULTS: Immunoreactivity in bile ducts was expressed by the PML-score (quotient of positive ducts to the total number of portal tracts multiplied by 2). PML-score was higher in PBC as compared to controls (P < 0.001). Using a cutoff of 0.18, PML-score proved highly sensitive (84.6%) and specific (89.7%) for confirming PBC as compared to only 5% of PSC, 9.1% of NASH and 13.5% of viral hepatitis patients (P < 0.001). Irrespective of the underlying disease, patients with PML-score > 0.18 were older (P = 0.007), more often females (P < 0.001) with higher ALP (P < 0.001), γ-GT (P = 0.001) and IgM (P < 0.001) compared to the patients with PML-score < 0.18. CONCLUSIONS: We postulate that a simple PML immunohistochemical test could be sufficient for histopathological discrimination of PBC in problematic cases of undefined cholestatic disorders, including small-duct PSC and AMA-negative PBC cases.

Alcoholic liver disease and autoimmune hepatitis: Sometimes a closer look under the surface is needed.

AIMS: Differential diagnosis of autoimmune hepatitis (AIH) incorporates various liver diseases, including alcoholic liver disease (ALD). We report on clinical, laboratory and outcome characteristics of AIH patients who were initially referred as ALD based on increased alcohol consumption (AIH/ALD). METHODS: From 2000-2019, we retrospectively identified 12 AIH/ALD patients [9 males, age: 61 (30-73) years] in our prospective data base of 317 AIH patients. RESULTS: AIH diagnosis was based on aminotransferases elevation in 10 patients, high IgG in 8, compatible autoantibody profile in all and typical/compatible histology in all 9 with available biopsy. There were no significant differences of baseline demographics, presentation, cirrhosis at diagnosis, response to treatment and simplified score compared to 45 age- and sex-matched AIH patients without alcohol consumption and 44 age- and sex-matched ALD patients. However, the AIH/ALD cohort was characterized by more frequent progression to cirrhosis, higher liver-related deaths and overall mortality compared to AIH, though similar to the ALD group. AST/ALT ratio>1 seems to bear a good positive (0.84) and negative predictive value (0.88) for ALD and AIH diagnosis, respectively, but cannot help in discriminating the AIH/ALD variant. CONCLUSIONS: AIH should not be forgotten in patients with alcohol use when clinical and laboratory features hint towards the diagnosis of AIH/ALD variant as this group seems to have worse outcome compared to those with AIH alone suggesting the need for closer follow-up and surveillance. Reliable autoantibody testing and cautious interpretation of liver histology appear mandatory for AIH diagnosis in these difficult to diagnose cases.

FibroMeter scores for the assessment of liver fibrosis in patients with autoimmune liver diseases.

INTRODUCTION AND OBJECTIVES: We assessed FibroMeter virus (FMvirus) and FibroMeter vibration-controlled transient elastography (FMVCTE) in 134 patients with autoimmune liver diseases [ALD, autoimmune hepatitis (AIH) and primary biliary cholangitis (PBC)], in order to assess new potential non-invasive biomarkers of liver fibrosis in patients with ALD, as similar data are missing. PATIENTS AND METHODS: The following groups were included: group 1: n = 78 AIH; group 2: n = 56 PBC. FMvirus and FMVCTE were determined in all 134 patients who underwent liver biopsy and TE the same day with sera collection. In addition, APRI and FIB-4 scores were calculated. RESULTS: The AUCs for TE and FMVCTE were significantly better (0.809; p < 0.001 and 0.772; p = 0.001, respectively for AIH and 0.997; p < 0.001 and 1; p < 0.001, for PBC) than the other three markers in predicting ≥ F3 fibrosis irrespective of the biochemical activity. FMVCTE and TE had good diagnostic accuracy (75.6% and 73%, respectively) for predicting severe fibrosis in AIH and performed even better in PBC (94.6% and 96.4%, respectively). The cut-offs of TE and FMVCTE had the best sensitivity and specificity in predicting ≥ F3 fibrosis in both AIH and PBC. CONCLUSIONS: FMVCTE seems to detect severe fibrosis equally to TE in patients with ALD but with better specificity. Biochemical disease activity did not seem to affect their diagnostic accuracy in ALD and therefore, could be helpful for the assessment of fibrosis, especially if they are performed sequentially (first TE with the best sensitivity and then FMVCTE with the best specificity).

