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Iron and Hepatitis C
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Current Hepatitis Reports November 2004, 3:140-147
James E. Nelson, PhD and Kris V. Kowdley, MD
Department of Medicine, Division of Gastroenterology, University of Washington Medical Center
TOPICS
Introduction
Are Serum Iron Indices Elevated in Patients with HCV?
What Do Increased Serum Iron Indices in the Patient with Chronic HCV Mean?
What Is the Role of Hepatic Iron in Chronic HCV Infection?
What Effect Do HFE Mutations Have in Chronic HCV Disease?
What Are the Potential Consequences of Excess Iron in Chronic HCV Infection?
Is Iron Depletion Therapy Beneficial for Patients with HCV?
Conclusions
References and Recommended Reading
Serum iron markers are often elevated in hepatitis C virus infection, particularly in African-American persons, although the clinical significance of this finding remains unclear. Although hepatic iron is usually only mildly elevated in hepatitis C virus, iron overload is associated with more advanced disease, nonresponse to interferon monotherapy, and increased risk of hepatocellular carcinoma. Iron status does not predict response to interferon and ribavirin combination therapy. Most studies indicate that HFE mutations are associated with increased iron stores and advanced fibrosis. Iron depletion therapy may delay disease progression.
Introduction
Iron homeostasis is critical for all multicellular organisms because iron is an essential element necessary for many basic biological processes; however, excess iron may also be highly cytotoxic. Mammals do not have an active mechanism to excrete excess iron and, therefore, have evolved a tight regulatory mechanism for the absorption and storage of iron. The liver is the main iron storage organ and it plays a fundamental role in iron metabolism. The iron transport protein, transferrin, and the major iron storage protein, ferritin, are both synthesized in the liver. Given this iron-rich environment of the liver, it seems likely that hepatotropic viruses would evolve a means to use this essential nutrient to their advantage in patients with increased hepatic iron stores. In fact, increased iron has been shown to enhance hepatitis C virus (HCV) replication in vitro [1], possibly by upregulating cellular translation factor eIF3 [2]. Although there are limited data suggesting a direct role of iron in HCV infection, cellular processes like respiration and energy metabolism are dependent on iron and are required for virus replication and persistence. Thus, iron load may have a profound indirect effect on HCV infection, and in turn the HCV may alter regulation of iron homeostasis. In this article, we describe the current understanding of the relationship between hepatic iron, serum iron indices, and HFE mutations in relation to HCV infection and treatment.
Are Serum Iron Indices Elevated in Patients with HCV?
Several cohort studies have demonstrated that serum ferritin, iron, and transferrin saturation (TS) are often elevated in patients with chronic HCV infection [3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,15*, 16, 17]. Although most of the studies performed to date were uncontrolled, several studies have compared serum iron markers between HCV-infected patients and non-HCV control subjects [3, 4, 5,16, 17]. All of these studies have reported a significant positive association between serum iron markers and HCV infection. However, even these controlled studies are limited, in that they fail to consider the confounding effect of a number of potential variables. Because serum iron indices are known to differ according to variables such as race, age, gender, body mass index (BMI), and alcohol use, any studies of the relationship between serum iron markers and HCV should control for these factors [18, 19*]. Moreover, variables such as the duration of HCV infection and HCV genotype are important factors that could likely skew any comparison of serum iron markers among HCV-infected individuals [18].
To attempt to clarify the contribution of these confounders, and in particular the effect of race, on the association of serum iron markers and HCV infection in the general population, we have recently examined this issue using data from the third National Health and Nutrition Examination Survey [19*]. HCV-infected individuals in this cohort were younger, leaner, more often male, consumed more alcohol, were less educated, and had a lower income. HCV infection was associated with elevated liver enzymes. There were also racial differences in serum iron studies. After adjustment for age, alcohol intake, gender, menopausal status, education, BMI, and poverty index, HCV-positive black persons with elevated liver enzymes had an increased risk of having increased iron stores (odds ratio, 17.8; 95% confidence interval, 5.1 to 63). By contrast, increased iron stores were much less common among HCV-positive non-black persons with (3.4%) or without (1.4%) abnormal liver enzymes and HCV-negative persons (0.9%). This study shows that African-American persons more often than other races have elevated serum iron indices in response to HCV infection and this further underscores the importance of race as a contributing factor in the natural history of viral hepatitis.
