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Iron in liver diseases other than hemochromatosis
Bonkovsky HL, Banner BF, Lambrecht RW, Rubin RB
Department of Medicine, University of Massachusetts Medical Center, Worcester 01655, USA.
Semin Liver Dis 1996 Feb;16(1):65-82

There is growing evidence that normal or only mildly increased amounts of iron in the liver can be damaging, particularly when they are combined with other hepatotoxic factors such as alcohol, porphyrogenic drugs, or chronic viral hepatitis. Iron enhances the pathogenicity of microorganisms, adversely affects the function of macrophages and lymphocytes, and enhances fibrogenic pathways, all of which may increase hepatic injury due to iron itself or to iron and other factors. Iron may also be a co-carcinogen or promoter of hepatocellular carcinoma, even in patients without HC or cirrhosis. Based on this and other evidence, we hope that the era of indiscriminate iron supplementation will come to an end. Bloodletting, a therapy much in vogue 2 centuries ago, is deservedly enjoying a renaissance, based on our current understanding of the toxic effects of iron and the benefits of its depletion.

[Markers of chronic hepatitis B in children after completion of therapy with isoprinosine]
Kowalik-MikoLajewska B; Barszcz T; Ladyzynska E; Wojnarowski M
Kliniki C Chorob Zakaznych i Paso.ANG.zytniczych Wieku Dzieciecego Instytutu Chorob Zakaznych i Paso.ANG.zytniczych AM, Warszawie.
Pol Tyg Lek (Poland) Mar 15-29 1993, 48 (11-13) p263-4

Fourteen children with chronic active hepatitis B treated with isoprinosine were followed-up for 3-8 years. In no child HBs antigen was eliminated. No seroconversion was noted in children in whom HBe antigen was eliminated. Anti-HBe antibodies were found in 11 children, including 6 children in whom they were present all the time following therapy, and 2 children in whom these antibodies reappeared after an initial elimination. These results suggest that the inhibition of hepatitis B virus replication produced by isoprinosine may be transient. Therefore, longer lasting immunomodulating therapy should be considered.

[Course of chronic virus hepatitis B in children and attempts at modifying its treatment]
Kowalik-MikoLajewska B
Kliniki Chorob Zakaznych i Paso.ANG.zytniczych Wieku Dzieciecego
Pol Tyg Lek (Poland) Mar 15-29 1993, 48 (11-13) p258-60

60 children with chronic virus hepatitis B were followed from there to nine years. 34 children received isoprinosine, 6 prednisone and 20 children were without any therapy. There were no cases of death. In 2 cases treated with isoprinosine cirrhosis was found. Eight children with chronic active hepatitis (4 treated with isoprinosine, 1 with prednisone, and 3 without any treatment) had histological recovery. Isoprinosine significantly accelerated seroconversion in HBe system in children with chronic active hepatitis but not in children with persistent, hepatitis. Isoprinosine shortened also the time of normalisation of aminotransferases activity children. Prednisone had no influence on the course of chronic active hepatitis B in treated group.

Isoprinosine in the treatment of chronic active hepatitis type B.
Cianciara J; Laskus T; Gabinska E; Loch T
Scand J Infect Dis (Sweden) 1990, 22 (6) p645-8

21 patients with chronic active hepatitis B (CAH-B) were treated for 1-2 years with isoprinosine, while another 18 patients served as control group. All patients were initially DNA polymerase (DNAp) and HBeAg positive. Nine (43%) treated patients became persistently negative for DNAp, seroconverted to anti-HBe and showed histological remission on follow-up biopsy. Among simultaneously followed controls 5 (28%) lost DNAp and 4 (22%) also lost their HBeAg. However, only 2 (11%) seroconverted to anti-HBe. Histological improvement was seen in 5 (28%) controls. Thus, it seems that isoprinosine may exert a beneficial effect on the course and outcome of CAH-B.

[Evaluation of the treatment of chronic active hepatitis (HBsAg+) with isoprinosine. II. Immunological studies]
Dabrowska-Bernstein B; Stasiak A; Dabrowski M; Pawinska A; Cianciara J; Loch T; Babiuch L
Pol Tyg Lek (Poland) Apr 16-30 1990, 45 (16-18) p347-51

A two-month treatment of the chronic active hepatitis (HBsAg+) with isoprinosine produced quantitative and functional T-cells populations in patients with cellular response disorders. Immunological studies have shown that such an effect of isoprinosine lasted for about 4-5 months. Repeated administration of isoprinosine for one month normalized recurrent abnormalities in the monitored immunological parameters.