Non-alcoholic steatohepatitis or autoimmune hepatitis? Sometimes a closer look under the surface is needed.

Non-alcoholic fatty liver disease (NAFLD) is nowadays the most common liver disease worldwide. Autoimmune hepatitis (AIH) is a relatively rare disease of the liver characterised by female predominance, circulating autoantibodies, polyclonal hypergammaglobulinaemia, interface hepatitis on histology and favourable response to immunosuppression. The possibility of an additional AIH diagnosis in patients with NAFLD (NAFLD/AIH concurrence) or the presence of AIH alone instead of a supposed NAFLD diagnosis represents a challenge for clinicians. We report herein two adult patients (a 33-year-old woman and a 59-year-old man) with a previous NAFLD diagnosis who proved finally to suffer from AIH alone. These two representative cases indicate how difficult and complicated could be sometimes the diagnosis of patients with AIH highlighting the range of disease manifestations and severity while they also underline that although NAFLD is by far the most frequent chronic liver disease this could not be always the case.

Belimumab is a promising third-line treatment option for refractory autoimmune hepatitis.

BACKGROUND & AIMS: Autoimmune hepatitis (AIH) is a disease of unknown aetiology with a favourable response to immunosuppression. However, in the clinic, it appears that <50% of patients achieve complete response on standard treatment. Serum B cell-activating factor (BAFF) levels are elevated in patients with AIH and are likely to contribute to disease pathogenesis. Given that belimumab, a BAFF inhibitor, has been shown to be effective in other autoimmune diseases, we investigated its use as a third-line add-on treatment option in patients with advanced AIH who did not respond to conventional treatment. METHODS: Herein, we report for the first time two patients, a 27-year-old female and a 58-year-old male, both with AIH-related compensated cirrhosis at diagnosis, who were refractory to standard immunosuppressive therapies and received add-on third-line therapy with belimumab. RESULTS: Both patients achieved a complete response and remained in remission while receiving low-dose corticosteroids. No adverse events related to belimumab and/or disease decompensation were observed. CONCLUSIONS: These preliminary findings indicate belimumab as a promising treatment option for patients with AIH and refractory and advanced liver-related fibrosis. LAY SUMMARY: A small proportion of patients with autoimmune hepatitis (AIH) are refractory to standard treatments; these patients bear the highest probability of developing decompensated cirrhosis and hepatocellular carcinoma because third-line treatment options are not well established. In this case study, we showed that third-line add-on therapy with belimumab, a B cell-activating factor inhibitor, could be an alternative and promising treatment option in patients with advanced AIH who did not respond to conventional treatment.

Glycogenic hepatopathy as a cause of severe deranged liver enzymes in a young patient with type 1 diabetes mellitus.

Glycogenic hepatopathy (GH) is a rare complication of poorly controlled type 1 diabetes mellitus (T1DM). We present a 19-year-old woman with T1DM and autoimmune thyroiditis who admitted to our department because of abrupt onset intermittent abdominal pain in the right upper quadrant accompanied by laboratory evidence of acute anicteric hepatitis. Physical examination revealed significant hepatomegaly but the common imagining studies were negative. Following exclusion of common causes of acute hepatitis and because of the presence of smooth muscle antibodies in a young female patient with already established two autoimmune diseases, a liver biopsy was performed in order to exclude the potential presence of autoimmune hepatitis. However, liver histology showed typical findings of GH. Intense treatment targeting strict glycemic control resulted in normalisation of liver biochemistry. This case underlines that GH should be considered as a rare cause of acute hepatitis in T1DM patients with poor glycemic control.

Prognostic significance of tumor genotypes and CD8+ infiltrates in stage I-III colorectal cancer.

