Hepatic iron concentration does not predict response to standard and pegylated-IFN/ribavirin therapy in patients with chronic hepatitis C

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-na?ve 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.     

African Americans at risk for increased iron stores or liver disease

Purpose

We sought to determine the prevalence of elevated measures of iron status in African Americans and whether the combination of serum ferritin concentration >200 μg/L for women or >300 μg/L for men and transferrin saturation in the highest quartile represents increased likelihood of mutation of HFE, self-reported iron overload or self-reported liver disease.

Subjects and Methods

A cross-sectional observational study of 27,224 African Americans ≥25 years of age recruited in a primary care setting was conducted as part of the multi-center, multi-ethnic Hemochromatosis and Iron Overload Screening (HEIRS) Study. Measurements included serum ferritin concentration, transferrin saturation, testing for HFE C282Y and H63D, and self-reported iron overload and liver disease.

Results

Serum ferritin concentration >200 μg/L for women or >300 μg/L for men occurred in 5263 (19.3%) of African Americans, while serum ferritin concentration in this range with highest-quartile transferrin saturation (>29% women; >35% men) occurred in 1837 (6.7%). Adjusted odds of HFE mutation (1.76 women, 1.67 men), self-reported iron overload (1.97 women, 2.88 men), or self-reported liver disease (5.18 women, 3.73 men) were greater with elevated serum ferritin concentration and highest-quartile transferrin saturation than with nonelevated serum ferritin concentration (each P <.05).

Conclusions

Serum ferritin concentration >200 μg/L for women or >300 μg/L for men in combination with transferrin saturation >29% for women or >35% for men occurs in approximately 7% of adult African American primary care patients. Patients with this combination of iron test results should be evaluated for increased body iron stores or liver disease.     

Biochemical expression of heterozygous hereditary hemochromatosis

Background: Hereditary hemochromatosis (HH) is a common autosomal recessive disease caused by an iron overload. Two mutations (C282Y and H63D) on the responsible HFE gene have been described. HH heterozygotes may have a slight iron overload that does not cause clinical disease. Compound heterozygosity may be associated with higher iron stores than C282Y heterozygosity. We studied biochemical iron parameters in HH C282Y and compound heterozygotes without a clinically significant iron overload. Methods: Data on hemoglobin, hematocrit, mean corpuscular volume, serum ferritin, serum iron, transferrin, and transferrin saturation were obtained from 40 C282 wild type controls (irrespective of H63D genotype), 61 C282Y heterozygotes, and 18 compound (C282Y/H63D) heterozygotes without clinical iron overload disease. Results: Serum ferritin levels were significantly higher in female HH heterozygotes, particularly in compound heterozygotes, than in normal women. In male heterozygotes, no difference in serum ferritin was found. We found higher mean serum iron and transferrin saturation levels in male and female HH heterozygotes than in normal controls, the highest in the group of compound heterozygotes. Conclusions: Mean serum ferritin (only in women), serum iron, and transferrin saturation are highest in compound heterozygotes and lowest in controls. C282Y heterozygotes seem to be an intermediate group between compound heterozygotes and the normal population.     

Changes in serum hepatitis C virus RNA titer and response to interferon therapy in patients with chronic hepatitis C

Response to interferon (IFN) therapy for chronic hepatitis C has been determined by the alteration of serum alanine aminotransferase (ALT) values. However, eradication of hepatitis C virus (HCV) could be another aim of the therapy. Thus, we serially measured serum HCV RNA levels during therapy and for at least 12 months after cessation of therapy in 65 patients with chronic hepatitis C who received IFN- (49 cases) or - (16 cases). The presence of HCV and its amount were measured by the combination of nested and competitive PCR. Twenty-seven patients, who were categorized as complete responders, showed sustained normalization of ALT values for more than six months posttreatment. The viral RNA titers at pretreatment were significantly lower in complete responders (logarithmic copy numbers/ml: 5.4±1.3,P<0.001) than in partial and nonresponders. Complete response rate was significantly higher in patients with HCV genotype III (68.4%,P<0.01) than those with type II (23.6%). Among 27 complete responders, HCV RNA became undetectable in only 13 patients six months after completion of therapy, and 11 still had low levels of viremia; however, none experienced relapse of the disease during follow-up of 12–24 months. Three complete responders showed lasting high-titered viremia, and their ALT values rose again during follow-up. Our data suggest that IFN treatment of chronic hepatitis C is often ineffective in eradicating HCV infection even in responders, and long-term follow-up study is necessary to determine the sustained beneficial effect of IFN.     

