Effectiveness of 1-year pemafibrate treatment on steatotic liver disease: the influence of alcohol consumption.

BACKGROUND/AIMS: Pemafibrate is a selective peroxisome proliferator-activated receptor α modulator that improves serum alanine aminotransferase (ALT) in dyslipidemia patients. We previously reported that pemafibrate significantly improves liver function, serum triglyceride (TG) levels and liver stiffness in non-alcoholic fatty liver disease patients, however the influence of alcohol consumption was not considered. Therefore, we explored pemafibrate efficacy in patients with steatotic liver disease (SLD) and alcohol-associated liver disease (ALD). METHODS: We retrospectively evaluated pemafibrate efficacy on liver enzymes and lipids in metabolic dysfunction-associated SLD (MASLD) (n = 93), MASLD plus increased alcohol intake (MetALD; n = 23) and ALD (n = 22) patients who had taken pemafibrate for at least 48 weeks. Liver shear wave velocity (SWV, n = 75) was also evaluated. RESULTS: In MASLD group, ALT, aspartate aminotransferase (AST), γ-glutamyl transpeptidase (γ-GTP) and TG values were significantly decreased from baseline to week 24 and week 48 ( P  < 0.0001). ALT and TG values in MetALD group and ALT and AST values in ALD group were also significantly decreased from baseline to week 24 and week 48. Study participant SWV values decreased from baseline to week 48. We observed no significant difference in changes to ALT, AST, γ-GTP and TG (value at week 24 or week 48 minus value at baseline) among the three groups. CONCLUSION: Pemafibrate improves liver function and liver stiffness thus making it a promising therapeutic agent for SLD, even in patients with excess alcohol consumption (MetALD and ALD groups).

Effect of pemafibrate on liver enzymes and shear wave velocity in non-alcoholic fatty liver disease patients.

Background/Aims: Pemafibrate is a selective peroxisome proliferator-activated receptor α modulator that improves serum alanine aminotransferase (ALT) in dyslipidemia patients. Pemafibrate was reported to reduce ALT in non-alcoholic fatty liver disease (NAFLD) patients, but efficacy was not clearly elucidated due to the small size of previous study populations. Therefore, we explored pemafibrate efficacy in NAFLD patients. Methods: We retrospectively evaluated pemafibrate efficacy on liver enzymes (n = 132) and liver shear wave velocity (SWV, n = 51) in NAFLD patients who had taken pemafibrate for at least 24 weeks. Results: Patient ALT levels were decreased from 81.0 IU/L at baseline to 48.0 IU/L at week 24 (P < 0.0001). Serum levels of aspartate aminotransferase (AST), γ-glutamyl transpeptidase (γ-GTP) and triglyceride (TG) were significantly decreased, and high-density lipoprotein cholesterol and platelet count were significantly increased, with no change in body weight being observed. Study participant SWV values decreased from 1.45 m/s at baseline to 1.32 m/s at week 48 (P < 0.001). Older age (P = 0.035) and serum TG levels (P = 0.048) were significantly associated with normalized ALT. Changes in AST, ALT, γ-GTP and body weight were significantly correlated with change in SWV. Conclusion: Pemafibrate significantly improves liver function, serum TG and liver stiffness in NAFLD patients. Pemafibrate is a promising therapeutic agent for NAFLD and may be a candidate for NAFLD patients with elevated TG.

Effect of branched-chain amino acids in patients receiving intervention for hepatocellular carcinoma.

