Severe Necroinflammatory Activity Research Articles

Prediction of liver histological lesions with biochemical markers in chronic hepatitis B patients in Iran.

Aim: In the current study, we aimed at identifying independent laboratory parameter to predict liver damage. Background: Although liver biopsy is frequently recommended in assessing disease severity and selecting antiviral treatment candidates, it has several limitations. Patients and methods: A total of 527 patients with untreated chronic hepatitis B virus infection were selected. A percutaneous liver biopsy was obtained. All of the patients were graded and staged for liver fibrosis (1-6) and inflammatory activity (1-18). Complete blood count, biochemical blood tests and Serum viral markers were detected for these patients. Results: 106 patients had moderate to severe necroinflammatory activity. Compared to patients with mild activity, this group was older and had significantly higher aspartate aminotransferase (AST), alanine aminotrasferase (ALT), alkaline phosphatase (Alk. P) and AST to platelet ratio index (APRI) and significantly lowers hemoglobin (Hb), fasting blood sugar (FBS) and platelet (PLT). By multiple regressions analysis Hb, AST, FBS and PLT were independently predictive of moderate to severe necroinflammatory activity. 109 patients had moderate to severe fibrosis. Compared to patients with mild fibrosis, the former patients were older. In addition, the mean of AST, ALT, PT and APRI were significantly higher, and WBC, serum Alb and PLT were significantly lower in patients with moderate to severe fibrosis. Also by multiple regressions analysis age, AST, serum Alb and PLT were independently predictive of moderate to severe fibrosis. Conclusion: Our study demonstrates the utility of biochemical markers for the diagnosis of moderate histological lesions in patients with chronic hepatitis B. Whereas millions of patients with chronic hepatitis B in the world are living, this approach will be useful and cost-benefit.

Impact of adefovir dipivoxil on liver fibrosis and activity assessed with biochemical markers (FibroTest–ActiTest) in patients infected by hepatitis B virus

The aim was to assess the utility of FibroTest-ActiTest (FT-AT) as noninvasive markers of histological changes in patients with chronic hepatitis. Patients with chronic hepatitis B (HBeAg+ and HBeAg-) randomized in two trials of adefovir (ADV) vs placebo, with available paired liver biopsies and FT-AT at baseline and after 48 weeks of treatment were included. The predictive value of FT-AT was assessed using the area under the receiver operating characteristics curves (AUROCs) for the diagnosis of bridging fibrosis, cirrhosis and moderate-severe necroinflammatory activity. The impact of treatment with ADV vs placebo was assessed on liver injury according to baseline stage and virological response at 48 weeks. The analysis of 924 estimates for the diagnosis of bridging fibrosis, cirrhosis and moderate or severe necroinflammatory activity yielded FT-AT AUROCs: 0.76 +/- 0.02 (standardized 0.81 +/- 0.02), 0.81 +/- 0.02 and 0.80 +/- 0.01, respectively. Similar impacts of ADV on liver fibrosis and activity were observed both with paired biopsy (fibrosis stage from 1.6 to 1.4, activity grade from 2.5 to 1.3) and paired biomarkers (FT from 0.44 to 0.40, AT from 0.62 to 0.25) (P < 0.0001). FibroTest-ActiTest provides a quantitative estimate of liver fibrosis and necroinflammatory activity in patients with chronic hepatitis B and may be an alternative to reduce the need for liver biopsy.

Herb-induced hepatitis by Teucrium polium L.: report of two cases and review of the literature

Herbal medicinal products are being increasingly used throughout the world. Herbal 'remedies' are, however, not risk free and many cases of hepatotoxicity have been reported. Teucrium polium grows mostly in the Mediterranean basin and is popular, because of hypoglycemic and hypolipidemic properties. We report two cases of T. polium-induced hepatitis in Greek female patients, who used the plant's extract to control the cholesterol levels. Both patients presented with very high aminotransferases after consuming herbal tea for 2 or 3 months. One patient also developed jaundice. Histologic examination of liver biopsies showed hepatitis with moderate or severe necroinflammatory activity. Discontinuation of the herbal remedy resulted in normalization of the liver enzymes in both patients. Our findings, and those of other authors, suggest that T. polium may not be safer than T. chamaedrys and T. capitatum, which have also been reported to occasionally cause hepatotoxicity.

