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Re: [GIWorld-Hepatitis] Digest Number 1651

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  • Burning the Dragon
    re: early combination therapy: Why on earth would anyone be first treated with interferon monotherapy these days? Its a good way to produce nonresponders for a
    Message 1 of 1 , Dec 7, 2004
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      re: early combination therapy:

      Why on earth would anyone be first treated with interferon monotherapy these days? Its a good way to produce nonresponders for a study if their lives do not matter to anyone, but worthless otherwise. This whole study seems like a monumental waste of time.

      MB
      ----- Original Message -----
      From: GIWorld-Hepatitis@yahoogroups.com
      To: GIWorld-Hepatitis@yahoogroups.com
      Sent: Friday, November 26, 2004 7:09 AM
      Subject: [GIWorld-Hepatitis] Digest Number 1651




      There are 6 messages in this issue.

      Topics in this digest:

      1. Hepatitis E virus may have spread from wild boar meat, Japan
      From: "Shshonee \(Alley\)" <shshonee@...>
      2. Early Combination Therapy Prevents Liver Cancer
      From: "Shshonee \(Alley\)" <shshonee@...>
      3. Yahoo! - Poor results for Rigel hepatitis drug Messenger
      From: "Shshonee \(Alley\)" <shshonee@...>
      4. Energex System's Experimental Non-Pharmicalogical Treatment Promising in Reduci
      From: "Shshonee \(Alley\)" <shshonee@...>
      5. Extrahepatic manifestations of chronic hepatitis C
      From: "Shshonee \(Alley\)" <shshonee@...>
      6. RNA interference could put clamp on good genes gone bad
      From: "Shshonee \(Alley\)" <shshonee@...>


      ________________________________________________________________________
      ________________________________________________________________________

      Message: 1
      Date: Thu, 25 Nov 2004 10:10:02 -0600
      From: "Shshonee \(Alley\)" <shshonee@...>
      Subject: Hepatitis E virus may have spread from wild boar meat, Japan

      Hepatitis E virus may have spread from wild boar meat, Japan
      24 Nov 2004

      Japanese government researchers have found the DNA of the hepatitis E virus in wild boars trapped in four prefectures, Health, Labor and Welfare Ministry research groups have reported.

      The DNA that was found is very similar to that found in hepatitis E patients who contracted the virus last year in Hyogo and Tottori prefectures, strongly suggesting that the people contracted the virus from wild boar meat.

      Noting that heat kills the virus, the ministry has urged people to cook wild boar thoroughly and avoid eating it raw or rare.

      Two research groups captured 85 wild boars in Nagano, Aichi, Wakayama, Hyogo and Nagasaki prefectures between last November and April CONTINUES. www.yomiuri.co.jp

      (... my comment ------- so we'll just put the people who eat the meat in the oven, right? :)

      HAPPY TURKEY DAY EVERYONE!

      ALLEY

      [Non-text portions of this message have been removed]



      ________________________________________________________________________
      ________________________________________________________________________

      Message: 2
      Date: Thu, 25 Nov 2004 10:29:58 -0600
      From: "Shshonee \(Alley\)" <shshonee@...>
      Subject: Early Combination Therapy Prevents Liver Cancer



      "AASLD: Early Combination Therapy Prevents Liver Cancer in Hepatitis C Patients Who Fail on Interferon Monotherapy"


      By Maria Bishop BOSTON, MA -- November 11, 2004 -- When patients with non-genotype 1 hepatitis C infection fail to achieve a sustained response on interferon monotherapy, they should be treated at an early stage with interferon plus ribavirin combination therapy -- especially older male patients with advanced fibrosis, who are at great risk of hepatocellular carcinoma (HCC). A 24-week course of combination therapy can prevent HCC has an 80% prevention rate in these patients, according to Japanese researchers speaking here on October 30[th at the 55th Annual Meeting of the American Society for Liver Diseases.
      In this study, Naoki Hiramatsu, assistant professor, Department of Dendritic Cell Biology and Clinical Applications, Osaka University Graduate School of Medicine, Osaka, Japan, and colleagues enrolled 742 chronic hepatitis C patients who received interferon monotherapy. Two groups of patients were analyzed separately: 348 individuals with genotype 1 and a high viral load (called the 1H group) and 394 others.

