Rheumatic manifestations of hepatitis C infection

Among chronic viral infections, hepatitis C virus (HCV) infection is uniquely associated with an array of rheumatic manifestations and autoimmune laboratory findings. These include, among others, arthralgias, arthritis, fatigue, fibromyalgia, vasculitis, and sialadenitis (Sjögren-like). The mechanisms that are involved in the pathogenesis of these diverse manifestations have not yet been clarified. Regardless of the direct or indirect pathogenetic role of HCV in these clinical entities, the concomitant presence of a chronic viral infection creates a number of diagnostic and therapeutic problems. This is particularly true when immunosuppressive therapy is needed for control of disease activity (eg, HCV-associated cryoglobulinemic vasculitis). The emerging treatment options for chronic HCV offer a major chance for viral eradication and conceivably for cure of these HCV-associated conditions. In this review, the recent advances in the epidemiology, pathogenesis, clinical findings, and treatment of HCV-associated rheumatic conditions are presented.     

Lack of association between occult hepatitis B virus DNA viral load and aminotransferase levels in patients with hepatitis C virus-related chronic liver disease

BACKGROUND AND AIM: Occult hepatitis B virus (HBV) infection in hepatitis C virus (HCV)-infected patients might enhance the severity of chronic liver disease (CLD). To elucidate the correlation between occult HBV infection and the clinical course of HCV-related CLD, we evaluated whether the fluctuation of occult HBV-DNA directly affects the serum alanine aminotransferase (ALT) level. METHODS: Forty-one patients with HCV-related CLD who received regular outpatient treatment and 42 age-, sex-, and antibody to hepatitis B core antigen positivity-matched healthy volunteers were enrolled. Serum HBV-DNA was quantitatively detected using real-time detection polymerase chain reaction (RTD-PCR). Serial serum samples in three patients were measured for HBV-DNA, ALT and HCV core antigen. RESULTS: Hepatitis B virus DNA was amplified in eight of the HCV-related CLD patients (19.5%), which was significantly higher than that of healthy volunteers (2.4%). No significant difference between the genotype 1 HCV-related CLD group and the genotype 2 group was found. Based on the analyses using serial serum samples, the elevation of HBV-DNA did not occur before the ALT flares, but occurred at the same time or after the ALT flares. CONCLUSIONS: The prevalence of occult HBV infection of HCV-related CLD is significantly higher than that of control. Occult HBV infection has no influence on ALT flares among patients with HCV-related CLD.     

Diabetes mellitus in chronic hepatitis B and C: prevalence and potential association with the extent of liver fibrosis

Diabetes mellitus has been reported to have an increased prevalence and to be associated with more severe fibrosis in patients with chronic hepatitis C. We evaluated the prevalence of diabetes mellitus in patients with chronic hepatitis B or C as well as the possible association between presence of diabetes and extent of liver fibrosis. In total, 434 consecutive patients with histologically documented hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (n = 174) or chronic hepatitis C (n = 260) were studied. The relationships of diabetes and epidemiological, somatomorphic, laboratory and histological patient characteristics were evaluated. Liver histological lesions were blindly evaluated according to the Ishak's classification. Diabetes was present in 58 (13%) patients, without any difference between those with chronic hepatitis B (14%) or C (13%). Diabetes was observed significantly less frequently in patients with fibrosis score 0-2 (7.7%) than 3-4 (10.4%) than 5-6 (29.2%) (P < 0.001). The presence of diabetes was independently associated with higher gamma-glutamyl-transpeptidase (GGT) levels and more severe fibrosis or presence of cirrhosis (P < 0.001) as well as with presence of hepatic steatosis and increased serum triglycerides levels (P < 0.02). In the noncirrhotic patients, diabetes was significantly associated with older age and higher GGT levels, but not with the extent of fibrosis. In conclusion, diabetes mellitus is observed in more than 10% of patients with either HBeAg-negative chronic hepatitis B or chronic hepatitis C. The presence of diabetes is strongly associated with more severe liver fibrosis, but such an association may be related to the high prevalence of diabetes in patients with cirrhosis.     

