With up to 400 million affected people worldwide, chronic hepatitis B virus (HBV) infection is still a major health care problem. During the last decade, several novel therapeutic approaches have been developed and evaluated. In most regions of the world, interferon-α, and nucleos(t)ide analogues (NUCs) are currently approved. Despite major improvements, none of the existing therapies is optimal since viral clearance is rarely achieved. Recently, a better understanding of the HBV life cycle and the development of novel model systems of HBV infection have led to the development of novel antiviral strategies and drug targets. This review will focus on current and potential future drug targets in the HBV life cycle and strategies to modulate the virus–host interaction.
HBV life cycle
Acute variceal bleeding (AVB) is a medical emergency and associated with a mortality of 20% at 6 weeks. Significant advances have occurred in the recent past and hence there is a need to update the existing consensus guidelines. There is also a need to include the literature from the Eastern and Asian countries where majority of patients with portal hypertension (PHT) live.
The expert working party, predominantly from the Asia–Pacific region, reviewed the existing literature and deliberated to develop consensus guidelines. The working party adopted the Oxford system for developing an evidence-based approach. Only those statements that were unanimously approved by the experts were accepted.
AVB is defined as a bleed in a known or suspected case of PHT, with the presence of hematemesis within 24 h of presentation, and/or ongoing melena, with last melanic stool within last 24 h. The time frame for the AVB episode is 48 h. AVB is further classified as active or inactive at the time of endoscopy. Combination therapy with vasoactive drugs (<30 min of hospitalization) and endoscopic variceal ligation (door to scope time <6 h) is accepted as first-line therapy. Rebleeding (48 h of T0) is further sub-classified as very early rebleeding (48 to 120 h from T0), early rebleeding (6 to 42 days from T0) and late rebleeding (after 42 days from T0) to maintain uniformity in clinical trials. Emphasis should be to evaluate the role of adjusted blood requirement index (ABRI), assessment of associated comorbid conditions and poor predictors of non-response to combination therapy, and proposed APASL (Asian Pacific Association for Study of the Liver) Severity Score in assessing these patients. Role of hepatic venous pressure gradient in AVB is considered useful. Antibiotic (cephalosporins) prophylaxis is recommended and search for acute ischemic hepatic injury should be done. New guidelines have been developed for management of variceal bleed in patients with non-cirrhotic PHT and variceal bleed in pediatric patients.
Management of acute variceal bleeding in Asia–Pacific region needs special attention for uniformity of treatment and future clinical trials.
Gastrointestinal hemorrhage; Cirrhosis; Portal hypertension; Vasoactive drugs; Endoscopy
Chronic hepatitis C progression is commonly attributed to the continuous activation of the immune response with an increased production of pro-inflammatory cytokines, leading to fibrosis and ultimately to cirrhosis. On the contrary, anti-inflammatory cytokines, mainly interleukin (IL)-10 have a modulatory effect on hepatic fibrogenesis. The association between individual polymorphisms within cytokine genes and hepatitis C outcome is often weak and non-informative. Interestingly, it has been demonstrated that a combination of specific genotypes may be a more significant and powerful approach for predicting disease risk.
This study is aimed at investigating the combined effect of single nucleotide polymorphism (SNP) in IL-18 (−607C/A, −137G/C), interferon (IFN)-γ (+874T/A) and IL-10 (−1082G/A) genes on cirrhosis risk in HCV-infected patients.
Seventy-seven chronic hepatitis C Tunisian subjects were included in this study. The patients were divided into two groups: the first included 31 non-cirrhotic patients, and the second included 46 liver cirrhosis patients. IL-18 genotyping was performed using the PCR amplification and the restriction fragment length polymorphism analysis (RFLP). IFN-γ and IL-10 polymorphisms were analyzed using the allele-specific PCR (AS-PCR).
The combined high-risk genotype (IL-18 −607C/*, IL-18 −137G/*, IFN-γ +874T/*, IL-10 −1082A/A) frequency was compared between patients with and those without cirrhosis. Individuals were classified according the number of high-risk genotypes as follows: (0–2), patients with at most two high-risk genotypes; (3–4), patients with at least three of the high-risk genotypes. The logistic regression analysis showed that patients harboring 3–4 putative high-risk genotypes have a fivefold higher risk for developing cirrhosis in comparison to those harboring at most two high-risk genotypes (OR = 5.19; 95% CI = 1.49–18.05; p = 0.009).
