Maintenance hemodialysis decreases serum hepatitis C virus (HCV) RNA levels in hemodialysis patients with chronic HCV infection

OBJECTIVE: Hepatitis C virus (HCV) infection is a major complication among hemodialysis patients the world over. To determine the natural course of HCV viremic levels in patients on maintenance hemodialysis, we prospectively quantified the HCV RNA levels in serial blood samples from hemodialysis patients and compared them with those in nonuremic subjects. METHODS: The population studied included 98 hemodialysis patients and 228 nonuremic subjects with chronic HCV infection. HCV RNA was detected by polymerase chain reaction (PCR) and the levels were determined by branched DNA probe assay. HCV RNA genotypes were determined by PCR using type-specific primers. RESULTS: HCV RNA levels were significantly lower in hemodialysis patients (median, 0.4x10(6) genome equivalent [Meq]/ml) than in nonuremic subjects (median, 3.0 Meq/ml) (p<0.05). HCV of genotype 1b was prevalent in the hemodialysis patients (81.6%) and nonuremic subjects (88.6%). HCV RNA levels in 20 hemodialysis patients with genotype 1b were significantly reduced after each hemodialysis procedure (p<0.05). The 3-yr prospective observation from 1995 to 1998 showed a significant decrease of HCV RNA levels in 47 hemodialysis patients with genotype 1b (median, 1.9-0.9 Meq/ml, p<0.05), whereas levels in 155 nonuremic subjects with genotype 1b did not decrease (median, 2.6-3.0 Meq/ml). There were no patients or nonuremic subjects with undetectable HCV RNA by a PCR assay during the observation period. CONCLUSIONS: These observations suggest that maintenance hemodialysis decreases the HCV RNA levels in hemodialysis patients with chronic HCV infection, but does not produce clearance of the viremia.     

Pharmacokinetics,efficacy and safety of daclatasvir plus asunaprevir in dialysis patients with chronic hepatitis C: pilot study

The aim of this study was to evaluate the pharmacokinetic profile of daclatasvir (DCV) and asunaprevir (ASV) dual therapy in haemodialysis patients infected with hepatitis C virus (HCV). Eighteen haemodialysis patients and 54 patients with normal renal function were treated with DCV and ASV dual therapy for 24 weeks. We evaluated the pharmacokinetic profiles of DCV and ASV and examined the rate of sustained virological response 12 weeks after the end of treatment (SVR₁₂) and incidence of adverse events during treatment of haemodialysis patients infected with chronic HCV genotype 1 infection. To adjust for potential differences in baseline characteristics between haemodialysis patients and patients with normal renal function, we used propensity scores case–control matching methods. Area under the plasma concentration time curve from 0 to 6 h (AUC_{0–6 h}) of DCV was slightly lower in haemodialysis patients than in patients with normal renal function (P > 0.6). AUC_{0–6 h} of ASV was significantly lower in haemodialysis patients (P = 0.012). SVR₁₂ rates were 100% (18/18) for haemodialysis and 96.2% (52/54) for patients with normal renal function. Changes in mean log₁₀ HCV RNA levels and viral response were higher in haemodialysis patients compared to patients with normal renal function. No discontinuations due to adverse events occurred. In conclusion, DCV and ASV dual therapy for HCV infection is effective and safe with similar results in haemodialysis patients compared to patients with normal renal function.     

Virological, immunological and histological aspects in adult beta-thalassemic patients with chronic hepatitis C virus infection.

OBJECTIVES: Multitransfused adult beta-thalassemic patients constitute a population with high prevalence of hepatitis C virus (HCV) infection, because of transmission of HCV from infected blood donors prior to the introduction of anti-HCV screening. The aim of this study was to compare them with otherwise normal patients with HCV infection. METHODS: Forty-two adult multitransfused beta-thalassemics and 49 otherwise normal patients of the same age, with chronic HCV infection were studied. Viral parameters, autoimmunity indices and liver histology were evaluated. RESULTS: Serum HCV RNA levels were found significantly lower in thalassemic (median: 65,150 international units per milliliter (IU/ml); range: 3 059 380 IU/ml) than in non-thalassemic (NT) patients (median: 580,000 IU/ml; range: 10,956,000 IU/ml; P=0.001). The most prevalent genotype in thalassemic group was genotype 4 (32.4%) while in NT group was genotype 3a (59.2%). Cryoglobulins were detected in 8/42 (19%) thalassemic patients and in 12/49 (24.5%) NTs. Thalassemic patients had significantly lower levels of C3 and C4 components of complement and higher incidence of anti-nuclear antibodies than those without thalassemia. In patients with thalassemia a lower grading score was noted in liver biopsy compared with those without thalassemia (4.41+/-1.98 vs 5.38 +/- 2.09, P=0.038). On the contrary, thalassemic patients were found to have a higher staging score (3.08 +/- 1.51 vs 2.33 +/- 1.34, P=0.024). CONCLUSIONS: Adult beta-thalassemic patients, compared with other patients with HCV infection, present lower necroinflammatory activity and lower viral load but higher staging score. Autoimmune features are marginally different. Age of acquiring the infection, iron overload and modulation of immune system by transfusions are the proposed causes of these differences.     

