Fixed dose of long-acting erythropoietic stimulating agents at higher frequency improves appetite, reduces inflammation and corrects anaemia in patients on haemodialysis.

Anaemia is an important issue in patients undergoing haemodialysis. We aimed to identify a better dosing schedule of a fixed monthly dose of continuous erythropoietin receptor activator (CERA) in patients with chronic kidney disease (CKD) on haemodialysis. The CERA dosing schedule included 100 µg once monthly for 2 months, 50 µg twice monthly for 2 months and then 100 µg once monthly for two months. The effectiveness was determined by comparing haematocrit, nutritional status (serum protein and albumin) and inflammatory markers (tumour necrosis factor (TNF)-α, interleukin (IL)-1, IL-6 and Hepcidin) at the beginning of the study with those at the end of the study. Forty-seven out of 67 patients completed the trial. At the end, haematocrit was significantly higher (34.51 vs 33.22%, P=.004), levels of inflammatory markers were significantly lower (TNF-α (30.71 vs 35.67 ng/mL, P=.007), IL-6 (5.12 vs 7.95 ng/mL, P=.033), hepcidin (60.39 vs 74.39 ng/mL, P=.002)), blood glucose levels were significantly lower (112.40 vs 139.02 mg/dL, P=.003) and albumin was significantly higher (4.11 vs 3.98, P=.001). Patients with a better than average response had a lower initial number of red blood cells (3.3 vs 3.6 × 10(6) /mm(3) , P=.025) and a lower IL-1 (3.8 vs 12.9 ng/mL, P=.01). They also had significantly lower blood glucose levels at the end. (91.3 vs 124.0 mg/dL, P=.03). We demonstrate that a fixed monthly dose of CERA at a twice monthly dosing schedule improves nutrition, reduces the inflammation and corrects anaemia in patients on haemodialysis. This finding may provide a new strategy for treating CKD-related anaemia.

Genotype polymorphisms of genes regulating nitric oxide synthesis determine long-term arteriovenous fistula patency in male hemodialysis patients.

OBJECTIVES: Nitric oxide (NO) is a pivotal vasoactive substance modulating arteriovenous fistula (AVF) patency for hemodialysis (HD). Since genetic background could be the predicting factor of AVF malfunction, we aimed to investigate whether the NO-related genotype polymorphisms determine AVF survival rates. METHODS: This is a retrospective, observational, multi-center study involving eight HD units in Taiwan, enrolled 580 patients initiating maintenance HD via AVFs. Genotype polymorphisms of NO-biosynthesis regulating enzymes (DDAH-1, DDAH-2, eNOS and PRMT1) were compared between HD patients with (n = 161) and without (n = 419) history of AVF malfunction. Subgroup analyses by gender were performed to evaluate the genetic effect in difference sexes. RESULTS: In overall population, statistically significant associations were not found between AVF malfunction and the genetic polymorphisms. In the male subgroup (n = 313), a single nucleotide polymorphism (SNP) of PRMT1, rs10415880 (IVS9-193 A/G), showed a significant association with AVF malfunction. Male patients with AA/AG genotype had inferior AVF outcomes compared to GG genotype, regarding primary patency (70.6% vs. 40.9%, p = 0.001), assisted primary patency (81.0% vs. 58.4%, p < 0.001) and secondary patency (83.7% vs. 63.3%, p < 0.001) at a 5-year observation period. From multivariate Cox regression model, the AA/AG genotypes of PRMT1 were an independent risk factor for AVF malfunction in men (HR: 4.539, 95% CI 2.015-10.223; p < 0.001). However, such associations were not found in women. CONCLUSIONS: rs10415880, the SNP of PRMT1 could be a novel genetic marker associated with AVF malfunction risk in male HD patients. Those with AA and AG genotypes of rs10415880 may predict a poorer long-term patency of AVF.

Association of Genetic Polymorphisms of Renin-Angiotensin-Aldosterone System-Related Genes with Arterio-Venous Fistula Malfunction in Hemodialysis Patients.

