A case of refractory hepatic hydrothorax due to pleuroperitoneal communication successfully controlled by diaphragmatic plication and subsequent peritoneovenous shunting.

In general, control of hepatic hydrothorax is difficult, and patients have a poor prognosis. A case in which hepatic hydrothorax was well controlled for a long time after diaphragm plication and subsequent Denver shunt placement is reported. A 70-year-old man with decompensated liver cirrhosis presented with progressive exertional dyspnea. 5 years before admission, hepatic ascites associated with portal hypertension appeared, and a left pleural effusion subsequently developed. The pleural effusion was not controlled by salt restriction and diuretics. Based on the clinical findings, the existence of pleuroperitoneal communication was strongly suspected, and surgical diaphragmatic plication was performed. After the treatment, the pleural effusion did not accumulate, but ascites increased significantly, and conservative therapy was ineffective. For the treatment of massive ascites, a peritoneovenous shunt (Denver shunt®) was placed. Although more than 2 years have passed, the thoracoabdominal effusions have not accumulated, and the patient has been asymptomatic. The present case suggests that multidisciplinary treatment may improve the prognosis of patients with refractory thoracoabdominal effusions.

Impact of body composition on patient prognosis after SARS-Cov-2 infection.

BACKGROUND: Since the first outbreak of coronavirus disease 2019 (COVID-19), it has been reported that several factors, including hypertension, type 2 diabetes mellitus, and obesity, have close relationships with a severe clinical course. However, the relationship between body composition and the prognosis of COVID-19 has not yet been fully studied. METHODS: The present study enrolled 76 consecutive COVID-19 patients with computed tomography (CT) scans from the chest to the pelvis at admission. The patients who needed intubation and mechanical ventilation were defined as severe cases. Patients were categorized into four groups according to their body mass index (BMI). The degree of hepatic steatosis was estimated by the liver/spleen (L/S) ratio of the CT values. Visceral fat area (VFA), psoas muscle area (PMA), psoas muscle mass index (PMI), and intra-muscular adipose tissue content (IMAC) were measured by CT scan tracing. These parameters were compared between non-severe and severe cases. RESULTS: Severe patients had significantly higher body weight, higher BMI, and greater VFA than non-severe patients. However, these parameters did not have an effect on disease mortality. Furthermore, severe cases had higher IMAC than non-severe cases in the non-obese group. CONCLUSIONS: Our data suggest high IMAC can be a useful predictor for severe disease courses of COVID-19 in non-obese Japanese patients, however, it does not predict either disease severity in obese patients or mortality in any obesity grade.

Recurrent hepatocellular carcinoma with osteoclast-like giant cells: a case report.

BACKGROUND: Hepatocellular carcinoma with osteoclast-like giant cells is very rare and has an extremely poor prognosis. Here, we report a case of hepatocellular carcinoma with osteoclast-like giant cells that had a relatively better prognosis. CASE PRESENTATION: A 70-year-old Japanese man with hepatitis B virus-related liver cirrhosis was admitted to our hospital for the treatment of recurrent hepatocellular carcinoma. At the age of 60 years, he was first diagnosed as having hepatocellular carcinoma in the right lobe (9 cm in diameter), and liver resection of segment 7/8 was performed. Histological findings showed well-differentiated hepatocellular carcinoma. Since then, imaging studies have been performed every 3 or 4 months. One year later, hepatocellular carcinoma recurred in the lateral segment, and radiofrequency ablation was performed. Nine years after the first presentation, hepatocellular carcinoma recurrences were detected in the caudate lobe and segment 5 by imaging studies. Surgical resection of the caudate lobe was performed, and ultrasonography-guided radiofrequency ablation was subsequently performed for the segment 5 tumor. The resected tumor was simple nodular, well-differentiated HCC; it measured 21 × 21 mm and contained many osteoclast-like giant cells. As neither vascular nor bile duct invasion was found, we believe that radical resection was achieved. Since then, the hepatocellular carcinoma has not recurred for over a year and a half. CONCLUSION: Hepatocellular carcinoma with osteoclast-like giant cells is very rare and the prognosis is extremely poor, but early detection can lead to a better clinical course.

