Serum angiotensin-converting enzyme level for evaluating significant fibrosis in chronic hepatitis B

AIM To evaluate the diagnostic performance of angiotensinconverting enzyme(ACE)on significant liver fibrosis in patients with chronic hepatitis B(CHB). METHODS In total,100 patients with CHB who underwent liver biopsy in our hospital were enrolled,and 70 patients except for 30 patients with hypertension,fatty liver or habitual alcoholic consumption were analyzed.We compared histological liver fibrosis and serum ACE levels and evaluated the predictive potential to diagnose significant liver fibrosis by comparison with several biochemical marker-based indexes such as the aspartate aminotransferase(AST)-to-platelet ratio index(APRI),the fibrosis index based on four factors(FIB-4),the Mac-2 binding protein glycosylation isomer(M2BPGi)level and the number of platelets(Plt). RESULTS Serum ACE levels showed moderately positive correlation with liver fibrotic stages(R2=0.181).Patients with significant,advanced fibrosis and cirrhosis(F2-4)had significantly higher serum ACE levels than those with early-stage fibrosis and cirrhosis(F0-1).For significant fibrosis(≥F2),the 12.8 U/L cut-off value of ACE showed 91.7%sensitivity and 75.0%specificity.The receiver-operating characteristic(ROC)curves analysis revealed that the area under the curve(AUC)value of ACE was 0.871,which was higher than that of APRI,FIB-4,M2BPGi and Plt. CONCLUSION The serum ACE level could be a novel noninvasive,easy,accurate,and inexpensive marker of significant fibrosis stage in patients with CHB.

Crosstalk between angiogenesis, cytokeratin-18, and insulin resistance in the progression of non-alcoholic steatohepatitis

AIM: To elucidate the possible crosstalk between angiogenesis, cytokeratin-18 (CK-18), and insulin resistance (IR) especially in patients with non-alcoholic steatohepatitis (NASH).METHODS: Twenty-eight patients with NASH and 11 with simple fatty liver disease (FL) were enrolled in this study and underwent clinicopathological examination. The measures of angiogenesis, CK-18, and IR employed were CD34-immunopositive vessels, CK-18immunopositive cells, and homeostasis model assessment of IR (HOMA-IR), respectively. The correlations of these factors with NASH were elucidated.RESULTS: Significant development of hepatic neovascularization was observed only in NASH, whereas almost no neovascularization could be observed in FL and healthy liver. The degree of angiogenesis was almost parallel to liver fibrosis development, and both parameters were positively correlated. Similarly, CK-18expression and HOMA-R were signifi cantly increased in NASH as compared with FL and healthy liver. Furthermore, CK-18 and HOMA-IR were also positively correlated with the degree of neovascularization. CONCLUSION: These results indicate that the crosstalk between angiogenesis, CK-18, and IR may play an important role in the onset and progression of NASH.

Combined treatment of vitamin K_2 and angiotensin-converting enzyme inhibitor ameliorates hepatic dysplastic nodule in a patient with liver cirrhosis

Although it is well known that the hepatocellular carcinoma (HCC) is an ominous complication in patients with liver cirrhosis, there has been no approved drug to prevent the development of HCC to date. We previously reported that the combined treatment of vitamin K2 (VK) and angiotensin-converting enzyme inhibitor (ACE-I) significantly suppressed the experimental hepatocarcinogenesis. A 66-year-old Japanese woman with hepatitis C virus (HCV)-related liver cirrhosis developed a dysplastic nodule in the liver detected by enhanced computed tomography along with elevation of the tumor markers, namely, alpha-fetoprotein (AFP) and lectin-reactive demarcation (AFP-L3), suggesting the presence of latent HCC. After oral administration of VK and ACE-I, the serum levels of both AFP and AFP-L3 gradually decreased without any marked alteration of the serum aminotransferase activity. After one-year treatment, not only the serum levels of AFP and AFP-L3 returned to the normal ranges, but also the dysplastic nodule disappeared. Since both VK and ACE-I are widely used without serious side effects, this combined regimen may become a new strategy for chemoprevention against HCC.