Patterns of viral load in chronic hepatitis B patients in Brazil and their association with ALT levels and HBeAg status

Serum hepatitis B virus (HBV) DNA level is a predictor of the development of cirrhosis and hepatocellular carcinoma in chronic hepatitis B patients. Nevertheless, the distribution of viral load levels in chronic HBV patients in Brazil has yet to be described. This cross-sectional study included 564 participants selected in nine Brazilian cities located in four of the five regions of the country using the database of a medical diagnostics company. Admission criteria included hepatitis B surface antigen seropositivity, availability of HBV viral load samples and age ≥ 18 years. Males comprised 64.5% of the study population. Mean age was 43.7 years. Most individuals (62.1%) were seronegative for the hepatitis B e antigen (HBeAg). Median serum ALT level was 34 U/L. In 58.5% of the patients HBV-DNA levels ranged from 300 to 99,999 copies/mL; however, in 21.6% levels were undetectable. Median HBV-DNA level was 2,351 copies/mL. Over 60% of the patients who tested negative for HBeAg and in whom ALT level was less than 1.5 times the upper limit of the normal range had HBV-DNA levels > 2,000 IU/mL, which has been considered a cut-off point for indicating a liver biopsy and/or treatment. In conclusion, HBV-DNA level identified a significant proportion of Brazilian individuals with chronic hepatitis B at risk of disease progression. Furthermore, this tool enables those individuals with high HBV-DNA levels who are susceptible to disease progression to be identified among patients with normal or slightly elevated ALT.     

Management of recurrent viral hepatitis B and C after liver transplantation

Liver transplant teams are often faced with the challenges of managing viral recurrence after liver transplantation. Hepatitis C virus (HCV) remains the most challenging viral disease in the transplant community. Strategies to prevent and delay viral recurrence have slowly developed over the past 5 years. Hepatitis B virus (HBV), previously a contraindication for liver transplantation due to recurrence and cholestasis with allograft failure, is now one of the more favorable indications for liver transplantation as a result of current therapeutic options. This review investigates the up-to-date information on treatment outcomes for HCV and HBV in the period following liver transplant.     

Increasing hepatitis B viral load is associated with risk of significant liver fibrosis in HBeAg‐negative but not HBeAg‐positive chronic hepatitis B

Background/aims: To evaluate the association between demographical features, serum ALT and HBV DNA and the prevalence of significant fibrosis and inflammation on liver biopsy in patients with chronic hepatitis B. Methods: In this cross‐sectional study of patients on St Vincent's Hospital HBV database, patients were classified into three groups on the basis of HBeAg status and HBV DNA level and the prevalence of significant (F2/3/4) fibrosis and (A2/3) inflammation in each group was established. Patients were also divided into HBeAg‐positive and ‐negative groups and examined for the prevalence of significant fibrosis/inflammation in the strata of HBV DNA and ALT. Predictors of significant fibrosis and inflammation in HBeAg‐positive and ‐negative patients were examined by logistic regression. Results: Three hundred and ninety four patients (HBeAg positive=198; HBeAg negative=196) with liver biopsy were identified. Fifty‐eight percent of HBeAg‐negative patients with HBV DNA >25 000 IU/ml had F2/3/4 fibrosis. HBV DNA and F2/3/4 were positively correlated in HBeAg‐negative patients [odds ratio (OR) 1.42, P=0.001] but inversely correlated in HBeAg‐positive patients (OR 0.71, P=0.03). HBV DNA was an independent predictor of significant fibrosis in HBeAg negative (P=0.03) but not HBeAg‐positive patients. In HBeAg‐positive patients, age was the only predictor of significant fibrosis (P=0.001) and ALT the only predictor of significant inflammation (P=0.003). In the whole cohort there was a close positive association between inflammation and fibrosis. Conclusion: Increasing levels of HBV DNA are associated with increasing prevalence of significant fibrosis only in patients with HBeAg‐negative CHB.     