Our study showed that the co-inheritance of IL-18, IFN-γ and IL-10 specific high-risk genotypes is associated with a greater risk for liver cirrhosis.
Hepatitis C; Cirrhosis; Cytokine; Polymorphism; Combined analysis
Background and aim
Hepatitis C virus (HCV) has been postulated to be an etiological agent for lymphoid malignancies. Whereas a high prevalence of HCV infection in non-Hodgkin’s lymphoma (NHL) patients has been shown to exist in many geographical areas of high HCV prevalence, studies from other parts have not established any form of association. In India, there is a scarcity of data to show either a positive or a negative association between NHL and HCV infection. Therefore, we determined the prevalence of HCV infection in patients with NHL.
A total of 228 subjects were included, out of which, the number of newly diagnosed consecutive patients with lymphoproliferative disorders (NHL and CLL) were 57 [mean age, 48.7 years (range: 18–80)] and the control group consisted of 171 subjects [mean age, 48.6 years (range: 18–80)]. We used third generation enzyme immunoassay to detect HCV antibodies. HCV RNA was detected by nested RT-PCR.
Among the 57 patients of NHL, 44 (77.2%) had high-grade disease (diffuse large B cell), 6 (10.5%) intermediate-grade (follicular lymphoma), and 7 (12.3%) low-grade (small lymphocytic); 26 patients had B symptoms at diagnosis. None of the patient tested positive for antibody to hepatitis C virus (anti-HCV) while 1 patient (1.75%) tested positive for HCV RNA. Among the age- and sex- matched controls, 2 (1.17%) subjects tested positive for anti-HCV; both were also positive for HCV RNA.
HCV infection is unlikely to be associated with lymphoproliferative disorders in northern India and does not play a major role in the pathogenesis of lymphoproliferative disorders.
Hepatitis C virus; Non-Hodgkin’s lymphoma; Lymphomagenesis
Livers from donors positive for antibody against anti-HBc can potentially transmit de novo hepatitis B (DNH) to their recipients. Despite a good outcome, prophylaxis is usually offered to such recipients. There is no consensus on the standard prophylactic regimen and hence prophylaxis varies among different transplant centres. Nonetheless, hepatitis B immune globulin (HBIG) is considered the mainstay of such prophylaxis, either alone or in combination with an oral antiviral treatment. We aim to provide a concise review of the current use of HBIG in prevention of DNH. We also address a few important questions regarding HBIG use.
Hepatitis B immune globulin; Liver transplant; De novo hepatitis B; Prophylaxis
Quantification of hepatic fibrosis is of critical importance in chronic hepatitis C not only for prognosis, but also for antiviral treatment indication. Two end points are clinically relevant: detection of significant fibrosis (indication for antiviral treatment) and detection of cirrhosis (screening for eosphageal varices and hepatocellular carcinoma). Until recently, liver biopsy was considered the reference method for the evaluation of liver fibrosis. Limitations of liver biopsy (invasiveness, sampling error, and inter-observer variability) have led to the development of non-invasive methods. Currently available methods rely on two different approaches: a “biological” approach based on the dosage of serum fibrosis biomarkers; and a “physical” approach based on the measurement of liver stiffness, using transient elastography (TE). This review is aimed at discussing the advantages and limits of non-invasive methods and liver biopsy and the perspectives for their rational use in clinical practice in the management of patients with chronic hepatitis C.
Chronic hepatitis C; Liver fibrosis; Non-invasive; Transient elastography; FibroScan; Serum biomarkers; Liver biopsy
Either combination treatment or monotherapy using agents with a high genetic barrier are recommended for hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (CHB). The aim of this study was to compare effect of naïve HBeAg-negative CHB patients with either de novo combination of lamivudine (LAM) and adefovir dipivoxil (ADV) or entecavir (ETV) monotherapy.
HBeAg-negative CHB patients (n = 71) with ALT levels between 2 and 10 times the upper normal limit and HBV DNA levels >104 copies/mL were enrolled. Patients were treated with either LAM 100 mg plus ADV 10 mg per day (n = 31) or ETV 0.5 mg per day (n = 40) for 48 weeks.