Expression Pattern of Plexin Domain Containing 2 in Human Hepatocellular Carcinoma.

Plexin domain containing 2 (PLXDC2) is expressed in endothelial cells of tumor stroma, neural progenitor cells, and pluripotent stem cells, but their respective tissue expression pattern is not fully understood. In this study, we investigated the expression pattern of PLXDC2 in human hepatocellular carcinoma (HCC) tissues using a highly specific anti-PLXDC2 rabbit monoclonal antibody, which was recently developed. PLXDC2 was expressed in human HCC tissues including HCC cells, tumor vascular endothelial cells, and some infiltrating cells. The developed anti-PLXDC2 antibody allowed for highly specific and low background staining. Based on these current findings of PLXDC2 expression in human HCC tissues, the window may now be open to explore the role of PLXDC2 in human HCC.

Changing clinical and molecular characteristics of hepatitis E virus infection in Mie Prefecture, Japan: Disappearance of indigenous subtype 3e strains.

AIM: To evaluate the clinical and molecular characteristics of hepatitis E virus (HEV) infection in Mie Prefecture, Japan, from 2004 through 2018. METHODS: The clinical information of hepatitis E cases was collected from 21 medical institutions in Mie Prefecture. The nucleotide sequences of infecting HEV strains were determined for cases with available serum samples. The origins or transmission routes were inferred from phylogenetic analyses of the nucleotide sequences. RESULTS: Fifty-three patients were diagnosed with HEV infection. The number of cases increased each year through 2012 and then decreased. Analyses of the clinical characteristics of the cases indicated that even mild cases were detected in the latter 10 years of the study. Nucleotide sequence analyses were undertaken on 38 of the 53 cases. The HEV subtype 3e (HEV-3e) strains identified for 13 cases were closely related to a swine HEV-3e strain that was isolated from the liver of a pig bred in Mie Prefecture. The number of cases infected with the indigenous Mie HEV-3e strains increased until 2012 but have not been reported since 2014. In the latter half of the study, cases involving various HEV strains of different genotypes and subtypes emerged. CONCLUSIONS: The disappearance of indigenous Mie HEV-3e strains appeared to be the primary cause for the decrease in hepatitis E cases in Mie Prefecture. The disappearance might have been associated with improved hygienic conditions on pig farms or the closure of contaminated farms. The results suggest that indigenous HEV strains can be eradicated by appropriate management.

Ratio between estimated glomerular filtration rates of creatinine and cystatin C predicts overall survival in patients with hepatocellular carcinoma.

AIM: Hepatocellular carcinoma (HCC) patients with sarcopenia have a poor survival, but there are no predictive markers for survival relating to muscle mass and liver function. Therefore, we investigated whether the ratio between estimated glomerular filtration rates of serum creatinine (Scre) and serum cystatin C (Scys) (eGFRcre/eGFRcys) can be used as a predictive marker of survival in HCC patients. METHODS: First, the correlation between Scre/Scys ratio and muscle mass was examined in 50 patients with chronic liver disease. Second, a change in Scre/Scys ratio relating to liver function was investigated in cirrhotic rats. Finally, the relationship between the eGFRcre/eGFRcys ratio and survival was assessed in 86 HCC patients. RESULTS: The Scre/Scys ratio was correlated with skeletal muscle mass index (r = 0.331, P = 0.019) and psoas muscle area index (r = 0.397, P = 0.004) in chronic liver disease patients. In cirrhotic rats, Scre and Scre/Scys ratio were decreased corresponding with liver function. Thirty-five of 86 HCC patients died within the average follow-up period of 35 months. The patients with an eGFRcre/eGFRcys ratio <1.26 had significantly longer rates of survival compared to patients with an eGFRcre/eGFRcys ratio ≥1.26 (28.8 vs. 18.5 months, P = 0.001). Using multivariate Cox regression analyses, the patient-related eGFRcre/eGFRcys ratio (hazard ratio [HR], 4.178; P = 0.007), as well as the tumor-related factors α-fetoprotein (HR, 1.000; P < 0.001) and Barcelona Clinic Liver Cancer stage (HR, 2.589; P < 0.001), were independent predictors of survival. CONCLUSION: The Scre/Scys ratio is associated with muscle mass and liver function. Furthermore, the eGFRcre/eGFRcys ratio could serve as a useful predictive marker for survival of HCC.