In vitro studies on the effect of certain natural products against hepatitis B virus.
Mehrotra R; Rawat S; Kulshreshtha DK; Patnaik GK; Dhawan BN
Indian J Med Res (India) Apr 1990, 92 p133-8

Picroliv (active principle from Picrorrhiza kurroa), its major components picroside I, catalpol, kutkoside I, kutkoside, andrographolide (active constituent of Andrographis paniculata), silymarin and Phyllanthus niruri extract were tested for the presence of anti hepatitis B virus surface antigen (anti HBs) like activity. HBsAg positive serum samples obtained from hepatitis B virus (HBV) associated acute and chronic liver diseases and healthy HBsAg carriers were used to evaluate the anti-HBs like activity of compounds/extract. The latter were mixed with serum samples and incubated at 37 degrees C overnight followed by HBsAg screening in the Elisa system. A promising anti-HBsAg like activity was noted in picroliv (and its major components) catalpol, P. niruri which differed from the classical viral neutralization. Picroliv also inhibited purified HBV antigens (HBsAg and HBsAg) prepared from healthy HBsAg carriers. The in vitro testing system appears to be a suitable model to identify an agent active against HBV, prior to undertaking detailed studies.

Effects of glycyrrhizin on hepatitis B surface antigen: a biochemical and morphological study.
Takahara T; Watanabe A; Shiraki K
J Hepatol (Denmark) Oct 1994, 21 (4) p601-9

Glycyrrhizin, a major component of a herb (licorice), has been widely used to treat chronic hepatitis B in Japan. This substance improves liver function with occasional complete recovery from hepatitis; its effects on the secretion of hepatitis B surface antigen (HBsAg) were examined in vitro. Glycyrrhizin suppressed the secretion of HBsAg and accumulated it dose-dependently in PLC/PRF/5 cells. Its action was further analyzed and determined in the HBsAg-expression system using the varicella-zoster virus. Glycyrrhizin suppressed the secretion of HBsAg, resulting in its accumulation in the cytoplasmic vacuoles in the Golgi apparatus area. HBsAg labeled with 35S-methionine and cysteine accumulated in the cells and its secretion was suppressed dose-dependently in glycyrrhizin-treated culture. The secreted HBsAg was modified by N-linked and O-linked glycans but its sialylation was inhibited dose-dependently by glycyrrhizin. Thus glycyrrhizin suppressed the intracellular transport of HBsAg at the trans-Golgi area after O-linked glycosylation and before its sialylation. HBsAg particles were mainly observed on the cell surface in the glycyrrhizin-treated culture but not in the untreated culture. This suggests that asialylation of HBsAg particles resulted in the novel surface nature of glycyrrhizin-treated HBsAg particles. We elucidated the unique mechanism of action of glycyrrhizin on HBsAg processing, intracellular transport, and secretion.

Glycyrrhizin withdrawal followed by human lymphoblastoid interferon in the treatment of chronic hepatitis B.
Hayashi J; Kajiyama W; Noguchi A; Nakashima K; Hirata M; Hayashi S; Kashiwagi S
Gastroenterol Jpn (Japan) Dec 1991, 26 (6) p742-6

Seventeen patients with chronic hepatitis B were treated with a 4-week administration of glycyrrhizin followed by a 4-week treatment with human lymphoblastoid interferon, then followed for 6 months after the end of treatment. All were positive for hepatitis B surface antigen (HBsAg), hepatitis B e antigen (HBeAg), and hepatitis B virus-associated DNA polymerase (DNA-p) for at least 6 months before entry. All patients were Japanese and none of them were homosexuals. Eleven patients lost DNA-p activity and 10 of them lost HBeAg. Three of these 10 patients had antibody to HBeAg. In 10 patients who became HBeAg-negative, alanine aminotransferase levels after glycyrrhizin administration were higher and initial DNA-p activities relatively lower than the levels found in seven patients who remained HBeAg-positive. The immunomodulator provided by a short course of glycyrrhizin before administration of human lymphoblastoid interferon may be an effective treatment for patients with chronic hepatitis B.