The average reduction in HBV DNA level compared with baseline were 5.16 ± 1.69 log in the LAM + ADV group and 5.36 ± 1.70 log in the ETV group by week 48 (P = 0.624). The virological response (VR) rates were 80.65 and 77.5%, the biochemical response (BR) rates were 93.55 and 90.00% at week 48 in the LAM + ADV and ETV groups, respectively. There was no significant difference in the VR and BR between the two groups. During the 48-week treatment period, virological breakthrough and serious side effects were not noted in any patient.
Both LAM + ADV combination therapy and ETV monotherapy are effective in naïve HBeAg-negative CHB patients, but further studies are needed to obtain long-term results.
Chronic hepatitis B; HBeAg-negative; Lamivudine; Adefovir dipivoxil; Combination treatment; Entecavir; Monotherapy
Myeloid sarcoma (MS) is a neoplasm of immature granulocytes, monocytes, or both involving extramedullary sites. MS with no evidence of leukemia (nonleukemic MS) is very rare and the initial diagnosis can be difficult. This report describes an unusual case of nonleukemic MS of the liver in a 16-year-old patient presenting as debilitating hepatomegaly. A liver biopsy revealed diffuse infiltration by neoplastic cells of myeloid lineage (CD68, myeloperoxidase). A bone marrow biopsy showed no evidence of medullary involvement. The patient subsequently developed heart failure. Autopsy revealed infiltration of most organs by neoplastic cells but failed to identify abnormal myeloid cells in bone marrow.
Myeloid sarcoma; Liver; Leukemia
To establish a method of assessing the malignant potential of hepatocellular carcinoma (HCC) using magnetic resonance imaging (MRI).
For 69 nodules [12 Edmondson (Ed)-I, 48 Ed-II, 9 Ed-III] in 54 HCC patients, signal intensity patterns and enhancement patterns of gadopentate dimeglumine (Gd-DTPA) dynamic studies were correlated with histological differentiation and serum lens culinaris agglutinin-reactive alpha-fetoprotein (AFP-L3) level, which is an indicator of poor prognosis.
Hypointensity on T1-weighted imaging was seen in 17, 72, and 89% of Ed-I, Ed-II, and Ed-III HCCs, respectively (P < 0.001). Meanwhile, hyperintensity on T2-weighted imaging was seen in 42, 88, and 89% (P < 0.005). Tumor stain during the arterial phase of Gd dynamic MRI was seen in 75, 86, and 89%. Tumor stain washout during the portal phase was seen in 43% of Ed-II and 100% of Ed-III HCCs (P < 0.005). In the Ed-II and Ed-III HCCs, hypointensity on T1-weighted imaging was seen in 65% of AFP-L3-negative HCCs and 90% of AFP-L3-positive HCCs (P = 0.071). Washout of tumor stain during the portal phase was seen in 39% of AFP-L3-negative HCCs and 75% of AFP-L3-positive HCCs (P < 0.05).
Although hyperintensity of tumor on T2-weighted imaging and arterial hypervascularity of tumor are considered to be useful for differential diagnosis between well differentiated HCCs and moderately/poorly differentiated HCCs, hypointensity of tumor on T1-weighted imaging and tumor stain washout during the portal phase of Gd-DTPA dynamic MRI reflected poorer histological differentiation of HCCs and correlated with AFP-L3 levels.
Hepatocellular carcinoma; Magnetic resonance imaging (MRI); Histological differentiation; Lens culinaris agglutinin-reactive alpha-fetoprotein (AFP-L3)
The aim of this study was to use the single cell gel (comet) assay to investigate whether blood, liver, heart, kidney, and brain are particularly sensitive organs for DNA damage in cirrhotic rats to predict genetic instability induced by cirrhosis.
A total of 16 male Wistar rats (negative control, n = 8; experimental, n = 8) were submitted to bile duct ligation during 28 days.
Cirrhosis was able to induce genetic damage in liver and brain cells, as depicted by the mean tail moment. No genetic damage was induced in blood, heart, or kidney cells (i.e., no significant statistically differences were noticed when compared with negative control).
In conclusion, our results suggest that cirrhosis could contribute to DNA damage in liver and brain cells.