Histologically confirmed case of complete atrioventricular block due to hepatocellular carcinoma.

A 72-year-old man, who had been diagnosed as having hepatocellular carcinoma (HCC) with multiple extrahepatic metastasis, complained a general fatigue which appeared 2 weeks before admission. Because bradycardia was detected on physical examination, ECG was performed which revealed the complete atrioventricular (AV) block. We stopped Ca-blocker and ß-blocker, but the bradycardia persisted. He was admitted to our hospital for an emergent pacemaker implantation. On admission, he complained dyspnoea. After the surgery, he died due to deterioration of heart failure. The autopsy revealed cardiac metastasis of HCC on AV node, so it was suspected that cardiac metastasis caused the AV block. We thought that the cause of his death was the exacerbation of heart failure associated with bradycardia. It was likely that complete AV block as a very rare complication caused by cardiac metastasis of HCC influenced the prognosis of this patient.

Changes in liver function and body composition by direct-acting antiviral therapy for hepatitis C virus infection.

AIM: Management of low skeletal muscle mass (LSM) is a very important topic as LSM affects patient mortality in liver diseases. Changes in body composition are unexplored in chronic hepatitis C virus (HCV) patients, including those with liver cirrhosis, who receive direct-acting antiviral (DAA) therapy. Body composition measurements and liver function tests were carried out before and after DAA therapy. METHODS: Blood examination, visceral fat area (VFA) and extremity skeletal muscle mass were measured using the multifrequency bioelectrical impedance analysis method: (i) at 24 weeks before DAA therapy; (ii) at the start of DAA therapy; (iii) at the end of DAA therapy; (iv) at 24 weeks after DAA therapy; and (v) at 48 weeks after DAA therapy. RESULTS: Serum albumin (Alb) levels were significantly increased at 48 weeks post DAA therapy, especially in patients with LSM. Skeletal muscle mass index (SMI) was significantly increased after DAA therapy (at 24 weeks and 48 weeks post DAA therapy) in patients with LSM (P < 0.05). An increase in SMI was associated with an increase in body weight or a decrease in VFA. CONCLUSIONS: We continuously measured body composition in HCV-infected patients who received DAA therapy and found that skeletal muscle mass was significantly increased, associated with an elevation of serum Alb levels and/or body weight or reduction in VFA, but only in patients who presented with LSM before DAA therapy.

Neutrophil gelatinase-associated lipocalin level is a prognostic factor for survival in rat and human chronic liver diseases.