Combination therapy of glycyrrhizin withdrawal and human fibroblast Interferon for chronic hepatitis B.
Hayashi J; Kashiwagi S; Noguchi A; Ikematsu H; Tsuda H; Tsuji Y; Motomura
Clin Ther (United States) 1989, 11 (1) p161-9

In ten carriers positive for chronic hepatitis B surface antigen (HBsAg), hepatitis B e antigen (HBeAg), and DNA polymerase, the authors investigated the efficacy of the combination therapy consisting of glycyrrhizin withdrawal and human fibroblast interferon (locally produced). Glycyrrhizin was given for four weeks and was stopped without tapering off the dose. Human fibroblast interferon was given continuously. Thirty-six weeks after the end of this treatment, three of the ten patients were HBeAg negative but not anti-HBe positive, and in one of these three DNA polymerase became undetectable. Another patient showed a loss of DNA polymerase with HBeAg. Transaminase levels decreased in nine of the patients. Glycyrrhizin appeared to act as an antiviral agent in four patients and had a corticoid-like effect in three. DNA polymerase decreased remarkably after interferon administration, and serum transaminase levels increased. No side effects were reported in patients receiving glycyrrhizin. In contrast, almost all patients receiving human fibroblast interferon had influenza-like symptoms, which, although initially severe, decreased with subsequent injections of interferon. Thus this combination therapy seems safe and effective.

Alpha-interferon combined with immunomodulation in the treatment of chronic hepatitis B.
Peters M
J Gastroenterol Hepatol (Australia) 1991, 6 Suppl 1 p13-4

Interferon has profound anti-viral, anti-proliferative and immunomodulatory effects. Future studies should be directed at observing how the immunomodulatory effects predict a response in certain groups of patients. Interferon is very useful in chronic hepatitis B but may require the addition of a steroid pulse. Individuals with low serum ALT appear to benefit most from a steroid pulse. Therapy should be given with a great deal of caution in patients with decompensated liver disease, as one may precipitate the untimely demise of the patient even though viral replication is decreased. One of the patients in the IFN study in fact did have decompensation after prednisone therapy, which subsequently led, a couple of months later, to a variceal haemorrhage. In summary, in treating hepatitis B viral infection, no single agent is totally effective and perhaps the combination of suppressing viral replication and augmenting the immune system is the optimal way to eradicate the virus. At present, an adequate response is found in only about 30-40% of patients even with 'optimal' therapy.

Improvement of liver fibrosis in chronic hepatitis C patients treated with natural interferon alpha.
Hiramatsu N; Hayashi N; Kasahara A; Hagiwara H; Takehara T; Haruna Y; Naito M; Fusamoto H; Kamada T
J Hepatol (Denmark) Feb 1995, 22 (2) p135-42

To investigate the histological change (change of liver fibrosis) produced by the anti-viral effect of interferon on hepatitis C virus, 40 patients with chronic hepatitis C treated with natural interferon alpha were divided according to the existence of viremia at the end of treatment and 6 months after the end of treatment. The condition of liver fibrosis was scored numerically with a new "hepatic fibrosis score" which is sensitive to more subtle changes than Knodell's fibrosis score. Each portal zone was evaluated separately. End-of-treatment biopsy for the HCV RNA-negative group (negative for HCV RNA at the end of treatment) showed a significant improvement of the "hepatic fibrosis score" as well as the alleviation of necrosis and inflammation. At the end of treatment and 6 months after that, serum procollagen type III peptide levels and serum type IV collagen-7s levels had also decreased significantly in the HCV RNA-negative group. The present study showed that treatment with interferon alpha could alleviate fibrosis in addition to necrosis and inflammation.