Cirrhosis; Rats; DNA damage; Single cell gel (comet) assay
We and others have reported that adding adefovir dipivoxil (adefovir) to lamivudine results in virological and biochemical improvement in cases of lamivudine resistance. The current study assessed the efficacy and safety of combined therapy after 104 weeks of combined treatment and analyzed the frequency of persistent lamivudine resistant HBV.
A total of 78 patients with compensated CHB (Group A) were maintained on either adefovir 10 mg daily (n = 38) or placebo (n = 40) while continuing lamivudine. An additional 38 patients with decompensated cirrhosis or post liver transplantation (Group B) received lamivudine plus adefovir. The primary endpoint was HBV DNA response at year 2.
At week 104 of therapy, a significantly greater proportion of patients in Group A on combination therapy (76%) had a decline in serum HBV DNA to ≤105 copies or >2 log10 reduction from baseline compared to those receiving lamivudine alone (13%; p < 0.001). Fifty-two percent of Group A patients on combination treatment continued to have the M204V/I HBV mutation compared to 92% receiving lamivudine alone (p = 0.0013). Virologic response occurred less frequently in patients expressing persistent lamivudine resistant HBV. In Group B, 87% of patients had HBV DNA response at week 104 (median change from baseline of −5.84 log10 copies/mL).
The combination of lamivudine and adefovir for 2 years generally proved effective in lamivudine-resistant cases, but there was a persistently high rate of detection of lamivudine resistant mutants and impaired virologic response in compensated patients.
Chronic hepatitis B; Resistance; Lamivudine; Adefovir dipivoxil; Combination therapy
Clevudine and entecavir are currently available in Korea as antiviral drugs against chronic hepatitis B (CHB). We aimed to compare the efficacy of clevudine and entecavir therapy.
Treatment-naïve CHB patients who received 30 mg of clevudine or 0.5 mg of entecavir a day were analyzed. Mean reduction of hepatitis B virus (HBV) DNA levels, complete virological response (cVR, undetectable HBV DNA by real-time PCR), biochemical response (recovery to normal ALT level), and hepatitis B e antigen (HBeAg) seroconversion rate at the 48th week of treatment were assessed.
A number of 59 patients in clevudine group and 61 patients in entecavir group were included. Mean HBV DNA reductions from baseline were similar in the clevudine and entecavir groups, −6.4 versus −6.8 log10 copies/mL in HBeAg-positive (p = 0.417) and −6.9 versus −7.0 log10 copies/mL in HBeAg-negative patients (p = 0.640). The proportion of patients who achieved cVR was not different between the two groups, 53 versus 55% in HBeAg-positive (p = 1.000) and 100 versus 95% in HBeAg-negative patients (p = 0.452). Biochemical response rates and HBeAg seroconversion rates were also similar in both the groups. Two (3.4%) patients in clevudine group showed virologic breakthrough with rtM204I mutation using direct sequencing analysis. Clinical myopathy occurred in two (3.4%) patients in clevudine group.
Mean reduction of viral loads was similar between clevudine and entecavir groups during 48 weeks. However, virologic breakthrough and significant myopathy were noted only in clevudine-treated patients. Therefore, more attention should be paid to patients receiving clevudine.
Hepatitis B virus; Clevudine; Entecavir
To determine the rate of vertical transmission (transmission from mother to child) of hepatitis C virus in low to middle socio-economic pregnant women.
This study was conducted at Sarwar Zuberi Liver Centre (SZLC) in collaboration with the department of Gynaecology and Obstetrics, Civil Hospital Karachi (CHK) and Abbasi Shaheed Hospital (ASH) for a period of 4 years from September 2005 to December 2009. Total 18,000 women seeking antenatal care were screened for hepatitis C antibodies (Anti-HCV) using 4th generation ELISA technique. Positive 1,043 women were further offered HCV ribonucleic acid (RNA) by polymerase chain reaction (PCR). Six hundred and forty women agreed to have PCR done, and 510 PCR positive women were finally included in the study, followed till delivery and treated if required. Newborns of 510 PCR positive mothers were advised HCV-RNA by PCR from 3 to 12 months of age and Anti-HCV at 18 up to 24 months and followed up to 3 years.
