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Genetic hemochromatosis and alpha1-antitrypsin (AAT) deficiency are frequent in white populations. Conflicting data on the association of the two conditions and on the severity of the disease in those in whom these disorders coexist have emerged from analyses of small numbers of patients. To determine if the frequency of AAT deficiency is increased in genetic hemochromatosis, we characterized this protein by isoelectric focusing and DNA analysis in 115 Italian patients with the disease and 290 controls. The frequency of AAT deficiency in patients with genetic hemochromatosis was similar to that in controls (10% and 9%, respectively). The prevalence of cirrhosis in patients with genetic hemochromatosis with MM phenotype was 53%, compared with 58% in those with non-MM phenotype; that of hepatocellular carcinoma, occurring only in cirrhotic patients, was 22% and 28%, respectively. In conclusion, the frequency of AAT deficiency was not increased in our large series of Italian patients with genetic hemochromatosis. Patients in whom the two defects coexisted did not appear to have a more severe disease, but the limited number of subjects with non-MM phenotype does not allow a conclusive evaluation of clinical differences between them and patients with genetic hemochromatosis with MM phenotype.

Hereditary hemochromatosis is a recessive condition characterized by iron accumulation in several organs, followed by organ damage and failure. The disorder is prevalently due to C282Y and H63D mutations in the HFE gene, but additional HFE and TFR2 mutations have been reported. Early iron overload may be assessed by biochemical parameters such as increased transferrin saturation and serum ferritin.Taking advantage of the collection of 178 DNA samples selected for increased transferrin saturation (50% in males and45% in females) from a previous large scale screening of Italian blood donors, we simultaneously assessed the presence of 14 hemochromatosis-associated molecular defects (11 of HFE and 3 of TFR2) by a reverse hybridization-based strip assay.In the series studied the overall C282Y allele frequency was 9% and that of the H63D and S65C was 22.2% and 1.4%, respectively. One rare HFE allele (E168Q), but no TFR2 mutation was detected. When checked at a second examination, transferrin saturation was significantly higher in C282Y homozygotes, H63D/ C282Y compound heterozygotes and H63D homozygotes as compared to wild-type subjects (p0.05).Our results confirm previous findings on C282Y and H63D mutations in Italy, show that the C282Y allele frequency is enriched in samples selected for altered iron parameters, and that a few rare genotypes are present in Northern Italy. None of the known TFR2 mutations was identified in this series confirming the preliminary indication of their rare occurrence. Subjects with hemochromatosis-associated genotypes show a persistently higher mean transferrin saturation than do those with wild type genotypes.

To evaluate the frequency of arthropathy and osteoporosis in genetic hemochromatosis (GH) and to quantify potential risk factors for these 2 conditions.Radiographic evidence of arthropathy was systematically sought in plain radiographs of 32 patients (28 men) with histologically proven GH (17 with hepatic cirrhosis). Bone mineral density was measured by x-ray absorptiometry of L2-L4 and osteoporosis was defined as a T scoreor = 2.5 standard deviation below the mean. Potential risk factors investigated were age, body mass index, cirrhosis, alcohol abuse, hepatitis B and C infections, HLA phenotype, serum free testosterone levels, and the amount of iron removed by phlebotomy to reach depletion. The independent role of risk factors for the presence of osteoporosis was tested by multiple logistic regression analysis.Radiologic signs of arthropathy were observed in 81.3% of cases. Patients with arthropathy were older than patients without (p0.001), but did not differ in the frequency of cirrhosis, amount of iron removed, and HLA typing. Osteoporosis was observed in 9 patients and was positively associated with the amount of iron removed and cirrhosis. However, in multivariate analysis, cirrhosis was not independently associated with osteoporosis, but patients with higher iron removed had a greater probability to have osteoporosis [odds ratio (OR) = 3.23 for any increase of 5 g, 95% confidence interval (CI): 1.09-9.58], whereas the presence of HLA-A3 was associated with a reduction of risk (OR 0.013, 95% CI: 0.0015-1.13).These findings indicate the high prevalence of osteoarticular involvement in Italian patients with GH. Neither cirrhosis nor the amount of iron removed was associated with arthropathy. In contrast, in univariate analysis the risk of osteoporosis was significantly increased by liver cirrhosis. With multivariate analysis we found that osteoporosis was highly influenced by the degree of iron overload, playing an independent role in accelerating bone loss in patients with GH.

Idiopathic hemochromatosis (IH) was considered a rare hereditary disease until population studies in the U.S.A. and Northern Europe indicated an unexpectedly high frequency. In this study we estimated the prevalence of IH in Italy by testing 1301 presumably healthy blood donors. Transferrin saturation (TS) and serum ferritin (SF) levels were used as screening methods. The subjects with TS greater than 50% and/or SF greater than 300 micrograms/l in men and greater than 160 micrograms/l in women were given a complete medical and laboratory examination and those with evidence of iron overload were asked to undergo liver biopsy. Five male donors but no female donors presented increased iron indexes. Diagnosis of homozygous IH in two of them was confirmed by liver biopsy, indicating a prevalence of the disease in this population of 0.2%; that is a gene frequency of 4.5% and a heterozygote frequency of 9%. Since our study might underestimate the true prevalence of the disease because blood donors are at high risk of iron depletion, IH could be one of the most frequent hereditary diseases in Italy. Large-scale screening of young adults based on TS and SF determinations should be proposed for early diagnosis and treatment.