      Patients were categorized into 8 groups according to risk factors identified by multivariate analysis (age, gender, fibrosis). The risk ratio and incidence of HCC were calculated in comparison with the mean incidence of HCC in interferon nonresponders.

      In the 1H group, the only significant risk factor for HCC was found to be age; with patients 55 years or older having a significantly higher risk ratio (RR = 3.77) than did those under 55 years (P =.0002).

      Males over 55 years of age with fibrosis had the highest third-year rate of HCC appearance, which was 4.6% in sustained responders, 4.8% in transient responders and 8.0% in nonresponders.

      In the non-1H group, the HCC incidence of transient responders and nonresponders was much higher than in the 1H group, although nearly the same values were obtained among sustained responders in both groups. Significant risk factors for HCC in this group were: age (RR = 4.37, P =.002), gender (RR = 5.59, P =.005), and degree of fibrosis (RR = 10.03, P =.002).


      [Presentation title: "Necessity of Early Re-Treatment For Patients With Chronic Hepatitis C Who Do Not Achieve Sustained Response By Interferon Monotherapy." Abstract 383]








      [Non-text portions of this message have been removed]



      ________________________________________________________________________
      ________________________________________________________________________

      Message: 3
      Date: Thu, 25 Nov 2004 10:35:51 -0600
      From: "Shshonee \(Alley\)" <shshonee@...>
      Subject: Yahoo! - Poor results for Rigel hepatitis drug Messenger

      Poor results for Rigel hepatitis drug
      Rigel Pharmaceuticals (NASDAQ: RIGL - news) [RIGL] has revealed disappointing results from its phase I/II clinical study of R803, a novel oral hepatitis C RNA polymerase inhibitor. Shares fell by four percent in response to the announcement.

      Rigel Pharmaceuticals [RIGL] has revealed disappointing results from its phase I/II clinical study of R803, a novel oral hepatitis C RNA polymerase inhibitor. Shares fell by four percent in response to the announcement.


      http://uk.biz.yahoo.com/041123/241/f76by.html

      [Non-text portions of this message have been removed]



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      Message: 4
      Date: Thu, 25 Nov 2004 10:38:27 -0600
      From: "Shshonee \(Alley\)" <shshonee@...>
      Subject: Energex System's Experimental Non-Pharmicalogical Treatment Promising in Reduci

      November 22, 2004 12:47 PM US Eastern Timezone

      Energex System's Experimental Non-Pharmicalogical Treatment Promising in Reducing Viral Load in Hepatitis C Patients

      BIOWIRE2K

      EMERSON, N.J.--(BUSINESS WIRE)--Nov. 22, 2004--Energex Systems, Inc. announced today that preliminary results of its Hepatitis C clinical trial have shown consistent and drastic reductions in viral load in trial participants treated with its Hemo-Modulator technology. The trial is being conducted under an Investigational Device Exemption (IDE) that was granted by the Federal Food and Drug Administration (FDA) in October, 2004.


      http://home.businesswire.com/portal/site/altavista/index.jsp?ndmViewId=news_view&newsId=20041122005667&newsLang=en

      [Non-text portions of this message have been removed]



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      Message: 5
      Date: Thu, 25 Nov 2004 09:58:11 -0600
      From: "Shshonee \(Alley\)" <shshonee@...>
      Subject: Extrahepatic manifestations of chronic hepatitis C

      http://www.gastrohep.com/reviews/review.asp?id=736

      Chinese Journal of Digestive Diseases

      2003;

      4

      ; 9399

      Extrahepatic manifestations of chronic hepatitis C

      Roderick REMOROZA & George Y WU

      Department of Medicine, Division of Gastroenterology-Hepatology, University of Connecticut Health Center,

      Farmington, CT, USA

      ABSTRACT

      Chronic hepatitis C virus (HCV) infection is associated

      with several extrahepatic disorders. Although the

      exact pathogenesis of these conditions is not fully

      understood, several studies have provided insight into

      the role of HCV in their development. This review

      discusses the different conditions that have been

      associated with HCV infection. Among the most

      commonly reported are cryoglobulinemia, membranoproliferative

      glomerulonephritis, leukocytoclastic

      vasculitis, Sjogrens syndrome, lichen planus and porphyria

      cutanea tarda. In some patients, these disorders

      are the first sign of HCV infection.