AIM: To investigate the usefulness of branched-chain amino acids (BCAA) before transarterial chemoembolization (TACE) or radiofrequency ablation (RFA). METHODS: We investigated the usefulness of pre-intervention with BCAAs by comparing patients treated with BCAAs at 12.45 g/d orally for at least 2 wk before TACE or RFA and those not receiving such pretreatment. A total of 270 patients with hepatocellular carcinoma complicated by cirrhosis were included in the study. Mean changes from baseline (Δ) in serum albumin (Alb), C-reactive protein (CRP), and transaminase levels, as well as peak body temperature were also determined and compared at days 2, 5, and 10 after the start of TACE or RFA. RESULTS: In patients who underwent TACE or RFA, BCAA pre-intervention significantly suppressed the development of post- intervention hypoalbuminemia and reduced inflammatory reactions during the subsequent clinical course. After TACE, the ΔAlb peaked on day 2, remained constantly lower in BCAA-treated patients, compared to the control group, and was -0.13 ± 0.42 g/dL in BCAA-treated patients and -0.33 ± 0.51 g/dL in untreated patients on day 10. The ΔCRP was also significantly lower in BCAA-treated patients on days 2, 5 and 10 after TACE. Like the trends noted after TACE, a similar tendency was noted as to the ΔAlb and ΔCRP after RFA. The changes in serum Alb level were inversely correlated with CRP changes; therefore, a possible involvement of the anti-inflammatory effect of BCAAs was inferred as a factor contributory to the suppression of decrease in serum Alb level. CONCLUSION: Pre-intervention with BCAAs may hasten the recovery of serum Alb level and mitigate post-operative complications in patients undergoing TACE or RFA.

Current state of Wilson disease patients in central Japan.

OBJECTIVE: This study evaluated the current state of patients with Wilson disease in central Japan. PATIENTS AND METHODS: Between 1999 and 2007, 30 patients were diagnosed as having Wilson disease with an International Diagnostic Score of 4 or more. The phenotypes, genotypes and post-diagnostic courses of these patients were analyzed. RESULTS: Twenty-six patients had ATP7B mutations responsible for Wilson disease. Four patients had a single mutant chromosome. There were 2 major mutations of 2333 G>T and 2871 delC (40%), and 6 novel mutations (13%) in our patients. The first clinical manifestation was the hepatic form in 22, neurological form in 5, and hemolysis in 3 patients. The hepatic form was diagnosed around the age of 13 years, followed by neurological complication with a time lag of 9 years. Thus, some patients, especially patients with the neurological form, did not undergo early diagnostic tests including ATP7B analysis. During the post-diagnosis period, 3 patients were hospitalized for recurrent liver disease, and 2 patients committed suicide. One female patient died from acute hepatic failure associated with encephalopathy after fertilization therapy, while 2 male patients recovered from encephalopathy-free, prolonged hepatic failure after noncompliance with drug therapy. The King's Scores for liver transplantation were below the cut-off in both cases. CONCLUSION: To minimize delayed diagnosis, ceruloplasmin determination and ATP7B analysis may be recommended to patients showing hepatic damage of unknown etiology. At gene diagnosis, appropriate management of patients including compliance education and emotional care to prevent suicide might be important.

Effect of lactoferrin in patients with chronic hepatitis C: combination therapy with interferon and ribavirin.

OBJECTIVES: Lactoferrin has been reported to inhibit hepatitis C virus (HCV) infection in cultured human hepatocytes and HCV viremia in patients with chronic hepatitis C (CHC). The aim of this study was to evaluate the effect of combined triple therapy of lactoferrin, interferon and ribavirin in patients with CHC. METHODS: A total of 111 Japanese patients with CHC were randomly assigned to a lactoferrin group (n = 50) and a control group (n = 61). The lactoferrin group was treated with lactoferrin for 8 weeks and then with lactoferrin, interferon and ribavirin for 24 weeks; the control group was treated with interferon and ribavirin for 24 weeks. Serum anti-lactoferrin antibody, clinical and laboratory measurement were determined. RESULTS: The mean HCV RNA titer significantly decreased at the end of lactoferrin monotherapy. Sustained virological response to therapy was significantly higher (P < 0.05) in the lactoferrin responder group (55%) than in the control group (18%). CONCLUSIONS: The results show that the decrease in HCV RNA titer by lactoferrin monotherapy contributes to the effectiveness of the combined therapy of interferon and ribavirin in patients with CHC. Lactoferrin is a potential useful adjunct treatment for patients with CHC.