Autoantibodies in chronic liver disease

Some hepatotropic viruses (HBV and HCV) are capable of triggering autoimmune phenomena and manifest the features of autoimmune hepatitis (AIH) in the course of the disease. Careful attention is required to differentiate between AIH and chronic viral hepatitis (CVH) before the selection of treatment. This study was performed to assess the prevalence of rheumatoid factor (RF), antinuclear antibodies (ANA), anti-smooth muscle antibodies (ASMA), anti-mitochondrial antibodies (AMA), anti-parietal cell antibodies (APCA), anti-liver/kidney microsomal antibodies type I (ALKMA1) and anti-neutrophil cytoplasmic antibodies (ANCA) among patients with chronic liver diseases (CLD), and to assess the diagnostic value of these autoantibodies and their relation to HCV viral load and genotype and treatment with interferon-alpha (IFN-alpha). Five groups of patients with CLD (HCV, HBV, HCC, AIH and schistosomal hepatic fibrosis {SHF}) as well as a group of age- and gender-matched healthy controls were enrolled in the study. All the studied persons were subjected to full clinical assessment and laboratory investigations, including liver function tests, hepatitis markers, and HCV RNA by PCR. Detection of ANA, ASMA, APCA, AMA and ALKMA-1 was done by indirect immunofluorescence technique, while ANCA and RF were detected by EIA and latex agglutination test respectively. Results showed a significantly higher prevalence of RF, ASMA and ANCA among patients with CHC, RF and ASMA among HCC patients and ASMA and ALKMA1, among AIH patients as compared to the control group. Patients with HBV and those with SHF had a non-significantly higher prevalence of RF, ASMA and ANCA compared to controls. However, AMA was not detected in this study, and APCA showed no significant difference between the studied groups. The occurrence of these autoantibodies was not significantly related to HCV viral load, HCV genotype or treatment with IFN-alpha. There was a significant association between the occurrence of RF, ANA, ASMA, and ALKMA1 and high ALT levels, and between the occurrence of ANA, ASMA and ALKMA-1 and high AST and ALP levels. In conclusion, autoantibodies are commonly found among patients with HCV infection. The co-existence of HCV infection and autoimmune hepatitis should be considered in patients who are positive for both viral markers and autoantibodies and thorough evaluation of patients must be performed before selection of treatment. Testing for RF, ASMA and ANCA may have a good diagnostic value, however, AMA is the least useful in diagnosis.     

Characteristics of complete responders to interferon among patients with chronic hepatitis C with high serum levels of RNA

Patients with chronic hepatitis C with high serum levels of HCV RNA are less likely to show a complete response to IFN therapy than those with a low serum levels of HCV RNA. The characteristics of patients with high serum levels of HCV RNA who show a complete response to IFN therapy have not been evaluated in detail. We retrospectively analyzed the 121 patients with high serum levels of HCV RNA (≥ 1.0 Meq/ml) before IFN therapy to determine the characteristics of complete responders. A complete response to IFN was observed in 12 (9.9%) of 121 patients. There was no difference between complete responders and non-responders in age, the result of liver function tests, or liver histology. In all complete responders, pretreatment serum level of HCV RNA was less than 5.0 Meq/ml, which was significantly lower than the level in the non-responders (P < 0.01). The fluctuation of HCV RNA level less than 0.5 Meq/ml was observed in ten of the 12 complete responders. The frequency of serotype 2 was significantly higher in the complete responders compared with the non-responders (P < 0.05). These findings suggest that complete responders are rare among patients with serum levels of HCV RNA ≥5.0 Meq/ml. In planning IFN therapy, fluctuations in the HCV RNA level, as well as the serotype, should be considered.     