Chronic hepatitis C and liver fibrosis

Chronic infection with hepatitis C virus (HCV) is a leading cause of liver-related morbidity and mortality worldwide and predisposes to liver fibrosis and end-stage liver complications. Liver fibrosis is the excessive accumulation of extracellular matrix proteins, including collagen, and is considered as a wound healing response to chronic liver injury. Its staging is critical for the management and prognosis of chronic hepatitis C (CHC) patients, whose number is expected to rise over the next decades, posing a major health care challenge. This review provides a brief update on HCV epidemiology, summarizes basic mechanistic concepts of HCV-dependent liver fibrogenesis, and discusses methods for assessment of liver fibrosis that are routinely used in clinical practice. Liver biopsy was until recently considered as the gold standard to diagnose and stage liver fibrosis. However, its invasiveness and drawbacks led to the development of non-invasive methods, which include serum biomarkers, transient elastography and combination algorithms. Clinical studies with CHC patients demonstrated that non-invasive methods are in most cases accurate for diagnosis and for monitoring liver disease complications. Moreover, they have a high prognostic value and are cost-effective. Non-invasive methods for assessment of liver fibrosis are gradually being incorporated into new guidelines and are becoming standard of care, which significantly reduces the need for liver biopsy.     

Hepatitis C virus-associated hypobetalipoproteinemia is correlated with plasma viral load,steatosis, and liver fibrosis

OBJECTIVES: A relationship between chronic hepatitis C virus (HCV) infection and lipid metabolism has recently been suggested. The aim of this study was to determine the correlation between lipid profile and virology, histologic lesions, and response to alpha interferon therapy in noncirrhotic, nondiabetic patients with hepatitis C. METHODS: A total of 109 consecutive untreated chronic hepatitis C patients were studied to assess the following: 1) the effects of HCV genotype, viral load, steatosis, hepatic fibrosis, and body mass index (BMI) on lipid profile; and 2) whether lipid parameters could predict response to antiviral therapy. RESULTS: The control group showed a significantly higher apolipoprotein B (apoB) concentration compared with patients with chronic hepatitis C. Hypobetalipoproteinemia (apo B <0.7 g/L) was found in 27 (24.7%) chronic HCV patients and in five (5.3%) control subjects (p = 0.0002). Levels of apo B were negatively correlated with steatosis and HCV viral load (r = -0.22; p = 0.03). This last correlation was strong for non-1 genotype and genotype 3 (r = -0.48; p = 0.0005, and r = -0.47; p = 0.007, respectively) but was not found in genotype 1. In multivariate analysis, low apo B concentration was significantly associated with fibrosis grade 2 or 3 versus grade 0 or 1 (p < 0.001), steatosis >5% (p < 0.001), low body mass index (p < 0.001), and high HCV viral load (p < 0.014). No correlation was found in the 76 treated patients between apo B and response to interferon therapy. CONCLUSIONS: In chronic HCV patients, hypobetalipoproteinemia occurs already in the early stages of HCV infection before the development of liver cirrhosis. The correlation between apo B levels and HCV viral load seems to confirm the interaction between hepatitis C infection and beta-lipoprotein metabolism.     

肝活检对HBV携带者的诊断意义

目的探讨肝活检对HBV携带者的诊断意义。方法回顾性分析134例HBV携带者,在B超引导下行1秒钟快速肝穿刺活检术,行肝组织病理学检查。结果在134例患者中,仅2例（1.49%）肝组织病理学检查完全正常（G0S0）;在105例HBV DNA≥10^5copies/ml（或HBeAg阴性者HBV DNA≥10^4copies/ml）的HBV携带者中,肝组织炎症活动度≥G2者80例（76.19%）,即可实施抗病毒治疗;在100例HBeAg（＋）与34例HBeAg（-）感染者,肝组织炎症活动度和纤维化程度比较无明显统计学差异（P=0.308）;在不同肝组织炎症活动度和纤维化程度感染者,HBV DNA载量无明显的统计学差异（P=0.557）,HBV DNA≥10^7copies/ml与HBV DNA〈10^7copies/ml感染者比,肝组织炎症活动度和纤维化程度存在统计学差异（P=0.007,P=0.001）。结论对于慢性HBV携带者,应及时进行肝组织活检。     