Chronic liver disease patients often have complications, such as hepatocellular carcinoma (HCC) and acute bacterial infection. Model for end-stage liver disease and Child-Pugh scores are useful prognostic factors for chronic liver diseases but not for all chronic conditions, such as HCC. Our investigative aim targeted the prognostic abilities of neutrophil gelatinase-associated lipocalin (NGAL) in rat and human chronic liver diseases. Blood NGAL levels were measured by enzyme-linked immunosorbent assay in rats with cirrhosis and 96 patients with chronic liver disease and HCC. We examined the correlation between blood NGAL levels and liver functions as well as survival. In our rat model, liver NGAL expression was assessed by immunostaining, real-time quantitative polymerase chain reaction, and immunoblot. In rats with cirrhosis, blood NGAL levels were continuously and significantly elevated in the deceased group and were significantly correlated with liver functions. Liver NGAL, toll-like receptor 4, and interleukin-6 levels were increased in the deceased group compared to the survival group. Blood NGAL levels were significantly correlated with liver NGAL levels, indicating blood NGAL was derived from the liver. In patients with chronic liver disease, blood NGAL levels were associated with liver function and renal function. Blood NGAL levels were significantly increased in patients with chronic liver disease with HCC compared to without HCC. For the survival group, 38 out of 96 patients were dead in the average follow-up period of 9.9 months. The patients with blood NGAL ≤119 ng/mL had significantly longer rates of survival compared to patients with blood NGAL >119 ng/mL. Conclusion: Blood NGAL predicts the survival rate in rat and human chronic liver diseases. Our findings suggest blood NGAL may be prognostic of survival in chronic liver diseases complicated by HCC. (Hepatology Communications 2017;1:946-956).

A case of a solitary Mycobacterium avium complex lesion of the liver.

A 70-year-old woman was admitted to our hospital on suspicion of liver tumor on regular abdominal ultrasonography. The abdominal ultrasonography identified a solitary, low-echoic lesion measuring 17mm in diameter in S7. This lesion was not enhanced in any phase of contrast-enhanced computed tomography (CT), and thus we performed a liver biopsy. Histopathological examination revealed a caseating granuloma. The chest CT showed pulmonary nodules, and Mycobacterium intracellulare was cultured from the bronchoalveolar lavage fluid. We diagnosed the individual with a Mycobacterium avium complex infection, and suspected that this was the cause of the solitary liver lesion.

Factors contributing to the development of overt encephalopathy in liver cirrhosis patients.

The aim of this study was to clarify the relationships among psychometric testing results, blood ammonia (NH3) levels, electrolyte abnormalities, and degree of inflammation, and their associations with the development of overt hepatic encephalopathy (HE) in liver cirrhosis (LC) patients. The relationships between covert HE and blood NH3, sodium (Na), and C-reactive protein (CRP) were examined in 40 LC patients. The effects of elevated NH3, hyponatremia, and elevated CRP on the development of overt HE were also investigated. The covert HE group had significantly lower serum Na levels and significantly higher serum CRP levels. During the median observation period of 11 months, 10 patients developed overt HE, and the results of multivariate analysis showed that covert HE and elevated blood NH3 were factors contributing to the development of overt HE. Electrolyte abnormalities and mild inflammation are involved in the pathogenesis of HE. Abnormal psychometric testing results and hyperammonemia are linked to subsequent development of overt HE.

Epigenetic regulation of proliferation and invasion in hepatocellular carcinoma cells by CBP/p300 histone acetyltransferase activity.

Altered epigenetic control of gene expression plays a substantial role in tumor development and progression. Accumulating studies suggest that somatic mutations of CREB binding proteins (CBP)/p300 occur in some cancer cells. CBP/p300 possess histone acetyltransferase (HAT) activity, and are involved in many cellular processes. In this study, we investigated the expression and functional role of CBP/p300 in hepatocellular carcinoma (HCC) using the specific inhibitor C646 of CBP/p300 HAT activity. We examined its effect on several apoptosis-related proteins and invasion-related genes. The results showed that CBP/p300 were highly expressed in HCC tissues and that expression of p300, but not of CBP, was strongly correlated with the malignant character of HCC. C646 inhibited proliferation of HCC cell lines in a dose dependent manner. C646 significantly augmented TRAIL-induced apoptotic sensitivity, which was accompanied by reduced levels of survivin, in HepG2, HLE and SK-HEP1 cells. C646 significantly inhibited invasion of Huh7, HLE and SK-HEP1 cells. The level of matrix metallopeptidase 15 (MMP15) mRNA expression was significantly reduced, whereas the level of laminin alpha 3 (LAMA3) and secreted phosphoprotein 1 (SPP1) mRNA expression was significantly increased in Huh7 cells following exposure to C646. In conclusion, our results suggest that CBP/p300 HAT activity has an important role in malignant transformation, proliferation, apoptotic sensitivity and invasion in HCC. CBP/p300 could be a promising therapeutic target in HCC.