Circulating autoantibodies to endogenous erythropoietin are associated with chronic hepatitis C virus infection-related anemia

BACKGROUND: Chronic hepatitis C virus(HCV) infection is associated with autoimmune phenomena and is often complicated by anemia. Circulating autoantibodies to endogenous erythropoietin(anti-EPO) have been detected in patients with chronic viral infections and were correlated to anemia. The present study aimed to determine anti-EPO prevalence in patients with chronic HCV infection and investigate its possible association with anemia.METHODS: Ninety-three consecutive patients(62 males and 31 females) with chronic HCV infection, who had never received antiviral therapy or recombinant EPO, were enrolled in the study. Circulating anti-EPO were detected in the serum by using an ELISA assay. Quantitative determination of serum EPO levels was done by radioimmunoassay. HCV RNA viral load measurement and genotype sequencing were also performed.RESULTS: Circulating anti-EPO were detected in 10.8% of HCV-infected patients and the prevalence of anti-EPO was significantly higher in patients with anemia(19.4% vs 5.3%, P=0.040) compared to that in those without anemia. Compared to anti-EPO negative cases, anti-EPO positive patients had higher frequency of anemia(70.0% vs 34.9%, P=0.030), lower EPO concentrations(median 16.35 vs 30.65 m U/m L, P=0.005), and higher HCV RNA viral load(median 891.5×103 vs 367.5×103 IU/m L, P=0.016). In multivariate regression analysis the presence of anti-EPO remained an independent predictor of anemia(adjusted OR: 14.303, 95% CI: 1.417-36.580, P=0.024). EPO response to anemia was less prominent among anti-EPO positive patients(P=0.001).CONCLUSIONS: Circulating anti-EPO are detected in a significant proportion of treatment-na?ve HCV-infected patients and are independently associated with anemia, suggesting a further implication of autoimmunity in the pathophysiology of HCV-related anemia.     

Hepatitis C Virus (HCV) RNA Level Determined by Second-Generation Branched-DNA Probe Assay as Predictor of Response to Interferon Treatment in Patients with Chronic HCV Viremia

Using first- and second-generation branched-DNA probe assays (1st- and 2nd-bDNA), we investigated the predictors of favorable clinical response to interferon (IFN) treatment in patients with chronic HCV viremia. A total of 122 patients (85 genotype 1b and 37 genotype 2a) with chronic HCV viremia received 24-week IFN- treatment. Patients with sustained clearance of serum HCV RNA by polymerase chain reaction at six months after IFN treatment were defined as having a sustained response (SR). HCV RNA level was determined by 1st- and 2nd-bDNA assays prior to treatment. Mean HCV RNA level by 1st-bDNA was significantly higher in genotype 1b patients [5.4 × 10⁶ HCV genome equivalent (Meq)/ml] than in genotype 2a patients (0.9 Meq/ml) (P < 0.05). There was no significant difference between patients with these genotypes in the level by 2nd-bDNA (1b: 5.2 Meq/ml and 2a: 3.1 Meq/ml). SR was achieved by 43 (35.2%) of 122 patients. Mean HCV RNA levels by both the 1st- and 2nd-bDNA of SR patients (1.0 and 1.9 Meq/ml) were significantly lower than those of non-SR patients (5.3 and 6.0 Meq/ml) (both P < 0.05). The SR rate in genotype 2a patients (59.5%) was significant higher than in genotype 1b patients (24.7%) (P < 0.05). Stepwise logistic regression analysis showed that HCV RNA level 1.0 Meq/ml by 2nd-bDNA (odds ratio = 7.6, compared to level > 1.0 Meq/ml, P < 0.05) was a significant predictive cutoff for SR. Using 2nd-bDNA, a significantly higher rate of SR was found in genotype 1b patients with level 1.0 Meq/ml (57.6%) than in those with level >1.0 Meq/ml (3.8%) (P < 0.05). The SR rate of genotype 2a patients with level >1.0 Meq/ml (68.6%) was somewhat higher than for those with level 1.0 Meq/ml (52.4%). These findings suggested that, using 2nd-bDNA, a low HCV RNA level of 1.0 Meq/ml was the most favorable marker of successful IFN treatment and that patients with genotype 2a, even those with level >1.0 Meq/ml, had a high rate of SR to IFN treatment.     