Prevalence of abnormal iron studies in heterozygotes for hereditary hemochromatosis: An analysis of 255 heterozygotes

Iron studies were compared in 434 patients from 80 hemochromatosis families classified as putative homozygotes, heterozygotes, and normal by HLA typing. There were 28 of 255 (11%) heterozygotes with an elevated serum ferritin and 22 of 255 (8.6%) with an elevated transferrin saturation. Serum ferritin (140 ± 10.2 μg/liter; mean ± standard error) was greater in heterozygotes than in normal subjects (87 ± 8.5 μg/liter; P < .05, Mann Whitney test). Transferrin saturation was greater in heterozygotes (38% ± 0.88%) than in normal patients (29% ± 1.1%; P < .0001). Mean hepatic iron concentration was 54 ± 6 μmol/g (n = 17), and the hepatic iron index was <2 in these patients. Most heterozygotes for hemochromatosis have a normal serum ferritin and transferrin saturation. Heterorygotes with minor elevations in serum ferritin or transferrin saturation do not have significant iron overload as assessed by hepatic iron concentration. © 1994 Wiley-Liss, Inc.     

Prognostic impact of iron parameters in patients undergoing allo-SCT

Iron overload contributes to increased transplant-related mortality, and serum ferritin is typically used to detect iron overload. Other iron parameters have received limited attention. We studied serum ferritin, transferrin, transferrin saturation, iron, soluble transferrin receptor (sTfR) and C-reactive protein (CRP) levels in 230 consecutive patients undergoing myeloablative allo-SCT. All iron parameters were significantly associated with survival. When analyzed individually, both sTfR and transferrin saturation were superior in prognostic power to ferritin (areas under the curve in receiver operating characteristic analysis: 0.670, 0.715, and 0.657, respectively). A combination of ferritin and transferrin saturation had the highest prognostic power: Patients with ferritin below the 30th percentile (<802?ng/mL) showed excellent survival (70±6% at 5 years), while transferrin saturation above the 80th percentile (≥69%) pointed to a high risk of transplant failure (5-year survival 5±5%). The remaining patients showed an intermediate outcome (5-year survival 52±5%). The prognostic impact of iron parameters was independent of other factors such as stage, conditioning regimen and CRP level, and operated similarly across diseases. Iron overload strongly influenced the outcome of allo-SCT. Low pre-transplant ferritin levels indicate a population at low risk, high transferrin saturations and a subgroup of patients with very poor outcome.     

Enzymatic determination of serum 3α-sulfated bile acids concentration with bile acid 3α-sulfate sulfohydrolase

A newly developed enzymatic method for determining urinary 3-sulfated bile acids was used to measure serum 3-sulfated bile acid levels in 114 patients with hepatobiliary diseases and 56 healthy subjects. The lowest measurable amount of the 3-sulfated bile acids was 0.5 µmol/liter. The standard curves for glycolithocholic acid 3-sulfate, glycoursodeoxycholic acid 3-sulfate, and lithocholic acid 3-sulfate were linear from 0.5 to 250 µmol/liter. Specificity of the assay was satisfactory and intra- and interassay variations ranged from 0.8 to 4.4% and from 1.2 to 7.9%, respectively. Analytical recovery was more than 91%. The values obtained by this assay were well correlated with those by gas-liquid chromatography measurement (r=0.91,P<0.01). The fasting serum 3-sulfated bile acids level in healthy subjects ranged from undetectable to 1.9 µmol/liter (mean±se; 0.9±0.1 µmol/liter). The percentage of 3-sulfated bile acids in total bile acids (sum of 3-sulfated and 3-hydroxy bile acids) in serum was 16.8±1.5%. In subjects with hepatobiliary diseases, serum 3-sulfated bile acids levels were elevated; however, the percentage of 3-sulfated bile acids in total bile acids was decreased and correlated with the severity of hepatocellular insufficiency. This enzymatic assay is simple, rapid, and accurate for the determination of serum 3-sulfated bile acids.     