Diagnosis and treatment of the major hepatotropic viruses.
Kiyasu PK; Caldwell SH
Am J Med Sci (United States) Oct 1993, 306 (4) p248-61

The hepatotropic viruses currently include hepatitis A, B, C, D, and E, and are associated with a spectrum of acute and chronic liver disease syndromes. The epidemiology and natural history of each are discussed, with emphasis on uncommon or newly recognized clinical presentations. The serodiagnosis of hepatitis A, B, and D is well established; the serodiagnosis of hepatitis C and E continues to evolve as serologic and virologic assays become refined. Hepatitis A and E only cause acute liver injury; current medical approaches therefore focus on vaccination strategies. Hepatitis B, C, and D can cause both acute and chronic liver injury. Sequelae of chronic liver disease, including portal hypertension and hepatocellular carcinoma, are not uncommon. Medical therapy of resulting chronic liver disease currently consists of interferon, though other anti-viral strategies are being explored. Advanced chronic liver disease due to hepatitis B, C, or D can be treated by orthotopic liver transplantation, but viral recurrence is near uniform and can be problematic. Further study of the hepatotropic viruses at the molecular biologic, epidemiologic, and clinical levels will continue to provide greater insight into the diagnosis and management of their associated clinical syndromes. (161 Refs.)

Treatment of chronic viral hepatitis.
Dusheiko GM; Zuckerman AJ
J Antimicrob Chemother (England) Jul 1993, 32 Suppl A p107-20

A substantial number of anti-viral compounds have been evaluated for the treatment of patients with chronic viral hepatitis. A few of these compounds have now achieved clinical applicability. alpha-Interferon is the most widely studied and remains the main treatment for chronic hepatitis B and C. Unfortunately in both these conditions only a minority of patients respond to interferon therapy, although the response can be complete in some patients. Some parameters have been identified which assist in the selection of patients for treatment. Several other cytokines, including thymosin, have been evaluated for the treatment of chronic hepatitis B. There are a number of promising new nucleosides which may inhibit hepatitis B virus and their action is being studied. Relapse rates are unknown however with these compounds. Ribavirin, a guanosine analogue, is also efficacious in treating a proportion of patients with chronic hepatitis C and the drug may be useful in treating patients with cirrhosis or patients who have an auto-immune diathesis. (88 Refs.)

[Mechanisms of the effect of interferon (IFN) therapy in patients with type B and C chronic hepatitis]
Karino Y
Hokkaido Igaku Zasshi (Japan) May 1993, 68 (3) p297-309

The relationship between 2', 5'-oligoadenylate synthetase (2-5AS) and HLA class I antigen in the hepatocyte of patients with type B or type C chronic hepatitis with and without interferon (IFN) therapy was investigated. The expression of HLA class I antigen of hepatocytes of biopsied specimen and PBL HLA class I antigen expression showed relevancy. Then, the HLA antigen expression of peripheral blood lymphocyte (PBL) and the 2-5AS activity of peripheral blood mononuclear cell (PBMC) were analyzed. In patients with type B or type C hepatitis, the mean activity of PBMC 2-5AS was significantly higher than that of healthy controls. Also the HLA class I antigen expression of PBL was significantly intense in patients with type B or type C hepatitis compared with healthy controls. In the acute exacerbated phase of type B chronic hepatitis, the HLA class I antigen expression of PBL and 2-5AS activity of PBMC increased along with elevation of serum GPT and then decreased with the remission of serum GPT. These results suggest that endogenously produced IFN leads the lysis of hepatocyte infected with hepatitis B virus (HBV) by cytotoxic T cells, and the restriction of HBV replication by activation of the 2-5A system simultaneously, and then leads the elimination of HBV. The activity of PBMC 2-5AS and the expression of PBL HLA class I antigen increased significantly during IFN therapy. In type B chronic hepatitis, the effective cases showed relatively high activity of serum 2-5AS compared with the non-effective cases. On the other hand, there were no significant differences in PBL HLA class I antigen expression between effective cases and non-effective cases. In type C chronic hepatitis, most patients with type III and type IV HCV genotype showed disappearance of HCV-RNA regardless of serum 2-5AS activity. In patients with type II HCV genotype, the serum 2-5AS activity was related to the anti-viral effect of IFN therapy.

A pilot study of ribavirin therapy for recurrent hepatitis C virus infection after liver transplantation.
Cattral MS; Krajden M; Wanless IR; Rezig M; Cameron R; Greig PD; Chung SW; Levy GA
Transplantation (United States) May 27 1996, 61 (10) p1483-8