Anticardiolipin autoantibodies in serum samples and cryoglobulins of patients with chronic hepatitis C infection

OBJECTIVE: Chronic hepatitis C virus (HCV) has been linked to extrahepatic autoimmune phenomena. In addition, a variety of autoantibodies are found in patients with HCV. The prevalence, nature, and clinical significance of anticardiolipin (aCL) autoantibodies in serum samples of patients with HCV were therefore investigated. PATIENTS AND METHODS: A prospective study of 48 consecutive patients with chronic HCV with no evidence of previous hepatitis B virus (HBV) infection or any other autoimmune disorder. Thirty patients with HBV and 50 healthy volunteers matched for age and sex served as control groups. Anticardiolipin antibodies in the serum samples and cryoprecipitates were measured by a sensitive enzyme linked immunosorbent assay (ELISA). The beta(2) glycoprotein I (beta(2)-GPI) dependency was determined by carrying out aCL assays in the presence or absence of fetal calf serum samples. RESULTS: High levels of IgG aCL antibodies were detected in serum samples of 21/48 (44%) patients with HCV. These autoantibodies showed no beta(2)-GPI dependency. The control groups had much lower levels of aCL antibodies (20% in the patients with HBV and none in the normal volunteers). Cryoprecipitates from four patients with HCV (three aCL positive; one aCL negative) were further isolated. In two of the three aCL positive patients, specific cardiolipin reactivity was shown in the cryoprecipitates. The group of patients with HCV and aCL antibodies in their serum showed significantly higher total IgG levels, a higher incidence of antinuclear antibodies, and viraemia (HCV RNA) than the aCL negative patients. None of the patients with HCV and aCL antibodies showed any clinical manifestations related to those autoantibodies. CONCLUSIONS: This study clearly shows a high prevalence of IgG aCL antibodies in the serum of patients with HCV and the localisation of these antibodies in some cryoprecipitates. The role of these autoantibodies on the course of HCV infection and their clinical significance has not yet been determined.     

Randomized controlled trial of lymphoblastoid interferon α for chronic hepatitis C (comparison of 9-MU and 6-MU doses)

Objective: We conducted a randomized controlled trial to compare the efficacy of two different dosages of lymphoblastoid interferon α (IFN) for the treatment of chronic hepatitis C. Methods: Eighty-four patients with chronic hepatitis C were enrolled and randomly assigned into the two groups; group A was treated with 6 million units (MU) and group B with 9 MU daily for the first 2 wk, and then thrice weekly for an additional 14 or 22 wk. Results: Eighty patients were evaluated (39 patients in group A and 41 in group B); 14 patients in group A (35.9%) and 15 in group B (36.6%) obtained sustained response. The percentages of patients who became negative for HCV RNA at the end of the second wk differed slightly between the groups, without statistical significance (56.4% and 68.3%). When assessed in detail, patients with genotype 1 and < 1 Meq/ml of viral load became negative for HCV RNA significantly more frequently in group B (eight of eight) than in group A (three of seven) (   p < 0.05  ) at the end of the second week, whereas the sustained response rate was similar between the groups (five of eight and four of seven). Predictors of sustained response by multivariate analysis were low viral load (< 1.0 Meq/ml) and negativity of HCV RNA at the end of the second wk of IFN. Conclusions: The results indicated that there was no difference in sustained response rate between the 6-MU and 9-MU doses. The earlier disappearance of HCV RNA, at the end of the second wk or at least by the end of the fourth week, is an essential condition for sustained response.     

Characterization and differentiation of autoimmune versus viral liver involvement in patients with Sjögren's syndrome