Hemodialysis (HD) is the most commonly-used renal replacement therapy for patients with end-stage renal disease worldwide. Arterio-venous fistula (AVF) is the vascular access of choice for HD patients with lowest risk of infection and thrombosis. In addition to environmental factors, genetic factors may also contribute to malfunction of AVF. Previous studies have demonstrated the effect of genotype polymorphisms of angiotensin converting enzyme on vascular access malfunction. We conducted a multicenter, cross-sectional study to evaluate the association between genetic polymorphisms of renin-angiotensin-aldosterone system and AVF malfunction. Totally, 577 patients were enrolled. Their mean age was 60 years old and 53% were male. HD patients with AVF malfunction had longer duration of HD (92.5 ± 68.1 vs. 61.2 ± 51.9 months, p < 0.001), lower prevalence of hypertension (44.8% vs. 55.3%, p = 0.025), right-sided (31.8% vs. 18.4%, p = 0.002) and upper arm AVF (26.6% vs. 9.7%, p < 0.001), and higher mean dynamic venous pressure (DVP) (147.8 ± 28.3 vs. 139.8 ± 30.0, p = 0.021). In subgroup analysis of different genders, location of AVF and DVP remained significant clinical risk factors of AVF malfunction in univariate and multivariate binary logistic regression in female HD patients. Among male HD patients, univariate binary logistic regression analysis revealed that right-side AVF and upper arm location are two important clinical risk factors. In addition, two single nucleotide polymorphisms (SNPs), rs275653 (Odds ratio 1.90, p = 0.038) and rs1492099 (Odds ratio 2.29, p = 0.017) of angiotensin II receptor 1 (AGTR1), were associated with increased risk of AVF malfunction. After adjustment for age and other clinical factors, minor allele-containing genotype polymorphisms (AA and CA) of rs1492099 still remained to be a significant risk factor of AVF malfunction (Odds ratio 3.63, p = 0.005). In conclusion, we demonstrated that rs1492099, a SNP of AGTR1 gene, could be a potential genetic risk factor of AVF malfunction in male HD patients.

Increased risk of osteoporotic fractures in patients with systemic sclerosis: a nationwide population-based study.

OBJECTIVES: To identify the incidence rate (IR) and risk factors of osteoporotic fractures (OFs) among systemic sclerosis (SSc) patients. METHODS: A cohort study was conducted using the Taiwan National Health Insurance database. Patients with SSc and respective age- and gender-matched controls without SSc were enrolled. The primary endpoint was the first occurrence of OF. The Cox proportional hazard model was used to investigate the risk factor of OFs in the SSc cohort. RESULTS: Among 1712 SSc patients (77.8% female, mean age 50.3 years) with a median follow-up of 5.2 years, 54 patients developed vertebral fractures, 17 patients developed hip fractures, and 7 patients developed radius fractures (IR: 6.99, 2.18 and 0.90 per 1000 person-years, respectively). Compared with the controls, the incidence rate ratios (IRRs) (95% CIs) among SSc patients were 1.78 (1.30 to 2.39, p<0.001) for vertebral fractures and 1.89 (1.05 to 3.22, p=0.026) for hip fractures. The IRRs for overall OFs were 1.74 (1.32 to 2.27, p<0.001) for women and 1.06 (0.33 to 2.66, p=0.856) for men. The SSc patients experienced hip fractures at a younger age (67.2 vs 75.2 years, p=0.005), and had a higher 1-year mortality rate (13% vs 3%, p=0.006) of vertebral fractures than did the controls. Multivariable Cox regression analyses indicated that older age, being female, using daily prednisolone equivalent to >7.5 mg, and bowel dysmotility treated with intravenous metoclopramide are associated with OF. CONCLUSIONS: SSc patients had a high IR of vertebral and hip fractures, especially those who were female, older, used a high dose of corticosteroid or experienced bowel dysmotility.

Effect of far infrared therapy on arteriovenous fistula maturation: an open-label randomized controlled trial.

