Multiple focal fatty changes in the liver in patients with porphyria cutanea tarda: A case series and review of the literature.

Porphyria cutanea tarda (PCT) is commonly diagnosed in cases where multiple hyperechoic nodules are observed in the liver. Pathologically, these nodules associated with PCT are focal fatty deposits. We report here, seven cases of PCT with fatty changes over multiple foci in the liver. Furthermore, the characteristics of ultrasonography (US) findings of 32 previously reported cases are summarized. The US features of these nodules showed a homogenous hyperechoic or hyperechoic rim pattern, partial confluence, and no mass effect in the vascular structures. Because multiple hyperechoic liver nodules occasionally mimic malignancies, and because their diagnosis can be challenging, clinicians should consider checking urine porphyrin levels to rule out PCT when such nodules are observed on US.

IL28B gene polymorphism is correlated with changes in low-density lipoprotein cholesterol levels after clearance of hepatitis C virus using direct-acting antiviral treatment.

BACKGROUND: Direct-acting antivirals (DAAs) rapidly clear hepatitis C virus (HCV), but the lipid dynamics after DAA treatment remain unknown. Low-density lipoprotein (LDL) cholesterolemia is the predicting factor for the onset and death of atherosclerotic cardiovascular diseases. Thus, in this study, we examined the frequency and risk of hyper-LDL cholesterolemia in HCV patients who achieved sustained virologic response (SVR) with DAA treatment. METHODS: A total of 121 patients with HCV genotype 1b, who achieved SVR with DAA treatment, were examined for serum levels of total cholesterol, LDL-cholesterol (LDL-C), high-density lipoprotein, and triglycerides from the start of treatment until 2 years after SVR (SVR-2y). ΔLDL-C was defined as the change in LDL-C levels from treatment initiation to SVR-2y. Hyper-LDL cholesterolemia was defined as ≥ 140 mg/dL LDL-C at SVR-2y. Stepwise multiple regression analysis was performed to determine whether ΔLDL-C and hyper-LDL cholesterolemia are associated with other factors, including viral kinetics. RESULTS: A total of 63, 3, and 55 patients were administered daclatasvir + asunaprevir, ombitasvir + paritaprevir + ritonavir, and ledipasvir + sofosbuvir, respectively. ΔLDL-C in patients with the IL28B (rs8099917) TG/GG genotype was significantly higher than in those with IL28B TT (27.3 ± 27.0 and 9.6 ± 27.3 mg/dL; P < 0.001). In addition, IL28B TG/GG was an independent risk factor for hyper-LDL cholesterolemia (odds ratio: 8.47; P < 0.001). CONCLUSIONS: An IL28B polymorphism is associated with ΔLDL-C and hyper-LDL cholesterolemia after achieving SVR. Thus, lipid markers should be carefully monitored in patients who achieve SVR with DAA.

Pilot Study of Hepatic Arterial Infusion Chemotherapy with Interferon-beta and 5-fluorouracil: A New Chemotherapy for Patients with Advanced Hepatocellular Carcinoma.

BACKGROUND/AIMS: The present pilot study aimed to evaluate the safety and efficacy of hepatic arterial infusion chemotherapy (HAIC) with interferon-beta (IFN-ß) and 5-fluorouracil (5-FU) in patients with advanced hepatocellular carcinoma (HCC). METHODOLOGY: We studied 10 patients with advanced HCC and who were unresponsive to previous HAIC using low-dose 5-FU and cisplatin. The median age was 67 years. Eight patients had portal vein tumor thrombosis and four patients had extrahepatic metastasis. Using a drug delivery system, patients were treated with HAIC of IFN-ß (600 MIU/body, three times/week) and 5-FU (250 mg/body, five times/week). Chemotherapy was repeated consecutively for 2 weeks every 4 weeks. RESULTS: Six (60%) patients had a decrease in tumor markers alpha-fetoprotein (APP) or des-gamma-carboxy prothrombin (DCP). The median overall survival was 108 days and the 1-year survival rate was 10.0%. Univariate analysis showed two significant prognostic factors related to long-term survival for more than 60 days: a decrease in APP or DCP 4 weeks after treatment (P = 0.035) and no extra hepatic metastasis (P = 0.035). Severe hepatic injury was not observed. CONCLUSIONS: HAIC with IFN-ß and 5-PU exerts modest antitumor effects and poses no particular safety concerns. This may be a new promising strategy for treatment of advanced HCC.