      KEY WORDS:

      arthritis, cryoglobulinemia, glomerulonephritis, porphyria, viral hepatitis.

      INTRODUCTION

      Chronic hepatitis C virus (HCV) infection is the most

      common cause of chronic viral hepatitis in the United

      States, affecting 4 million people there and an estimated

      170 million people worldwide.

      1

      Previous

      studies on the natural history of this disease showed

      that 1020% of patients with chronic HCV infection

      would develop cirrhosis, and this subgroup of

      patients are also at risk for developing hepatocellular

      carcinoma.

      2

      End-stage liver disease because of chronic

      HCV infection has become the most common indication

      for orthotopic liver transplantation in the United

      States. As with chronic hepatitis B, chronic HCV infection

      predisposes patients to the development of

      disorders involving other organ systems such as the

      hematological, renal, dermatologic, rheumatologic

      and ocular systems. Recognition of these extrahepatic

      manifestations of chronic hepatitis C will lead to early

      diagnosis and treatment of these diseases as well as

      treatment of the hepatitis. Table 1 shows the reported

      prevalence of extrahepatic manifestations of chronic

      hepatitis C.

      CRYOGLOBULINEMIC AND HEMATOLOGIC

      MANIFESTATIONS

      Cryoglobulinemia

      Cryoglobulins are immunoglobulins (Ig) that precipitate

      as serum is cooled below body temperature and

      redissolve on rewarming. They consist of an antibody

      complex in which IgM with rheumatoid factor (RF)

      activity binds to IgG that are in turn bound to HCV

      virions. These complexes then precipitate in the walls

      of small and medium-sized vessels, producing lesions

      similar to leukocytoclastic vasculitis. According to

      Brouet

      et al.

      3

      there are three types of cryoglobulinemia

      based on the composition of the Ig. Type I is

      composed of a monoclonal Ig that has been associated

      with lymphoproliferative disorders such as

      multiple myeloma, B-cell lymphoma and Waldenstroms

      macroglobulinemia. Type II or mixed

      cryoglobulinemia (MC) is composed of a polyclonal

      Ig, usually IgG, and a monoclonal component of IgM,

      IgG or IgA (rheumatoid factor) directed against the

      polyclonal IgG. In Type III MC, both the IgG and the

      RF IgM are polyclonal. Both type II and III MC are

      associated with viral, bacterial and parasitic infections,

      autoimmune diseases and lymphoproliferative

      diseases.

      4

      Correspondence to: George Y. WU, Division of Gastroenterology-

      Hepatology, University of Connecticut Health Center, 263 Farmington

      Avenue, Farmington, CT 060301845, USA. Email: wu@...

      94

      R Remoroza and GY Wu

      Chinese Journal of Digestive Diseases

      4

      , 9399

      The association of HCV infection and MC is widely

      reported in the literature. Different reports show that

      the prevalence of cryoglobulinemia in patients with

      HCV varies from 40% to 90%.

      5,6

      In a cohort of 226

      patients with chronic liver disease (127 hepatitis C, 40

      hepatitis B and 59 other liver diseases), the overall

      incidence of cryoglobulinemia was 41%. There was a

      higher incidence in patients with hepatitis C (54%)

      than in the patients with hepatitis B (15%).

      7

      The

      pathogenesis of MC in chronic HCV remains to be

      elucidated. One hypothesis is that the binding of HCV

      to CD81 in the B-lymphocytes turns on a signaling

      complex in the cell surface of the B-lymphocytes thus

      lowering the threshold for B-cell activation, which in

      turn facilitates production of more autoantibodies.

      8

      In some patients with high concentrations of

      cryoglobulins, it is not uncommon to have negative

      HCV RNA and anti-HCV during testing because the

      virions and the antibody are incorporated into the

      precipitate. Qualitative PCR tests are more sensitive.

      Another factor that should be considered is the

      manner in which collection, handling and testing of

      the specimen are performed. There are considerable

      variations in the ability to detect cryoglobulins among

      the different laboratories that perform the test.

      9

      Laboratories that perform the test more frequently

      have higher detection rates than laboratories that do

      not routinely do the test.