Liver biopsy assessment in chronic viral hepatitis: a personal, practical approach

The terminology for assessment of chronic viral hepatitis in liver biopsy specimens has become confusing with the proliferation of grading and staging schemes that have paralleled the rise of the hepatitis C epidemic and the importance of mixed viral infections. This review represents a personal approach to the interpretation of these biopsy specimens, aiming at clarifying and simplifying the important points for the general pathologist confronted by these diagnostic dilemmas. The most commonly used schemes—Ishak modification of the Knodell ‘hepatic activity index', Scheuer, Metavir, Batts–Ludwig classifications—are presented with evaluation of their pros and cons. Which scheme is selected is less important than the consistent use of a single scheme and the clear naming of that scheme in pathology reports. The importance and clinical implications of identifying severe necroinflammatory activity in the form of ‘confluent necrosis' is discussed. Pathologists must also be clear about assessing concomitant diseases, in particular, alcoholic or non-alcoholic fatty liver disease, and be aware that grading/staging schemes for chronic hepatitis do not apply to mixed disease conditions. Other important features to be evaluated in all chronic hepatitis biopsy specimens include iron (which may represent hereditary hemochromatosis or secondary uptake) and neoplasia-associated changes, namely large cell change and small cell change; these findings and their clinical import are updated and reviewed. Sample approaches to composing useful diagnostic reports are also presented.

Hepatitis C virus genotypes in Serbia and Montenegro: The prevalence and clinical significance

To investigate the prevalence of hepatitis C virus (HCV) genotypes in Serbia and Montenegro and their influence on some clinical characteristics in patients with chronic HCV infection. A total of 164 patients was investigated. Complete history, route of infection, assessment of alcohol consumption, an abdominal ultrasound, standard biochemical tests and liver biopsy were done. Gene sequencing of 5' NTR type-specific PCR or commercial kits was performed for HCV genotyping and subtyping. The SPSS for Windows (version 10.0) was used for univariate regression analysis with further multivariate analysis. The genotypes 1, 2, 3, 4, 1b3a and 1b4 were present in 57.9%, 3.7%, 23.2%, 6.7%, 6.7% and 1.8% of the patients, respectively. The genotype 1 (mainly the subtype 1b) was found to be independent of age in subjects older than 40 years, high viral load, more severe necro-inflammatory activity, advanced stage of fibrosis, and absence of intravenous drug abuse. The genotype 3a was associated with intravenous drug abuse and the age below 40. Multivariate analysis demonstrated age over 40 and intravenous drug abuse as the positive predictive factors for the genotypes 1b and 3a, respectively. In Serbia and Montenegro, the genotypes 1b and 3a predominate in patients with chronic HCV infection. The subtype 1b is characteristic of older patients, while the genotype 3a is common in drug abusers. Association of the subtype 1b with advanced liver disease, higher viral load and histological activity suggests earlier infection with this genotype and eventually its increased pathogenicity.

