Yoko Soroida

Increased activity of serum mitochondrial isoenzyme of creatine kinase in hepatocellular carcinoma patients predominantly with recurrence

BACKGROUND & AIMS Mitochondrial isoenzyme of creatine kinase (MtCK) is reportedly highly expressed in hepatocellular carcinoma (HCC). Clinical relevance of serum MtCK activity in patients with HCC was assessed using a novel immuno-inhibition method. METHODS Among patients with cirrhosis caused by hepatitis B or C virus, 147 patients with HCC (12 with the first occurrence and 135 with recurrence) and 92 patients without HCC were enrolled. RESULTS Serum MtCK activity was higher in cirrhotic patients with HCC than in those without HCC or healthy subjects. Elevated serum MtCK activity in HCC patients decreased after radiofrequency ablation. In case of prediction of HCC, MtCK had a sensitivity of 62.6% and a specificity of 70.7% at a cut-off point of 8.0 U/L, with an area under the receiver operating curve of 0.722 vs. 0.713 for alpha-fetoprotein (AFP) and 0.764 for des-gamma-carboxy prothrombin (DCP). Among the HCC patients, serum MtCK activity was elevated in 52.9% individuals with serum AFP level < 20 ng/ml and 63.2% individuals with serum DCP level < 40 mAu/ml. Even in patients with a single HCC ≤ 2 cm, the sensitivity of serum MtCK activity for the prediction of HCC was 64.4%, which was comparable to the overall sensitivity. This increased activity was due to an increase in ubiquitous MtCK, not sarcomeric MtCK, and the enhanced mRNA expression of ubiquitous MtCK was observed in cell lines originating from HCCs in contrast to healthy liver tissues. CONCLUSIONS Serum MtCK activity merits consideration as a novel marker for HCC to be further tested as for its diagnostic and prognostic power.

High ubiquitous mitochondrial creatine kinase expression in hepatocellular carcinoma denotes a poor prognosis with highly malignant potential

We previously reported the increased serum mitochondrial creatine kinase (MtCK) activity in patients with hepatocellular carcinoma (HCC), mostly due to the increase in ubiquitous MtCK (uMtCK), and high uMtCK mRNA expression in HCC cell lines. We explored the mechanism(s) and the relevance of high uMtCK expression in HCC. In hepatitis C virus core gene transgenic mice, known to lose mitochondrial integrity in liver and subsequently develop HCC, uMtCK mRNA and protein levels were increased in HCC tissues but not in non‐tumorous liver tissues. Transient overexpression of ankyrin repeat and suppressor of cytokine signaling box protein 9 (ASB9) reduced uMtCK protein levels in HCC cells, suggesting that increased uMtCK levels in HCC cells may be caused by increased gene expression and decreased protein degradation due to reduced ASB9 expression. The reduction of uMtCK expression by siRNA led to increased cell death, and reduced proliferation, migration and invasion in HCC cell lines. Then, consecutive 105 HCC patients, who underwent radiofrequency ablation with curative intent, were enrolled to analyze their prognosis. The patients with serum MtCK activity >19.4 U/L prior to the treatment had significantly shorter survival time than those with serum MtCK activity ≤19.4 U/L, where higher serum MtCK activity was retained as an independent risk for HCC‐related death on multivariate analysis. In conclusion, high uMtCK expression in HCC may be caused by hepatocarcinogenesis per se but not by loss of mitochondrial integrity, of which ASB9 could be a negative regulator, and associated with highly malignant potential to suggest a poor prognosis.

Potential associations between perihepatic lymph node enlargement and liver fibrosis, hepatocellular injury or hepatocarcinogenesis in chronic hepatitis B virus infection

Although perihepatic lymph node enlargement (PLNE) is frequently observed in chronic liver disease, little is known about PLNE in chronic hepatitis B virus (HBV) infection. We aimed to evaluate this issue.

Perihepatic lymph node enlargement is a negative predictor for sustained responses to pegylated interferon‐α and ribavirin therapy for Japanese patients infected with hepatitis C virus genotype 1

 Although perihepatic lymph node enlargement (PLNE) is reportedly associated with the negative outcome of interferon therapy for chronic hepatitis C, there were limitations in that the results were obtained in patients with various genotypes, viral loads and treatment regimens. We aimed to precisely clarify the significance of PLNE in interferon therapy for chronic hepatitis C.

Increased serum mitochondrial creatine kinase activity as a risk for hepatocarcinogenesis in chronic hepatitis C patients

Serum mitochondrial creatine kinase (MtCK) activity was reportedly increased in cirrhotic patients although less prominent than that in hepatocellular carcinoma (HCC) patients. To elucidate the clinical significance of serum MtCK activity in chronic liver disease, 171 chronic hepatitis C patients were enrolled. Serum MtCK activity in study subjects was correlated with serum albumin, platelet counts, liver stiffness values and serum aspartate and alanine aminotransferase. In mouse fibrotic liver induced by bile duct ligation, ubiquitous MtCK mRNA and protein expressions were significantly enhanced and its immunoreactivity was increased, predominantly in hepatocytes. During the mean follow‐up period of 2.7 years, HCC developed in 21 patients, in whom serum MtCK activity was significantly higher than that in patients without HCC development. Multivariate Cox regression analysis revealed that higher serum MtCK activity was a risk for HCC development. A cutoff value of MtCK for the prediction of HCC development was determined as 9.0 U/L on receiver operating characteristics analysis, where area under receiver operating characteristics curve was 0.754, with a sensitivity of 61.9%, a specificity of 92.8% and a high negative predictive value of 94.2%. Cumulative incidence of HCC was significantly higher in patients with serum MtCK activity of >9.0 U/L compared to those with serum MtCK activity of ≤9.0 U/L even in patients with elevated liver stiffness value, >15 kPa. In conclusion, serum MtCK activity may be increased correlatively with the stage of liver fibrosis and hepatocellular damage. Increased serum MtCK activity is an independent risk for hepatocarcinogenesis in chronic hepatitis C patients.