Lack of association between TTV viral load and aminotransferase levels in patients with hepatitis C or non-B-C

TT virus (TTV) is a newly identified un-enveloped single-stranded DNA virus. Although TTV was initially thought to be a new hepatitis virus, it is still unclear whether it causes hepatitis. To clarify the natural history and pathogenesis of TTV infection, serial serum samples from patients with chronic hepatitis were analysed. TTV DNA was quantified by real-time detection polymerase chain reaction assay (RTD-PCR), which was adapted for TTV. Five patients with chronic hepatitis, 4 with hepatitis C and 1 with non-B-C, were studied. The study period ranged from 9 to 50 months. In 3 patients there were frequent increases in TTV DNA titres, but no concomitant elevation of the aminotransferase (ALT) levels. In 2 patients who were treated with interferon, the changes in TTV titres were not synchronized with those of the ALT levels. Thus, in cases of chronic hepatitis, no correlation was observed between the serum TTV DNA titres and the ALT levels.     

Hepatocellular carcinoma in Sweden: its association with viral hepatitis, especially with hepatitis C viral genotypes

Viral markers of chronic hepatitis were tested for in 95 frozen serum samples from 299 patients from Malm?, Sweden, with hepatocellular carcinoma (HCC), diagnosed between 1977 and 1994. Hepatitis B analysis included anti-HBc, HBsAg and, if anti-HBc positive, HBV DNA. Hepatitis C infection analysis included anti-HCV screening, RIBA, HCV RNA and HCV genotyping. HCV genotyping was also carried out in 9 HCV-viraemic HCC-patients from Gothenburg. HCV genotype distribution in HCC cases was compared with Swedish HCV-infected blood donors. Among the 95 patients from Malm?, 28 (29%) had anti-HBc, but only 5 (5%) were chronic HBV carriers, compared with 16 (17%) with chronic hepatitis C (p = 0.021). HCV-related HCC was more common among immigrants (8/16 vs. 8/79; p < 0.001). Genotyping of 25 HCV-infected cases showed genotype 1a in 6 (24%), genotype 1b in 13 (52%), genotype 2b in 4 (16%), and genotype 3a in 2 (8.0%) patients. Genotype 1b was more common among HCC patients than among blood donors (p < 0.001), but 8 of 13 genotype 1b-infected patients were from countries where genotype 1b is predominant. Among native Swedes there was no difference between the HCV genotypes infecting blood donors and those found in HCC patients.     

The association of HIV viral load with indirect markers of liver injury

This study assessed the association of HIV RNA with indirect markers of liver injury including FIB-4 index, liver enzymes and platelet counts in a high-risk Hispanic population. The data were derived from a prospective study that included 138 HIV/hepatitis C (HCV)-coinfected and 68 HIV-infected participants without hepatitis C or B co-infection (mono-infected). In unadjusted analyses, detectable HIV viral load (vs undetectable, <400 copies/mL) was associated with a 40% greater odds (OR 1.4, 95% CI: 1.1-1.9, P = 0.016) of FIB-4 > 1.45 in the HIV/HCV-coinfected group and 70% greater odds of FIB-4 > 1.45 (OR 1.7, 95% CI: 1.0-2.8; P = 0.046) in the HIV-mono-infected group. In multivariable analyses, a 1 log(10) increase in HIV RNA was associated with a median increase in FIB-4 of 12% in the HIV/HCV-coinfected group and 11% in the HIV-mono-infected group (P < 0.0001). Among the HIV/HCV-coinfected group, the elevating effect of HIV RNA on FIB-4 was strongest at low CD4 counts (P = 0.0037). Among the HIV-mono-infected group, the association between HIV RNA and FIB-4 was independent of CD4 cell counts. HIV RNA was associated with alterations in both liver enzymes and platelet counts. HIV antiretroviral therapy was not associated with any measure of liver injury examined. This study suggests that HIV may have direct, injurious effects on the liver and that HIV viral load should be considered when these indirect markers are used to assess liver function.     