HFE mutations in Caucasian participants of the Hemochromatosis and Iron Overload Screening study with serum ferritin level <1000 μg/L

BACKGROUND:

Many patients referred for an elevated serum ferritin level <1000 μg/L are advised that they likely have iron overload and hemochromatosis.

AIMS:

To determine the prevalence of HFE mutations in the hemochromatosis gene for 11 serum ferritin concentration intervals from 200 μg/L to 1000 μg/L in Caucasian participants in a primary care, population-based study.

METHODS:

The Hemochromatosis and Iron Overload Screening study screened 99,711 participants for serum ferritin levels, transferrin saturation and genetic testing for the C282Y and H63D mutations of the HFE gene. This analysis was confined to 17,160 male and 27,465 female Caucasian participants because the HFE C282Y mutation is rare in other races. Post-test likelihood was calculated for prediction of C282Y homozygosity from a ferritin interval. A subgroup analysis was performed in participants with both an elevated serum ferritin level and transferrin saturation.

RESULTS:

There were 3359 male and 2416 female participants with an elevated serum ferritin level (200 μg/L to 1000 μg/L for women, 300 μg/L to 1000 μg/L for men). There were 69 male (2.1%) and 87 female (3.6%) C282Y homozygotes, and the probability of being a homozygote increased as the ferritin level increased. Post-test likelihood values were 0.3% to 16% in men and 0.3% to 30.4% in women.

CONCLUSIONS:

Iron loading HFE mutations are unlikely to be the most common cause of an elevated serum ferritin level in patients with mild hyperferritinemia. Patients should be advised that there are many causes of an elevated serum ferritin level including iron overload.     

Increased serum levels of transforming growth factor-α in patients with colorectal cancer

PURPOSE: This study was conducted to investigate the serum levels of transforming growth factor- in patients with colorectal cancer and to investigate the clinical significance of these levels in association with tumor stage and histologic differentiation. Also, serum levels of transforming growth factor- were measured after curative surgical resection. METHODS: Serum levels of transforming growth factor- were measured in 42 consecutive patients with colorectal cancer before surgery, in 21 patients after surgical resection (part of the 42 preoperative patients), and in 20 healthy volunteers. We used TGF- Assay. RESULTS: Serum levels of transforming growth factor- in patients with colorectal cancer were significantly higher than in the healthy control group (P=0.001). Significant elevations in serum levels of transforming growth factor- were found in 50 percent (21/42) of patients with colorectal cancer when the mean + 2 standard deviations (80.4 pg/ml) of the control group were used as the upper limit of the normal range. Serum levels of transforming growth factor- tended to decrease with increasing tumor size (n=31;r=–0.52;P=0.002). Serum levels of transforming growth factor- before surgery (89.7±44.4 pg/ml; n=21) significantly decreased to 60.3±19.8 pg/ml after surgical resections of tumors (P=0.017). Serum levels of transforming growth factor- completely decreased to the same serum levels of the control group after surgical resections in all patients who had serum levels of transforming growth factor- greater than mean + 2 standard deviations (80.4 pg/ml) of the control group preoperatively (n=11;P=0.002). CONCLUSIONS: Levels of preoperative transforming growth factor- in patients with colorectal cancer appeared to be higher than levels measured in control subjects. Serum levels of transforming growth factor- before surgery significantly decreased after surgical resections of tumors. Additional studies are warranted to determine if serum levels of transforming growth factor- may be useful as a potential biomarker in the management of patients with colorectal cancer.Supported by a grant from Ewha Womans University Mokdong Hospital, Seoul, Korea.Read at the meeting of The American Society of Colon and Rectal Surgeons, Philadelphia, Pennsylvania, June 22 to 26, 1997.     