Decreased protein C activation in patients with fulminant hepatic failure.

OBJECTIVE: Abnormalities of the blood coagulation system have an influence on outcome in patients with fulminant hepatic failure (FHF). The protein C (PC) pathway is one of the main modulators of the blood coagulation system. The role of the PC pathway in FHF is not clear. In the present study, we evaluated endothelial cell injury and the grade of activated protein C (APC) generation in FHF patients. MATERIAL AND METHODS: The effect of APC on the expression of tumor necrosis factor (TNF)-alpha and monocyte chemoattractant protein (MCP)-1 from LI90 stellate cells was also evaluated. This study comprised 5 patients with FHF, 6 with acute hepatitis (AH), 12 with chronic hepatitis (CH) and 20 healthy subjects. RESULTS: The plasma concentrations of thrombin-antithrombin complex and thrombomodulin were significantly increased in FHF patients compared with those in AH patients and healthy subjects. The circulating levels of activated protein C-protein C inhibitor (APC-PCI) complex and the APC-PCI/PC ratio were significantly decreased in patients with FHF compared to healthy controls. APC significantly inhibited in vitro the expression of TNFalpha and MCP-1 from LI90 stellate cells. CONCLUSIONS: This study demonstrated enhanced endothelial cell injury in association with decreased PC activation and hypercoagulability in FHF.

Evaluation of cingulate gyrus blood flow in patients with liver cirrhosis.

Although neuropsychological tests are commonly applied to detect minimal hepatic encephalopathy (HE) in patients with liver cirrhosis (LC), they provide no information about the cerebral regions involved. Recently, it has been reported that some populations of alcoholic cirrhotics, with mild HE, have reduced cerebral metabolic rate for glucose in bifrontal cortices and in the anterior cingulate gyrus. We evaluated the degree of reduction in blood flow at the anterior cingulate gyrus and the frontal lobes in cirrhotic patients who underwent single photon emission computed tomography (SPECT). Data were obtained from 47 cirrhotic patients and 47 subjects without LC. Three radiologists unaware of the results of laboratory tests visually evaluated the transaxial, coronal, and sagittal views of SPECT. The area and the degree of blood flow reduction in the anterior cingulate gyrus and frontal lobes were scored. Reduced blood flow in the anterior cingulate gyrus was observed in most LC patients. In patients without overt HE, poor performance in neuropsychological tests was correlated with reduced cerebral blood flow in the anterior cingulate gyrus. Blood flow in the anterior cingulate gyrus as measured by SPECT may be a simple and good indicator of cerebral functional changes in patients with LC.

A significant reduction in serum alanine aminotransferase levels after 3-month iron reduction therapy for chronic hepatitis C: a multicenter, prospective, randomized, controlled trial in Japan.

BACKGROUND: Increasing evidence indicates that iron cytotoxicity plays an important role in the pathogenesis of chronic hepatitis C (CHC). However, the biochemical effects of iron reduction therapy on CHC remain to be confirmed in a controlled study. This study aimed to test whether iron removal by repeated phlebotomy improves serum alanine aminotransferase (ALT) levels in patients with CHC. METHODS: Patients were randomly assigned to an iron reduction therapy or control group. The patients in the treatment group received 3-month iron reduction therapy by biweekly phlebotomy, while the patients in the control group were followed up for 3 months with regular blood tests alone. RESULTS: Thirty-three patients completed the 3-month treatment, while 29 patients received the complete follow-up. The serum ALT levels were reduced from 118 +/- 79 to 73 +/- 39 IU/L in the treatment group, but did not change in the control group (106 +/- 45 versus 107 +/- 48 IU/L). Posttreatment enzyme activity was decreased significantly from the baseline. Furthermore, it was significantly lower than the 3-month control level. Although 5 patients withdrew from the study, none was affected by any side effects of repeated phlebotomy that required them to discontinue the treatment. CONCLUSIONS: This short-term controlled trial demonstrated the biochemical efficacy and safety of iron reduction therapy for patients with CHC.