OBJECTIVE: To analyze the prevalence and clinical significance of liver involvement in patients with Sj?gren's syndrome (SS), focusing on the characterization and differentiation of autoimmune versus chronic viral liver disease. METHODS: We investigated liver involvement (clinical signs, analytical data, chronic viral infections, and autoantibodies) in 475 consecutive patients with SS. All patients fulfilled 4 or more of the 1993 European Community Study Group criteria for SS. RESULTS: Liver involvement was detected in 129 (27%) patients. After ruling out chronic illnesses or use of hepatotoxic drugs, the main etiologies were chronic viral liver disease in 64 (13%) cases [chronic hepatitis C virus (HCV) infection in 63 and HBV infection in one] and autoimmune liver diseases in 24 (5%; primary biliary cirrhosis in 16 patients and type-1 autoimmune hepatitis in 8). The analytical liver profile was not useful in differentiating between viral and autoimmune liver disease. In contrast, patients with SS and autoimmune liver disease presented higher mean values of erythrocyte sedimentation rate (p = 0.044), circulating gammaglobulins (p = 0.007), and a higher prevalence of antinuclear antibodies (p < 0.001), antimitochondrial antibodies (p < 0.001), anti-smooth muscle antibodies (p = 0.026), anti-Ro/SSA (p < 0.001), and anti-La/SSB (p = 0.01), while patients with chronic viral liver disease had a higher frequency of cryoglobulinemia (p < 0.001) and hypocomplementemia (p < 0.001). CONCLUSION: Chronic viral liver disease (associated overwhelmingly with HCV) was the main cause of liver involvement in our patients with SS, with a prevalence of 13%, nearly 3-fold greater than that observed for autoimmune liver involvement. The immunological pattern played a key role in the differentiation of viral (predominance of cryoglobulins and low complement levels) and autoimmune (higher frequency of autoantibodies) liver involvement.     

Different turnover rate of hepatitis C virus clearance by different treatment regimen using interferon-beta

BACKGROUND/AIM: Since patients with high viral load and HCV subtype 1b are known to respond poorly to interferon (IFN) therapy, the viral dynamics of HCV RNA after initiation of interferon therapy were examined in the present study with respect to two different administration regimens, once vs. twice a day. METHODS: Twenty-two patients with chronic hepatitis C confirmed by liver biopsy and with >1 Meq/ml of HCV RNA and HCV subtype 1b were randomly assigned to two different IFN administration regimens (6 million units of IFN once a day or 3 million units of IFN twice a day), and the serum HCV RNA level was serially measured. RESULTS: Graphs of HCV RNA levels vs. treatment time showed an initial rapid fall, followed by a slower clearance phase. Fitting the data to a model for HCV decay proposed by Neumann et al. showed that the treatment efficacy was significantly higher with twice daily administration. Negativity for HCV RNA measured by Amplicor assay in the twice-a-day administration group was 18%, 73% and >89% at 1, 2 and 3 weeks, respectively, in contrast to 0%, 0%, and 18%, respectively, with once-a-day administration. However, a significant reduction of platelet count and albumin level, a marked increase in serum aspartate aminotransferase/alanine aminotransferase, and a high incidence of renal toxicity (proteinuria) were found in patients receiving IFN twice a day in comparison with those receiving it once a day. CONCLUSION: The twice-a-day administration of IFN accelerated the clearance of HCV RNA from serum, leading to a more efficient virological response for patients with chronic hepatitis C, but with a high rate of renal toxicity.     

Efficacy of interferon monotherapy to 394 consecutive naive cases infected with hepatitis C virus genotype 2a in Japan: therapy efficacy as consequence of tripartite interaction of viral,host and interferon treatment-related factors

BACKGROUND/AIMS: The mechanism of variable response to interferon (IFN) monotherapy in patients infected with HCV genotype 2a is still unclear. Here we investigated the response in a large group of patients infected with genotype 2a. METHODS: We evaluated 394 consecutive non-cirrhotic naive patients infected with genotype 2a who received IFN monotherapy for 24 weeks, including initial aggressive induction therapy. Of these, 97 were also evaluated for early viral kinetics in serum and treatment efficacy. RESULTS: The overall sustained response (SR) rate was 68.3% (viral load <1.0 Meq/ml (82.4%); >/=1.0 (52.4%)). Multivariate analysis identified five independent factors associated with SR; viral load <1.0 Meq/ml, total IFN dose > or =700 million units, hepatocyte steatosis none or mild, albumin > or =3.9 g/dl, and alanine aminotransferase > or =75 IU/l. The kinetic study showed that serum viral clearance at < or =1 week was the best predictor of SR, and persistence at > or = 4 weeks was a predictor of non-SR. CONCLUSIONS: Our study suggests that viral, host and IFN treatment-related factors determine the response to IFN monotherapy in patients infected with HCV genotype 2a. Further, we report that IFN monotherapy is very effective for patients with genotype 2a, especially for those with low viral load; and that early viral kinetics is useful as a predictor of the response.     