Ribavirin is a guanosine analogue that normalizes serum liver enzymes in most nontransplant patients with chronic hepatitis C virus (HCV) infection. We conducted an uncontrolled pilot study of ribavirin in 9 liver transplantation recipients that had persistently elevated liver enzymes, active hepatitis by liver biopsy, and HCV RNA in serum by polymerase chain reaction. Ribavirin was given orally at dosages of 800-1200 mg per day for 3 mo. All 9 patients promptly responded to ribavirin: mean (+/- SD) ALT decreased from 392 +/- 377 IU/L immediately before treatment to 199 +/- 185 and 68 +/- 37 IU/L after 1 and 12 weeks of treatment, respectively, complete normalization of enzymes occurred in 4 patients. None of the patients cleared the virus from their serum during therapy, and biochemical relapse occurred in all patients 4 +/- 4.2 weeks after cessation of therapy. The hepatitis activity index of liver biopsy specimens obtained before and at the cessation of therapy was similar. Ribavirin treatment was resumed in 4 patients because of increasing fatigue (2 patients), rising bilirubin (3), or increasing necroinflammation on liver biopsy (2); the biochemical response to the second course of therapy was similar to the first course in all 4 patients. Ribavirin caused reversible hemolysis in all patients, including symptomatic anemia in 3 patients that resolved after reduction of drug dosage. These results suggest that ribavirin may be of benefit in the treatment of HCV infection after liver transplantation. Further studies are needed to determine the optimal dosage and duration of therapy.

Ribavirin as therapy for chronic hepatitis C. A randomized, double-blind, placebo-controlled trial.
Di Bisceglie AM; Conjeevaram HS; Fried MW; Sallie R; Park Y; Yurdaydin C;
Ann Intern Med (United States) Dec 15 1995, 123 (12) p897-903

OBJECTIVE: To evaluate ribavirin, an oral antiviral agent, as therapy for chronic hepatitis C.

DESIGN: Randomized, double-blind, placebo-controlled study.

SETTING: Clinical Center of the National Institutes of Health, a tertiary referral research hospital.

PATIENTS: 29 patients with chronic hepatitis C who received oral ribavirin (600 mg twice daily) for 12 months and 29 controls with chronic hepatitis C who received placebo for 12 months.

MEASUREMENTS: Effects of therapy were evaluated by measuring serum aminotransferase and hepatitis C virus (HCV) RNA levels before, during, and for 6 months after therapy and by histologic examination of liver specimens before and at the end of treatment.

RESULTS: Patients treated with ribavirin had a prompt decrease in serum aminotransferase levels (54% overall) compared with levels before treatment and levels in controls (5% decrease). Serum aminotransferase levels became normal or nearly normal in 10 patients treated with ribavirin (35% [95% CI, 18% to 54%]) but in no controls (0% [CI, 0% to 12%]). Aminotransferase levels remained normal in only 2 patients after ribavirin therapy was discontinued (7% [CI, 1% to 23%]). Serum HCV RNA levels did not change during or after therapy. Liver biopsy specimens showed a decrease in hepatic inflammation and necrosis among ribavirin-treated patients whose aminotransferase levels became normal.

CONCLUSIONS: Ribavirin has beneficial effects on serum aminotransferase levels and histologic findings in the liver in patients with chronic hepatitis C, but these effects are not accompanied by changes in HCV RNA levels and are not sustained when ribavirin therapy is discontinued. Thus, ribavirin alone for periods as long as 12 months is unlikely to be of value as therapy for chronic hepatitis C.

Treatment with ribavirin+alpha interferon in HCV chronic active hepatitis non-responders to interferon alone: preliminary results.
Scotto G; Ferrara S; Mangano A; Conte PE
J Chemother (Italy) Feb 1995, 7 (1) p58-61

Alpha interferon (IFN-alpha) represents the best therapy for HCV active chronic hepatitis, but only 25% of treated patients achieve a complete recovery. Several attempts have been made to increase this percentage. The objective of our study is to verify whether the combination ribavirin (R)+ IFN-alpha can lead to positive results in non-responders to treatment with IFN-alpha alone. The preliminary results for 5 subjects, all non-responders to IFN, treated with R+ IFN for 60 days and then IFN alone for 4 months more show that during the R+IFN treatment, 2 subjects presented a reduction in transaminase; a month after the suspension of R, ALT returned to pre-treatment values. The results are preliminary but we can say that this combination in the proposed doses and times in these subjects, cannot be considered adequate to modify the natural course of this disease.