VASCULAR PARKINSONISM IN AN ELDERLY WOMAN WITH MIXED CRYOGLOBULINEMIA ASSOCIATED WITH HEPATITIS C INFECTION

To the Editor: Central nervous system (CNS) involvement is rarely reported in patients infected with hepatitis C virus (HCV).1 Stroke, transient ischemia, lacunar infarction, or encephalopathic syndrome may occur. Mechanisms related to vasculitis induced by the mixed cryoglobulinemia frequently associated with HCV infection seem to generate neurological lesions.1, 2 Vascular parkinsonism (VP) is now recognized as a distinct clinicopathological entity,3, 4 especially in older people,5 although the validity of VP as a concept has been called into question since the original work of Critchley.6 VP accounts for 3% to 6% of all cases of parkinsonism in studies in which imaging or pathological analysis is used to support diagnosis.7 We report here a case of VP associated with mixed HCV-related cryoglobulinemia. An 83-year-old woman was hospitalized for rehabilitation after a gradual loss of autonomy related to gait problems, postural instability, and mild depression, all of which worsened after an episode of severe bronchopneumonia. Parkinson's disease had been diagnosed 6 years previously, but no improvement was observed on levodopa treatment. Four years after the onset of symptoms, the patient was admitted to a neurological facility. Magnetic resonance imaging showed microhypersignal for the basal ganglia (striatum, insula, thalamus), external capsule, periventricular white matter, and, to a lesser extent, geniculate bodies, cerebellar peduncles, and dentate nuclei. VP was diagnosed. The dose of levodopa was increased, but no real improvement followed. The patient had been diagnosed with chronic hepatitis C (Stage 6 of the Knodell classification based on liver biopsy) 10 years earlier. She had refused treatment and was reluctant to attend follow-up visits. One year before admission, biochemical markers (Fibrotest and Actitest) indicated severe fibrosis (A3-A4) and necroinflammatory activity (A3). Polymerase chain reaction tests showed that the patient was infected with HCV of genotype 1. The patient again refused treatment. She had a long history of hypertension more or less controlled by treatment. A consultant neurologist reexamined and found gait problems, postural instability with retropulsion, hypertonia involving all four limbs but most severe in the legs, and an absence of rest tremor. The neurologist reported generalized apraxia, no real cognitive impairment, and a Mini-Mental State Examination score of 29 of 30. She confirmed the diagnosis of VP. Cryoglobulinemia (type III) was detected. This is the first description of a case of VP associated with mixed HCV-related cryoglobulinemia. A causal effect is possible in this case. Disease of the small arteries and arterioles that penetrate the brain cortex and reach the underlying structures of the white and deep gray matter, such as the basal ganglia, are the primary cause of approximately one third of symptomatic strokes.8 Arteriolosclerosis probably affected these small vessels in our patient, who, like most patients with VP, had hypertension,3-5 but because few patients with hypertension develop parkinsonism, another determinant must also have been involved. We suspect that cryoglobulinemia may have played a role by increasing the burden on these small vessels affected by arteriolosclerosis. A previous study found9 that 40% of patients with VP had anticardiolipin antibodies (ACLA), which are associated with hypercoagulable states and stroke risk, but found no difference in vascular risk factors, such as hypertension, between ACLA-positive and -negative patients. Thus, as proposed in previous studies1, 3-5, 9 we suggest that a more-precise definition of the relationship between diseases of the small vessels in the brain and other conditions, such as HCV infection, is required. In particular, it would appear to be worthwhile to test patients with VP for HCV infection and cryoglobulinemia. Financial Disclosure: None. Author Contributions: All authors were involved in the analysis and interpretation of clinical data and the preparation of the manuscript. Sponsor's Role: None.

Histopathology of chronic hepatitis C in relation to virus genotype

The natural history of hepatitis C virus (HCV) infection is variable and the factors determining the course of the illness are unclear. There are geographical variations in the distribution of different HCV genotypes, and some of them are related to the specific infection routes. Regarding our country, the dominant genotype is genotype 1b. It is unclear and still remains a question whether the distinct histopathological manifestations are related to the particular genotypes of HCV. Thus, the aim of this study was to determine whether the distinct histopathological manifestations of HCV infection might be in relation to the individual virus genotype. In this study we examined 126 patients with chronic HCV infection regarding the histopathological features, demographic data, and virus genotype. The observed groups of patients were predominantly infected with HCV genotypes 1b and 3a. In this study we found that the patients infected with HCV genotype 1b had more frequently moderate or severe necroinflammatory activity of the disease, significantly higher grading score as compared with other genotypes (p < 0.0001). A higher degree of fibrosis was, also, more common in the patients infected with genotype 1b of HCV as compared with other genotypes (p < 0.05). There were no significant correlations between the necroinflammatory activity of the disease and the stage of fibrosis in 1b, 4 and mixed genotypes. The present data support the hypothesis that distinct genotypes of HCV are associated with the particular histopathological manifestation of the disease.

The impact of prior hepatitis B virus infection on liver histology and the response to interferon therapy in chronic hepatitis C

Patients with chronic hepatitis C frequently have antibodies to the hepatitis B core antigen (anti-HBc), indicative of prior hepatitis B virus (HBV) infection. In these patients, persistence of HBV may exacerbate liver injury and diminish the response to treatment. The aim of this study was to evaluate the relationship between previous HBV infection and liver histology and the sustained virologic response (SVR) to interferon (IFN)-based therapy in patients with chronic hepatitis C. A total of 132 HBsAg-negative, treatment-naive patients were evaluated. Using multiple logistic regression analysis, the impact of anti-HBc-positivity on the rate of SVR was determined. Progression to bridging fibrosis or cirrhosis was assessed using Cox proportional hazards regression and Kaplan-Meier survival analysis. The median age of the patients was 47 years (IQR, 37-60), 57% were male, and 73% had genotypes 1, 4, 5, or 6. Fifty-one patients (39%) were anti-HBc-positive. The prevalence of moderate to severe necroinflammatory activity (P = 0.36) and progression to bridging fibrosis or cirrhosis (log-rank P = 0.83) was similar between anti-HBc-positive and -negative patients. After a median of 48 weeks (IQR, 26-52) of therapy (IFN, n = 116; IFN and ribavirin, n = 16), 23 patients (17%) achieved a SVR; the rate of response was similar in anti-HBc-positive and -negative patients (18%vs 17%, P = 1.00). After controlling for age, gender, genotype, fibrosis, and treatment regimen, anti-HBc status did not independently affect the rate of SVR (anti-HBc-positive vs negative: odds ratio, 1.36; 95% confidence interval, 0.45 to 4.06; P = 0.58). In conclusion, previous HBV infection does not affect liver histology or the response to IFN-based therapy in patients with chronic hepatitis C.