Eosinophilic cholecystitis along with pericarditis caused by Ascaris lumbricoides: A case report

Although the etiology of eosinophilic cholecystitis is still obscure, the postulated causes include allergies, parasites, hypereosinophilic syndrome, and eosinophilic gastroenteritis. It is sometimes accompanied by several complications, but a simultaneous onset with pericarditis is very rares. A 28-year-old woman complained of acute right hypocondrial pain and dyspnea associated with systemic eruption. Several imaging modalities revealed acute cholecystitis and pericarditis with massive pericardial effusion. A marked peripheral blood eosinophilia was observed, and the eruption was diagnosed as urticaria. Her serum had a high titer of antibody against Ascaris lumbricoides . Treatment with albendazole drastically improved all clinical manifestations along with normalization of the imaging features and eosinophilia. We report herein a rare case of simultaneous onset of acute cholecystitis and pericarditis associated with a marked eosinophilia caused by parasitic infection.

Interferon augments the anti-fibrotic activity of an angiotensin-converting enzyme inhibitor in patients with refractory chronic hepatitis C

AIM： To evaluate the effect of combination treatment with the interferon （IFN） and angiotensin-converting enzyme inhibitor （ACE-Ⅰ） on several fibrotic indices in patients with refractory chronic hepatitis C （CHC）. METHODS： Perindopril （an ACE-Ⅰ; 4 mg/d） and/or natural IFN （3 MU/L; 3 times a week） were administered for 12 mo to refractory CHC patients, and several indices of serum fibrosis markers were analyzed. RESULTS： ACE-Ⅰ decreased the serum fibrosis markers, whereas single treatment with IFN did not exert these inhibitory effects. However, IFN significantly augmented the effects of ACE-Ⅰ, and the combination treatment exerted the most potent inhibitory effects. The serum levels of alanine transaminase and HCV-RNA were not significantly different between the groups, whereas the plasma level of transforming growth factor-β was significantly attenuated almost in parallel with suppression of the serum fibrosis markers. CONCLUSION： The combination therapy of an ACE-Ⅰand IFN may have a diverse effect on disease progression in patients with CHC refractory to IFN therapy through its anti-fibrotic effect.

DNA methylation of angiotensin Ⅱ receptor gene in nonalcoholic steatohepatitis-related liver fibrosis

AIM To clarify whether Agtr1 a methylation is involved in the development of nonalcoholic steatohepatitis(NASH)-related liver fibrosis in adult rats.METHODS A choline-deficient amino acid(CDAA) diet model was employed for methylation analysis of NASH-related liver fibrosis.Agtr1 a methylation levels were measured in the livers of CDAA- and control choline-sufficient amino acid(CSAA)-fed rats for 8 and 12 wk using quantitative methylation-specific PCR.Hepatic stellate cells(HSCs) were isolated by collagenase digestion of the liver,followed by centrifugation of the crude cell suspension through a density gradient.Agtr1 a methylation and its gene expression were also analyzed during the activation of HSCs.RESULTS The mean levels of Agtr1 a methylation in the livers of CDAA-fed rats(11.5% and 18.6% at 8 and 12 wk,respectively) tended to be higher(P = 0.06 and 0.09,respectively) than those in the livers of CSAA-fed rats(2.1% and 5.3% at 8 and 12 wk,respectively).Agtr1 a was not methylated at all in quiescent HSCs,but was clearly methylated in activated HSCs(13.8%,P < 0.01).Interestingly,although Agtr1 a was hypermethylated,the Agtr1 a m RNA level increased up to 2.2-fold(P < 0.05) in activated HSCs compared with that in quiescent HSCs,suggesting that Agtr1 a methylation did not silence its expression but instead had the potential to upregulate its expression.These findings indicate that Agtr1 a methylation and its upregulation of gene expression are associated with the development of NASH-related liver fibrosis.CONCLUSION This is the first study to show that DNA methylation is potential y involved in the regulation of a renin-angiotensin system-related gene expression during liver fibrosis.