Combined treatment with interferon alpha-2b and ribavirin for chronic hepatitis C in patients with a previous non-response or non-sustained response to interferon alone.
Schvarcz R; Yun ZB; Sonnerborg A; Weiland O
J Med Virol (United States) May 1995, 46 (1) p43-7

Ten patients with chronic hepatitis C, six of whom had not responded and four of whom had responded in a non-sustained fashion to interferon-alpha treatment alone, were given interferon alpha-2b and ribavirin in combination during 24 weeks. Interferon alpha-2b was given subcutaneously, at a dose of 3 MU thrice weekly, together with ribavirin orally, at a dose of 1,000-1,200 mg/day. All four patients with a prior non-sustained response to interferon alone had normal alanine aminotransferase (ALT) levels at the end of treatment as well as during follow-up (> or = 24 weeks post treatment). Furthermore, all four lost serum HCV-RNA at the end of treatment and three continued to be negative during follow-up. Among patients with a prior non-response to interferon alone three of six had normal ALT levels at the end of treatment and one at follow-up. Two of six became HCV-RNA negative at cessation of treatment, one of whom was negative also at follow-up. All former non-sustained responders and one of six non-responder patients thus showed a sustained biochemical response with eradication of HCV-RNA from serum in all cases but one. It is concluded that combination therapy with interferon alpha-2b and ribavirin offers a chance of sustained biochemical response with eradication of the viremia in patients who have not shown a persistent response to interferon-alpha alone.

Increase in hepatic iron stores following prolonged therapy with ribavirin in patients with chronic hepatitis C.
Di Bisceglie AM; Bacon BR; Kleiner DE; Hoofnagle JH
Liver Diseases Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Md 20892.
J Hepatol (Denmark) Dec 1994, 21 (6) p1109-12

Ribavirin, an oral nucleoside analogue being evaluated as therapy for chronic hepatitis C, is associated with hemolysis. Other hemolytic conditions are known to be associated with accumulation of iron within the liver. We therefore examined hepatic iron stores before and after 6 to 12 months of therapy with ribavirin in 15 patients with chronic hepatitis C. Although there were no significant changes in serum iron or ferritin levels, hepatic iron staining increased in almost all patients. Using a ranking system to quantitate the amount of hepatic iron staining, we found that the mean rank increased from 3.9 to 8.5 after therapy (p < 0.01). In six patients in whom hepatic tissue was available for determination of hepatic iron, concentrations also increased in all cases from a mean of 826 to 1857 micrograms/g dry weight (p < 0.01). The average rate of iron accumulation in these six patients was approximately 1500 micrograms/g per year. Thus hepatic iron concentrations might enter the range clearly associated with hepatic fibrosis after approximately 15 years of continuous therapy.

Therapy for chronic hepatitis C.
Davis GL; Lau JY; Lim HL
Gastroenterol Clin North Am (United States) Sep 1994, 23 (3) p603-13

Hepatitis C is the silent epidemic of the 1970s and 1980s. Interferon alfa is currently the only effective treatment. Enthusiasm for interferon therapy must be tempered because advanced disease usually requires years or even decades to develop and does not occur in all patients. Few patients with chronic hepatitis C derive long-term improvement from a single 6-month course of interferon therapy. Most initial responders relapse and require long-term interferon treatment to suppress the virus. Obviously, the initial goals and expectations for interferon therapy require rethinking. Therapy should not be undertaken by physician or patient with the idea that therapy will be limited to 6 months. The most appropriate goal of therapy now appears to be the long-term control of the biochemical, virologic, and histologic activity of the disease. Unfortunately, the most effective therapeutic regimen for achieving this goal is not yet known and will require continued clinical research. (52 Refs.)

Treatment of chronic viral hepatitis.
Marcellin P; Benhamou JP
Baillieres Clin Gastroenterol (England) Jun 1994, 8 (2) p233-53