Real-time detection system for quantitation of hepatitis C virus RNA: a comparison with the other three methods

Real-time detection (RTD) system for quantitation of hepatitis C virus (HCV) was developed. Its sensitivity and usefulness were compared with the other three commercially available methods for quantitation of HCV. The sera of 166 patients positive for serum HCV RNA by Amplicor HCV test were assessed. HCV was detected in 78.5% (128/163) by branched DNA assay, in 88.8% (111/125) by HCV core protein assay, in 94.5% (156/165) by Amplicor HCV Monitor test, and in 97.0% (161/166) by the RTD system. The values of viral load by the RTD system were significantly well correlated with those obtained by the other three methods. In the 50 patients treated by interferons (IFNs), the range which predicts the highest sustained response rate was less than 0.5 Meq/ml for branched DNA assay (sustained response rate: 57.9% (11/19)), less than 1 kcopies/ml for Amplicor HCV Monitor test (85.7% (6/7)), and less than 10⁴ copies/ml for RTD system (100% (7/7)). None of the patients with greater than or equal to 2.8 Meq/ml by branched DNA assay (n=14), greater than or equal to 250 kcopies/ml by Amplicor HCV Monitor test (n=19), or greater than or equal to 2×10⁶ copies/ml by RTD system (n=16) obtained sustained response. In conclusion, RTD system was demonstrated to be the most sensitive method for quantitation of HCV, and useful for the prediction of sustained response to IFN therapy.     

Prevalence of cryoglobulinaemia in hepatitis C virus‐ and hepatitis C virus/human immunodeficiency virus‐infected individuals: implications for renal function

Background and aims: Hepatitis C virus (HCV) and human immunodeficiency virus (HIV) demonstrate an affinity towards lymphocytes B, stimulating the production of cryoglobulins. Deposits of cryoprecipitates contribute to glomerulonephritis and renal failure. The presence of cryoglobulins was investigated in the sera of HCV‐monoinfected and HCV/HIV‐coinfected individuals. Associations between types of cryoglobulins and HCV genotypes, viral load and renal function tests were also evaluated. Patients and methods: Seventy‐seven patients were enrolled in this study. Forty‐four were HCV infected and 33 were HCV/HIV coinfected. Cryoglobulins were detected in the sera by electrophoresis and immunofixation. Serum urea and creatinine concentration, glomerular filtration rate (GFR) and serum cystatin C concentration (CC) were analysed to evaluate renal function. The control group included 16 healthy individuals. Results: The occurrence of cryoglobulinaemia in HCV‐monoinfected patients was 55%, whereas in HCV/HIV‐coinfected patients it was 64%. Mixed cryoglobulinaemia type II was determined in 34%, whereas type III in 25%. The prevalence of cryoglobulinaemia was significantly higher in infection with HCV genotype 1 vs. genotype 3 (65 vs. 50%; P<0.01). The most frequently occurring heavy chains were γ‐type (96%). Light chains, the κ‐type, were detected in all patients. The CC concentration was significantly higher in HCV/HIV‐coinfected patients compared with controls (718 vs. 392 ng/ml; P<0.005) or HCV‐monoinfected patients (508 ng/ml; P<0.007). There was correlation between the serum CC concentration and the incidence of cryoglobulinaemia (R=0.44; P<0.00015), which was particularly evident in HCV monoinfection (R=0.43; P<0.0034). Conclusions: Genotype‐1 infection is an important risk factor for cryoglobulinaemia. Standard renal function tests are not sufficient for the prediction of renal failure in HCV‐infected patients. Serum CC concentration allows to establish an early diagnosis of renal insufficiency related to cryoglobulinaemia.     

High serum inhibin concentration discriminates autoimmune oophoritis from other forms of primary ovarian insufficiency