Efficacy of long-term dietary restriction of total calories, fat, iron, and protein in patients with chronic hepatitis C virus.

OBJECTIVES: A diet restrictive in total calories, fat, iron, and protein intake reduces serum alanine aminotransferase levels in patients with long-term hepatitis C virus infection. However, whether long-term dietary therapy causes adverse effects such as malnutrition and anemia due to a shortage of energy intake is not clear. We evaluated the balance of energy intake and changes in physical and hematologic indices of nutrition after a long-term dietary therapy. METHODS: Twenty-two patients with long-term hepatitis C virus infection that did not respond to or who were able or unwilling to take interferon therapy were enrolled in this study. Our prescriptions included 7 mg/d or less of iron, 30 kcal. kg(-1). d(-1) of energy, 1.1 to 1.2 g. kg(-1). d(-1) of protein, and a fat energy fraction of 20%. Patients were followed for 24 mo. RESULTS: Mean body fat percentage was 24.6% at entry and was significantly reduced after the diet prescription. Mean serum ferritin decreased significantly from 376 ng/mL at entry to 141 ng/mL after 24 mo. Mean serum alanine aminotransferase levels decreased significantly from 66 to 49 IU/L. Mean levels of hemoglobin, serum albumin, and cholinesterase did not change significantly during the follow-up period. CONCLUSIONS: These results suggest that restriction of energy, fat, iron, and protein intakes is safely tolerated, so its long-term use should be recommended to patients with long-term infection with hepatitis C virus.

Different hepatitis C virus dynamics of free-virions and immune-complexes after initiation of interferon-alpha in patients with chronic hepatitis C.

BACKGROUND/AIMS: To elucidate the mechanisms of action of interferon (IFN) against hepatitis C virus (HCV), we studied the serum HCV dynamics of free-virions (FV) and immune-complexes (IC) in patients treated with IFN. METHODS: FV and IC were separated by immunoprecipitation using anti-human immunoglobulin and quantified serially using real-time detection-polymerase chain reaction. RESULTS: Initially [1st phase (0-24 h)], the FV decreased more rapidly compared to IC [exponential decay slope (EDS)=1.78+/-0.42 vs. 0.99+/-0.31 log10/day, P<0.001; half-life=5.65+/-2.02 vs. 12.5+/-2.83 h, P<0.0001], but at the 2nd phase (1-14 days), half-life of FV was significantly longer than that of IC (101+/-117 vs. 14.2+/-1.08 h, P<0.005). Regarding response to IFN, the decline slope was not significantly different at the 1st phase, but at the 2nd phase, the FV-HCV RNA decreased more slowly in non-responders than in sustained responders to IFN (EDS=0.05+/-0.02 vs. 0.34+/-0.19 log10/day, P<0.005; half-life=186+/-112 vs. 15.3+/-1.85 h, P<0.005). CONCLUSIONS: The presence of escape mutants from the neutralizing antibodies may be involved in resistance to IFN. Analyzes of FV- and IC-HCV dynamics are useful for predicting the IFN efficacy and understanding the mechanism of IFN action in chronic hepatitis patients.

Improvement of regional cerebral blood flow after treatment with branched-chain amino acid solutions in patients with cirrhosis.

OBJECTIVE: The administration of solutions rich in branched-chain amino acids leads to mental recovery from acute hepatic encephalopathy in patients with liver cirrhosis. However, the mechanism of action of branched-chain amino acids remains unclear. The purpose of this study was to evaluate the effect of intravenous infusion of branched-chain amino acids on brain perfusion in patients with liver cirrhosis. METHODS: Single photon emission computed tomography scans were performed in 14 patients with liver cirrhosis before and after the administration of branched-chain amino acids in a single-day split-dose protocol. The per cent change in regional brain perfusion was calculated in high frontal, parietal, temporal, occipital lobes and cerebellum. Thereafter, statistical parametric mapping was performed to identify brain regions with abnormal cerebral perfusion. RESULTS: Intravenous infusion of solutions enriched with branched-chain amino acids induced a 13-20% increase in regional cerebral blood flow. Cirrhotic patients had regions of significant hypoperfusion, as determined by statistical parametric mapping, in the left superior parietal and posterior cingulate as compared to the control group. This hypoperfusion of parietal and cingulate regions was not detected after treatment with solutions of branched-chain amino acids. CONCLUSIONS: The results of the present study suggest that administration of solutions enriched with branched-chain amino acids improves cerebral perfusion in patients with cirrhosis.