Limitation of repeated radiofrequency ablation in hepatocellular carcinoma: proposal of a three (times) × 3 (years) index.

BACKGROUND AND AIM: Percutaneous radiofrequency ablation (RFA) has been shown to be a highly effective treatment for hepatocellular carcinoma (HCC). We investigated the controllability of HCC and explored the algorithm of therapeutic strategy for HCC in patients who met the RFA criteria. METHODS: We enrolled 472 patients with HCC who met the RFA criteria (≤ 3 nodules, ≤ 3 cm) and underwent RFA for initial therapy. Patients who underwent repeated RFA were evaluated retrospectively when HCC exceeded the RFA criteria, or the functional hepatic reserve progressed to Child-Pugh grade C. RESULTS: Overall survival rates were: 1 year, 96%; 3 years, 79%; and 5 years, 56%. In 5 years, 14% of patients progressed to Child-Pugh grade C. Meanwhile, 47% of patients exceeded the RFA criteria. Annually, 8% of patients deviated from the RFA criteria. The percentage of patients who were able to receive RFA significantly decreased at the fourth session compared with up to the third session. The survival rates decreased at the rate of 7% annually until the third year after the initial RFA. Afterwards, it shifted to a decrease at the rate of 12% annually. In a multivariate analysis, the presence of hepatitis C virus infection and the existence of a single tumor were identified as significant independent factors contributing to probabilities exceeding the RFA criteria. CONCLUSIONS: HCC was controlled by RFA up to three RFA treatments and 3 years from the initial therapy. On this basis, we propose a "three (times) × 3 (years) index" for considering a shift from RFA to other treatment modalities.

The increased mortality from witnessed out-of-hospital cardiac arrest in the home.

BACKGROUND: Research in 2008 demonstrated that the majority of out-of-hospital cardiac arrests (OHCAs) occur in the home, and many important characteristics differ between private and public locations. However, the influence of the location of collapse on survival from OHCA is not well understood. Furthermore, most of the reports have been from Western countries; there is little research from Asia that differentiates the conditions of OHCA. OBJECTIVE: To investigate the influence of the location of collapse on being discharged alive from OHCA and whether the location of collapse is also an independent predictor of survival from OHCA in Japan. METHODS: We analyzed 463 consecutive cases of witnessed OHCA with cardiac etiology that occurred between October 2004 and September 2008 in Japan. We investigated the characteristics of OHCA patients who collapsed in private and public locations, and assessed the influence of the location of collapse on survival from OHCA. RESULTS: Patients who collapsed outside the home were younger, more likely to be male, more likely to receive bystander cardiopulmonary resuscitation (CPR), and more likely to have ventricular fibrillation (VF)/pulseless ventricular tachycardia (VT) and had a shorter time interval between collapse and 9-1-1 call than patients who collapsed in the home. Mortality was significantly higher in the group who collapsed in the home. The independent influence of the location of collapse was eliminated by additional adjustment for time interval from collapse to 9-1-1 call, age, bystander CPR, and initial cardiac rhythm. Finally, VF/pulseless VT as the initial rhythm and bystander CPR were independently associated with the patient's being discharged alive; the location of collapse was not an independently associated variable. CONCLUSIONS: The present analysis demonstrated that there were significant differences in survival between groups of patients who suffered from cardiac arrest inside and outside the home in Japan. The outside-the-home group had a higher rate of survival from OHCA; however, the location of collapse was not an independent predictor of survival from OHCA. Education of the families of high-risk patients in placing a rapid emergency call and performing effective CPR might be needed to improve survival from cardiac arrest in the home.

Circadian, weekly, and seasonal mortality variations in out-of-hospital cardiac arrest in Japan: analysis from AMI-Kyoto Multicenter Risk Study database.