      Only 10% of patients with cryoglobulins become

      symptomatic and the majority of them are clinically

      silent. Patients who have been infected with HCV for

      longer periods, older patients and female patients are

      more susceptible to develop clinical manifestations.

      Patients with leukocytoclastic vasculitis and HCVassociated

      MC should be considered for antiviral

      treatment. There are no large studies that address the

      efficacy of interferon and ribavirin combination

      therapy in patients with HCV and MC, but this would

      probably be more effective than interferon monotherapy.

      As with non-cryoglobulinemic patients with

      HCV, the response rate to treatment is not 100%.

      Improvement in symptoms, decrease in cryocrit and

      increase in serum complement parallel the response

      to treatment. In some patients, the cryoglobulinemic

      symptoms are so debilitating that even if the liver

      disease is very mild and does not warrant treatment,

      the potential improvement in quality of life of the

      patient alone may justify antiviral therapy.

      Lymphoma

      Chronic HCV infection has been linked to some types

      of B-cell non-Hodgkins lymphoma (NHL). In an

      Italian study of 527 patients with lymphoproliferative

      disorders, the prevalence and the relative risk (RR) of

      being infected by HCV were increased only among

      B-cell NHL (9%; RR 3.24;

      P

      < 0.0001). Furthermore,

      a strong prevalence of HCV was found only in a

      subgroup of patients with immunocytomas (30%; RR

      10.27;

      P

      < 0.0001).

      10

      Zuckerman

      et al

      . reported similar

      findings in a study of B-cell NHL patients. HCV infection

      was detected in 26 patients (22% [95% CI:

      1530%]) with B-cell lymphoma, compared with 7 of

      154 patients (4.5%) in control group 1 composed of

      patients with other hematologic malignancies and 6

      of 114 patients (5%) in control group 2 (

      P

      < 0.001)

      composed of patients with no malignancy.

      11

      Conversely, a large hospital based casecontrol study

      of 34 204 veterans with HCV infection and 136 816

      control subjects by El-Serag

      et al

      . failed to show a

      statistically significant association between HCV

      infection and NHL.

      12

      A report by Hermine

      et al.

      provided therapeutic

      evidence linking HCV and lymphomagenesis, although

      this may only be applicable to a subtype of lymphoma.

      Their report described nine patients with splenic

      lymphoma with villous lymphocytes and HCV infection,

      and of them six had clinical and biochemical

      evidence of cryoglobulinemia. All nine patients had

      negative HCV RNA after treatment. Seven patients

      who received interferon alpha monotherapy and had

      a sustained response 36 months after treatment

      showed a hematologic remission of their lymphoma

      over a median follow-up period of 27 months (range

      1540). The two remaining patients who had detectable

      HCV RNA and no hematologic remission after

      6 months received ribavirin and both subsequently

      cleared HCV RNA and had hematological remission

      as well. There were six patients with splenic

      lymphoma and villous lymphocytes without HCV

      infection who received interferon-alpha, but none

      Table 1. Reported prevalence of extrahepatic

      manifestations of chronic hepatitis C virus infection

      Extrahepatic manifestation Prevalence (%)

      Cryoglobulinemia 4090

      Rheumatologic 1931

      Porphyria cutanea tarda 12

      Lymphoma 042

      Renal 510

      Autoimmune 1420

      Lichen planus 12

      Neurologic 59

      Ocular < 1

      Hepatitis C related disorders

      95

      Chinese Journal of Digestive Diseases

      4

      , 9399

      responded to therapy. The symptoms of cryoglobulinemia

      resolved in all six patients with

      cryoglobulinemia. Thus, it is reasonable to screen

      patients for HCV infection in patients with splenic

      lymphoma as well as other types of low-grade B-cell

      NHL.

      13

      DERMATOLOGIC MANIFESTATIONS

      A number of dermatologic manifestations have been

      associated with chronic hepatitis C. Cutaneous vasculitis,

      lichen planus (LP), porphyria cutanea tarda

      (PCT) and urticaria are the most common conditions

      that have been associated with HCV infection. Other

      disorders such as erythema multiforme and nodosum,

      malakoplakia and AdamantiadisBechet syndrome

      have been linked to HCV infection, but further studies

      are needed to confirm the link between these disorders

      and HCV.