慢性乙型肝炎患儿HBV DNA载量与肝脏病理、肝功能、肝纤维化血清学指标的相关性分析

目的探讨慢性乙型肝炎(CHB)患儿HBV DNA载量与肝脏病理及肝功能、肝纤维化血清学指标的关系。方法收集2010年7月-2015年6月湖南省儿童医院肝病中心收治的确诊为CHB的患儿79例,根据患儿血清HBV DNA载量分为低载量组(103拷贝/mlHBV DNA载量≤105拷贝/ml,n=8)、中载量组(105拷贝/mlHBV DNA载量≤107拷贝/ml,n=54)和高载量组(107拷贝/mlHBV DNA载量,n=17),比较各组间肝脏病理变化程度及血清ALT、AST、Ⅲ型前胶原(PCⅢ)、层黏连蛋白(LN)、透明质酸(HA)、Ⅳ型胶原CⅣ水平。计量资料组间比较采用Kruskal-Wallis秩和检验,相关性分析采用Kendall's tau-b等级相关检验。结果 3组肝脏病理炎症程度分级均以G1为主,分别占75%、74.1%、64.7%,高载量组G2比例上升(35.5%);3组肝组织纤维化分期均以S1为主,分别占75.0%、72.2%、70.6%,低载量组出现S4(12.5%)。HBV DNA载量与肝组织炎症分级和纤维化分期均无相关性(r值分别为0.069、-0.047,P值均0.05)。随着HBV DNA载量的增高,各组间血清ALT、AST水平逐渐增高,3组间ALT水平比较差异有统计学意义(χ2=5.37,P=0.048)。随着HBV DNA载量的增高,各组间血清HA、LN、PCⅢ和CⅣ水平则逐渐降低,3组间PCⅢ水平比较差异有统计学意义(χ2=6.26,P=0.044)。结论 CHB患儿HBV DNA载量与肝脏病理无显著相关性。临床综合分析HBV DNA载量及肝功能、肝纤维化血清学指标,结合肝活组织病理检查,才能更加客观、准确地评估CHB的病情。     

Determination of the relationship of serum hyaluronic Acid levels to the degree of liver fibrosis in biopsies of patients with chronic viral hepatitis B and C

Background and Aims

Determining the stage of liver fibrosis and the grade of necroinflammation is important in predicting the prognosis and treatment response of patients with chronic viral hepatitis. Liver biopsy is associated with several technical problems and complications; therefore, its repetitive performance as a procedure in evaluating treatment response and in following up patients is not recommended. This study was performed to determine the correlation of serum hyaluronic acid (HA) levels with the stage and grade of histopathologic liver changes in patients with chronic hepatitis B and C.

Methods

This analytical cross-sectional study was performed on 69 patients with chronic hepatitis B or C in Mashhad, Iran, who were referred to our clinic and underwent liver biopsy and blood sampling simultaneously in 2006-2007. None of the patients were on medication that would affect the serum levels of (HA) and patients with signs of arthropathy were excluded from the study.

Results

Out of the 69 patients i this study, 48 (69.6%) were male and 21 (30.4%) were female. The causative virus in 29 patients (42%) was hepatitis C and in the rest (n = 40, 58%) hepatitis B. The severity of liver fibrosis (stage) had a direct correlation (r = 0.25, P = 0.042) with the levels of (HA) and an inverse correlation with the platelet level (r = 0.37, P = 0.002). The degree of liver necroinflammation (grade) did not have a significant correlation with the levels of (HA) and alanine transaminase (r = -0.01, P = 0.9; r = 0.21, P = 0.09 respectively); instead, there was an inverse correlation with platelet levels (r = 0.36, P = 0.003).

Conclusions

Our study results correspond with those of other international studies; thus suggesting that the (HA) serum level is a useful marker in determining the severity of fibrosis in patients with chronic viral hepatitis. To form a definite conclusion, further studies on large groups should be performed.