1,043/18,000 (5.79%) mothers were Anti-HCV positive, of which PCR results of 640 mothers are available where 510/640 (79.7%) were PCR positive, 357/510 (70%) delivered by spontaneous vaginal delivery (SVD), 33 (6.4%) by forceps delivery, 70 (13.7%) had elective, and 50 (9.8%) had emergency caesarian section. Premature rupture of membranes (PROM) was present in 81 mothers. Data of 510 babies from 3 months to 3 years of age was available of which only 215 had their laboratory tests done (HCV-RNA-PCR in 86 and Anti-HCV in 129). Mean birth weight (kg), height (cm) and OFC (cm) were 2.74 ± 0.43, 52.4 ± 7.5, and 35 ± 4. Apgar score median at 1 and 5 min was 7 (range 2–10), 8 (range 4–10), respectively. Low birth weight was present in 49 (9.6%), 37 (7.2%) had history of Neonatal Intensive Care Unit (NICU) admission. PCR of none of the 86 babies done at 3–12 months was positive. Five babies out of 129 were Anti-HCV positive at 18 months of age. Of this, 3/5 was HCV-RNA-PCR positive. Rate of vertical transmission of HCV was 1.39.
In spite of the high hepatitis C positivity in pregnant population, the rate of vertical transmission to the neonate is low.
Vertical transmission; HCV; Pregnant; Karachi
Survival post-liver transplantation (LT) has improved; however, patients are considered at the, risk of malignancy due to prolonged immunosuppression. The long-term outcome of patients developing de novo neoplasm (DN) at our centre was evaluated.
Between October 1988 and December 2007, 800 LT were performed in 742 patients. Patients were divided into two study periods according to the time of LT; first: October 1988–December 1995; second: January 1996–December 2007.
After a mean follow-up of 5 ± 4.6 years, 71 DN (9.5%) were detected in 742 patients. The cumulative risk of DN development increased with the time from LT although no differences at 3, 5, and 10 years were found when first and second periods were compared (3, 7, 16% vs. 2, 4, 11%, respectively; p = 0.4). DN incidence was higher in the first compared with the second period (10.7 vs. 7.8%; p < 0.04); no significant differences were observed in mortality rate (50 vs. 27%; p = 0.052). Actuarial patient survival post-DN at 1, 3, and 5 years: 67, 48, 45% versus 82, 71, 65%, in the first versus second period, respectively, p < 0.04.
DN incidence has decreased in recent years; however, as survival post-LT increases, so does the incidence of DN. Surveillance programmes are necessary to diagnose DN at early stages.
De novo neoplasms; Immunosuppression; Surveillance; Survival
Studies have suggested that glutamine synthetase (GS) is a potential marker of hepatocellular carcinoma (HCC). We aimed to evaluate the expression of GS in non-malignant liver tissue and serum GS levels in HCC, liver cirrhosis (LC), chronic hepatitis B (CHB), five kinds of extrahepatic diseases patients and healthy subjects. Immunohistochemistry (IHC) was used to assess GS expression in 260 liver tissue samples (from 120 HCC, 90 CHB stage 4, and 50 CHB stage 1–3 patients). Enzyme-linked immunosorbent assays of 325 samples (from 100 healthy donors, 33 CHB stage 1–3, 43 CHB stage 4, 111 HCC, and 45 extrahepatic diseases patients) were used to further analyze GS levels in serum. IHC studies showed the expression of GS in 70% of HCC patients, 46.7% of CHB stage 4 patients and 38% of CHB stage 1–3 patients. The χ2 tests showed significant difference between HCC samples and non-tumor tissues (P = 0.001 for HCC vs. CHB stage 4, P = 0.000 for HCC vs. CHB). Consistent with this, serum GS levels are increased in HCC and CHB stage 1–4 patients. There are significant differences among all samples (P = 0.000 for all), except CHB stage 1–3 versus CHB stage 4 (P = 0.552). Based on multiple linear regressions, HCC, CHB stage 1–4 and AFP were significantly associated with serum GS levels. In addition, in HCC group, TNM and Child-Pugh were significantly associated with GS levels. Expression of GS is increased in HCC, LC, and CHB. It may be a new serum marker for liver disease.