      9

      Cutaneous vasculitis presenting as

      palpable purpuric lesions associated with cryoglobulinemia

      is the most commonly associated skin lesion

      in hepatitis C. Vitiligo has been reported in several

      case reports as a side-effect of interferon therapy in

      patients with hepatitis C.

      14,15

      El-Serag

      et al.

      found a

      2-fold increase in vitiligo and LP in HCV-infected

      patients, compared with control.

      12

      Their study,

      however, did not determine with certainty whether

      the patients with vitiligo had received interferon.

      Their data showed that only 5% of HCV patients

      received antiviral therapy, making it is unlikely that

      this observation would be related to interferon treatment.

      They recommend testing patients with vitiligo

      for the presence of HCV infection.

      The same study showed a 12-fold increase (12.27 OR,

      95%CI 9.6315.64) in PCT among cases, compared

      with controls.

      12

      PCT is the most common of the hepatic

      porphyrias. Porphyrias are caused by biochemical

      defects in one or more enzymes in the synthesis of

      heme. In PCT, there is a hereditary or acquired defect

      in the enzyme urophorhyrinogen decarboxylase.

      There are two major forms of PCT, familial and

      sporadic, which are characterized by the appearance

      of erythema, vesicles and bullae in areas of the skin

      that have been exposed to the sun or minor trauma.

      The back of the hands and forearms, back of the neck

      and the face may be affected. Hirsutism, hyper- or

      hypopigmentation and sclerodermatous changes will

      also develop over time. The exact role of HCV in the

      pathogenesis of PCT is unclear. It is hypothesized that

      chronic HCV infection increases oxidative stress

      within hepatocytes, causing a shift of the reactions to

      the direction of urophorpyrin. The same mechanism

      may be involved in the development of PCT by excess

      iron, estrogen and alcohol.

      16

      The prevalence of HCV infection in patients with PCT

      is 7080% in Spain and Italy, and 5060% in the

      United States. Moreover, the prevalence of

      HFE

      gene

      mutations in North American patients with PCT is

      also high (73%).

      17,18

      It is therefore recommended to

      test for

      HFE

      mutations and HCV infection in patients

      who present with PCT. Patients with PCT should stop

      alcohol, estrogens and iron supplements. Foods that

      are high in iron, such as red meats and liver, should

      be limited. Therapeutic phlebotomy is performed as

      in the treatment of hereditary hemochromatosis. Antimalarial

      drugs are also used in the treatment of PCT.

      Bonkovsky

      et al.

      recommended iron depletion of all

      patients with PCT and chronic hepatitis C before initiation

      of antiviral therapy.

      18

      Lichen planus is a chronic inflammatory mucocutaneous

      disease process that usually presents as small,

      purplish, flat-topped papules. The flexor wrists and

      forearms, extensor hands and ankles, lumbar region,

      shins, and genital area are the usual distribution of LP.

      Lesions in the mucous membrane are usually the

      white lace-like Wickhams striae, which are particularly

      seen in the lateral buccal mucosa, but can also

      involve the lips, gingivae and tongue. Histologically,

      it is characterized by a cellular inflammatory response

      consisting mainly of a subephithelial band-like

      infiltrate of lymphocytes. Other histologic findings

      include hyperparakeratosis or parakeratosis, acanthosis

      and liquefactive degeneration of both the basal

      cell layer and the inflammatory cells. Several studies

      from Southern Europe, the United States and Japan

      have shown an association between HCV infection

      and oral and cutaneous LP.

      1921

      Two studies from

      France and Britain, however, failed to determine any

      association.

      22,23

      The variability in results may stem

      from the differences in prevalence in different

      geographic locations. None of the 55 patients from

      the Netherlands with LP were positive for HCV,

      whereas in a report from Japan where the prevalence

      of HCV infection is much higher, the prevalence of LP

      is as high as 62%.

      24,25

      El-Serag

      et al

      . found a statistically

      significant association between HCV infection

      and LP in a large cohort of HCV-infected patients.

      12

      A

      study of 7 anti-HCV positive patients with oral LP

      (OLP) provided direct evidence that HCV plays a role

      in the pathogenesis. That study was able to demonstrate

      the presence of HCV-specific CD4

      +

      and CD8

      +

      cells in the intralesional infiltrates in OLP associated

      with HCV infection.