CONTEXT: Primary ovarian insufficiency (POI) is defined by hypergonadotropic amenorrhea occurring before the age of 40 yr. In 4-5% of women with POI, an ovarian autoimmune process can be demonstrated. DESIGN: We have determined the serum concentrations of total inhibin and inhibin B by sensitive ELISAs in 22 women with autoimmune POI (aPOI), 71 women with non-autoimmune idiopathic POI (iPOI), 77 postmenopausal women, and 90 healthy, fertile women (HW). Diagnosis of aPOI was made according to the presence of steroid cell autoantibodies and/or 17alpha-hydroxylase autoantibodies and/or cytochrome P450 side-chain cleavage autoantibodies. All aPOI patients were also positive for adrenal autoantibodies. RESULTS: Total inhibin levels were significantly higher in women with aPOI (median, 281 pg/ml) than in women with iPOI (median, 74 pg/ml) or HW (median, 133.5 pg/ml) (P < 0.001). Levels of inhibin B were also significantly higher in women with aPOI (median, 109 pg/ml) than in women with iPOI (median, 18 pg/ml) (P < 0.001) or HW (median, 39 pg/ml) (P < 0.05). Serum concentrations of total inhibin and inhibin B were significantly higher in women with POI than in postmenopausal women (P < 0.001), irrespective of the presence/absence of autoantibodies. At receiver-operating characteristic analysis, cutoff values of 133 pg/ml for total inhibin and 60.5 pg/ml for inhibin B ensured 86.4% sensitivity and 81-84.5% specificity for aPOI vs. iPOI. CONCLUSIONS: We conclude that a variable degree of ovarian function is preserved in women with POI and that aPOI is characterized by increased inhibin production resulting from a selective theca cell destruction, with initial preservation of granulosa cells.     

Thyroid function and anti-thyroid autoantibodies in untreated children with vertically acquired chronic hepatitis C virus infection

Objective The reported data on thyroid function and anti‐thyroid autoantibodies in adults with untreated hepatitis C virus (HCV) infection are controversial. Data are scarce for HCV‐infected children, and only in those treated with interferon‐α (IFN‐α). We investigated thyroid function and anti‐thyroid autoantibodies in a cohort of untreated children with vertically acquired, chronic, HCV infection. Design and patients FT4 and TSH serum levels (measured by immunometric assays) and anti‐thyroglobulin (TgA) and anti‐thyroperoxidase (TPOA) antibodies (evaluated by fluorescence enzymatic immunoassays) were studied in 36 consecutive HCV‐infected children and 150 age‐ and sex‐matched controls. The prevalence of thyroid involvement was also related to family history of autoimmune disease, distribution of HCV genotypes, and duration and activity of HCV infection. Results Four out of 36 (11·1%) HCV‐infected children and 4/150 controls (2·7%) showed subclinical hypothyroidism [P = 0·04; relative risk (RR) 4·56, 95% confidence interval (CI) 1·08–19·21]. None of these had anti‐thyroid autoantibodies. Two out of 36 (5·6%) HCV‐infected children and 1/150 (0·7%) controls had increased TgA values with normal levels of TSH (P > 0·05). Subclinical hypothyroidism and anti‐thyroid autoantibodies were not related to family history of autoimmune disease, duration of infection, HCV viral load, liver function or different HCV genotype distribution, but seemed to be related to the presence of active HCV infection. Conclusions Our data suggest a role for HCV infection in the development of nonautoimmune thyroid disease in untreated HCV‐infected children, confirming previous studies in adults. Clinicians should be aware of thyroid dysfunction even in untreated children.     

Prevalence and significance of thyroid autoantibodies in patients with chronic hepatitis C virus infection: a prospective controlled study

OBJECTIVE: To clarify controversies on the prevalence and clinical significance of thyroid autoimmunity in hepatitis C virus (HCV) infection. DESIGN: A prospective controlled and follow-up study. PATIENTS AND MEASUREMENTS: Serum thyroid microsomal antibody (TMA) and thyroid stimulating hormone were assayed and compared in a consecutive, unselected series of 130 patients with chronic HCV infection, 130 sex/age (+/- 2 years)-matched patients with chronic hepatitis B virus (HBV) infection and 260 matched normal controls. RESULTS: The prevalence of thyroid autoantibodies in male patients with chronic HCV was < 2%. The prevalence of TMA (< 1:400) in female patients with chronic HCV infection was significantly higher than that of HBV controls (22.1 vs. 1.6%; P < 0.001), and higher but not significant compared with normal controls (13.5%). However, the trend of increasing prevalence with age in normal controls was not observed in HCV patients. TMA seropositive female HCV patients were not different from seronegative counterparts in age, duration of infection, HLA haplotype, associated autoantibodies and liver histology but had a significantly higher prevalence of genotype 1b/2b mixed infection (P < 0.01) and anti-GOR (P < 0.05). Of the 23 HCV patients seropositive for thyroid autoantibodies, seven had Hashimoto's thyroiditis, two had Graves' disease and three had received subtotal thyroidectomy. During follow-up, four of 15 female patients showed a 14-16-fold increase in TMA titre and one developed hyperthyroidism. Patients with thyroid autoantibodies did not show a propensity to develop thyroid dysfunction during interferon therapy. CONCLUSIONS: These results suggest a weak association between HCV and thyroid autoimmunity in females. As in the ordinary population with thyroid autoantibodies, they should be evaluated for thyroid status and be followed-up if thyroid autoimmunity is evident. However, seropositivity of thyroid autoantibodies is not a contraindication to interferon therapy.     