Another important factor that will influence the levels of serum ferritin, iron, and TS is the stage of disease. Elevated serum iron markers have been associated with cirrhosis from a number of different causes [20]. In fact, a significant difference in the level of serum iron indices has been shown between cirrhotic patients with HCV and patients with HCV at an earlier fibrosis stage [5, 14]. Thus, the inclusion of cirrhotic patients is another confounding factor that most studies did not control for, making the interpretation of their conclusions difficult. In summary, although many studies have reported that serum iron markers are elevated in HCV, large controlled studies that adjust for confounding factors suggest that serum iron studies may be elevated among black patients with HCV but not among non-black patients. Among patients with end-stage liver disease, patients with HCV appear to have higher serum iron and TS compared to patients with cholestatic or autoimmune liver disease [20].
What Do Increased Serum Iron Indices in the Patient with Chronic HCV Mean?
The cause of elevated serum iron indices in some HCV-infected individuals is not clear. The presence of a concomitant elevation in serum alanine aminotransferase (ALT) levels suggests that iron and ferritin are released from damaged hepatocytes as a result of hepatic necroinflammation. [4, 6, 7, 15*, 16]. Other studies have not confirmed this finding, but have instead favored a direct cytopathic role for HCV in altering hepatic cellular iron homeostasis [12, 21, 22].
To clarify this issue, several recent studies have directly compared histologically detectable iron, serum iron indices, and liver morphology in patients with HCV. These studies have found that all three serum iron markers were significantly associated with the degree of fibrosis (staging) by univariate analysis [9, 12]. Fabris et al. [9] also found a significant association of inflammation activity (grading) with all three serum iron indices. In contrast, Metwally et al. [12] failed to find an association between any of the serum iron indices and inflammation. Chino et al. [6] reported ferritin was correlated to staging and grading in male patients only. Tung et al. [15*] showed that serum ferritin, TS, hepatic iron concentration (HIC), and hepatic iron index (HII) were significantly higher in end-stage liver disease compared with compensated liver disease using a logistic regression analytic model. Metwally et al. [12] reported a significant correlation between ferritin and advanced fibrosis, whereas Fabris et al. [9] found a significant association of TS and inflammation. These conclusions should be viewed with caution because serum iron markers are often elevated during chronic hepatitis and, therefore, are not reflective of hepatic iron status.
Irrespective of the mechanism leading to elevation of serum iron markers, this finding is clinically significant in the patient with HCV and warrants further investigation by the clinician. As discussed earlier, a number of studies have found a significant association between serum iron markers and HCV disease severity. Although the extent of this relationship needs further study, the concept that serum iron markers are correlated to disease progression has been proposed for several other diseases [23]. Furthermore, serum iron markers, and in particular ferritin, have been found to predict a negative response to interferon monotherapy [24, 25, 26, 27] and interferon/ribavirin or pegylated interferon/ribavirin combined therapy [8, 10]. Lastly, the highest level of ferritin has been observed in patients infected with HCV genotype 1b, which is also the genotype that is associated with higher disease severity and resistance to interferon therapy [4]. These findings provide further evidence for the existence of a relationship between elevated serum markers of iron stores (ie, ferritin), disease severity, and response to interferon therapy.
What Is the Role of Hepatic Iron in Chronic HCV Infection?
Hepatic iron concentration has been shown in several studies to be only mildly to moderately elevated in HCV infection. In the majority of studies reporting HIC, the range of mean HIC was 450 to 700 mg/g. Moreover, only a small proportion of patients (10% to 20%) showed even moderate iron overload, defined as greater than 1500 mg/g. The range of the mean HII in most studies is only 0.4 to 0.6 [28]. In contrast, patients with HCV and cirrhosis are more likely to have increased hepatic iron accumulation. As many as 50% of HCV-positive cirrhotic patients (particularly with end-stage disease) have HIC above the upper limit of normal or have an HII of greater than 1.9 [28].