BACKGROUND: Malfunction of the arteriovenous fistula (AVF) is an important cause of morbidity and hospitalization in hemodialysis (HD) patients. The aim of this study is to evaluate the effect of far infrared therapy on the maturation and patency of newly created AVFs in patients with chronic kidney disease stage 4 or 5. STUDY DESIGN: Randomized controlled study. SETTING & PARTICIPANTS: Patients with estimated glomerular filtration rate of 5-20 mL/min/1.73 m². INTERVENTION: 40 minutes of far infrared therapy 3 times weekly for a year. OUTCOMES: The primary outcome is the rate of AVF malfunction within 12 months, with malfunction defined as either: (1) thrombosis without thrill for AVFs not undergoing HD or (2) receiving any type of interventional procedure due to a lower Kt/V (<1.2) for patients undergoing HD. Secondary outcomes include: (1) cumulative primary unassisted AVF patency, defined as time from creation of the AVF to the first episode of AVF malfunction; (2) physiologic maturation of the AVF by the definition of AVF access blood flow (Qa) ≥500 mL/min and AVF diameter ≥4 mm at 3 months; and (3) clinical maturation of the AVF suitable for HD at 1 year. MEASUREMENTS: AVF Qa was measured by Doppler ultrasonography at 2 days and 1, 2, 3, and 12 months. RESULTS: We enrolled 122 patients who were randomly allocated to the intervention (n = 60) and control (n = 62) groups. In comparison to controls, patients in the intervention group had higher Qa values at 1, 2, 3, and 12 months; a higher rate of physiologic maturation (90% vs 76%; P = 0.04) at 3 months; and a lower rate of AVF malfunction (12% vs 29%; P = 0.02) but higher rates of AVF cumulative unassisted patency (87% vs 70%; P = 0.01) and clinical maturation (82% vs 60%; P = 0.008) within 12 months. LIMITATIONS: This is a single-center nonblinded study. CONCLUSIONS: Far infrared therapy improves the access flow, maturation, and patency of newly created AVFs in patients with chronic kidney disease stages 4 and 5.

Length polymorphisms of heme oxygenase-1 determine the effect of far-infrared therapy on the function of arteriovenous fistula in hemodialysis patients: a novel physicogenomic study.

BACKGROUND: The objective of this study was to evaluate the interaction between the length polymorphism of the guanosine thymidine repeat [(GT)n] in the heme oxygenase-1 (HO-1) gene and far-infrared (FIR) therapy on access flow (Qa) and arteriovenous fistula (AVF) patency in hemodialysis (HD) patients. METHODS: A total of 280 HD patients were randomized into a control group (n = 141) and the FIR group (n = 139) who received 40 min of FIR therapy three times weekly for a year during the study period from May 2005 to December 2007. Access flow was measured during HD. The [(GT)n] was determined with the definition of long (L) allele as [(GT)n] ≥ 30 and short (S) allele as [(GT)n] < 30. RESULTS: The Qa decreased from S/S to S/L and further to the L/L group but increased by FIR therapy with the highest Qa increase in the S/S group. The incidence of AVF malfunction decreased both from the L/L, S/L to S/S group (32.4 versus 17.2 versus 10.9%, P = 0.007) and from the control group to FIR group (27.5 versus 12.6%, P = 0.004). Significant associations were found between AVF malfunction and the following factors (hazard ratio, P-value): a past history of AVF malfunction (2.45, P = 0.044), FIR therapy (0.369, P = 0.03) and L/L genotypes of HO-1 (2.531 versus S/S + S/L genotypes). The 1-year unassisted patency decreased from 91.9 and 77.6% in S/S and S/L subgroups with and without FIR therapy to 75.8 and 60% for L/L subgroup with and without FIR therapy, respectively (P < 0.001). CONCLUSIONS: FIR therapy improves Qa and patency of AVF in HD patients, with the best protective effect in those with S/S genotype of HO-1.

Far-Infrared Therapy Improves Arteriovenous Fistula Patency and Decreases Plasma Asymmetric Dimethylarginine in Patients with Advanced Diabetic Kidney Disease: A Prospective Randomized Controlled Trial.

Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthase and plays a significant role in the pathogenesis of arteriovenous fistula (AVF) dysfunction. The aim of this study is to evaluate the effect of far-infrared (FIR) therapy on the maturation and patency of newly-created AVFs in patients with advanced diabetic kidney disease (DKD) as well as the concurrent change in plasma ADMA. The study enrolled 144 participants with advanced DKD where 101 patients were randomly allocated to the FIR therapy group (N = 50) and control group (N = 51). Patients receiving FIR therapy had a decreased AVF failure rate within 12 months (16% versus 35.3%; p = 0.027); decreased incremental change of ADMA concentration at the 3rd and 12th month; increased AVF blood flow at the 1st, 3rd, and 12th month; increased 3-month physiologic maturation rate (88% versus 68.6%; p = 0.034); increased 1-year unassisted AVF patency rate (84% versus 64.7%; p = 0.017); and increased clinical AVF maturation rate within 12 months (84% versus 62.7%; p = 0.029) compared to the control group. The study demonstrates that FIR therapy can reduce the incremental changes in plasma ADMA concentration, which may be associated with the improvement of AVF prognosis in patients with advanced DKD.