Glutamine synthetase; Hepatocellular carcinoma; Liver cirrhosis; Chronic hepatitis B; Regeneration; Receiver operating characteristic curve; Sensitivity and specificity
Background and aims
Acute-on-chronic liver failure (ACLF) is associated with a high mortality rate in the absence of liver transplantation. There is limited data on predictors of survival in ACLF in children. Therefore, we prospectively studied the predictors of outcome of ACLF in children.
A prospective evaluation of 31 children in the age group of 1–16 years who fulfilled the criteria for ACLF according to Asian Pacific Association for the Study of the Liver (APASL) 2008 consensus was done. All consecutive children were evaluated for etiology, diagnosis and severity of ACLF. For grading of organ dysfunction, the sequential organ failure assessment (SOFA) score was calculated. SOFA constitutes the parameters of respiration, coagulation, cardiovascular system, central nervous system, and renal and liver functions. We evaluated possible correlation between outcomes and different variables.
Of the 31 children who fulfilled the criteria for ACLF, the common underlying chronic liver diseases (CLD) were autoimmune hepatitis (AIH) in 41.9% and Wilson disease in 41.9% of the patients. Superinfection with hepatitis A virus (HAV) (41.9%) was the most common etiology of acute deterioration. To find the best predictor for outcome, linear regression analysis was performed. Multivariate analysis revealed that the SOFA score and the International Normalized Ratio (INR) were predictors of survival. Six (19.4%) patients died. Causes of death were multiorgan failure in four and liver failure in two patients.
The mortality in ACLF is 19.4% and the causes of death were multiorgan failure and liver failure. The SOFA score and INR were predictors of outcome of ACLF in children.
Acute-on-chronic liver failure; Predictors of mortality; Sequential organ failure assessment
Background and aims
There are insufficient data comparing long-term prognoses after radiofrequency ablation (RFA) and surgery.
We compared the baseline characteristics and survival rates of patients (single, ≤3 cm, and Child-Pugh class A) treated surgically (n = 215) and with RFA (n = 255) from January 2000 to December 2007 at our institution.
The surgery group was characterized by younger age, higher prevalence of HBsAg, less cirrhosis, and an increased chance of Child-Pugh score of 5 and CLIP score of 1, compared to the RFA group. During the median follow-up period of 42 months (range 1–109), the 3-, 5- and 7-year overall survival rates in the surgery group were 98, 94, and 94%, respectively, which were significantly higher than those in the RFA group (92, 87, and 76%, respectively, P = 0.002). The 3- and 5-year recurrence-free survival rates were 72 and 66%, respectively, in the surgery group, which were significantly higher than those in the RFA group (34 and 24%, respectively, P < 0.001). The superiority of the survival rates in the surgery group persisted in most patients throughout the subgroup analysis, based on the Child-Pugh score and CLIP score. Multivariate analysis showed that age and surgery as a procedure type were the significant predictive factors for both overall survival [HR = 1.04 (CI 1.001–1.08), P = 0.047 for age; HR = 2.97 (CI 1.19–7.45), P = 0.02 for surgery] and recurrence-free survival [HR = 1.02 (CI 1.01–1.04), P = 0.01 for age; HR = 2.44 (CI 1.76–3.37), P < 0.001 for surgery].
The long-term outcome after surgery for Child-Pugh class A and single small HCC is superior to that after RFA.
Hepatocellular carcinoma; Hepatectomy; Radiofrequency cather ablation; Survival; Recurrence; Prognosis
To investigate the efficacy and safety of aldosterone antagonist, eplerenone in the treatment of spironolactone-induced painful gynaecomastia in cirrhotic patients.
A number of 19 consecutive patients with cirrhosis due to alcohol abuse or chronic hepatitis B, who had been administered spironolactone and suffered from painful gynaecomastia, have been included in the study. Substitution of spironolactone with eplerenone was followed for 3 months under close inspection. Age and gender, along with Child–Pugh stage of cirrhosis, pain (in a 1–5 visual analogue scale), Na+, K+, FSH, LH, 17 (OH) progesterone, DHEA-S, testosterone, and prolactin were measured at the beginning and the end of the study.
All 19 patients expressed alleviation of pain (P < 0.001). Two patients deteriorated and two other ameliorated as far as the Child–Pugh score is referred. All biochemical and hormonal parameters remained unchanged.