Hepatic iron overload does not prevent a sustained virological response to interferon-alpha therapy: a long term follow-up study in hepatitis C-infected patients with beta thalassemia major

OBJECTIVES: Transfusion-acquired chronic hepatitis C infection and systemic iron overload are common in patients with beta thalassemia major. The magnitude of hepatic iron overload has been associated with a poor response to interferon-based antiviral therapy for hepatitis C. The aim of this study was to evaluate the effect of hepatic iron concentration (HIC) on response to interferon monotherapy in patients with massive hepatic iron overload. METHODS: Twenty-eight patients with beta thalassemia major, transfusion-acquired iron overload, and chronic hepatitis C infection were prospectively treated with interferon for 6 months. HIC was measured by atomic absorption spectroscopy before treatment. Serum iron, ferritin, hepatitis C virus genotype, viral load, and liver histology were analyzed. RESULTS: Eight patients (28%) achieved a sustained virological response that has been durable after a mean of 66 months of follow-up. The median HIC was 2583 microg/g dry weight. There was no difference in HIC between responders and nonresponders to therapy. Serum hepatitis C virus RNA was lower in responders than in nonresponders. Genotype 1 was more frequent in nonresponders, and non-1 genotypes were more frequent in responders, although this did not reach statistical significance because of patient numbers. CONCLUSIONS: A long term response to interferon is unrelated to HIC in this patient group, and a durable response can occur despite massive iron overload. HIC may be a factor in liver cell injury, but it does not reliably predict a response to interferon therapy.     

Serum hepcidin measured with an improved ELISA correlates with parameters of iron metabolism in patients with myelodysplastic syndrome

Patients with myelodysplastic syndromes (MDS) often show elevated serum ferritin levels at diagnosis, probably caused by increased intestinal iron uptake attributable to ineffective erythropoiesis. Many patients also develop transfusional iron overload. Hepcidin, a pivotal regulator of iron homeostasis, controls iron uptake in the duodenum as well as iron release from macrophages and is potentially involved in iron distribution to different organs. We measured serum hepcidin, together with other laboratory parameters related to iron metabolism and hematopoiesis (ferritin, transferrin, transferrin saturation, soluble transferrin receptor, erythropoietin, and hemoglobin), and C-reactive protein as marker of inflammation, in 89 MDS patients. Hepcidin levels were measured with two different competitive ELISAs: (a) EIA-4705 as described by Schwarz et al. (J Gastroenterol 46:648–656; 2011) and (b) Hepcidin 25 bioactive ELISA (EIA-5258), which was develop by DRG Diagnostics, Marburg, in 2012. Median hepcidin levels with EIA-5258 were as follows: entire cohort 17.5 ng/ml (n?=?89), RA/RARS 5.9 ng/ml (n?=?5), RCMD 17.8 ng/ml (n?=?38), RS-RCMD 8.7 ng/ml (n?=?7), RAEB I/II 29.1 ng/ml (n?=?22), CMML I/II 16.9 ng/ml (n?=?10), and MDS with del(5q) 26.3 ng/ml (n?=?7). Hepcidin levels of the RA/RARS patients were significantly lower than in the other groups except RS-RCMD. RS-RCMD had significantly lower levels than RAEB and 5q? patients. There was a positive correlation between hepcidin levels and serum ferritin and transferrin saturation, and a negative correlation between hepcidin and hemoglobin and transferrin. Malcovati et al. (Blood 112:2676a, 2008), Santini et al. (PLoS One 6:e23109, 2011), and Ambaglio et al. (Haematologica 98:420–423, 2013), using mass spectrometry, reported similar results. We further assessed transfusional status and could show that patients who had been transfused have significantly higher hepcidin levels (median 33.3 versus 8.8 ng/ml (p?<?0.001)). A dichotomized hepcidin level correlated with worse survival. EIA-4705 as described by Schwarz showed no correlation with markers of iron metabolism. Measurement of serum hepcidin with an improved ELISA yield results that correlate with other parameters of iron metabolism as well as survival and transfusion needs.     