BACKGROUND: We explored the clinical significance of tumor genotypes and immunophenotypes in non-metastatic colorectal cancer (CRC). METHODS: In primary tumors (paraffin blocks) from 412 CRC patients treated with adjuvant chemotherapy, we examined pathogenic mutations (panel NGS; 347 informative); mismatch repair (MMR) immunophenotype (360 informative); and CD8+ lymphocyte density (high - low; 412 informative). The primary outcome measure was disease-free survival (DFS). RESULTS: We evaluated 1713 pathogenic mutations (median: 3 per tumor; range 0-49); 118/412 (28.6%) tumors exhibited high CD8+ density; and, 40/360 (11.1%) were MMR-deficient. Compared to MMR-proficient, MMR-deficient tumors exhibited higher CD8+ density (chi-square, p<0.001) and higher pathogenic mutation numbers (p=0.003). High CD8+ density was an independent favorable prognosticator (HR=0.49, 95%CI 0.29-0.84, Wald's p=0.010). Pathogenic BRCA1 and ARID1A mutations were inversely associated with each other (p<0.001), were not associated with MMR-deficiency or CD8+ density, but both independently predicted for unfavorable DFS (HR=1.98, 95%CI 1.12-3.48, p=0.018 and HR=1.99, 95%CI 1.11-3.54, p=0.020, respectively). CONCLUSION: In non-metastatic CRC, high CD8+ lymphocyte density confers a favorable prognosis and may be developed as a single marker in routine diagnostics. The unfavorable prognostic effect of pathogenic BRCA1 and ARID1A mutations is a novel observation that, if further validated, may improve treatment selection.

Postinfantile Giant Cell Hepatitis with Features of Acute Severe Autoimmune Hepatitis Probably Triggered by Diclofenac in a Patient with Primary Myelofibrosis.

Giant cell hepatitis (GCH) is commonly reported in neonatal and infantile liver diseases but rarely in adults where the term postinfantile GCH (PIGCH) is used. PIGCH is associated with many diseases, including drugs toxicity, viruses, and autoimmune liver diseases, with autoimmune hepatitis (AIH) being the most prevalent. We present a case of PIGCH in a 76-year-old female without known history of liver disease who suffered from an acute severe episode of hepatitis. After careful exclusion of other hepatitis causes by imaging, virological, immunological, and microbiological investigations, a diagnosis of acute severe AIH (AS-AIH) was established. The patient was started on corticosteroids but she did not respond and died 3 days later because of advanced acute liver failure. Postmortem liver biopsy showed typical PIGCH lesions. Physicians must keep this catastrophic entity in mind in cases of unexplained acute liver injury as, contrary to our case, prompt rescue therapy with corticosteroids may be life-saving.

Geoepidemiology, clinical manifestations and outcome of primary biliary cholangitis in Greece.

BACKGROUND & AIMS: Primary biliary cholangitis (PBC) is a disease with rising prevalence and considerable geographical variation. To describe the prevalence, spatial and time distribution, baseline characteristics, response to treatment, outcome and the validity of GLOBE score in a large cohort of Greek PBC patients as an independent validation of this score has not been done so far. METHODS: The last 16years, 482 PBC patients (86.5% females) were evaluated and analysed retrospectively, using a prospectively collected database. Special attention was paid to the assessment of treatment response according to GLOBE score. RESULTS: Age at initial evaluation was 56.3±13.7years. Among 432 Thessaly residents, prevalence was 582/million (non-homogeneous distribution). Nineteen districts showed a prevalence >800/million. Symptomatic disease onset could be identified in 91 patients, with a significant peak during spring (P=0.03). At diagnosis, 43.6% were asymptomatic and 16.2% cirrhotic. Male sex (P=0.02), older age (P<0.001), alcohol consumption (P<0.01) and concomitant liver disease (P<0.001) were negative prognostic factors for cirrhosis. During a median [interquartile range, range] follow-up of 5.1 (7.8, 15.7) years, 62 patients died or underwent liver transplantation. Patients with GLOBE score>0.30 had significantly worse prognosis (P<0.001) with 5-, 10-, and 15-year survival rates of 84%, 50% and 42%. CONCLUSIONS: There is increased PBC prevalence in Thessaly with remarkable geographic clustering and seasonal variability. PBC is diagnosed at early stages although males had a more advanced disease. GLOBE score applies perfectly in Greek patients and this will likely help detecting patients that may benefit from new therapies.

COMP serum levels: A new non-invasive biomarker of liver fibrosis in patients with chronic viral hepatitis.