BACKGROUND: Several studies have reported circadian, weekly, and seasonal variations in the rates of out-of-hospital cardiac arrest (OHCA). However, variations in the mortality of OHCA are not well known. METHODS AND RESULTS: We investigated the 1396 consecutive cases of OHCA with cardiac etiology between October 2004 and September 2008. There were 2 peaks in the occurrence of OHCA in early morning and late evening. There was a weekly pattern with an increased incidence on Mondays. We found a significant seasonal variation in the frequency of events, with a maximum during winter. There was a trend of reduced mortality in warmest 3 months, especially among a subgroup of ventricular fibrillation/pulseless ventricular tachycardia with arrest witnessed. CONCLUSION: The present analyses demonstrated circadian, weekly and seasonal variations in the occurrence, and a seasonal variation in mortality in OHCA. Changes in temperature might influence the severity of OHCA and change the rate of success of cardiopulmonary resuscitation.

Sustained upregulation of sodium taurocholate cotransporting polypeptide and bile salt export pump and downregulation of cholesterol 7α-hydroxylase in the liver of patients with end-stage primary biliary cirrhosis.

To examine the mRNA expression of hepatobiliary transporters in primary biliary cirrhosis (PBC) patients and to compare bile acid absorption, synthesis, and efflux in patients with non-end-stage and end-stage PBC, we obtained liver samples from PBC patients by percutaneous needle biopsy. End-stage PBC was defined as follows: histological stage IV; cirrhosis; serum total bilirubin, ≥4.0 mg/dl; and Child-Pugh Class C. The mRNA expression levels of sodium taurocholate cotransporting polypeptide (NTCP), bile salt export pump (BSEP), and hepatic cholesterol 7α-hydroxylase (CYP7A1) were significantly higher in the PBC patients than in the controls (P < 0.01). The mRNA levels of NTCP and BSEP were significantly higher in the end-stage PBC patients than in the controls (P < 0.01). However, hepatic CYP7A1 mRNA expression decreased significantly (by 70%) in the patients with end-stage PBC as compared to the controls and the patients with non-end-stage PBC (P < 0.01). The hepatic expression of transporters mediating bile acid influx and efflux showed sustained elevation, whereas that of the rate-limiting enzyme for bile acid biosynthesis was attenuated in the end-stage PBC patients. Thus, mechanisms may be present preventing the accumulation of toxic bile acids in the hepatocytes of end-stage PBC patients.

Alternative transporter pathways in patients with untreated early-stage and late-stage primary biliary cirrhosis.

BACKGROUND/AIMS: The hepatic expression of bile acid transporters is altered in experimental cholestasis and it is unclear whether regulation exists in human cholestatic diseases. We investigated the expression of genes involved in bile acid detoxification, basolateral export and nuclear factor regulation in untreated primary biliary cirrhosis (PBC). METHODS: Liver tissues were obtained from patients with early-stage and late-stage PBC. The hepatic expression levels of messenger RNAs were determined by the real-time reverse transcription polymerase chain reaction. RESULTS: The hepatic expression of multidrug-resistance protein 4 messenger RNA was significantly upregulated in early-stage and late-stage PBC patients compared with controls. The hepatic expression of multidrug-resistance protein 2 and multidrug-resistance protein 3 messenger RNAs was significantly elevated only in early-stage PBC patients. The hepatic expression levels of farnesoid X receptor, fetoprotein transcription factor and constitutive androstane receptor mRNAs were correlated with those of multidrug-resistance protein 2, multidrug-resistance protein 3 and multidrug-resistance protein 4 respectively. CONCLUSIONS: The hepatic expression of multidrug-resistance protein 4 was enhanced in patients with untreated PBC at all stages. However, the hepatic expression of multidrug-resistance protein 2 and multidrug-resistance protein 3 was enhanced only in early-stage patients. The lack of upregulation of these proteins might contribute to the progression of PBC.

Lethal arrhythmia and corticosteroid insufficiency.

We describe a case of isolated adrenocorticotropic hormone deficiency that showed ventricular fibrillation associated with QT prolongation. A 72-year-old man was admitted because of consciousness disorder caused by severe hypoglycemia. On the second hospital day, QT intervals were unexpectedly prolonged and ventricular fibrillation occurred. Electrical defibrillation was performed and restored hemodynamically stable condition without neurologic deficits. He was diagnosed with endocrine tests as having isolated adrenocorticotropic hormone deficiency. QT prolongation was improved after hydrocortisone replacement therapy. We considered the QT prolongation was caused by corticosteroid insufficiency. We should be aware that corticosteroid insufficiency may provoke QT prolongation responsible for sudden cardiac death.