Corrigendum: Human ß-defensin-3 inhibits migration of colon cancer cells via downregulation of metastasis-associated 1 family, member 2 expression.

In this article, Fig. 2 is incorrect. The corrected Fig. 2 is shown using data from the tissue array samples. The new figure demonstrates the same findings as the original figure. Accordingly, in the paragraph of Materials and methods, the sentence '...surgically resected colon cancer tissues' and 'This study was...research committee' and in the paragraph of Results, the sentence 'Similar results were...tissue array samples' should be deleted. The above changes do not alter the original conclusions of this study. [the original article was published in the International Journal of Oncology 45: 1059-1064, 2014 DOI: 10.3892/ijo.2014.2507].

Pulmonary tuberculoma in a patient with chronic hepatitis C: a clinical pitfall in the treatment strategy.

We herein report a clinical pitfall regarding the treatment of a case of pulmonary tuberculoma in a patient with chronic hepatitis C. The patient presented with both chronic hepatitis C and pulmonary tuberculoma, and we initiated treatment of the chronic hepatitis C first due to the potential for liver injury; however, the patient's condition worsened in terms of the pulmonary tuberculosis. This case highlights the need to select the initial treatment for pulmonary tuberculoma, not chronic hepatitis C. In addition, we report that, although the administration of anti-tuberculosis chemotherapy regimens containing pyrazinamide (PZA) substantially increases the incidence of drug-induced hepatitis in patients with chronic hepatitis, we were fortunately able to use PZA without observing drug-induced hepatitis in this case because we closely monitored the patient's liver function.

Resveratrol sensitizes HepG2 cells to TRAIL-induced apoptosis.

Resveratrol is a natural polyphenol found in a wide variety of plants, including grapes, berries, and peanuts. Resveratrol can modulate a wide spectrum of molecular targets, including those involved in cancer signaling pathways. Here, we evaluated the role of resveratrol in tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and examined the molecular mechanisms in the human hepatocellular carcinoma cell line HepG2. We used the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay to assess cell viability, flow cytometry to analyze cell cycle and apoptosis, and immunoblotting to detect protein expression. Resveratrol decreased cell viability at a concentration of 100 µmol/l or higher. At a concentration of 50 µmol/l, resveratrol induced S phase arrest of the cell cycle without apoptosis. In addition, phospho-AMPK increased significantly in a dose-dependent manner. Resveratrol was found to synergistically augment TRAIL-induced apoptosis. The rates of early apoptosis were 3.4, 9.6, and 49.6% on treatment with 50 µmol/l resveratrol, 10 ng/ml TRAIL, and both reagents, respectively. Resveratrol significantly downregulated the expression of survivin in a dose-dependent manner. In conclusion, we found that that resveratrol could augment TRAIL sensitivity by downregulating survivin. These results suggest that combination resveratrol with TRAIL may be an effective new strategy for the treatment of hepatocellular carcinoma.

Human ß-defensin-3 inhibits migration of colon cancer cells via downregulation of metastasis-associated 1 family, member 2 expression.