Comparative analysis of noninvasive models to predict early liver fibrosis in hepatitis B e Antigen-negative Chronic Hepatitis B.

BACKGROUND: Portal or bridging fibrosis is an indication for antiviral treatment in patients with chronic hepatitis B (CHB). An early marker predictive of liver fibrosis in hepatitis B e antigen (HBeAg)-negative CHB patients can alert clinicians to plan for treatment before disease progression. GOALS: To predict early and significant liver fibrosis (Ishak score ≥2) in HBeAg-negative CHB by validating several noninvasive markers derived from CHC. STUDY: One hundred seventy-seven consecutive treatment-naive HBeAg-negative CHB patients who underwent liver biopsy were divided into a training group (n=121) and a validation group (n=56). Factors associated with liver fibrosis were analyzed. RESULTS: Multivariate analysis identified Lok's model ≥0.87, cirrhosis discriminant score greater than 4, and positive alanine aminotransferase ratio platelet score as independent factors associated with liver fibrosis in the training group. The area under the receiver operating characteristic curve revealed that Lok's model was better than cirrhosis discriminant score in predicting liver fibrosis in both the training and the validation groups. In patients with hepatitis B virus DNA greater than 2000 IU/mL or greater than 20,000 IU/mL, Lok's model showed equal prediction value (area under the receiver operating characteristic curve 0.709 and 0.704, respectively). Lok's model could also discriminate high and low hepatitis B virus DNA loads. In general, liver biopsy can be avoided in one-third (58 of 177) of patients by Lok's model. CONCLUSIONS: Lok's model ≥0.87 can be an early marker of liver fibrosis in HBeAg-negative CHB patients. Lok's model has clinical applications not only for CHC, but also for HBeAg-negative CHB.

A new prognostic model for hepatocellular carcinoma based on total tumor volume: the Taipei Integrated Scoring System.

BACKGROUND & AIMS: The currently used staging systems for hepatocellular carcinoma (HCC) are not satisfactory. The optimal prognostic model for HCC is still under intense debate. This study aimed to propose a new staging system for HCC based on total tumor volume (TTV) and to compare it with the currently used systems. METHODS: A total of 2030 HCC patients undergoing different treatment strategies were retrospectively analyzed. TTV was defined as the sum of the volume of each tumor [(4/3)x3.14x(radius of tumor in cm)(3)]. The discriminatory ability of the TTV-based staging system and the four current systems, including the Barcelona Clinic Liver Cancer, Cancer of the Liver Italian Program (CLIP), Japan Integrated Staging system, and Tokyo system, was examined by comparing the Akaike information criterion (AIC) using the Cox proportional hazards model. RESULTS: A higher TTV correlated well with the decreased survival in HCC patients (p<0.001). Among the 12 TTV-based staging systems, the TTV-Child-Turcotte-Pugh (CTP)-alpha-fetoprotein (AFP) combination provided the lowest AIC value. The TTV-CTP-AFP model consistently showed a better prognostic ability in comparison to the current four staging systems. In 936 HCC patients receiving curative treatment, the TTV-CTP-AFP model provided the second best predictive accuracy following the CLIP score. Alternatively, in 1094 patients undergoing non-curative treatment, the TTV-CTP-AFP model exhibited the smallest AIC value. CONCLUSIONS: TTV may be a feasible tumoral prognostic predictor for HCC. In this single-hospital study that included patients with early to advanced cancer stages, the TTV-CTP-AFP model provides the best prognostic ability among 12 TTV-based and currently used staging systems.

Renal failure in patients with hepatocellular carcinoma and ascites undergoing transarterial chemoembolization.