Twice-a-day versus once-a-day interferon-beta therapy in chronic hepatitis C.

BACKGROUND/AIMS: The intravenous administration of interferon-beta may be effective for the treatment of chronic hepatitis C, as is intramuscular interferon-beta. We compared the efficacy and safety of twice-a-day versus once-a-day of natural interferon-beta for the initial treatment of patients with chronic hepatitis C. METHODOLOGY: Forty-nine patients with chronic hepatitis C, with less than 5 Meq/mL serum hepatitis C virus-RNA, were randomly assigned into one of the two treatment groups A and B and treated with natural interferon-beta following two different protocols. Twenty-two patients were treated with twice-a-day interferon-beta (3 MU) for 3 weeks followed by once-a-day interferon-beta (6 MU) for 5 weeks (group A), and 20 patients were treated with once-a-day interferon-beta (6 MU) for 8 weeks (group B). Seven patients did not complete the treatment protocol. Efficacy was assessed by measuring the serum levels of hepatitis C virus-RNA and aminotransferase. RESULTS: The rate of sustained virological response was significantly higher in group A (14 of 22 patients, 63.6%) than in group B (6 of 20 patients, 30.0%) (P < 0.05). Among patients with hepatitis C virus-RNA level less than 1 Meq/mL, the sustained virological response rate was significantly higher in group A (13 of 15 patients, 86.7%) than in group B (5 of 12 patients, 41.7%) (P < 0.05). However, the sustained virological response rate in patients with hepatitis C virus levels more than 1 Meq/mL was not significantly different between group A (1 of 7 patients, 14.3%) and group B (1 of 8 patients, 12.5%). CONCLUSIONS: Twice-a-day interferon-beta therapy is more effective than once-a-day interferon-beta for the treatment of chronic hepatitis C patients with hepatitis C virus-RNA levels less than 1 Meq/mL.

Nonimmune complexed HCV RNA titer in serum as a predictor of interferon response in patients with chronic hepatitis C.

OBJECTIVE: Hepatitis C virus (HCV) has been reported to exist in the circulation of patients in various forms such as free virions, immune complexes, and nucleocapsids. To clarify the clinical significance of serum HCV titers according to the forms of virus particles, we evaluated the immune complexed (IC) and nonimmune complexed (NIC) HCV RNA titers in 77 chronic hepatitis patients treated with interferon (IFN). METHODS: IC and NIC forms in pretreatment serum were separated by immunoprecipitation using antihuman immunoglobulin antibody, and quantified by reverse transcription polymerase chain reaction. RESULTS: Serum titers of NIC HCV RNA were correlated with those of whole serum HCV RNA (r = 0.96, p < 0.01) and IC HCV RNA (r = 0.98, p < 0.01), but they were not with the aminotransferase levels, gamma-globulin concentration, and grading or staging of liver histology. Nonresponders to IFN had significantly high NIC HCV RNA titers compared with sustained responders (10(4.93 +/- 0.81) copies/ml vs 10(4.06 +/- 0.69) copies/ml, p < 0.01). It is noteworthy that the relative amount of NIC HCV RNA to whole serum HCV RNA was also significantly higher in nonresponders than in sustained responders (0.66 +/- 0.10 vs 0.50 +/- 0.11, p < 0.0001). Multivariate analysis showed that low NIC HCV RNA titer (p < 0.01) and genotype 2 (p = 0.02) were independent variables contributing to sustained response to IFN, but the whole serum HCV RNA titer was not. CONCLUSIONS: Pretreatment NIC HCV RNA titer is a more reliable predictive marker than genotype or whole serum HCV RNA of a sustained response to IFN monotherapy. This finding suggests that humoral immunity may affect the response to IFN.