Postoperative recurrence in hepatocellular carcinoma: Comparison between percutaneous ethanol injection and radiofrequency ablation.

AIM: Recently percutaneous ethanol injection (PEI) turned into percutaneous radiofrequency ablation (PRFA), and it has become widely used for the treatment of hepatocellular carcinoma (HCC). The present study was to compare the incidence in postoperative HCC recurrence between these two therapeutic approaches. METHODS: One hundred and sixty-eight first-time HCC in patient cases were chosen for PEI (n=94) and PRFA (n=74). The localized recurrence rate based on the operator's experience in percutaneous treatment for HCC (on <5 years versus >/=5 years experience) was examined. RESULTS: The PRFA group demonstrated a significantly lower localized recurrence rate within 2 years than the PEI group (8% and 22%, respectively, P<0.01). The local recurrence rate of HCC within 2 years after PEI was significantly lower in those for whom the operator's experience was more than 5 years compared to those for whom it was less than 5 years (12% versus 24%, respectively, P<0.05). In contrast, after PRFA there was no significant difference between these two groups of <5 years and of >/=5 years experience (8% versus 8%, respectively, P=0.98). CONCLUSION: The present study demonstrated that PRFA resulted in a lower rate of local recurrence in comparison to conventional PEI, regardless of the operator's experience.

Rapid-onset primary biliary cirrhosis resembling drug-induced liver injury.

A 54-year-old woman was admitted to our hospital because of acute liver injury. Since she had a history of having used a diet product, drug-induced liver injury (DILI) was initially considered. However, the patient was subsequently diagnosed as suffering from primary biliary cirrhosis (PBC) based on the findings of liver histology and serum anti-mitochondrial antibody positivity. Overlap syndrome between PBC and autoimmune hepatitis (AIH) was also suspected, however, serum levels of aspartate aminotransferase, alanine aminotransferase and alkaline phosphatase became normal three months later, after treatment with combination therapy comprising ursodeoxycholic acid plus bezafibrate. We therefore concluded that the liver disease in this patient was actually PBC, but that it resembled overlap syndrome or DILI. In cases of PBC, a rapid onset, as frequently seen in the case of DILI, viral hepatitis or AIH, is not common. We herein report a rare case of PBC which resembled DILI.

Adjusting the starting dose of telaprevir according to renal function decreases adverse effects and affects the sustained virological response rate.

BACKGROUND: Telaprevir (TVR) plays a major role in renal damage and anemia associated with TVR/pegylated interferon/ribavirin therapy for chronic hepatitis C. Adjusting the TVR starting dose may reduce these adverse effects. We aimed to determine whether adjusting the starting dose according to renal function reduces TVR-associated renal damage and anemia and affects the sustained virological response (SVR). PATIENTS AND METHODS: Our study included 112 patients infected with hepatitis C genotype 1 treated with pegylated interferon/ribavirin/TVR triple therapy. The TVR starting dose adjusted according to renal function was calculated as TVR/unadjusted estimated glomerular filtration rate (eGFR) ratio=TVR/(eGFR×body surface area/1.73). RESULTS: A TVR/unadjusted eGFR ratio of 32 or greater was a predictor of renal impairment and anemia in multivariate analysis (odds ratio 12.09, P<0.001, and OR 4.14, P<0.001, respectively). Patients with a TVR/unadjusted eGFR ratio of 32 or greater developed significant renal impairment and anemia (P<0.001 and P=0.002, respectively). SVR was significantly reduced in patients with a TVR/unadjusted eGFR ratio less than 23 versus 23 or greater (66.7 and 87.2%, respectively, P=0.045). SVR tended to increase stepwise [<23.0 (66.7%), ≥23 to <32 (84.8%), and ≥32 (89.6%), respectively]. The TVR/unadjusted eGFR ratio was correlated significantly with the serum TVR concentration (r=0.541, P<0.001). CONCLUSION: Adjusting the TVR starting dose according to the TVR/unadjusted eGFR ratio decreased adverse effects and affected the SVR rate. The TVR starting dose should be adjusted by a TVR/unadjusted eGFR ratio of 23 or greater to less than 32 to safely achieve SVR.

Nonalcoholic steatohepatitis associated with psoriasis vulgaris.