BACKGROUND & AIMS: Recently we have shown that cartilage oligomeric matrix protein (COMP), a fibrillar collagen assembly regulator, is strongly associated with cirrhosis and hepatocellular carcinoma progression. Therefore, we assessed whether serum COMP levels can be used as a non-invasive fibrosis marker in patients with chronic viral hepatitis (CVH) and compared this marker with standard methods for disease stage assessment [histology, transient elastography (TE), APRI, FIB-4]. METHODS: Sera from 116 CVH patients, 66 HBV [24 female; median age 53(22-76)] and 50 HCV [21 female; median age 48.5(25-69)] were investigated by COMP-ELISA. APRI and FIB-4 score was calculated in all along with TE. Liver biopsy was performed in 61. Patients were divided into two groups (F1/F2 and F3/F4) according to Metavir score. RESULTS: 55/116 (47%) CVH patients were classified in F3/F4-group according to TE [14.3(9.3-75)kPa]. APRI score was >1.5 in 21/116 and FIB-4>3.25 in 20/116. Liver histology revealed 24/61 (39%) patients with significant fibrosis (stage 3-4), while 12/61 (19.7%) had cirrhosis. COMP levels correlated with TE measurements (r=0.5; p<0.001) and APRI score (r=0.23; p<0.02). The diagnostic accuracy of COMP in detecting cirrhosis was as good as TE, APRI and FIB-4 index (AUC 0.884) with sensitivity and specificity of 83.3% and 83.7% (cut-off 11.5U/L). CONCLUSIONS: COMP serum levels performed as well as TE, APRI and FIB4 score in detecting cirrhosis in CVH patients, suggesting COMP as a sensitive non-invasive, easy to perform biomarker of liver fibrosis. Further studies are needed in order to validate our findings in CVH patients.

Low Serum Hepcidin in Patients with Autoimmune Liver Diseases.

Hepcidin, a liver hormone, is important for both innate immunity and iron metabolism regulation. As dysfunction of the hepcidin pathway may contribute to liver pathology, we analysed liver hepcidin mRNA and serum hepcidin in patients with chronic liver diseases. Hepcidin mRNA levels were determined in liver biopsies obtained from 126 patients with HCV (n = 21), HBV (n = 23), autoimmune cholestatic disease (primary biliary cirrhosis and primary sclerosing cholangitis; PBC/PSC; n = 34), autoimmune hepatitis (AIH; n = 16) and non-alcoholic fatty liver disease (NAFLD; n = 32). Sera sampled on the biopsy day from the same patients were investigated for serum hepcidin levels. Hepatic hepcidin mRNA levels correlated positively with ferritin and negatively with serum γ-GT levels. However, no correlation was found between serum hepcidin and either ferritin or liver hepcidin mRNA. Both serum hepcidin and the serum hepcidin/ferritin ratio were significantly lower in AIH and PBC/PSC patients' sera compared to HBV, HCV or NAFLD (P<0.001 for each comparison) and correlated negatively with serum ALP levels. PBC/PSC and AIH patients maintained low serum hepcidin during the course of their two-year long treatment. In summary, parallel determination of liver hepcidin mRNA and serum hepcidin in patients with chronic liver diseases shows that circulating hepcidin and its respective ratio to ferritin are significantly diminished in patients with autoimmune liver diseases. These novel findings, once confirmed by follow-up studies involving bigger size and better-matched disease subgroups, should be taken into consideration during diagnosis and treatment of autoimmune liver diseases.

Cartilage oligomeric matrix protein: A novel non-invasive marker for assessing cirrhosis and risk of hepatocellular carcinoma.