Interferon-α 2b Therapy Is Efficacious in Asian-Americans with Chronic Hepatitis B Infection: A Prospective Controlled Trial

Chronic hepatitis B virus infection is endemicin Asian communities in the United States. The purposeof the current study was to compare the antiviralefficacy of interferon-_2b in a groupof adult Asian patients chronically infected withhepatitis B with active replication compared to acontrol group of Caucasian patients treated with thesame regimen. Patients with entry aminotransferase (ALT)levels greater than three times the upper limit ofnormal received interferon-_2b, 5million units, subcutaneously daily for 16 weeks.Patients with pretreatment ALT levels 1.5-3 times theupper limit of normal received prednisone for a total of sixweeks prior to interferon starting at 60 mg daily withreduction in dosage by 20 mg every two weeks with atwo-week period between finishing prednisone and starting interferon-_2b. Eight(62%) of the 13 Asians and six (60%) of the 10Caucasians cleared HBeAg and HBV DNA from serum (NS). Bythe end of one year of follow-up after therapy, four(67%) of six Caucasian responders but none of the Asianresponders had cleared hepatitis B surface antigen fromserum (P < 0.05). Loss of serum markers of activereplication appeared less durable in the Asian responders compared to the Caucasians withreappearance of serum HBeAg in two (25%) of eight of theformer but only one (17%) of the latter group. Threeother Asian patients subsequently redeveloped HBeAg in serum. It is concluded that adultAsian-Americans have an identical initial response rateto antiviral therapy withinterferon-_2b; however, the responsemay be less durable and does not usually lead to loss of HBsAg.     

Evidence for heterogeneity in hereditary hemochromatosis: Evaluation of 174 persons in nine families

Hereditary hemochromatosis is an autosomal recessive disease in which the gene is linked to the HLA system. Investigation of nine unrelated probands and their family members has revealed distinct groups based on biochemical and clinical manifestations of the disease. Four different types of disease expression were identified: Group I—classic hereditary hemochromatosis with elevated transferrin saturation, serum ferritin levels, and liver iron content; Group II—severe iron overload, accelerated disease manifesting at an early age; Group III—elevated total body iron stores, normal transferrin saturation and serum ferritin levels; Group IV—markedly elevated findings on serum biochemical tests, e.g., transferrin saturation, serum ferritin levels, with minimal elevation in total body iron stores. This evidence for several clearly distinguishable modes of expression in different families suggests that more than one genetic lesion in iron metabolism may be responsible for iron overload in hereditary hemochromatosis. This genetic heterogeneity may be helpful in delineating the fundamental abnormalities in iron metabolism in this group of disorders.     

Biological variability of transferrin saturation and unsaturated iron-binding capacity

Background

Transferrin saturation is widely considered the preferred screening test for hemochromatosis. Unsaturated iron-binding capacity has similar performance at lower cost. However, the within-person biological variability of both these tests may limit their ability at commonly used cut points to detect HFE C282Y homozygous patients.

Methods

The Hemochromatosis and Iron Overload Screening Study screened 101,168 primary care participants for iron overload using transferrin saturation, unsaturated iron-binding capacity, ferritin, and HFE C282Y and H63D genotyping. Transferrin saturation and unsaturated iron-binding capacity were performed at initial screening and again when selected participants and controls returned for a clinical examination several months later. A missed case was defined as a C282Y homozygote who had transferrin saturation below the cut point (45% for women, 50% for men) or unsaturated iron-binding capacity above the cut point (150 μmol/L for women, 125 μmol/L for men) at the initial screening or the clinical examination, or both, regardless of serum ferritin.