Currently, it is difficult to determine whether the increased HIC seen in individuals with cirrhotic HCV may facilitate disease progression toward end-stage liver disease or simply result from increased iron deposition in the cirrhotic liver compared with the precirrhotic liver. In order to address this question, we have recently performed a pilot study to determine if histologic changes in serial liver biopsies would correlate with an increase in HIC [29]. The results of this study showed that histologic progression was not correlated with increased HIC at early stages of fibrosis, but iron accumulation appeared to occur after the development of cirrhosis. Prospective, controlled studies will be necessary to identify the relationship between histologic and clinical progression and hepatic iron loading in HCV.
Many studies have shown that a high HIC is a good predictor of nonresponse to interferon monotherapy [24, 26, 30, 31, 32, 33]. These studies suggest that an HIC above 1100 mg/g is associated with nonresponse to interferon alpha therapy in greater than 80% of cases, and has been proposed as a predictive threshold above which failure of interferon monotherapy is likely [24, 33]. In contrast, recent studies have shown that HIC does not correlate with response to interferon/ribavirin or pegylated interferon/ribavirin combination therapy [10, 27, 34]. These results indicate that the addition of ribavirin to the HCV therapeutic regimen is able to offset the detrimental effects of high HIC on the success of interferon monotherapy. A third study did find a significant correlation between hepatic iron staining and nonresponse to combination therapy using a univariate analysis [8]. However, these authors did note that this nonresponder group had a disproportionate number of men and viral genotype 1, two factors that have been associated with greater disease severity [4, 35].
It is important to note that perhaps even more pertinent than the amount of hepatic iron, as determined biochemically, is the distribution of the iron within the HCV liver. There is relatively good agreement that iron deposition in HCV-infected livers is found not only in hepatocytes, but also in the portal tracts and sinusoidal mesenchymal cells [6, 12, 30, 31, 36, 37, 38, 39, 40]. This is in contrast to the mainly hepatocellular distribution pattern seen in hereditary hemochromatosis [41]. Periportal iron deposition seems to be the most clinically relevant iron staining pattern. Several studies have shown a significant association between portal iron staining and nonresponse to interferon therapy [30, 31, 39]. Furthermore, periportal iron [6, 31, 37, 38, 40, 42] and sinusoidal iron [37] have been associated with increased histologic stage. Increased histologic grade is associated with total iron deposition regardless of location, possibly due to portal inflammation and interface hepatitis [6, 36, 37, 42]. It is possible that excess iron within endothelial cells may represent phagocytosed hepatocytes and may inhibit their normal role in cellular immunity, thus leading to increased severity of HCV [40].
What Effect Do HFE Mutations Have in Chronic HCV Disease?
Hereditary hemochromatosis is an autosomal recessive disease marked by hepatic iron overload, which if not removed may lead to advanced fibrosis and cirrhosis. Since the 1996 discovery of the HFE gene, which is responsible for roughly 90% of all cases of hemochromatosis [43], an association between heterozygosity for HFE mutations and increased severity of liver disease due to mild to moderate iron loading has been proposed for many different diseases [44]. The role of HFE mutations in the natural history of HCV infection remains unclear. Many studies have found a correlation between serum iron indices and HFE mutations in patients with HCV [11, 15*, 45, 46, 47, 48, 49, 50, 51]. However, many studies did not find an association between HFE genotype and hepatic iron. The most important question in regard to HFE mutations is whether or not they predispose an individual to increased fibrosis and more severe disease. This issue continues to remain a topic of debate. Recently, several studies have shown a significant association between HFE genotype, hepatic iron, serum iron indices, and advanced fibrosis [15*, 45, 46, 47, 48]. To date, approximately twice as many studies have found a significant association between advanced fibrosis stage and the presence of HFE mutations [15*, 37, 45, 46, 47, 48,50, 51], compared with those finding no relationship [11, 49, 52, 53].
There are a number of plausible explanations for the perceived discrepancies in these studies. Increased levels of ferritin, TS, and serum iron observed in some studies may be more indicative of viral-induced hepatic necroinflammation than to increased hepatic iron deposition. Slightly less than half of all published reports have shown a correlation between hepatic iron and fibrosis. Although not all of these studies evaluated histology, all but two found that patients carrying HFE mutations were more likely to have advanced fibrosis in the setting of increased hepatic iron stores. This may suggest that HFE mutations may be one of several factors leading to increased hepatic iron that accelerates progression to advanced fibrosis. Factors such as ethnicity, age, gender, alcohol use, BMI, insulin resistance, presence of steatosis, duration of HCV infection, and HCV genotype are all are potential confounders that could contribute to disease severity. Recent work by Tung et al. [15*] showing that HFE mutations were significantly associated with cirrhosis but not end-stage liver disease underscores the fact that HFE genotype and iron alone are not sufficient to cause progression to hepatic decompensation and liver failure.