AIM: To assess serum cartilage oligomeric matrix protein (COMP) as a marker of cirrhosis and risk of progression to hepatocellular carcinoma (HCC). METHODS: A COMP enzyme-linked immunosorbent assay was used to test 187 patients with chronic liver diseases at the time point of first evaluation. The selected patients included 72 with chronic hepatitis B infection, 75 with chronic hepatitis C infection, 22 with primary biliary cirrhosis, 7 with autoimmune hepatitis type 1, and 11 with alcoholic liver disease. Demographic, biochemical, histological and clinical characteristics of the patients were recorded at the first evaluation. One hundred and forty-seven patients were followed for a median [interquartile range (IQR)] duration of 96.5 (102) mo. The clinical, biochemical and histological data, as well as the development of cirrhosis, HCC according to internationally accepted criteria and in case of death, a liver-related cause during the follow-up period, were recorded at the electronic database of our clinic. COMP determination was also performed in 43 healthy individuals who served as the control study group. RESULTS: COMP positivity (> 15 U/L) was detected in 22%-36% among chronic liver disease groups. Strikingly, almost 83% of COMP-positive patients were cirrhotic at baseline, independently of cause of liver disease. Among the patients who developed HCC during follow-up, 73.7% (14/19) were COMP positive at baseline. COMP positivity was significantly associated with older age (P < 0.001), advanced fibrosis (P = 0.001) and necroinflammatory activity (P = 0.001), higher aspartate aminotransferase (P < 0.001), alanine aminotransferase (P < 0.02), γ-glutamyl transpeptidase (P = 0.003), alkaline phosphatase (P = 0.001), bilirubin (P < 0.05), international normalized ratio (P = 0.002) and alpha-fetoprotein levels (P < 0.02), and lower albumin (P < 0.001), and platelet count (P = 0.008). COMP levels [median (IQR)] were significantly higher in cirrhotics compared to non-cirrhotics [13.8 (7.9) U/L vs 9.8 (4.6) U/L, respectively; P < 0.001]. On multivariate logistic regression analysis, COMP-positivity was independently associated only with cirrhosis (OR = 4.40, 95%CI: 1.33-14.69, P = 0.015). Kaplan-Meier analysis showed that COMP positivity was significantly associated with HCC development (P = 0.007) and higher incidence of liver-related death (P < 0.001). CONCLUSION: Elevated COMP levels are strongly associated with cirrhosis and HCC progression. Serum COMP is a new promising non-invasive biomarker for HCC risk assessment in surveillance programs.

Oxidative stress and antioxidant status in patients with autoimmune liver diseases.

OBJECTIVE: To estimate oxidative stress and antioxidant components during different stages of autoimmune liver diseases and assess their possible implication on disease progression. METHODS: We determined several markers of oxidative injury (isoprostane, aldehydes, protein carbonyls, 3-nitrotyrosine, and myeloperoxidase) and antioxidant components (glutathione, glutathione peroxidase, glutathione reductase, superoxide dismutase, and catalase) in whole blood, serum, and urine in 49 patients with autoimmune cholestatic liver diseases (AC) and 36 patients with autoimmune hepatitis (AIH) and healthy subjects matched for sex and age. RESULTS: Both AC and AIH patients had increased levels of all lipid and protein oxidative injury products and significantly decreased whole blood glutathione levels compared to controls. AIH patients had significantly higher levels of aldehydes and glutathione peroxidase activity and significantly lower protein carbonyl levels compared to AC patients. Protein carbonyl and isoprostane levels increased and glutathione levels decreased gradually with progression from mild fibrosis to severe fibrosis and cirrhosis in both AC and AIH patients. In addition, both cirrhotic AC and AIH patients had significantly higher protein carbonyls compared to non-cirrhotics. DISCUSSION: We provide novel findings in support of a major contribution of oxidant/antioxidant imbalance in the progression of liver injury in AC and AIH.

Safety and efficacy of transcatheter arterial chemoemboliazation in the real-life management of unresectable hepatocellular carcinoma.

BACKGROUND: Trans-arterial chemoembolization (TACE) is associated with better survival in BCLC-stage B patients with hepatocellular carcinoma (HCC) and Child-Pugh A whereas in Child-Pugh B there is no definite evidence of benefit. OBJECTIVES: To assess the safety and efficacy of TACE during routine clinical practice in a consecutive Greek cohort of patients with unrespectable HCC. PATIENTS AND METHODS: Seventy one patients enrolled for this study (mean follow-up:24.6 months). 100 mg cisplatin, 50 mg doxorubicin and 10 ml lipiodol as well as embolic materials were used. CT-scans and blood tests were obtained prior and post-TACE. Kaplan-Meier method and Cox proportional hazard model were used to evaluate survival and factors affecting survival. RESULTS: Survival at 1-year, 2-years, 3-years and 5-years was 73.2%, 45.4%, 33.2% and 14.9% respectively. Procedure-related mortality was 1.4%. Multivariate analysis showed lesion diameter, Child-Pugh classification, alcohol abuse, tumor response and AFP prior TACE as independent prognostic factors of survival. Patients diagnosed during surveillance had significantly better survival rates compared to those diagnosed after development of symptoms (HR = 0.58, 95%CI: 0.33-1.01, P < 0.05). CONCLUSIONS: TACE is safe and efficient for unrespectable HCC. Alcohol abuse, tumor burden, response criteria, Child-Pugh and AFP prior to the session were identified as independent predictors of survival whereas, adherence to surveillance programs resulted in significantly better survival in these patients.