Results

There were 209 C282Y previously undiagnosed homozygotes with transferrin saturation and unsaturated iron-binding capacity testing performed at the initial screening and clinical examination. Sixty-eight C282Y homozygotes (33%) would have been missed at these transferrin saturation cut points (19 men, 49 women; median serum ferritin level of 170 μg/L; first and third quartiles, 50 and 474 μg/L), and 58 homozygotes (28%) would have been missed at the unsaturated iron-binding capacity cut points (20 men, 38 women; median serum ferritin level of 168 μg/L; first and third quartiles, 38 and 454 μg/L). There was no advantage to using fasting samples.

Conclusions

The within-person biological variability of transferrin saturation and unsaturated iron-binding capacity limits their usefulness as an initial screening test for expressing C282Y homozygotes.     

Genetic screening for HFE hemochromatosis in 6,020 Danish men: penetrance of C282Y, H63D, and S65C variants

The aim of this epidemiologic population survey was to assess the penetrance of the most frequent hemochromatosis (HFE) gene variants in ethnic Danish men. A cohort of 6,020 men aged 30–53 years was screened for HFE C282Y, H63D, and S65C variants by restriction fragment length polymorphism analysis. Subsequently, iron status markers (serum transferrin saturation, serum ferritin) were analyzed in 1,452 men. The C282Y allele was present in 5.6%, H63D in 12.8%, and S65C in 1.8% of the men. We found 23 out of 6,020 (0.38%) C282Y homozygotes, of whom two had been treated with phlebotomy. Among untreated C282Y homozygotes (n = 21) with available iron status markers (transferrin saturation n = 18, ferritin n = 16), 89% had elevated transferrin saturation ≥50%, 94% had elevated ferritin ≥300 μg/L, and 88% had elevation of both iron status markers; seven out of 16 (44%) had ferritin values >800 μg/L. One C282Y homozygote had normal iron status markers possibly due to nonexpressivity. Among C282Y/H63D compound heterozygotes (n = 66), 23% had elevated transferrin saturation, 27% elevated ferritin, and 9% elevation of both iron status markers. Among H63D/H63D homozygotes (n = 74), 15% had elevated transferrin saturation, 19% elevated ferritin, and 5.4% elevation of both iron status markers. Among C282Y/wild type (wt) heterozygotes (n = 255), 9% had elevated transferrin saturation, 9% elevated ferritin, and 1.2% elevation of both iron status markers. Among H63D/wt heterozygotes (n = 600), 8% had elevated transferrin saturation, 12% elevated ferritin, and 2% elevation of both iron status markers. None of the men with the S65C variant displayed elevation of both iron status markers. In conclusion, this study demonstrates a high penetrance of the C282Y variant in Danish men followed by the H63D variant while the S65D variant had no significant impact on iron status markers.     

Preventive Effect of FK 506 (Tacrolimus Hydrate) on Experimentally Induced Acute Liver Injury in Rats

The aim of the study was to investigate the effect of the immunosuppressant FK 506 (tacrolimus hydrate) on acute liver injury induced by Propionibacterium acnes and lipopolysaccharide (LPS). Acute liver injury was induced in male Wistar rats by injecting the animals with P. acnes (10 mg/rat), and administering LPS (10 g/rat) seven days later. One group was given FK 506 (1 mg/kg) 24 and 2 hr before administration of LPS, and the other group was given the same dose of saline. The 24-hr survival rate, serum alanine aminotransferase (ALT) concentration, and tumor necrosis factor (TNF) - mRNA and protein concentrations in the liver and spleen were then compared. Hepatic macrophages were also isolated from rats seven days after P. acnes injection, LPS, and FK 506 or saline were added to the culture supernatant, and TNF- production was studied. The 24-hr survival rate was 100% in the FK 506-treated group, in contrast with 16.6% in the saline group. Four hours after LPS injection, the serum ALT concentration was 755 ± 401 in the saline group versus 119 ± 42 units/ml (P < 0.01) in the FK 506-treated group. The serum TNF- concentration was lower in the FK 506-treated group (1419 ± 957 pg/ml) than in the saline group (9205 ± 2215) (P < 0.01). The mRNA and protein concentrations in the liver and spleen in the two groups did not differ significantly 1 hr after LPS injection but were significantly lower in the FK 506-treated group after 4 hr. FK 506 did not directly inhibit TNF- production by isolated cultured hepatic macrophages. FK 506 is unable to inhibit initial TNF- production by hepatic macrophages (or probably that by splenic macrophages either) stimulated by injection of LPS in P. acnes + LPS-induced acute liver injury. However, the immunosuppressant does limit hepatic damage by inhibiting subsequent aggravation of inflammation by the cytokine network.     