It is important to note that many previous studies did not employ multivariate regression analysis to control for the effect of the aforementioned confounders, thus making direct comparison between studies difficult. Lastly, due to their small sample size, several of these studies lack sufficient power to determine with standard statistical significance (a < 0.05) if the relationship between HFE genotype and advanced fibrosis is robust. Our findings that HFE mutations were associated with accelerated progression to cirrhosis warrant confirmation by larger multi-institutional studies that will enable the power and statistical rigor necessary to control for potential confounders [15*].
Because almost all cases of hepatocellular carcinoma (HCC) occur in the presence of cirrhosis in HCV, it is reasonable to consider whether the escalating incidence of HCC over the past two decades correlates with the parallel rise of chronic HCV cases [54]. Several studies have addressed the relationship between hepatic iron content and HFE mutations in patients with HCV with HCC. Chapoutot et al. [55] found that the presence of iron deposits was more frequent in HCV-related cases of cirrhosis with HCC than in those without HCC. However, Ganne-Carrie et al. [56] failed to find a significant association between hepatic iron and HCC among 229 patients with either HCV-related or alcoholic cirrhosis. There is a paucity of data with regard to the impact of HFE genotype and HCC. Hellerbrand et al. [57] have reported a higher prevalence of C282Y heterozygosity (12.4%) in patients with cirrhosis and HCC versus cirrhotic patients without HCC (3.7%) or normal control subjects (4.8%). In contrast, Lauret et al. [58] described a higher prevalence of C282Y heterozygosity in patients with HCC and cirrhosis compared with cirrhosis alone, but only in alcoholic liver disease (20.9% vs 4.4%) and not in cases of viral-related cirrhosis with (8.8%) or without HCC (7.8%) or noncirrhotic control subjects (6.9%).
What Are the Potential Consequences of Excess Iron in Chronic HCV Infection?
The pathogenic role of hepatic iron via the generation of oxidative stress is well established. Iron mediates this process by catalyzing the production of reactive oxygen species (ROS) through the Fenton reaction. When ROS accumulation overwhelms the cellular antioxidant capacity, a state of "oxidative stress" occurs. In this situation, organic membranes are damaged by lipid peroxidation, resulting in organelle dysfunction, cell injury, and death. Moreover, ROS are known to disrupt protein structure and cause DNA damage, which may eventually lead to HCC [59]. This cascade of events is thought to potentiate liver damage at several levels. First, in addition to their direct cytotoxic effect described above, ROS are thought to directly stimulate a variety of proinflammatory, profibrogenic, and cytotoxic pathways through induction of the redox sensitive transcription factor nuclear factor-kB (NF-kB) in Kupffer cells [60]. NF-kB in turn activates the pleiotropic cytokines tumor necrosis factor-a and interleukin-6. These acute phase reactants, together with transforming growth factor-b, are the primary mediators of the inflammatory and fibrogenic responses [61, 62**]. A key step in this paracrine fibrogenesis cascade is the activation of hepatic stellate cells. During this process, morphologic changes occur that transform this normally quiescent storage cell into a proliferative fibroblast-like cell, producing key components of the extracellular matrix, such as collagen type I and III [63]. Activation of hepatic stellate cells can also occur by iron-mediated ROS production in hepatocytes independent of necroinflammation. This pathway is thought to be mediated by the transcription factor c-myb [64].