Radiofrequency ablation combined with chemoembolization in hepatocellular carcinoma: treatment response based on tumor size and morphology.

PURPOSE: To evaluate local therapeutic efficacy of radiofrequency (RF) ablation after chemoembolization for hepatocellular carcinoma (HCC) based on tumor size and morphology. MATERIALS AND METHODS: Sixty-four patients underwent RF ablation under ultrasonographic or real-time computed tomographic (CT) fluoroscopic guidance within 2 weeks after chemoembolization. One hundred eight lesions were treated. Sixty-five lesions were small (

Dietary iron restriction improves aminotransferase levels in chronic hepatitis C patients.

BACKGROUND/AIMS: It is generally accepted that iron overload plays an important role in the pathogenesis of liver cell injury in chronic hepatitis C. The present study was undertaken to evaluate whether low-iron diet improves liver function tests in patients with chronic hepatitis C. METHODOLOGY: Seventeen patients with chronic hepatitis C (13 men and 4 women, 54 +/- 14 years old) that did not respond to, or were unsuitable for interferon therapy, were enrolled in this study. All patients had been pretreated with ursodeoxycholic acid for more than 12 months before the beginning of the study. Dietary iron intake was restricted to less than 7 mg/day, and the patients were followed up for 18 months. RESULTS: Mean daily iron intakes, calculated from food records, were 5.9 and 6.4 mg after 6 and 12 months, respectively. The mean serum ferritin decreased significantly from 362 ng/mL at entry to 179 ng/mL after 18 months. The serum unsaturated iron binding capacity level increased significantly from 163 micrograms/dL at entry to 203 micrograms/dL after 18 months. The serum aspartate aminotransferase decreased significantly from 62 IU/L at entry to 47 IU/L after 18 months, and serum alanine aminotransferase from 68 IU/L at entry to 53 IU/L after 18 months. Serum iron, hepatitis C virus-RNA titer and platelet count remained unchanged throughout the study. CONCLUSIONS: These results suggest that iron-restricted diet may be an important therapeutic modality for improving liver injury in patients with chronic hepatitis C.

Early diagnosis of hepatocellular carcinoma using a sensitive assay for serum des-gamma-carboxy prothrombin: a prospective study.

BACKGROUND/AIMS: Measurement of des-gamma-carboxy prothrombin by conventional methods is of limited use for the early detection of hepatocellular carcinoma for its low sensitivity. The aim of the present study was to investigate the usefulness of measuring des-gamma-carboxy prothrombin by a highly sensitive assay for the early diagnosis of hepatocellular carcinoma in patients with chronic liver disease and for the detection of recurrence after treatment of hepatocellular carcinoma. METHODOLOGY: Des-gamma-carboxy prothrombin levels by a sensitive assay and alpha-fetoprotein levels were sequentially measured in 188 patients with type B or C chronic liver disease and in 63 patients with hepatocellular carcinoma. RESULTS: The positive rate of des-gamma-carboxy prothrombin was 62% in all of hepatocellular carcinoma patients. Hepatocellular carcinoma was detected in 14 of 188 chronic liver disease patients during their follow-up period, the positive rate of des-gamma-carboxy prothrombin and of alpha-fetoprotein being 57% and 71% in these 14 patients, respectively. Des-gamma-carboxy prothrombin level normalized in 67% of 39 patients after the treatment of hepatocellular carcinoma. Of the 19 patients with tumor recurrence, 84% showed re-elevation of des-gamma-carboxy prothrombin level. CONCLUSIONS: Measurement of des-gamma-carboxy prothrombin by this highly sensitive assay combined with alpha-fetoprotein is useful for detecting hepatocellular carcinoma in chronic liver disease patients and for monitoring recurrence after treatment of hepatocellular carcinoma.