The innate immune system plays an important role as the first line of defense against many types of microbes. Accumulating reports suggest that human ß-defensins (hBDs) are expressed by and have certain roles in some cancer cells. In this study, we investigated the roles of hBD-3 in colon cancer cells. The expression of hBD-3 was examined by reverse transcriptase-polymerase chain reaction analysis of colon cancer cell lines and immunohistochemical staining of colon cancer tissues. The effect of hBD-3 on proliferation of colon cancer was assessed using the MTT assay and a real-time cell analyzer, and the effect of hBD-3 on the migration of colon cancer cells was also examined. The results showed that hBD-3 is not expressed in colon cancer cells but is produced by tumor-infiltrating monocytes. Migration of colon cancer cells was significantly inhibited by hBD-3 in a dose-dependent manner, although proliferation of colon cancer cells was not affected by administration of hBD-3. Moreover, reduced expression of metastasis-associated 1 family, member 2 (MTA2) mRNA in colon cancer cells was associated with exposure to hBD-3. In conclusion, progression of colon cancer was inhibited by hBD-3 in a paracrine fashion. Therefore, hBD-3 may be a potent new agent for treating colon cancer.

Collagen triple helix repeat containing 1 is overexpressed in hepatocellular carcinoma and promotes cell proliferation and motility.

Although several therapeutic options are available for hepatocellular carcinoma (HCC), the outcome is still very poor. One reason is the complexity of signal transduction in the pathogenesis of HCC. The aim of this study was to identify new HCC-related genes and to investigate the functions of these genes in the pathogenesis and progression of HCC. Whole genomes of 15 surgically resected HCC specimens were examined for copy number alterations with comparative genomic hybridization. Gene expression was compared between HCC and normal liver tissues. The roles of the new genes in the progression of HCC were studied using cultured cell lines. Copy number gain in chromosome 8q was detected in 53% of HCC tissues examined. The gene that coded for collagen triple helix repeat containing 1 (CTHRC1), located at chromosome 8q22.3, was overexpressed in HCC compared with normal or liver cirrhosis tissues and identified as a new HCC-related gene. CTHRC1 deletion with short hairpin RNA significantly reduced proliferation, migration and invasion of HepG2 and Huh7 cells. In addition, mRNA of integrins ß-2 and ß-3 was downregulated, with deletion of CTHRC1 in these cells. Immunohistochemical staining on resected HCC tissues showing positive staining areas for CTHRC1 was significantly greater in poorly-differentiated HCC compared with well­differentiated HCC. Moreover, some cases showed strong staining for CTHRC1 in invasive areas of HCC. CTHRC1 has the potential to be a new biomarker for the aggressive HCC, and to be a new therapeutic target in treating HCC.

Splenectomy increases the number of circulating hematopoietic stem/progenitor cells in patients with hepatitis C virus-associated liver cirrhosis.

AIM: The spleen is not believed to contribute to hematopoiesis in healthy adults. However, several reports have demonstrated that the spleen in adults contains a large number of hematopoietic stem/progenitor cells (HSC). Although splenectomy increases platelet and leukocyte counts, the effects of splenectomy on circulating HSC have not been elucidated. In this study, we evaluated the association between the number of circulating HSC and splenectomy in patients with hepatitis C virus (HCV)-associated liver cirrhosis (LC). METHODS: In 48 patients with various stages of HCV-associated chronic liver disease and seven patients with LC who underwent splenectomy, and 10 healthy volunteers, we determined the numbers of circulating CD34+ cells and colony-forming unit culture by flow cytometry and methylcellulose culture, respectively. Plasma stromal cell-derived factor-1α (SDF-1α) concentrations were measured using an enzyme-linked immunosorbent assay. RESULTS: The numbers of circulating CD34+ cells and colony-forming unit culture decreased but the plasma SDF-1α concentration increased with the progression of liver disease. There was an inverse correlation between the number of circulating HSC and the plasma SDF-1α concentration. The numbers of circulating HSC and platelets were determined before and after splenectomy in seven patients with LC. In these patients, the numbers of circulating HSC and platelets increased significantly after splenectomy and the enhancing effect persisted for a long time. CONCLUSION: Our data suggest that the spleen plays an important role in modulating HSC dynamics in patients with HCV-associated chronic liver disease. Our results also imply that splenectomy may improve liver function in patients with LC.