The mechanism of liver damage by HCV alone is similar in some aspects to pathogenic iron overload. Both agents potentiate free radical formation, induce cytokine responses through activation of NF-kB, and ultimately result in fibrogenic and inflammatory conditions. However, HCV core protein has been shown to directly trigger apoptosis by upregulation of the tumor suppressor p53 and downregulation of the cell cycle regulators p21 and p38 [62**]. HCV core protein also directly alters lipid metabolism by 1) upregulating hepatic lipogenesis via activation of peroxisome proliferator-activated receptor-a [65]; 2) increasing lipoprotein flux by enhancing b oxidation of fatty acids [62**]; and 3) interacting with apolipoprotein A1 to downregulate microsomal lipid transfer protein [66]. The resulting steatosis may lead to ROS formation and lipid peroxidation.
The combined hepatotoxic effects of iron and HCV together most likely exacerbate the effects of either one alone, resulting in even worse liver damage. This is especially plausible because iron and HCV cause liver damage by overlapping and independent pathways. However, this hypothesis has not been tested using prospective case-controlled studies, although accelerated fibrosis has been shown in individuals with combined hereditary hemochromatosis and chronic HCV compared to control subjects with either disease alone [67].
To define the pathologic effects of iron loading in HCV disease, Bassett et al. [68] undertook a direct experimentation approach by feeding chimpanzees a high iron diet. Comparison of iron-loaded chimps with or without HCV disease revealed that 1) the HCV-infected chimps had greater histology activity index scores and higher ALT levels than uninfected chimps; 2) the HCV-infected animals experienced more rapid iron loading, which also persisted longer in the absence of a high iron diet; and 3) HCV-infected chimps had higher serum TS prior to iron loading. These results support the conclusion that HCV combined with excess iron results in greater liver pathology (ie, increased histology activity index and ALT levels) than iron alone. Second, HCV infection resulted in altered iron metabolism, as evidenced by the differential time course of iron loading in the HCV-infected animals compared with control subjects. It is tempting to speculate that HCV infection results in increased intestinal iron absorption followed by modified iron storage patterns. An alternative explanation is that HCV induces upregulation of transferrin receptors. This hypothesis is in agreement with the finding that HCV-infected chimps had higher TS prior to iron loading.
Iron overload may potentially facilitate HCV viral persistence and pathogenesis by altering the normal host cytotoxic T-lymphocyte response. Several studies have shown that CD8+ cytotoxic T cells are decreased in experimental iron overload [69, 70], hereditary hemochromatosis (C282Y+/+) [71, 72, 73], and HCV infection [71, 72]. Moreover, two recent studies have used immunohistochemistry to show that C282Y+/+ patients with decreased CD8+ cells have statistically more stainable iron and advanced fibrosis [71, 72]. The number of CD8+ cells in hemochromatosis patients with cirrhosis was significantly lower than patients with either alcoholic cirrhosis (P < 0.006) or HCV-related cirrhosis (P < 0.009). These findings led these authors to suggest that a blunted cell-mediated immune response due to decreased CD8+ cells in conjunction with excess iron facilitates liver disease progression [71, 72].
Iron may also be important in maintaining the balance between Th1 and Th2 T-helper subsets [68, 74, 75]. Cytokines produced by the CD4+ T-helper cell subset Th1, such as interferon-g and interleukin-2, are pivotal to the host immune response to viral infections. In contrast, cytokines produced by Th2 cells control the shift from cell-mediated immunity to humoral immunity. An imbalance between these T-cell subsets results in decreased viral immunity and has been implicated in the development of a number of pathologic conditions, including cirrhosis and HCC [74, 75]. Weiss et al. [76**] have shown that increased TS is significantly associated with disease severity and a Th2 cytokine profile in a cohort of 55 HCV-positive patients compared with HCV-negative patients. This study also showed that there was a significant negative correlation (P < 0.05) between TS and nitric oxide, which is a marker of macrophage activation, in patients with HCV. Iron has previously been shown to limit macrophage activation in vitro by reducing the efficiency of interferon-g [77]. Thus, iron may contribute to chronic HCV infection through downregulation of Th1 cell activity and inhibition of macrophage activation.
Is Iron Depletion Therapy Beneficial for Patients with HCV?