      26

      96

      R Remoroza and GY Wu

      Chinese Journal of Digestive Diseases

      4

      , 9399

      RENAL MANIFESTATIONS

      Membranoproliferative glomerulonephritis

      The most frequent renal disease associated with HCV

      infection is cryoglobulinemic or non-cryoglobulinemic

      membranoproliferative glomerulonephritis (MPGN).

      27,28

      The prevalence of HCV-associated MPGN varies with

      geographic location. Yamabe

      et al.

      reported a 60%

      prevalence of anti-HCV antibody in Japanese patients

      with MPGN, a higher rate compared with other renal

      diseases.

      28

      As with LP, it is less commonly reported

      in France. Patients with MPGN usually present with

      hypertension, weakness and peripheral edema. Microscopic

      hematuria, proteinuria (usually in the nephrotic

      range > 3.5 g/day) and less commonly, red cell casts

      in the urine are also seen. Other laboratory abnormalities

      include decreased complement concentrations,

      the presence of RF and cryoglobulins, abnormal

      serum transaminases and hypoalbuminemia. Histopathologic

      findings on renal biopsy show proliferative

      glomerular lesions characterized by the deposition of

      IgG, IgM and C3 on capillary walls, and subendothelial

      and mesangial immune deposits.

      27

      Membranous nephropathy

      Membranous nephropathy (MN) may be idiopathic

      or secondary and is characterized by the presence

      of electron-dense deposits across the glomerular

      basement membrane in the subepithelial space.

      Although not as commonly reported as MPGN, MN

      has been reported to be associated with HCV infection

      and some success with treatment with interferon has

      been reported.

      29

      Clinically, the presentation of HCVassociated

      MN does not differ from idiopathic MN. It

      has been reported to occur

      de novo

      in renal transplant

      recipients. Unlike MPGN, there are no circulating

      cryoglobulins and RF in patients with MN. Complement

      concentrations are either normal or minimally

      reduced. These patients usually have persistent

      massive proteinuria and progressive deterioration of

      renal function over time.

      30

      A case of a 20-year-old

      woman developing rapidly progressive glomerulonephritis

      during the course of active HCV infection

      also has been reported.

      31

      The exact pathogenesis of HCV-related renal disease

      still remains unclear. Studies suggest that HCVassociated

      glomerulonephritis is most likely caused

      by the deposition of circulating immune complexes

      made of HCV antigen, anti-HCV antibodies (IgG or

      IgM), complements and RF.

      32

      Sansonno

      et al.

      reported

      in a study of 12 kidney biopsy specimens from HCVinfected

      patients with MPGN and type II MC and 8

      control subjects that specific HCV-related proteins

      were detected in glomerular and tubulo-interstitial

      vascular structures in 8 (66.7%) HCV-positive MC

      patients and in none of the HCV RNA, anti-HCVnegative

      controls. Those findings indicate that in MC

      patients with HCV-associated MPGN, the kidney

      deposits consist of HCV-containing immune complexes

      that are likely to play a direct pathogenetic role in the

      renal damage.

      33

      Some authors recommend combination

      antiviral treatment (interferon and ribavirin) for

      patients with HCV-induced renal disease and normal

      renal function even in the absence of hepatic indications.

      Because ribavirin is decreased in patients with

      renal failure and is not cleared by hemodialysis,

      patients with creatinine clearance below 50 mL/min

      should receive interferon monotherapy.

      34

      RHEUMATOLOGIC AND AUTOIMMUNE

      MANIFESTATIONS

      Fatigue, polyarthralgia and myalgia are common

      manifestations of HCV infection. Fatigue can sometimes

      cause some impairment in the quality of life,

      but rarely does it become severe. In a study by

      Poynard

      et al

      . of 1614 patients with HCV infection,

      fatigue was present in 53% and associated with either

      arthralgia or myalgia (fibromyalgia) in 19% of

      patients.

      35

      Buskila

      et al.

      interviewed 90 anti-HCVpositive

      patients and found rheumatologic manifestations

      in 28 (31%), including arthralgias, arthritis,

      cryoglobulinemia, sicca symptoms and polymyositis.