Recent advances have been made in the treatment of chronic viral hepatitis, mainly with recombinant interferon (IFN) alpha. However, the present treatment of chronic viral hepatitis is not entirely satisfactory because the efficacy is inconstant and/or incomplete. In chronic hepatitis B IFN-alpha induces a sustained interruption of hepatitis B virus (HBV) replication, with a HBeAg to anti-HBe seroconversion in about 30% of patients. Patients most likely to respond are those with no immunosuppression, HBV infection acquired during adulthood or active liver disease with low HBV replication. Responders usually show a significant decrease in serum HBV DNA levels during the first 2 months of therapy, followed by a significant increase in the level of aminotransferases. New nucleoside analogues might be useful in combination with IFN-alpha in the treatment of those who do not respond to IFN therapy. In chronic hepatitis B-D, the rate of sustained response to IFN-alpha therapy is low. To be effective, IFN-alpha must be used at a high dosage (9-10 mega units) with a long duration (1 year). In chronic hepatitis C, IFN-alpha at a dosage of 3 mega units over 6 months, induces a sustained response in about 20% of patients. A higher dosage of IFN (5-10 mega units) and a longer duration of treatment increases the rate of sustained response but is associated with poor tolerance. Non-responders to a first course of IFN do not respond to a second course of treatment. In patients who respond but relapse after treatment, the rate of sustained response after a second course of IFN needs to be assessed. Ribavirin, which has a significant antiviral effect on hepatitis C virus, might be useful in combination with IFN-alpha. At the dosage (3-6 mega units) usually used, IFN-alpha is relatively well tolerated. In about 10% of the patients therapy is interrupted, mainly because of severe fatigue, thyroid dysfunction or depression. (84 Refs.)

Elevated serum iron predicts poorresponse to interferon treatment in patients with chronic HCV infection.
Arber N; Moshkowitz M; Konikoff F; Halpern Z; Hallak A; Santo M; Tiomny E ; Baratz M; Gilat T
Dig Dis Sci (United States) Nov 1995, 40 (11) p2431-3

To date, there are no firm clinical, demographic, biochemical, serologic, or histologic features predicting which patients with chronic hepatitis C are more likely to respond to therapy with interferon-alpha. Serum iron, total iron-binding capacity, transferrin saturation, and ferritin were measured in the fasting state. The amount of stainable iron in liver biopsy specimens was evaluated histochemically as well. All patients received subcutaneous recombinant human IFN-alpha 2a three million units thrice weekly by self-administration. Eleven of 13 (84%) responders had low to normal serum iron levels as compared to one of 26 (4%) nonresponders (P < 0.001). The serum transferrin was similar in both groups, but iron saturation was significantly lower in responders (30 +/- 10%) than in nonresponders (53 +/- 12%) (P< 0.001). Serum ferritin and hepatic iron content were higher in nonresponders (NS). It is suggested that increased serum iron and transferrin saturation blunt the action of interferon, as they have opposite effects on the immune system. Iron overload can thus lead to a poor response to interferon. It remains to be seen whether reducing iron overload will improve the response to interferon therapy.

Distribution of iron in the liver predicts the response of chronic hepatitis C infection to interferon therapy
Barton AL; Banner BF; Cable EE; Bonkovsky HL
Am J Clin Pathol (United States) Apr 1995, 103 (4) p419-24
[published erratum appears in Am J Clin Pathol 1995 Aug;104(2):232]

Recent evidence suggests that patients with chronic hepatitis C virus (CHCV) who respond to interferon-alpha (IFN) therapy have a lower hepatic iron concentration than those who do not. The object of this study was to assess the concentration and distribution of iron in liver biopsies from 15 patients with CHCV seen at the authors' medical center between June 1992 and March 1993. Patients with complete response to IFN were compared to those with non-complete response with respect to quantitative hepatic iron concentration, serum iron indices, and a detailed analysis of histologic features of hematoxylin-and-eosin and iron-stained pre-IFN biopsies. Patients with non-complete response had significantly higher scores for stainable iron in sinusoidal cells (P = .02) and portal tracts (P = .05) than did patients with complete response. Total hepatic iron scores, mean quantitative hepatic iron, and mean serum ferritin were higher in patients with noncomplete response, but the differences were not significant. In conclusion, iron deposition in sinusoidal cells and portal tracts is significantly less frequent in patients with complete response to IFN than in those with poor or no response, and may be a useful, objective predictor of response to IFN therapy.