Iron reduction therapy holds great promise as an effective treatment for those infected with HCV. Iron reduction via phlebotomy was first used as an adjuvant to interferon therapy, because patients with high HICs often failed to respond successfully to interferon treatment. Phlebotomy is a simple and safe procedure that may be beneficial either when combined with interferon therapy or alone as a treatment alternative for individuals who cannot tolerate interferon. It is universally observed that iron reduction therapy leads to improvements in serum aminotransferases. Although phlebotomy alone does not lead to reduced HCV viral load, when used in conjunction with interferon, HCV-RNA levels decreased at the end of treatment in interferon-naive patients 10% to 20% more often than interferon alone [78, 79, 80, 81]. The sustained response rate (for at least 6 months) was, on average, 15% greater when interferon therapy was preceded by phlebotomy compared with interferon alone [78, 79, 80, 81].
The efficacy of phlebotomy has also been studied in patients who had previously failed to respond to interferon treatment alone. With the exception of one study, these results were much less encouraging. Success rates for the phlebotomy and interferon treatment in the previous nonresponder cohort have ranged from 0% to 15% [82, 83, 84, 85]. A sustained response was almost never observed in any of these studies. In contrast, Van Thiel et al. [33] reported an 80% end-of-treatment response rate in nonresponders re-treated with interferon and concurrent phlebotomy. In this study, the authors randomized 30 previous interferon alpha nonresponders into a treatment regimen of interferon alone or interferon coupled with weekly phlebotomy until iron depleted. A sustained response for at least 6 months was observed in 60% of cases in the phlebotomy/interferon treatment groups. In comparison, only 13% of patients treated with interferon alone showed a sustained response for 6 months. It is important to note that whereas most of the other studies to date have used the standard interferon dosage of 3 MU three times per week, this study used a much greater dosage of 5 MU of interferon daily for 6 months. To our knowledge, these results have not been confirmed by others. Taken together, these studies may indicate that there is a subset of patients (ie, the interferon nonresponders) in whom iron may play a role in the persistence of HCV infection. It is theoretically possible using high-dose interferon therapy combined with phlebotomy to achieve sustained virologic response in these individuals.
It is tempting to think that phlebotomy may also lead to improvement in liver pathology or delayed progression of fibrosis in HCV disease, as has been shown for hereditary hemochromatosis [86]. Some studies have reported a decrease in hepatic inflammation scores following phlebotomy [78, 80, 81, 82,87]. Improvement in hepatic inflammation (measured either by the method of Knodell [88] or Ishak [89]) reached statistical significance in three of the five studies. Iron depletion has not been shown to improve fibrosis when paired biopsy samples were scored before and after treatment. However, two studies have reported that fibrosis did not worsen in a majority of their patients undergoing phlebotomy [81, 87]. Therefore, iron depletion therapy, either alone or in conjunction with interferon, may be useful to slow disease progression and improve hepatic function.
The long-term benefit of iron depletion therapy still remains to be determined. The longest follow-up period reported to date is 5 years [87]. In this study, patients were iron depleted until serum ferritin levels reached 10 ng/mL or less. Ferritin levels were then maintained at 20 ng/mL for the 5-year duration of the study. Serum aminotransferase levels remained significantly decreased for the duration of the follow-up period. In other studies that did not maintain iron depletion, normalization of ALT levels was not sustained [90]. The degree of iron loading necessary to produce liver pathology in association with chronic HCV infection remains unknown. The observation that liver histology does not show a linear relationship to iron staining has led to the proposal that there is a threshold amount of iron necessary to cause a pathologic effect. Long-term trials of phlebotomy therapy to maintain an iron-depleted state are needed to examine whether this treatment delays disease progression in HCV.
Conclusions
For more than a decade, the comorbidity of iron and HCV has been an area of active clinical research. Although several studies have shown elevation of serum iron markers in patients with HCV, the clinical importance of this finding is debatable because there is not a conclusive association with disease severity. Hepatic iron content is usually only mildly elevated in chronic HCV infection, although elevated HIC is strongly predictive of response to interferon monotherapy and is associated with advanced disease. HFE mutations appear to cause acceleration of disease progression in HCV. Some, but not all, studies have shown a significant association between HFE genotype, HIC, and disease progression. It is likely that iron overload worsens liver disease in HCV through induction of oxidative stress and modification of cellular immunity. Iron depletion therapy clearly reduces serum aminotransferases, and may prove beneficial in delaying disease progression among patients who have not responded to interferon and ribavirin therapy.
REFERENCES
(8) Raised serum ferritin predicts non-response to interferon and ribavirin treatment in patients with chronic hepatitis C infection.