A 24-year-old man was admitted to our hospital because of liver dysfunction. He had been diagnosed as having psoriasis vulgaris at 18 years of age. Physical examination demonstrated obesity, general erythema, and hepatomegaly. Laboratory data revealed elevated serum levels of aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, and glucose. A histological examination of the liver revealed macrovesicular fatty change and infiltration of inflammatory cells, including lymphocytes and polymorphonuclear cells, within the liver lobules. Pericentral fibrosis and pericellular fibrosis were also recognized. He was diagnosed as having nonalcoholic steatohepatitis (NASH), based on the fact that he had no habit of drinking alcohol, as well as psoriasis vulgaris and diabetes mellitus. We herein report a very rare case of NASH associated with psoriasis vulgaris.

Hepatocellular carcinoma in a patient with liver cirrhosis associated with negative serum HCV tests but positive liver tissue HCV RNA.

A 70-year-old woman was admitted to our hospital because of a liver tumor. Laboratory data revealed mild liver dysfunction. Neither serum anti-HCV antibody nor HCV-RNA was detected. Computed tomography revealed a tumor lesion measuring 2 cm in diameter within the liver. Histological examination of the tumor revealed moderately differentiated hepatocellular carcinoma while the non-tumorous liver tissue demonstrated liver cirrhosis. By the RT-PCR method, HCV-RNA was detected from the non-tumorous liver tissue. We herein report a very rare case of hepatocellular carcinoma in a patient with liver cirrhosis associated with negative serum HCV findings, but positive finding for liver tissue HCV RNA.

Late-evening snack with branched-chain amino acids improves liver function after radiofrequency ablation for hepatocellular carcinoma.

AIM: This prospective study was designed to examine whether consumption of a branched-chain amino acid (BCAA)-enriched nutrient mixture as a late-evening snack (LES) helps maintain and/or improve liver functioning in liver cirrhosis (LC) patients who have undergone radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC). METHODS: An equal number (10) of 30 LC patients who had undergone RFA for HCC was randomly assigned to a standard diet group (control) group, a morning BCAA (M-BCAA) administration group, or a LES with BCAA (LES-BCAA) administration group. Liver function testing was performed and Child-Pugh scores (CPS) calculated for each group to assess the improvement at 1, 4 and 12 weeks post-RFA. RESULTS: Compared to the control and M-BCAA groups, the LES-BCAA group experienced a rapid and significant improvement in albumin and total serum bilirubin levels and in CPS that began during the initial post-RFA period. These results indicate that LES with BCAA supplementation significantly improved the CPS of the LES-BCAA group at 4 and 12 weeks post-RFA. Although no patients experienced serious adverse effects, two patients who had been diagnosed with diabetes mellitus before undergoing RFA required blood sugar management to improve glycemic control and one subject withdrew due to supplement-induced vomiting. CONCLUSION: LES with BCAA supplementation significantly and rapidly improves liver functioning and CPS in LC patients who have undergone RFA for HCC. Control of blood sugar levels is necessary when calorie-containing BCAA is administrated to LC patients with impaired glucose tolerance.

Mid-ventricular obstruction occurred in hypertrophic left ventricle of heterozygous Fabry's disease-Favorable effects of cibenzoline: A case report.

A 54-year-old woman visited our hospital because of palpitation and dizziness. Systolic ejection murmur, Levine IV/VI, was heard at the left sternal border and atrial gallop was auscultated at apex. Echocardiogram demonstrated diffuse hypertrophy of the left ventricular walls extending to the apex. The left ventricular walls increased symmetrically; the septal and the posterior wall measured approximately 26 mm and 30 mm in thickness, respectively. Apical two-chamber views revealed a narrow outflow of the left ventricular cavity at apex with a distinct convergence zone, where color flow Doppler imaging showed turbulent jet flow from mid to late systole. The leukocyte α-galactosidase A activity was lower than normal. Percutaneous endomyocardial biopsy showed specific change for Fabry's disease by electron microscopy. On cardiac catheterization, mid-ventricular resting pressure gradient of approximately 90 mmHg was shown. This pressure gradient dramatically disappeared after intravenous administration of 70 mg of cibenzoline. We describe a rare case of Fabry's disease that revealed diffuse hypertrophy having dynamic obstruction at mid-left ventricle, like mid-ventricular obstruction, and the administration of cibenzoline had beneficial effects on pressure gradient of mid-left ventricle.