BACKGROUND: Ascites is often present in patients with hepatocellular carcinoma (HCC) with cirrhosis. Advanced cirrhosis may predispose to renal dysfunction. Acute renal failure (ARF) may occur after transarterial chemoembolization (TACE) for HCC because of radiocontrast agents. This study aimed to investigate the incidence and risk factors of ARF and prognostic predictors in HCC patients with ascites undergoing TACE. METHODS: A total of 591 HCC patients receiving TACE were enrolled. RESULTS: In a mean follow-up duration of 19+/-17 months, 239 (40.4%) patients undergoing TACE died. Ascites, which was present in 91 (15.4%) patients at entry, independently predicted a poor prognosis in the Cox proportional hazard model [risk ratio (RR): 1.71, P=0.002]. Of these, 11 (12.6%) of 87 patients with complete follow-up developed ARF after TACE. Serum albumin level <3.3 g/dl (odds ratio: 7.3, P=0.009) was the only independent risk factor associated with ARF in the logistic regression analysis. ARF (RR: 2.17, P=0.036), alpha-fetoprotein >400 ng/ml (RR: 1.84, P=0.04), multiple tumours (RR: 2.11, P=0.013), tumour size > or = 5 cm (RR: 2.32, P=0.006) and serum sodium level <139 mmol/L (RR: 2.4, P=0.005) were independent poor prognostic predictors for HCC patients with ascites receiving TACE. CONCLUSIONS: Pre-existing ascites is associated with increased mortality in HCC patients receiving TACE. In HCC patients with ascites, hypoalbuminaemia is associated with the occurrence of post-TACE ARF. Post-TACE ARF is a poor prognostic predictor in this subset of HCC patients.

Diabetes mellitus as an independent prognostic predictor and its association with renal dysfunction in patients with hepatocellular carcinoma.

BACKGROUND: Patients with hepatocellular carcinoma (HCC) often have coexisting cirrhosis, which may predispose to the development of diabetes mellitus (DM). Diabetic HCC patients may have renal insufficiency and a subsequent worse outcome. This study investigated the interaction between DM, cirrhosis and renal dysfunction and the impact of these factors on HCC. METHODS: A prospective database of 1713 HCC patients was analysed. RESULTS: A total of 392 (22.9%) patients were diabetic. Diabetic patients had a significantly higher Child-Turcotte-Pugh (CTP) score, model for end-stage liver disease score and serum creatinine level, but had significantly lower serum albumin, sodium, alanine aminotransferase, aspartate aminotransferase and bilirubin levels. The serum creatinine level progressively increased and correlated well with increasing CTP class in both diabetic and non-diabetic patients. After a mean follow-up of 18+/-16 months, DM was shown to be an independent predictor of mortality in the Cox proportional hazard model after adjusting for other predictors [hazard ratio (HR): 1.2, 95% confidence interval (CI): 1.02-1.42]. Diabetic patients more often had renal insufficiency, defined as serum creatinine>1.5 mg/dl (17.3 vs 8.3%, P<0.0001). Renal insufficiency was an independent prognostic predictor in diabetic patients (HR: 2.26, 95% CI: 1.57-3.24) but not in non-diabetic patients, because it was significantly associated with the severity of cirrhosis in the non-diabetic group (P<0.001) but not in the diabetic group (P=0.143). CONCLUSIONS: DM is associated with inadequate liver reserve and independently predicts decreased survival in HCC patients. Both advanced cirrhosis and DM are associated with renal insufficiency, which is a poor prognostic predictor for HCC.

Correlation between clinical indication for treatment and liver histology in HBeAg-negative chronic hepatitis B: a novel role of alpha-fetoprotein.

BACKGROUND: It is unclear whether clinical indication for antiviral treatment is in agreement with histological indication in HBeAg-negative chronic hepatitis B (CHB). This study aimed to clarify this relationship and identify factors associated with liver histology. PATIENTS AND METHODS: We investigated 152 consecutive, treatment-naïve, HBeAg-negative CHB patients who had undergone liver biopsies at a tertiary medical centre in Taiwan. Clinical indications for treatment included a serum alanine aminotransferase level more than twice the upper limit of normal and an hepatitis B virus DNA level > 2000 IU/ml. Factors associated with the histological indication (Ishak's grade > or = 7 and/or stage > or = 2) were analysed. RESULTS: The association between the clinical and the histological indications was significant (P=0.011). However, the agreement was poor (kappa value=0.197). In patients satisfying the clinical indication, age > 52 years [odds ratio (OR)=2.669, P=0.042], serum alpha-fetoprotein (AFP) level > 7 ng/ml (OR=7.070, P<0.001) and platelet count < 130 x 10(9)/L (OR=11.720, P=0.025) were identified to be independent factors associated with histological indication. In patients who did not satisfy the clinical indication, multivariate analysis revealed that only an AFP level > 7 ng/ml (OR=10.345, P=0.021) was independently associated with histological indication. Combining the clinical indication and/or AFP level > 7 ng/ml to predict liver histology, the sensitivity and the negative predictive value could improve from 86 to 94.4% and 66.7 to 81% respectively. CONCLUSION: AFP level is associated with liver histology in HBeAg-negative CHB. Serum AFP level can serve as a surrogate indicator to identify patients who need antiviral treatment.