Liver • 2002 Jun;22(3):269-75
Abstract
BACKGROUND/AIM: Previous studies have indicated that response to interferon therapy is inversely proportional to the amount of body iron stores. We have studied the relationship between serum ferritin, transferrin saturation, liver iron, presence of HFE-C282Y gene mutation and response to treatment in patients with chronic hepatitis C infection. METHODS: Two hundred and fifty-six naive, HCV-RNA positive patients (60% males, median age 38 years, range 21-70) were treated with interferon and ribavirin for 6 months. Iron indices and the presence of the C282Y mutation were measured. In 242 (94%) patients iron deposition were determined by Perls staining method. Patients with negative HCV-RNA at 6 months after the end of treatment were defined as sustained viral responders. RESULTS: Non-responders (n = 127) had significantly higher median s-ferritin values compared with sustained viral responders (130 microg/L vs. 75 microg/L P < 0.001). There was no difference in transferrin saturation among the two response groups. Only 23% (4/7) of patients with Perls grade 1 in liver biopsies responded to treatment vs. 54% (122/225) patients without iron deposition (P = 0.02), however, 10/13-non-responders had HCV genotype one. Two patients (0.8%) were homozygous for the C282Y mutation, 36 patients were heterozygous (14%). Among mutation carriers 26/38 achieved sustained response compared with 102/216 non-carriers (68% vs. 48%, P = 0.02). In a multivariate analysis s-ferritin (P = 0.030) and C282Y carrier status (P = 0.012) remained independent predict of sustained response. CONCLUSIONS: Raised s-ferritin values predicate non-response to interferon-ribavirin therapy in hepatitis C patients. Response rate in C282Y mutation carriers seems greater than in non-carriers.
(10) Hepatic iron concentration does not predict response to standard and pegylated-IFN/ribavirin therapy in patients with chronic hepatitis C.
J Hepatol • 2004 Jun;40(6):1018-22
Abstract
BACKGROUND/AIMS: Iron overload is common among patients with chronic hepatitis C (CHC). In this study the role of hepatic iron concentration (HIC) and serum iron parameters was assessed to determine response to standard and pegylated interferon (IFN)/ribavirin combination therapy in patients with CHC. METHODS: Liver biopsies were obtained from 169 IFN-naïve patients (m=115, f=54, age: 40.8+/-10.7) with CHC. 140 patients were treated with standard IFN/ribavirin, 29 patients with pegylated-IFN/ribavirin. Biopsy specimens were evaluated according to the DiBisceglie scoring system and iron grading. HIC was determined by atomic absorption spectroscopy. Ferritin and transferrin saturation and presence of HFE-C282Y and H63D gene mutations were determined at baseline. RESULTS: Nonresponders to combination therapy had higher serum ferritin levels at baseline (p<0.01). There was no difference of HIC, transferrin saturation levels, and the HFE-mutation status between responders and nonresponders. Logistic regression analysis revealed serum ferritin as an independent predictor of response. HIC correlated with the DiBisceglie score (r=0.352, p<0.001), iron grading (r=0.352, p<0.001) and serum ferritin (r=0.335, P<0.001). CONCLUSIONS: Pretreatment liver iron concentration does not predict response to combination therapy in patients with CHC. In contrast, high baseline serum ferritin levels are predictors of poor response to antiviral therapy.
Author Address
Department of Internal Medicine IV, Division of Gastroenterology and Hepatology, Medical University of Vienna, Waehringerguertel 18-20, A-1090 Vienna, Austria.
(24) Hepatic iron concentration as a predictor of response to interferon alfa therapy in chronic hepatitis C.