In cirrhotic patients with painful gynaecomastia, the use of eplerenone instead of spironolactone might reverse pain and seems to be safe and clinically acceptable option.
Eplerenone; Spironolactone; Cirrhosis; Gynaecomastia
In this study, we examined the effects of LY52, a caffeoyl pyrrolidine derivative designed to fit the S′1 active pocket of gelatinases, on the expressions of matrix metalloproteinases and invasion abilities of hepatocellular carcinoma cells.
The effects of LY52 on the proliferations of HepG2 (hepatitis B virus (HBV) negative) and HepG2.2.15 (HBV-producing) cells were detected by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Gelatin zymography was used to detect the effects of LY52 on matrix metalloproteinases expressions and Western blot was used to detect matrix metalloproteinase-2 expressions. Transwell chamber assay was used to detect the effects of LY52 on invasion of the cells.
Gelatin zymography and Western blot showed that matrix metalloproteinase-2 expressions were inhibited by LY52 in a dose-dependent manner, and inhibitory rates of LY52 on HepG2 cells were higher than on HepG2.2.15 cells. Transwell chamber showed that LY52 could significantly inhibit the invasion of both cells, although the inhibitory effects of LY52 on HepG2.2.15 cells were was not as obvious as on HepG2 cells.
These results suggested that LY52 might inhibit the invasion of hepatocellular carcinoma cells by suppressing matrix metalloproteinase-2, although the inhibitory effects of LY52 on HBV-negative cells were more obvious than that of HBV-infected cells.
LY52; Hepatocellular carcinoma; Matrix metalloproteinases; Invasion
There are many studies on changes in Doppler waveforms of hepatic veins in cirrhotic liver. It is postulated that dampening of phasic oscillations appears with worsening of liver function. Our aim was to reevaluate the significance of Doppler waveforms of hepatic vein in cirrhotic patients and to correlate with hepatic blood flow.
Patients and method
One hundred and thirty-five consecutive patients of liver cirrhosis and 60 age and sex matched non-cirrhotic controls were enrolled in this study. Doppler waveforms were obtained from right hepatic vein during normal respiration. Other parameters measured were flow volume of portal trunk, right portal vein and proper hepatic artery.
Waveforms of the hepatic vein were classified into triphasic, biphasic and flat patterns. Flat waveform was rare and appeared in only 3% cases. There was no correlation between liver dysfunction and patterns of waveforms. Inflow, particularly to the right lobe, was significantly elevated in cases associated with the non-triphasic waveforms.
This study shows that the flat waveforms have no diagnostic value. Role of hepatic blood flow seems to be important suggesting hemodynamic changes rather than liver dysfunction as a plausible cause of change in waveforms.
Hepatic vein waveform; Liver cirrhosis; Doppler ultrasound
To examine the rate of early HBeAg loss and predictors of HBeAg loss in HBeAg-positive chronic hepatitis B (CHB) patients with acute exacerbation (AE) treated with lamivudine.
A total of 146 patients diagnosed with CHB and AEs were included in this retrospective study. Patients were divided into two groups: decompensated and compensated.
The mean treatment duration for the decompensated and compensated groups was 18.1 and 19.9 months, respectively. Decompensated patients were significantly older and had a higher prevalence of cirrhosis and genotype B infection than compensated patients. Compared to compensated patients, decompensated patients achieved a higher rate of HBeAg loss (25.8 vs. 14.3%; P = 0.0805) at 3 months of therapy, a higher rate of serum HBV DNA negativity (53.2 vs. 29.8%; P = 0.0042), and a lower rate of rtM204V/I mutation (3.2 vs. 16.7%; P = 0.0139) after 12 months of lamivudine therapy. The rates of HBeAg loss after 6 and 12 months of lamivudine therapy were similar between the two groups. Logistic regression analysis revealed that female gender and baseline ALT level ≥1,000 IU/L, but not decompensations, were significant predictors of HBeAg loss at 3 months; however, only female gender was a significant predictor of HBeAg loss after 6 and 12 months of lamivudine therapy. The early HBeAg losers showed a significantly higher sustained remission rate off lamivudine therapy.
Female gender and baseline serum ALT level ≥1,000 IU/L were independent predictors of early HBeAg loss during lamivudine therapy in HBeAg-positive CHB patients with AE.