Serum lipid profile and hepatic steatosis of adult beta-thalassaemia patients with chronic HCV infection

OBJECTIVES: The aim of this study was to evaluate the serum lipid profile and to assess the prevalence of hepatic steatosis in adult beta-thalassaemic patients with chronic hepatitis C virus (HCV) infection. METHODS: Thirty-five adult HCV infected, multi-transfused, beta-thalassaemia patients (beta-HCV patients), 63 otherwise normal patients with chronic HCV infection (HCV patients) and 54 beta-thalassaemia patients without chronic viral hepatitis (beta patients) were studied. Total cholesterol, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglycerides, viral markers and liver histology were evaluated. RESULTS: Serum total cholesterol, HDL-C and LDL-C were found at significantly lower levels in beta-HCV and beta patients than in HCV patients. Triglyceride levels were significantly lower in the HCV group compared with the beta group. Nine (25.7%) of the 35 beta-HCV patients had mild hepatic steatosis. Thirteen (23.6%) of 55 HCV patients presented mild and 4/55 (7.3%) moderate hepatic steatosis. None of the beta group presented steatosis. When we compared beta-HCV and HCV patients with steatosis, we found that beta-HCV patients had a lower degree of steatosis (11.1+/-7% vs 22.9+/-17.2%, P=0.021). Multivariate logistic regression analysis showed that the only independent predictor associated with hepatic steatosis in beta-HCV and HCV patients was genotype 3a (OR, 3.61; 95% CI, 1.22-10.71, P=0.021). CONCLUSIONS: Adult beta-thalassaemia patients, compared to other patients with chronic HCV infection, present lower cholesterol levels (total cholesterol, HDL, LDL) and similar frequency but a lower degree of hepatic steatosis. This difference in the degree of steatosis is most likely due to the higher prevalence of genotype 3a in the non-beta-thalassaemia group.     

Silent cerebral infarction in patients with type 2 diabetic nephropathy. Effects of antiplatelet drug dilazep dihydrochloride

BACKGROUND: To determine whether diabetic nephropathy is a risk factor for silent cerebral infarction and whether antiplatelet drug dilazep dihydrochloride decreases the occurrence of silent cerebral infarction in type 2 diabetes patients with microalbuminuria. METHODS: Two hundred four type 2 diabetes patients (124 men, 80 women; age, median 56 years, range 42-74 years) and 60 healthy age-matched subjects (no diabetes, normal renal function) were recruited for brain magnetic resonance imaging. The diabetes patients included 40 without nephropathy (group A), 42 with microalbuminuria (20-200 microg/min) (group B), 44 with macroalbuminuria (>200 microg/min) and normal renal function (blood creatinine <132.7 micromol/L) (group C), 33 with chronic renal failure but not undergoing haemodialysis (blood creatinine >132.7 micromol/L; mean creatinine 335.9 micromol/L) (group D) and 45 undergoing haemodialysis (duration; median 4 years, range 3-6 years) (group E). RESULTS: Silent cerebral infarction was found in 20, 29, 34, 45, 53 and 8% of group A, B, C, D, E and control patients respectively. The incidence of silent cerebral infarction was increased with diabetic nephropathy. Thirty group B patients with no silent cerebral infarction were divided into two groups: (B1) 15 treated with dilazep dihydrochloride and (B2) 15 not treated with dilazep dihydrochloride. Treatment continued for 24 months. The incidence of silent cerebral infarction was significantly lower in the dilazep-treated patients (6.7%) than in the untreated patients (33.3%) (p < 0.01). CONCLUSIONS: These data suggest that diabetic renal dysfunction increases the risk of silent cerebral infarction and that dilazep dihydrochloride prevents its onset in early type 2 diabetic nephropathy patients.