A case of severe acalculous cholecystitis associated with sorafenib treatment for advanced hepatocellular carcinoma

Sorafenib,a multikinase inhibitor,is the first and only drug,which improves significantly the overall survival in patients with advanced hepatocellular carcinoma(HCC).However,many patients experience diverse side effects,some of them severe and unexpected.To date,acute acalculous cholecystitis has not been documented in association with a HCC patient treated with sorafenib.Here,we report the case of a 43-yearold woman with hepatitis C virus-related advanced HCC.She received sorafenib,and later complained ofa sudden onset of severe right hypocondrial pain with rebound tenderness and muscle defense.Laboratory examination showed mild elevation of transaminases,biliary enzymes,bilirubin,inflammation markers,and a marked peripheral eosinophilia.Abdominal computed tomography(CT) revealed a swollen gallbladder with exudate associated with severe inflammation without stones or debris.Consequently,sorafenib treatment was stopped immediately,and steroid-pulse therapy was performed.Steroid therapy drastically improved all clinical manifestations along with normalization of CT findings,eosinophilia,and liver functions.In summary,we herein report a rare case of acute severe acalculous cholecystitis associated with sorafenib in the patient with advanced HCC.

Acylcarnitine: Useful biomarker for early diagnosis of hepatocellular carcinoma in non-steatohepatitis patients

BACKGROUND Early diagnosis of hepatocellular carcinoma(HCC)is necessary to improve the prognosis of patients.However,the currently available tumor biomarkers are insufficient for the early detection of HCC.Acylcarnitine is essential in fatty acid metabolic pathways.A recent study reported that a high level of acylcarnitine may serve as a useful biomarker for the early diagnosis of HCC in steatohepatitis(SH)patients.In contrast,another study reported that the level of acetylcarnitine(AC2)-one of the acylcarnitine species-in non-SH patients with HCC was decreased vs that reported in those without HCC.AIM To investigate the usefulness of acylcarnitine as a biomarker for the early diagnosis of HCC in non-SH patients.METHODS Thirty-three non-SH patients(14 with HCC and 19 without HCC)were enrolled in this study.Blood samples were obtained from patients at the time of admission.The levels of acylcarnitine and AC2 in the serum were determined through tandem mass spectrometry.The levels of vascular endothelial growth factor(VEGF)and VEGF receptor 2(VEGFR-2)were determined by enzymelinked immunosorbent assay.Univariate and multivariate analyses were used to determine early diagnostic factors of HCC.RESULTS The level of acylcarnitine was significantly lower in non-SH patients with HCC vs those without HCC(P<0.05).In contrast,the level of lens culinaris agglutininreactive fraction ofα-fetoprotein(AFP)-AFP-L3%-was significantly higher in non-SH patients with HCC vs those without HCC(P<0.05).However,the levels of total carnitine,free carnitine,AFP,des-γ-carboxy prothrombin,VEGF,and VEGFR-2 were not different between patients with and without HCC.The multivariate analysis showed that a low level of acylcarnitine was the only independent factor for the early diagnosis of HCC.The patients with a low level of AC2 had a significantly higher level of VEGF vs those with a high level of AC2(P<0.05).CONCLUSION The metabolic pathways of fatty acids may differ between SH HCC and non-SH HCC.Further studies are warranted to investigate these differences.

A histologically proven case of progressive liver sarcoidosis with variceal rupture

Sarcoidosis is a chronic multi-systemic granulomatous disease,and liver involvement frequently occurs.in most cases,no evidence of liver dysfunction is ob-served,and portal hypertension due to sarcoid liver diseases is a rareoccurrence.Moreover,no case of liver sarcoidosis has ever been reported with confirma-tion of the disease progression.Herein we describe a patient having hepatic sarcoidosis with severe portal hypertension and liver dysfunction.The diagnosis was histologically confirmed from granulomatous status to established liver cirrhosis over 10 years.A 46-year-old woman developed massive hematemesis due to the rupture of gastric cardial varices.She underwent emer-gency endoscopic injection sclerotherapy,and clear evi-dence of chronic hepatic failure.Twelve years ago,she was diagnosed as having sarcoidosis with respiratoryclinicalsymptoms.Liver biopsy revealed asymptomatic incidental granulomas without fibrosis development.After a couple of years,features of liver dysfunction were manifest and progressed.Ten years after the first biopsy,a second liver biopsy was performed,and well established dense fibrosis was revealed.Although significant liver dysfunction with portal hypertension is rarely seen in sarcoidosis,this case indicates that we have to consider the possibility that sarcoidosis may cause end-stage liver cirrhosis.