Selecting an optimal cutoff value for creatinine in the model for end-stage liver disease equation.

BACKGROUND: The model for end-stage liver disease (MELD) is used for organ allocation in liver transplantation. The maximal serum creatinine (Cr) level for MELD is set at 4.0 mg/dL; however, there was no outcome data to justify this strategy. METHODS: Ninety-two patients with cirrhosis with Cr level >4 mg/dL were selected from 1438 patients and compared with MELD score-matched controls for three-month and six-month mortality. RESULTS: At three months, patients with Cr level >4 mg/dL had a significantly higher mortality rate than the 184 controls with a lower Cr level (44.6% vs. 29.3%, p = 0.015). This trend was still significant at six months: the mortality rate was 62% in the index group vs. 45.1% in the control group (p = 0.011). The difference between the index and control groups was the smallest (2.5% at three months and 3.4% at six months) when Cr was up-scaled to 5.5 mg/dL. The predictive accuracy of the MELD was estimated by using area under receiver-operating characteristic (AUC) curve. Only the cutoff of 5.5 mg/dL at six months displayed a higher AUC (0.753). CONCLUSIONS: A cutoff at 5.5 mg/dL may be more appropriate for the MELD. The MELD for patients with cirrhosis with advanced renal insufficiency deserves re-evaluation.

Transarterial chemoembolization in patients with hepatocellular carcinoma and renal insufficiency.

BACKGROUND: Renal dysfunction is often present in patients with cirrhosis and hepatocellular carcinoma (HCC). Acute renal failure (ARF) may occur after transarterial chemoembolization (TACE) owing to radiocontrast agent. This study investigated the incidence and risk factors of ARF and prognostic predictors in HCC patients with preexisting renal insufficiency undergoing TACE. METHODS: A total of 566 HCC patients undergoing TACE were enrolled. Renal insufficiency was defined as an estimated glomerular filtration rate less than 60 mL/min/1.73 m. RESULTS: In a mean follow-up duration of 18+/-16 months, 231 (40.8%) patients undergoing TACE died. Renal insufficiency that was present in 134 (23.7%) patients at baseline, independently predicted a poor prognosis in the Cox proportional hazards model [risk ratio (RR): 1.47, P=0.012]. Of them, 13 (10%) and 6 (5%) patients had transient and prolonged ARF after TACE, respectively. Post-TACE gastrointestinal bleeding [odds ratio (OR): 16.54, P=0.001] and higher Cancer of the Liver Italian Program (CLIP) scores (> or =2; OR: 4.22, P=0.02) were independent risk factors for ARF in the multivariate logistic regression analysis. In the Cox model, prolonged ARF (RR: 3.28, P<0.001) and higher CLIP scores (> or =2; RR: 2.13, P<0.001) were independent poor prognostic predictors for HCC patients with renal insufficiency receiving TACE. CONCLUSIONS: Gastrointestinal bleeding and higher CLIP scores are associated with the development of ARF in patients with HCC and renal insufficiency undergoing TACE. Higher CLIP scores and renal insufficiency, either preexisting before TACE or as a complication of TACE, are poor prognostic predictors in HCC patients receiving TACE.

Risk factors for early and late recurrence in hepatitis B-related hepatocellular carcinoma.

BACKGROUND/AIMS: Hepatitis B virus (HBV) levels correlate with the development of hepatocellular carcinoma (HCC), but the role of viral load in HCC recurrence after tumor resection remains unclear. Herein we aimed to investigate the role of viral load in HCC recurrence following tumor resection. METHODS: From 1990 to 2002, 193 HBV-related HCC patients who underwent tumor resection in Taipei Veterans General Hospital were enrolled. Serum HBV DNA level and mutations were analyzed for association with early and late recurrence, together with other clinical variables. RESULTS: During a follow-up of 58.2+/-44 months, 134 patients had HCC recurrence. Multivariate analysis showed that multinodularity (Hazard ratio [HR], 95% confidence interval [CI]; 2.232, 1.021-4.878), macroscopic venous invasion (4.693, 1.645-13.391), AFP >20 ng/ml (3.891, 1.795-8.475), and cut margin 6 (4.658, 1.970-11.017), multinodularity (3.266, 1.417-7.526), ICG-15 >10% (2.487, 1.095-5.650) and HBV DNA level >10(6) copies/ml (2.548, 1.040-6.240) were significantly associated with late recurrence (>two years after resection). Patients with high viral loads tended to have higher Ishak inflammatory (7.00+/-3.07 vs. 5.33+/-2.96, p=0.001) and fibrosis scores (4.17+/-2.01 vs. 3.20+/-2.41, p=0.007) than those with lower loads. CONCLUSIONS: Tumor factors were associated with early HCC recurrence while high viral loads and hepatic inflammatory activity were associated with late recurrence. Pre- and post-operative antiviral and anti-inflammatory therapies may be crucial in reducing late recurrence.