A case of hepatitis C-associated osteosclerosis that was improved with the combination therapy of peginterferon alfa-2b and ribavirin.

Hepatitis C-associated osteosclerosis (HCAO) is a rare disorder characterized by a marked increase in skeletal mass in patients who are infected with hepatitis C virus (HCV). The clinical presentation is an acquired deep bone pain with increased serum alkaline phosphatase (ALP) activity. We present a case of a patient with HCAO who was treated with antiviral therapy. A 42-year-old Japanese man presented with severe, stabbing pain in his lower limbs. He was diagnosed with hepatitis C secondary to intravenous drug use 20 years earlier. Serum biochemical studies revealed markedly elevated ALP activity and osteocalcin levels. Skeletal radiographs showed diffuse bony sclerosis with marked cortical thickening in the long bones. The bony findings and clinical symptoms were attributed to HCAO. The HCV RNA viral load was high and the genotype was 2a. The patient was treated with peginterferon alfa-2b and ribavirin for 24 weeks. After 24 weeks of the combination therapy, the patient had a sustained virological response and clinical remission of bone pain and a decrease in the level of serum ALP. In conclusion, HCAO was improved by the combination therapy of peginterferon alfa-2b and ribavirin when the patient achieved sustained virological response. It was confirmed that HCAO was one of the extrahepatic manifestations of HCV.

Clinical features of Wilson disease: Analysis of 10 cases.

AIM: The diagnosis of Wilson disease is based on the results of several clinical and biochemical tests. This study aimed to clarify the clinical features and spectrum of Wilson disease, including severe Wilson disease. METHODS: Between 1985 and 2009, 10 patients with clinical, biochemical or histological evidence of Wilson disease were either diagnosed or had a previously established diagnosis confirmed at Fukuoka University Hospital. Severe Wilson disease was defined by a serum prothrombin time ratio of more than 1.5 or serum prothrombin activity of less than 50%. The 10 Wilson disease patients were divided into two groups, one containing three non-severe patients and the other containing seven severe patients, and the biochemical features of the patients in these two groups were compared. RESULTS: The mean age at diagnosis was 21.5 ± 11.7 years (range, 7-39). Decreased serum ceruloplasmin, enhanced 24-h urinary copper excretion, presence of Kayser-Fleischer rings and histological signs of chronic liver damage were confirmed in 100%, 100%, 66.7% and 100% of patients, respectively. Severe Wilson disease patients had higher levels of serum ceruloplasmin and serum copper (P < 0.05, P < 0.05, respectively) than non-severe patients. CONCLUSION: In severe Wilson disease patients, the serum ceruloplasmin and serum copper levels were higher than those in non-severe Wilson disease patients.

Intermediate fixed coronary artery stenosis at the site of ergonovine-provoked spasm as a predictor of long-term major adverse cardiac events of patients with coronary spastic angina.

BACKGROUND: Organic coronary artery stenosis is a significant prognostic factor in patients with coronary spastic angina (CSA), so the present study was focused on assessing the impact of intermediate fixed stenosis at sites of provoked spasm on the long-term outcomes of CSA patients. METHODS AND RESULTS: CSA patients diagnosed on the basis of ergonovine-provoked spasm were enrolled and the clinical background and long-term prognosis of CSA patients with intermediate fixed stenosis at the site of provoked spasm (with-fixed-stenosis group, n=37) and those without fixed stenosis (without-fixed-stenosis group, n=126) were retrospectively compared. During the follow-up period (average 4.01 years for with-fixed-stenosis, 4.47 years for without-fixed-stenosis), the with-fixed-stenosis group had a significantly lower event-free survival rate, as well as a higher frequency of admission for unstable angina and percutaneous coronary intervention than the without-fixed-stenosis group, whereas the survival rate did not differ significantly between the 2 groups. In the multivariate analysis, intermediate fixed stenosis at the site of provoked spasm was a predictor of long-term major adverse cardiac events (MACE). CONCLUSIONS: Intermediate fixed stenosis at the site of ergonovine-provoked spasm is an independent risk factor for MACE during the long-term period in CSA patients.