      HCV-related arthritis commonly presents as symmetrical

      inflammatory arthritis involving mainly small

      joints or less commonly as mono- or oligoarthritis of

      the large joints.

      36

      Because the joints involved in HCV

      arthropathy resemble that of rheumatoid arthritis

      (RA), it may be difficult to differentiate from true RA

      in patients with positive RF. HCV arthropathy is

      usually non-deforming and there are no bony

      erosions in the joints. The erythrocyte sedimentation

      rate is elevated in only half of the patients and

      subcutaneous nodules are not present.

      37

      In a study of

      71 RF seropositive patients, antikeratin antibodies

      were detected in 20/33 (60.6%) patients with RA

      compared with only 2/25 (8%) patients with HCVassociated

      arthritis and 2/13 (15.3%) in patients with

      autoimmune diseases other than RA.

      38

      This marker

      may be helpful in distinguishing patients with HCVrelated

      arthritis from patients with RA. Zuckerman

      et al.

      reported 28 patients with HCV-related arthropathy

      of whom 3 responded to anti-inflammatory

      Hepatitis C related disorders

      97

      Chinese Journal of Digestive Diseases

      4

      , 9399

      medications. The 25 patients who did not respond to

      anti-inflammatory medications were given interferon

      for a median period of 12 months

      .

      39

      A complete

      response of arthritis-related symptoms were seen in

      42%, and partial response in 32%. However, only

      5 (20%) patients had a virological response at the

      end of treatment. Although there are no controlled

      trials that have addressed this issue, it is recommended

      that patients with HCV-related arthropathy

      be treated with combination antiviral therapy of

      interferon and ribavirin.

      39

      Non-organ specific autoantibodies are frequently

      found in patients with HCV infection. In a review of

      117 patients with chronic HCV infection, Clifford

      et al.

      found a high prevalence of anti-smooth muscle

      antibodies (66%) and RF (76%), and antinuclear

      antigen (> 1 : 160) was found in 13% of these

      patients (46%).

      40

      Cassani

      et al.

      studied 290 patients

      with chronic hepatitis C and 35 control cases with

      autoimmune hepatitis. ANA, SMA and anti-LKM antibodies

      occurred in 9%, 20% and 6%, respectively, of

      the patients. The overall prevalence of any autoantibody

      was 30%. Subspecific autoantibodies,

      namely SMA-antiactin and homogenous ANA, were

      not detected in patients with HCV infection. In the

      same study, the autoantibodies were more frequently

      positive in women and were associated with higher

      biochemical and histological activities.

      41

      Haddad

      et al

      . first reported the association between

      HCV infection and sicca syndrome and lymphocytic

      sialodenitis in 1992.

      42

      They performed labial salivary

      gland biopsies in 28 HCV-infected patients and 20

      controls, and found that histological changes characteristic

      of Sjogrens syndrome (SS) were significantly

      more common in the HCV infected patients (57%)

      compared with the controls (5%). A study of 45 HCV

      infected patients with oral dryness (14 with oral and

      eye dryness) found that 24 (53%) patients had SS by

      the European criteria, 25 (56%) by the Manthorpe

      criteria, and 4 (8%) by the Fox criteria. This subgroup

      of patients with SS and HCV infection differ from

      patients with primary SS in that they do not have

      pulmonary and kidney involvement, as well as the

      absence of autoantibodies against SSA and SSB.

      43

      Testing for HCV infection in patients with primary SS

      or subgroup SS is therefore recommended.

      Case reports relate an association between autoimmune

      thyroid disease and HCV infection. It is also

      widely reported that the incidence of thyroid autoantibodies

      increases after interferon treatment.

      However, a large study of HCV infected veterans did

      not show a statistically significant association between

      autoimmune thyroiditis and HCV infection. The same

      study also failed to show a significant association

      between HCV infection and SS and diabetes.

      11

      OCULAR MANIFESTATIONS

      Retinopathy is a well-recognized complication of

      interferon therapy. Guyer

      et al.

      reported 10 cases of

      retinal ischemia associated with the use of interferonalpha

      for various illnesses.