Characteristics and outcome of patients with dual hepatitis B and C-associated hepatocellular carcinoma: are they different from patients with single virus infection?

BACKGROUND: Patients with hepatocellular carcinoma (HCC) caused by dual hepatitis B and C virus (HBV, HCV) infection may constitute a distinct disease group that is different from patients with single virus infection. This study compared the clinical characteristics and outcomes of patients with HBV, HCV and dual virus infection. METHODS: A prospective database of 1215 HCC patients with chronic hepatitis B, C or dual virus infection was investigated. RESULTS: Patients with HCV infection (n=388) were significantly older (mean age, 69 years) than patients with dual virus (n=75, 65 years) and HBV (n=752; 60 years) infection (P<0.0001). The male-to-female ratios for the HBV, dual virus and HCV groups were 5.2, 3.4 and 1.3 respectively (P<0.0001). Patients in the HBV group more often had higher total tumour volume (mean, 409 cm(3)) than those in the dual virus group (244 cm(3)) and HCV (168 cm(3)) group (P<0.0001). No significant differences of the severity of liver cirrhosis, performance status, cancer staging and tumour cell differentiation were noted among the three groups. Patients in the HCV group had a significantly poor survival in comparison with the HBV group only in the subset of patients with small tumour volume (<50 cm(3)) in the Cox proportional hazards model (relative risk, 1.44; P=0.041). CONCLUSIONS: Dual HBV and HCV virus infection does not accelerate the speed of HCC formation in patients with chronic hepatitis B, and appears to have a modified course of carcinogenesis pathway that is diverted away from the biological behaviour of HBV and HCV infection.

Fatal reactivation of hepatitis B virus in a patient who was hepatitis B surface antigen negative and core antibody positive before receiving chemotherapy for non-Hodgkin lymphoma.

Patients who are hepatitis B surface antigen (HBsAg) positive are at risk for hepatitis flare when receiving cytotoxic or immunosuppressive therapy. It has been reported that as high as 50% of HBsAg-positive individuals who undergo chemotherapy develop elevation of liver transaminases. According to current Association for the Study of Liver Diseases guidelines, prophylactic lamivudine should be routinely administered to HBsAg-positive patients with malignancy before chemotherapy. However, occult hepatitis B virus (HBV) infection, defined as HBsAg negative and HBV DNA positive, regardless of HBV core antibody (anti-HBc) status, is not infrequent in HBV endemic areas. Here, we report the case of a B-cell non-Hodgkin lymphoma female patient who was negative for HBsAg, but positive for anti-HBc at the time of chemotherapy. Unfortunately, she developed a fatal HBV reactivation after completing the course of chemotherapy. This case highlights the potential role of lamivudine or other nucleos(t)ide analogue prophylaxis in anti-HBc-positive malignant patient who is about to undergo chemotherapy to provide better coverage for occult HBV infection.

Selecting a short-term prognostic model for hepatocellular carcinoma: comparison between the model for end-stage liver disease (MELD), MELD-sodium, and five cancer staging systems.