Haemophilia protects against ischaemic heart disease: a study of risk factors

We determined the prevalence of iron overload due to homozygous haemochromatosis in an asymptomatic Australian (predominantly Caucasian) population by surveying 1968 employees of two large corporations. Subjects were screened by measurement of transferrin saturation and serum ferritin concentration and, in all subjects with elevation of both indices, percutaneous liver biopsy was performed to establish whether significant iron overload was present. The prevalence of iron overload due to haemochromatosis in this population was 0.36%. The prevalence rate was not significantly different between males and females, suggesting that this autosomal recessive disease is expressed equally in females given an adequate dietary iron supply. The positive predictive value of a transferrin saturation consistently greater than 45% together with an elevated serum ferritin concentration was 64%. It is concluded that the prevalence of significant iron overload due to homozygous haemochromatosis warranting treatment is approximately 1:300 and that transferrin saturation should be included in existing adult health screening programmes.     

State of the iron metabolism in patients with chronic hepatitis C type C does not influence antiviral treatment with interferon and ribavirin

BACKGROUND/AIMS: Comparison of the iron status in patients who responded and did not respond to combination treatment with interferon alpha and ribavirin in chronic hepatitis C. METHODOLOGY: The study group comprised of 61 patients with chronic hepatitis C (genotype 1) treated with alpha 2b interferon and ribavirin. The iron metabolism was evaluated based on serum iron level, total iron binding capacity, transferrin saturation, serum ferritin concentration and hepatic iron concentration. In the evaluation of antiviral treatment efficacy biochemical and virological responses were taken into account. RESULTS: End of treatment response was observed in 38 patients (62%). Significant differences in iron parameters were not observed between responders and non-responders. Also, sustained viral response, 6 months after treatment completion, was reached in 32 patients (52.5%). Iron metabolism parameters did not differ significantly in the group of sustained responders versus non- responders. Finally, ALT normalization was observed in 42 patients (68.9%). Again, no significant differences in iron status were observed between patients with and without biochemical response excluding significantly higher serum ferritin concentration in non-responders. CONCLUSIONS: Results of this study show that iron status does not significantly influence the efficacy of treatment with interferon and ribavirin in patients with chronic hepatitis C.     

Randomized,double-blind,placebo-controlled trial of eight-week course of recombinant α-interferon for chronic non-A,non-B hepatitis

Forty-nine Japanese patients were enrolled in a randomized, placebo-controlled, doubleblind trial of -interferon for chronic non-A, non-B hepatitis: 24 patients received 3 million units of recombinant human alpha -interferon (-2a) thrice weekly for eight weeks, and 25 patients received placebo in a similar schedule. The mean serum alanine aminotransferase (ALT) dropped from 155±91 (sd) to 69±72 during interferon treatment, but remained unchanged (158±140 to 147±130) during placebo treatment (P<0.001). Serum ALT level fell to the normal range in 29% of interferon-treated patients, but in only 4% of placebo-treated patients. Pre- and posttreatment liver biopsies were obtained in all but one case. Average histological activity indices (HAI) were markedly improved in the interferon-treated group (9.5±3.7 to 7.0±4.3), but were unchanged in the placebo group (8.5±4.3 to 8.5±4.9). In addition, we compared the efficacy of interferon treatment between anti-hepatitis C virus (HCV) antibody positive and negative groups. Biochemical and histological improvements were similar and statistically significant in patients with and without antibody to hepatitis C virus. These data indicate that a eight-week course of -interferon induces biochemical and histological improvement in more than half the patients with chronic non-A, non-B hepatitis.This study was supported by a grant from Japanese Ministry of Health and Welfare.