Gastroenterology • 1995 Apr;108(4):1104-9
Abstract
BACKGROUND/AIMS: It has been reported that hepatic iron concentration (HIC) may influence response to therapy in chronic viral hepatitis. The aim of this study was to determine the relationship between HIC and response to interferon alfa therapy in patients with chronic hepatitis C. METHODS: HIC was measured in liver biopsy specimens from 58 patients with chronic hepatitis C treated at three centers. Three patients had mild chronic hepatitis C, 35 had moderate to severe chronic hepatitis C, and 20 had active cirrhosis. Serum ferritin levels were measured in 51 of these 58 patients. Response to therapy was defined as normalization of alanine aminotransferase levels at the end of treatment. RESULTS: Twenty-four patients (41%) responded to therapy. HICs were generally within the normal range (< 1500 micrograms/g). The mean HIC in nonresponders (860 +/- 100 micrograms/g; range, 116-2296 micrograms/g) was significantly higher than in responders (548 +/- 85 micrograms/g; range, 29-1870 micrograms/g) (P < 0.05). Eighty-eight percent of patients with an HIC of > 1100 micrograms/g and 87% of patients with an elevated serum ferritin concentration did not respond to interferon alfa therapy. CONCLUSIONS: HIC seems to influence response to interferon alfa therapy among patients with chronic hepatitis C. A subgroup of patients with chronic hepatitis C has been identified for which an HIC of > 1100 micrograms/g predicted nonresponse in 88% of patients.
Author Address
Division of Gastroenterology and Hepatology, St. Louis University Health Sciences Center, Missouri.
(25) Response related factors in recombinant interferon alfa-2b treatment of chronic hepatitis C.
Gut • 1993;34(2 Suppl):S139-40
Abstract
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.
Author Address
Gastroenterology Unit, Hospital Central de Asturias, School of Medicine, Oviedo, Spain.
(26) Iron stores, response to alpha-interferon therapy, and effects of iron depletion in chronic hepatitis C.
Liver • 1996 Aug;16(4):248-54
Abstract
We studied 81 patients with chronic hepatitis C to investigate the relationship between iron and alpha-interferon response. Sixty-one patients (group A) were given alpha-interferon irrespective of iron status, whereas 20 (group B) with iron overload, were iron depleted before alpha-interferon therapy. In group A, 21 patients responded to alpha-interferon and 40 were non-responders. Increased iron indices were significantly more frequent in non-responders than responders. Multivariate analysis showed that among the independent variables evaluated, only gamma-GT and liver iron concentration predicted therapy outcome. After phlebotomy treatment, serum alanine aminotransferase fell significantly both in patients of group B (196 +/- 122 IU/l vs 82 +/- 37 IU/l, p < 10(-6)) and in 12 non-responders of group A (198 +/- 89 IU/l vs 107 +/- 81 IU/l, p < 10(-6)). In 16 iron depleted patients, eight from each group, subsequent treatment with alpha-interferon produced a response in only one patient. These results suggest that increased liver iron is a negative prognostic factor for alpha-interferon response in chronic hepatitis C. Iron depletion had a beneficial effect on serum alanine aminotransferase in all the patients treated, but did not improve the response to alpha-interferon.
(27) Hepatic iron concentration does not influence response to therapy with interferon plus ribavirin in chronic HCV infection.
J Interferon Cytokine Res • 2002 Apr;22(4):483-9
Abstract
In patients with chronic hepatitis C, prior studies have suggested that increased hepatic iron concentration (HIC) is predictive of a poor response to interferon (IFN) monotherapy. The aim of this study was to assess the importance of HIC on the virologic response to therapy with IFN alone or when combined with ribavirin. Records of 91 patients were reviewed for inclusion in this study. Fifty-one received IFN alone, and 40 received IFN plus ribavirin. HIC and serum iron studies, alanine aminotransferase (ALT) values, hepatitis C virus (HCV) genotype, and HCV RNA were determined prior to therapy. Sustained response was defined as the absence of HCV RNA 6 months after the end of therapy. In the IFN monotherapy group, mean HIC was higher for nonresponders (803 + 89 microg/g, range 130-2808 microg/g) compared with sustained responders (241 + 54 micro g/g, range 187-295 microg/g) (p < 0.01). In contrast, in the combination therapy group, the mean HIC was similar for both groups (533 + 86 microg/g, range 79-1338 microg/g in the nonresponders, and 662 + 95 microg/g, range 94-2031 microg/g, in the sustained responders). No difference between transferrin saturation and serum ferritin level was observed in sustained responder or nonresponder patients treated with IFN plus ribavirin. IFN monotherapy nonresponder patients tended to have a higher HIC. With IFN plus ribavirin, the sustained virologic response rate was not affected by the HIC.
References and Recommended Reading
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