Increased serum iron and iron saturation without liver iron accumulation distinguish chronic hepatitis C from other chronic liver diseases.
Arber N; Konikoff FM; Moshkowitz M; Baratz M; Hallak A; Santo M; Halpern
Dig Dis Sci (United States) Dec 1994, 39 (12) p2656-9

One hundred twenty-three patients with chronic liver diseases of various etiologies were evaluated for their iron status. The patients were divided into four distinct groups: chronic hepatitis C (63), chronic hepatitis B (14), B + C (3) and nonviral chronic liver diseases (43). In 107 patients (87%) the chronic liver disease was confirmed by biopsy. Mean serum iron (+/- SD) levels in the above four groups were: 166 +/- 62, 103 +/- 52, 142 +/- 48, and 115 micrograms/dl; iron-binding capacity was 346 +/- 80, 325 +/- 72, 297 +/- 27, and 374 +/- 75 micrograms/dl, and iron saturation 50 +/- 18, 32 +/- 16, 48 +/- 16, and 28 +/- 10%, respectively. Serum ferritin, increased in all four groups, was highest in HCV; however, no evidence of hepatic iron accumulation could be found in any of the patients. There were no significant differences in liver function parameters measured in the four groups. We conclude that serum iron, iron saturation, and ferritin are increased in patients with hepatitis C in comparison to hepatitis B or other nonviral, nonhemochromatotic liver diseases. The increased iron status in hepatitis C patients is not manifested by increased liver iron. Awareness of these distinct features of chronic hepatitis C is essential in the diagnosis and treatment of chronic liver diseases.

Response related factors in recombinant interferon alfa-2b treatment of chronic hepatitis C.
Perez R; Pravia R; Linares A; Rodriguez M; Lombrana JL; Suarez A; Riestra
Gut (England) 1993, 34 (2 Suppl) pS139-40

In an analysis of the clinical and laboratory variables that can influence the response to interferon alfa-2b treatment, 48 patients with chronic hepatitis C virus infection received interferon 5 million units (MU) subcutaneously three times weekly for eight weeks followed by 3 MU three times weekly for seven months. Response related factors on univariate analysis were found to be age > 40 years, non-parenteral source of infection, pretreatment positive antinuclear antibodies (ANA), cirrhosis, and high serum iron, ferritin, gamma glutamyl transferase, and IgM. An independent predictive value (multivariate analysis) was also found for cirrhosis, ANA, serum iron, and ferritin. A baseline aspartate aminotransferase/alanine aminotransferase ratio of 0.5 and a striking increase during interferon treatment were associated with a complete response.

Measurements of iron status in patients with chronic hepatitis
Di Bisceglie AM; Axiotis CA; Hoofnagle JH; Bacon BR
Gastroenterology (United States) Jun 1992, 102 (6) p2108-13

Eighty patients with chronic viral hepatitis were screened for evidence of iron overload. Elevated serum iron values were noted in 36% of cases; serum ferritin values were above normal in 30% of men and 8% of women. Twenty-eight additional patients with chronic hepatitis for whom liver tissue was available for determination of iron content were evaluated to study the significance of iron overload in association with chronic hepatitis. Although 46% had elevated serum iron, ferritin, or transferrin-saturation levels, the hepatic iron concentration was elevated in only four cases, and the hepatic iron index was in the range for hereditary hemochromatosis (greater than 2.0) in only two of these. Serum aspartate aminotransferase activities correlated with serum ferritin levels in these patients, suggesting that ferritin and iron levels were increased in serum because of their release from hepatocellular stores associated with necrosis. Thus, in patients with chronic hepatitis in whom hereditary hemochromatosis is suspected, a liver biopsy should be performed with quantitation of hepatic iron and calculation of the hepatic iron index to confirm the diagnosis.

[Effect of green tea on iron absorption in elderly patients with iron deficiency anemia]
Kubota K; Sakurai T; Nakazato K; Morita T; Shirakura T
Department of Medicine, Kusatsu Branch Hospital, Gunma University School of Medicine.
Nippon Ronen Igakkai Zasshi (Japan) Sep 1990, 27 (5) p555-8

The effect of green tea on iron absorption from tablets containing sodium ferrous citrate was investigated in four elderly patients with iron deficiency anemia and in eleven normal elderly subjects. In both groups, the serum iron level reached a maximum value from 2 to 4 hours after taking iron tablets and returned to the baseline value after 24 hours. No inhibitory effect of green tea on iron absorption was recognized.

[Current knowledge in the treatment of chronic hepatitis C]
Pirotte J
Service d'Hepato-Gastroenterologie, Universite de Liege.
Rev Med Liege (Belgium) Dec 1995, 50 (12) p501-4, (29 Refs.)

No abstract.

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