      44

      The retinal findings

      include cotton-wool spot formation, capillary nonperfusion,

      arteriolar occlusion, and hemorrhage. The

      retinopathy may sometimes be reversible when the

      treatment is stopped. Independent of interferon

      treatment, HCV infection has been found to be associated

      with ischemic retinopathy as well. Abe

      et al

      .

      studied 85 untreated HCV-infected patients and 100

      matched control subjects, and reported a prevalence

      of ischemic retinopathy in at least one eye of 31.8%

      of HCV-infected patients, compared with 6% in the

      control group (

      P

      < 0.001). HCV-associated retinopathy

      involved hemorrhage at the posterior pole

      retina in 21 (77.8%), cotton-wool patches in 9

      (33.3%), and hemorrhage at the peripheral retina

      in 7 (25.9%) cases. The retinopathy worsened or

      recurred in all 7 cases treated with interferon.

      45

      They

      suggest that the pathogenic mechanism involves

      formation of a microemboli from immune complexes

      as a result of HCV infection, which then cause

      vasoocclusion. Further studies are needed to determine

      the exact pathogenesis of HCV-related ischemic

      neuropathy.

      Keratoconjunctivitis sicca (dry eyes) is part of SS.

      Mooren ulcer is a rapidly progressive, painful, ulcerative

      keratitis that initially affects the peripheral cornea

      and may spread circumferentially and then centrally.

      The diagnosis is made by exclusion of other infectious

      or systemic causes of corneal ulcer. Previous case

      reports have related an association of HCV infection

      to Moorens ulcer. Wilson

      et al

      . reported two patients

      with HCV infection and Mooren ulcer in whom the

      ulcer failed to respond to steroid and cyclosporine

      drops or systemic cyclophosphamide treatment,

      but responded to interferon-alpha-2b.

      46

      However, a

      casecontrol study from India did not show an association

      between HCV infection and Mooren ulcer. In

      that study, 21 patients with Mooren ulcer and 40

      control subjects underwent a detailed ophthalmic

      history and examination and serologic testing for

      HCV and other disease markers. None of the patients

      with Mooren ulcer were positive for HCV.

      47

      98

      R Remoroza and GY Wu

      Chinese Journal of Digestive Diseases

      4

      , 9399

      NEUROLOGIC MANIFESTATIONS

      Although less commonly reported, HCV infection has

      been associated with the development of neurologic

      symptoms. Neuropathic symptoms presenting as

      chronic sensory polyneuropathy or as acute multineuropathy

      often superimposed over a sensory

      polyneuropathy are the most frequent symptoms.

      48

      Acute or subacute encephalopathy manifesting as

      somnolence, confusion have also been reported.

      49

      These symptoms are most frequently associated with

      cryoglobulinemia and necrotizing vasculitis. Restless

      leg syndrome and GuillainBarr syndrome in HCV

      infected patients have been reported as well.

      50

      Whether HCV has a role in the development of these

      diseases or is just associated by chance is unclear.

      Treatment with corticosteroids, cyclophosphamide

      and interferon has been attempted with varying

      success.

      CONCLUSION

      In summary, chronic hepatitis C increases the risk of

      developing a number of extrahepatic disorders. The

      clinician must be aware of these, and testing for HCV

      infection should be done in people who manifest the

      symptoms. Further studies should be done to determine

      the efficacy of the current antiviral therapy of

      interferon and ribavirin in the resolution of these

      symptoms, and to find alternative therapies.


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      ________________________________________________________________________
      ________________________________________________________________________

      Message: 6
      Date: Thu, 25 Nov 2004 10:14:12 -0600
      From: "Shshonee \(Alley\)" <shshonee@...>
      Subject: RNA interference could put clamp on good genes gone bad

      RNA interference could put clamp on good genes gone bad

      Tue Nov 23, 7:46 AM ET

      By Dan Vergano, USA TODAY
      RNA, the lesser-known chemical cousin of DNA, finally may be coming into its own, say biomedical researchers.

      A lab technique for silencing genes called "RNA interference" is suddenly looking good as a treatment for cancer, diabetes and other ailments. "RNA interference is an extremely potent process," says biologist Timothy Nilsen of Case Western Reserve University in Cleveland. "And we're seeing how this basic science discovery can lead rapidly to clinical applications."

      http://news.yahoo.com/news?tmpl=story&u=/usatoday/20041123/ts_usatoday/rnainterferencecouldputclampongoodgenesgonebad


      [Non-text portions of this message have been removed]



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