Perihepatic lymph node enlargement observed at a general health examination: A cross‐sectional study

Although perihepatic lymph node enlargement (PLNE) is known as a common finding in chronic liver disease, it can be found occasionally at a general health examination. We aimed to clarify the clinical significance of PLNE in general.

Eradication of hepatitis C virus is associated with the attenuation of steatosis as evaluated using a controlled attenuation parameter

Chronic hepatitis C virus (HCV) infection was shown to cause hepatic steatosis or suppression of serum lipid levels. However, little is known about the changes in hepatic steatosis following HCV eradication. We aimed to evaluate this issue using the controlled attenuation parameter (CAP), which was recently shown to provide a standardized non-invasive measure of hepatic steatosis. We enrolled 70 patients with chronic HCV infections and steatosis (CAP of over 248 dB/m) who had achieved a sustained viral response at 12 weeks after discontinuation of antiviral treatment using direct-acting antivirals (DAA). We then evaluated the state of hepatic steatosis before and after HCV eradication. We also investigated the changes in serum parameters such as cholesterol and glucose levels. The median value of CAP level decreased significantly after HCV eradication from 273 dB/m to 265 dB/m (P = 0.034). Also, LDL and HDL cholesterol levels increased significantly after HCV eradication (P = 0.002 and P = 0.027, respectively). In conclusion, a decrease in hepatic steatosis after HCV eradication with DAA was revealed in chronic hepatitis C patients with significant steatosis. Cancellation of the viral effect is a possible underlying cause of hepatic steatosis improvement and increase in HDL and LDL cholesterol levels.

Disappearance of Perihepatic Lymph Node Enlargement after hepatitis C viral eradication with direct acting antivirals

Perihepatic lymph node enlargement (PLNE) which has been shown to be negatively associated with hepatocellular carcinoma (HCC) occurrence is frequently observed in chronic liver disease; however, changes in the state of perihepatic lymph nodes after eradication of hepatitis C virus (HCV) have not been investigated yet. We aimed to evaluate this issue. We enrolled 472 patients with chronic HCV infection who achieved viral eradication with direct‐acting antivirals (DAA). We investigated whether the status of perihepatic lymph nodes changed before and after HCV eradication (primary endpoint). We also evaluated the association between PLNE and clinical findings such as liver fibrosis or hepatocellular injury before HCV eradication (secondary endpoint). Perihepatic lymph node enlargement was detected in 164 of 472 (34.7%) patients before DAA treatment. Surprisingly, disappearance of PLNE was observed in 23.8% (39 patients) of all PLNE‐positive patients after eradication of HCV. Disappearance of PLNE was not associated with baseline clinical parameters or changing rates of clinical findings before and after DAA treatment. At baseline, presence of PLNE was significantly associated with a lower serum HCV‐RNA level (P = .03), a higher serum AST level (P = .004) and a higher ALT level (P < .001) after adjustment for sex and age. In conclusion, PLNEs became undetectable after DAA treatment in 23.8% of PLNE‐positive patients. Further study with a longer follow‐up period is needed to clarify the clinical importance of this phenomenon especially in relationship with the risk of HCC development.

Identification of liver fibrosis using the hepatic vein waveform in patients with Fontan circulation: Liver fibrosis in Fontan patients

Liver fibrosis caused by congestive hepatopathy has emerged as an important complication after Fontan procedure. We evaluated the utility of the hepatic vein (HV) waveform using Doppler ultrasound for identification of liver fibrosis in Fontan patients.

The power Doppler twinkling artefact associated with periarticular calcification induced by intra-articular corticosteroid injection in patients with rheumatoid arthritis

Intra-articular corticosteroid injections are widely used to treat rheumatoid arthritis (RA).1 Although they are useful in combination with other antirheumatic agents, some side effects have been reported including subcutaneous atrophy, septic arthritis, avascular necrosis, and rarely, periarticular calcification.2–4 We report here two RA cases that presented with periarticular calcification. Case 1. A 51-year-old woman suffering from RA for 6 years was treated with methotrexate 16 mg weekly, abatacept 500 mg monthly and triamcinolone acetonide injection on the radial side of the right third proximal interphalangeal (PIP) joint approximately once a month (22 times for the third PIP joint in total). While disease activity scores for 28 joints maintained low disease activity, a hand radiograph showed progressive periarticular calcifications on the injected radial side (figure 1A–C). Joint ultrasonography revealed hyperechoic regions in the joint cavity with posterior power Doppler (PD) signals (figure 2A). Spectral Doppler sonography was performed to evaluate the nature of the PD signals, and an artefactual spectral signal without any definable flow pattern was observed (figure 2B). This finding was obviously different from the true RA synovitis finding detected on her right first metacarpophalangeal joint (figure 2C). …