Electronic supplementary material
The online version of this article (doi:10.1007/s12072-010-9227-x) contains supplementary material, which is available to authorized users.
Acute exacerbation; Chronic hepatitis B; Decompensation; HBeAg loss; Lamivudine
Non-alcoholic fatty liver disease (NAFLD) is a major cause of chronic liver disease globally and commonly associated with insulin resistance and metabolic syndrome (MS). Peroxisome proliferator-activated receptor-γ (PPARγ) is a transcription factor abundantly expressed in adipocytes and plays a key role in the regulation of adipocyte differentiation, lipid and glucose homeostasis. Pro12Ala variant has been earlier associated with obesity, type 2 diabetes and MS.
The present study aimed to determine the genotype frequencies of the Pro12Ala variant in NAFLD patients and any further association with other phenotype in the patients.
Patients and methods
Ninety-eight NAFLD patients and 280 matched controls were genotyped for presence of the Pro12Ala variant. Genomic DNA was extracted and polymerase chain reaction–restriction fragment length polymorphism using Bst-UI was performed for the detection of C–G change at codon 12 position of PPAR γ2 gene. Genotype and allele frequencies were compared between patients and controls. The Hardy–Weinberg equilibrium was tested by comparing expected/observed genotype frequencies by χ2 test.
The frequencies of Pro/Ala genotype were comparable between NAFLD patients and controls. In the controls, 213 (75.7%) were homozygous for the wild-type (Pro/Pro) genotype and 67 (23.9%) were heterozygous (Pro/Ala). In NAFLD patients, genotypic distribution of wild type, heterozygous and homozygous were 63 (64.3%), 34 (34.7%) and 1 (1%), respectively. Heterozygous genotype was found to be significantly higher in the patients (P = 0.01). We also analyzed related phenotypic association of the patients with Pro12Ala genotype. We observed that the Pro12Ala (heterozygous) genotype was significantly higher in the patients who had body mass index >25 kg/m2 (P = 0.025).
Pro12Ala variation of the PPAR γ2 gene is associated with NAFLD and might play a role in the pathogenesis of NAFLD.
Non-alcoholic fatty liver Disease (NAFLD); Peroxisome proliferator-activated receptor γ (PPAR γ); Body mass index (BMI)
Hemophagocytic syndrome is a potentially fatal complication that rarely occurs after liver transplantation. We present a 25-year-old man with a history of Still’s disease who presented with fever, arthralgia, and elevated serum ferritin levels 6 months after undergoing liver transplantation for fulminant hepatic failure due to autoimmune hepatitis potentially triggered by infliximab therapy. Liver biopsy demonstrated features consistent with hemophagocytic syndrome. The patient was successfully treated with a course of high dose steroids and had complete resolution of his symptoms and normalization of liver chemistry test abnormalities. Patients with Still’s disease may rarely complicate with fulminant hepatic failure with infliximab therapy. Hemophagocytic syndrome a rare potentially life threatening condition may occur in such patients following liver transplantation.
Rheumatoid arthritis; Macrophage activation syndrome; Liver transplantation
Toll-like receptor 4 (TLR4) is a pattern recognition receptor that functions as lipopolysaccharide (LPS) sensor and whose activation results in the production of several pro-inflammatory, antiviral, and anti-bacterial cytokines. TLR4 is expressed in several cells of healthy liver. Despite the constant confrontation of hepatic TLR4 with gut-derived LPS, the normal liver does not show signs of inflammation due to its low expression of TLR4 and ability to modulate TLR4 signaling. Nevertheless, there is accumulating evidence that altered LPS/TLR4 signaling is a key player in the pathogenesis of many chronic liver diseases (CLD). In this review, we first describe TLR4 structure, ligands, and signaling. Later, we review liver expression of TLR4 and discuss the role of LPS/TLR4 signaling in the pathogenesis of CLD such as alcoholic liver disease, nonalcoholic fatty liver disease, chronic hepatitis C, chronic hepatitis B, primary sclerosing cholangitis, primary biliary cirrhosis, hepatic fibrosis, and hepatocarcinoma.
Toll-like receptor 4; Lipopolysaccharide; Chronic liver diseases