BACKGROUND: The model for end-stage liver disease (MELD) and MELD-sodium (MELD-Na) are prognostic models for cirrhotic patients with or without hepatocellular carcinoma (HCC). This study compared the predictive accuracy between the MELD, MELD-Na, TNM (tumor, node, metastasis), Cancer of the Liver Italian Program (CLIP), Barcelona Clinic Liver Cancer (BCLC), Japan Integrated Scoring (JIS), and Tokyo score for 3-month and 6-month mortality in HCC patients. METHODS: A total of 953 patients were prospectively enrolled. The predictive accuracy was compared between different models using the area under receiver operating characteristic curve (AUC). RESULTS: The CLIP system had the highest AUC (0.875) for predicting 3-month mortality, followed by the Tokyo score (0.874), JIS (0.868), BCLC (0.855), MELD-Na (0.829), MELD (0.803), and finally, TNM (0.795) system. At 6 months, the top 3 models and their AUCs were the CLIP (0.882), Tokyo (0.861), and JIS (0.85). MELD-Na consistently had significantly better predictive accuracy than the MELD at 3 and 6 months. The MELD and MELD-Na were better prognostic models in predicting the mortality for surgical patients (AUC, 0.719 to 0.740), whereas the CLIP and Tokyo systems were the 2 better models in staging nonsurgical (AUC, 0.849 to 0.884) and high-risk patients (AUC, 0.790 to 0.846), defined as having at least 2 independent risk factors of mortality, at 3 and 6 months. CONCLUSIONS: The MELD-Na may improve the prognostic ability of the MELD system for patients with HCC. Both the CLIP and Tokyo systems are better short-term prognostic models. These findings are helpful in designing future clinical trials for HCC.

Comparison of four model for end-stage liver disease-based prognostic systems for cirrhosis.

Serum sodium (Na) has been suggested for incorporation into the Model for End-Stage Liver Disease (MELD) to enhance its prognostic ability for patients with cirrhosis. Three Na-containing models--the Model for End-Stage Liver Disease with the incorporation of serum sodium (MELD-Na), the integrated Model for End-Stage Liver Disease (iMELD), and the Model for End-Stage Liver Disease to sodium (MESO) index--were independently proposed for this purpose. This study investigated the accuracy of these 4 MELD-based models for outcome prediction. The c-statistic equivalent to the area under the receiver operating characteristic curve (AUC), used to predict 3- and 6-month mortality, was calculated and compared in 825 patients with cirrhosis. The MELD score tended to be lower with increasing Na level. At 3 months of enrollment, the iMELD had the highest AUC (0.807) and was followed by the MELD-Na (0.801), MESO (0.784), and MELD (0.773); the difference between the MESO and MELD was statistically significant (P = 0.013). At 6 months, the iMELD still had the highest AUC (0.797) and was followed by the MELD-Na (0.778), MESO (0.747), and MELD (0.735); all comparisons showed significant differences between each other (all P < 0.01), with the exception of iMELD and MELD-Na (P = 0.18). With the most discriminative cutoffs, the specificity and negative predictive value were 70%-85% and 89%-97%, respectively, at 3 and 6 months for the 4 models. Patients with spontaneous bacterial peritonitis (SBP) consistently had significantly higher MELD-derived scores in all 4 models compared to patients without SBP (all P < 0.01). Patients with hepatic encephalopathy also had higher scores in all 4 models, although the statistical significance was established only for the iMELD (41.0 +/- 11.5 versus 37.6 +/- 9.1, P = 0.037). In conclusion, the incorporation of Na into the MELD may enhance prognostic accuracy. Both the iMELD and MELD-Na are better prognostic models for outcome prediction in patients with cirrhosis. Patients with SBP have a higher MELD-derived score. Future studies are warranted to define the optimal MELD-based prognostic model for cirrhosis.

Natural history and prognostic factors of primary biliary cirrhosis in Taiwan: a follow-up study up to 18 years.

PURPOSE: The natural history of primary biliary cirrhosis (PBC) has been little studied in Asia. We conducted a Taiwanese cohort study on the natural history of PBC and analysed the prognostic factors. METHODS: This study enrolled 96 consecutive PBC patients between 1985 and 2006 to evaluate the baseline characteristics and outcomes. RESULTS: There were 74 females and 22 males. Eighty-five were positive for antimitochondrial antibodies in sera, and 11 were negative. The clinical manifestations and prognosis were similar between these two groups. In a median follow-up of 47.5+/-55.8 months, 27 patients died. Multivariate analysis indicated that the independent prognostic factors were serum albumin (P=0.021), creatinine (P=0.033) and ursodeoxycholic acid treatment (P=0.008). Besides, 42 patients developed adverse outcomes. Albumin (P<0.001), bilirubin (P=0.019) and prothrombin time (PT) (P=0.010) were significant factors. Moreover, a Mayo risk score <5, a Model for End-Stage Liver Disease (MELD) score <6, a Child-Pugh stage A and early liver histology were associated with favourable outcomes. CONCLUSION: Serum albumin, bilirubin and PT were independent prognostic factors of adverse outcomes for Taiwanese PBC patients. Besides, the Mayo risk score, the MELD score, the Child-Pugh stage and liver histology were also validated to predict survival.