Semiquantitative assessment of IgM antibody to hepatitis B core antigen and prediction of the severity of chronic hepatitis B.

Controversial results have been reported concerning the correlation between serum levels of IgM antibodies to hepatitis B core antigen (IgM HBcAb) and the histological activity of chronic hepatitis B. In this study, paired serum samples and liver biopsies were collected from 200 consecutive chronic hepatitis B patients (mean age 39.2 +/- 0.8 years; M:F 154:46; 41 hepatitis B e antigen (HBeAg) positive) and tested for IgM HBcAb using a semiquantitative highly sensitive assay (IMx CORE-M(R)). The severity of liver disease was assessed by the Ishak score, grading the necroinflammatory activity (by using the histology activity index, HAI) and staging the fibrosis. The index values of IgM HBcAb were significantly different among patients with mild (HAI < or = 6), moderate (HAI 7-12) and severe (HAI > or = 13) necroinflammatory activity but the stage of fibrosis was unrelated to the IgM HBcAb. According to the index value of IgM HBcAb, we selected three groups of patients: Group A included 36 patients with an index value below 0.200; Group B, 99 patients with an index value between 0.200 and 0.500; and Group C, 65 patients with an index value over 0.500. The mean HAI grading in Group A was 5.3 +/- 0.4, in Group B it was 7.4 +/- 0.3 and in Group C it was 8.9 +/- 0.4 (f = 16.5, P < 0.0001). A mild HAI grading was observed in 77.8% of Group A, in 47.5% of Group B and in 23.1% of Group C patients; conversely, severe grading was detected in 0% of Group A, in 11.1% of Group B and in 18.5% of Group C patients (P < 0.0001). An index value of IgM HBcAb below 0.200 was 75% predictive of a mild necroinflammatory activity (29% sensitivity and 91.6% specificity) and ruled out a severe activity. Therefore, the quantitative assessment of IgM HBcAb appears to be a useful clinical tool in the prediction of the necroinflammatory activity of chronic hepatitis B. A serum index value of IgM HBcAb consistently below 0.200 could be considered a surrogate marker of remission of hepatitis B virus-induced liver disease.

Relationships between serum aminotransferase levels, liver histologies and virological status in patients with chronic hepatitis C in Taiwan.

In patients with chronic hepatitis C, the relationships between serum alanine aminotransferase (ALT) levels, histological liver injury and serum hepatitis C virus (HCV) RNA titres remain controversial. To evaluate these relationships, 93 Chinese patients with histological diagnosis of chronic hepatitis C were enrolled for this study. Serum ALT levels, HCV-RNA titres and HCV genotypes were examined. The histology was evaluated according to a modified histological activity score based on the degree of periportal necro-inflammation, intralobular necro-inflammation, portal inflammation, total necro-inflammation and fibrosis. The mean serum ALT level was significantly higher in patients with severe intralobular necro-inflammation activity than in patients with mild or no activity (P = 0.013). However, scores of intralobular activity were only weakly correlated with serum ALT levels (r = 0.27) and could not be used to adequately predict ALT values. Serum ALT levels showed no significant correlation with the scores of portal inflammation, periportal necro-inflammation, total necro-inflammation and fibrosis. Also, there was no significant difference in the mean serum ALT level among different serum HCV-RNA levels and HCV genotypes. Serum HCV-RNA titres and genotypes showed no significant correlation with liver histology and serum HCV-RNA titres were only weakly correlated with the total necro-inflammatory score (r = 0.27). In conclusion, although serum ALT levels were higher in patients with more severe intralobular necro-inflammatory activity, the correlation was not strong enough to adequately predict ALT values. Serum HCV-RNA titres and genotypes also showed no significant correlation with serum ALT levels and liver histologies.