Aims: The aim of this study was to assess the incidence of fatal, life-threatening side effects and the de novo appearance of non-hepatic morbidity during interferon alfa therapy for chronic viral hepatitis. The relationship of these adverse events to actual total dose and duration of interferon was also evaluated. Methods: We conducted a retrospective study at 73 Italian centers of 11 241 consecutive patients with chronic vital hepatitis who underwent interferon alfa treatment. Results: Five patients died during interferon therapy due to liver failure ( n =4) or complications arising from sepsis. Life-threatening side effects were observed in eight patients: two cases where depression developed and led to a suicide attempt and six patients with bone marrow suppression (granulocytes 3 or platelets 3 ). These symptoms and signs completely disappeared after interferon withdrawal. During interferon treatment, 131 patients developed the following de novo non-hepatic disorders: symptomatic thyroid disease ( n =71), impotence ( n =5), systemic autoimmune disease ( n =5), immune-mediated dermatologic disease ( n =14), diabetes mellitus ( n =10), cardiovascular disease ( n =7), psychosis n =10), seizures ( n =4), peripheral neuropathy ( n =3) and hemolytic anemia ( n =2). Most of these complications are reversible or can be ameliorated. Fatal or life-threatening side effects were not related to actual total dose or duration of interferon alfa, while the majority of patients with de novo non-hepatic morbidity received medium/high doses ( > 200 million units) of interferon alfa or were treated for periods longer than 16 weeks (68% and 80%, respectively). Conclusions: Treatment with interferon alfa may have fatal or life-threatening side effects, their incidence in this study being low (0.04% and 0.07%, respectively) and perhaps no different than in untreated patients with chronic viral hepatitis. Moreover de novo non-hepatic morbidity occurred in 1.2% of patients, and the dose and duration of interferon therapy seem important in determining the frequency of this complication. The development of clinically-overt thyroid disease was most common.

Neoplastic disease affect the immunity in cancer patients. The immune alterations in human neoplasms, however, need to be further defined. The present study was carried out to analyze T lymphocyte subsets in patients with solid tumors. The study included 93 patients suffering from early or metastatic solid neoplasms. T helper and T suppressor subsets were measured on venous blood samples by using flow cytometry and monoclonal antibodies. As controls, 58 healthy subjects were included in the study. The T mean helper/suppressor ratio (CD4/CD8) was significantly lower in metastatic cancer patients with respect to that observed either in controls or in patients without metastases. A low CD4/CD8 ratio was seen in 25 of 93 cancer patients (26.9%), 8 of whom had no metastases, while the other 17 showed a metastatic disease. Within the nonmetastatic group, the decline in the CD4/CD8 ratio was due to increases in the T suppressor subset alone in 7. On the contrary, the percentage of cases with decreased T helper subset was significantly higher in metastatic than in the nonmetastatic patients. The results of this study suggest that the decrease in the CD4/CD8 ratio mainly depends on an increase in T suppressor cells in patients without metastases whereas it is due to a decrease in the T helper subset in most patients with metastatic diseases.

Many agents have been reported to cause hemolytic anemia in glucose-6-phosphate dehydrogenase (G6PD) deficient subjects. We investigated whether cimetropium bromide, a new antispasmodic drug, can be safely given to these patients. In the first study, ten healthy volunteers were given 50 mg, p.o. 3 times per day, before meals for 1 week. Blood samples were drawn before and after treatment and stimulation of the hexose monophosphate shunt (HMS) was evaluated. No significant stimulation of HMS was observed. In a second study, 12 G6PD-deficient patients with spastic colon were given cimetropium bromide and placebo according to a double blind, cross-over design. None of the patients showed any significant abnormalities in any of the several hematologic parameters tested.

The Authors describe the results obtained by administering for 2-3 months a combination containing the coenzymes of vitamins B1, B6 and B12 to 16 patients with alcoholic liver disease. The patients showed a statistically significant improvement of red blood cells, haemoglobin, packed cell volume, general symptoms, together with a better utilization of iron. The Authors conclude confirming the efficacy of this product and its good tolerability.

Hereditary spherocytosis encompasses a heterogenous group of inherited disorders due to alteration of r.b.c. surface/volume ratio. Spectrin deficiency is the most common observed defect. We analyzed a case of HS associated with band 3 deficiency without spectrin reduction.In the study of a family originating from southern Italy, we show that a 20% deficiency of band 3 with normal spectrin content may be responsible for dominantly inherited hereditary spherocytosis (HS). The proband is a 12 years old girl consulting for jaundice, chronic anaemia and splenomegaly. Her mother had a similar haematologic phenotype.Electrophoretic analysis of erythrocyte membrane proteins showed a deficiency in band 3 protein. Band 3 protein chymotryptic fragments, deglycosylated band 3, and its isolated cytoplasmic domain, all displayed normal electrophoretic migrations. Furthermore, the tryptic peptides profile of the cytoplasmic domain of the protein did not demonstrate any abnormality, nor did the amino acid composition of the peptides. Analysis of the membrane proteins during erythrocyte ageing, evaluated in density-fractionated red cells, showed that band 3 content was normal in the lighter fraction, whereas in the denser fraction band 3 deficiency was more pronounced than in membranes from non fractionated red blood cells.This case describes HS due to anion exchange transporter deficiency. Our results on fractioned red cells support the hypothesis that the defect was probably due to a band 3 protein loss during cell ageing and not to a primitive quantitative defect.

Iron overload is frequently present in patients with thalassemia intermedia, and it becomes evident mainly after the second and third decades of life. The degree of the iron load is heterogeneous ranging from mild to severe. In this study we evaluated the iron status of 38 adult patients with thalassemia intermedia and we looked for factors possibly related to the observed heterogeneity of the iron status. The levels of transferrin saturation (TS), serum ferritin (SF) and desferrioxamine-induced urinary iron excretion (DFU) were spread in a wide range from normal to markedly increased. These indices did not correlate with other parameters such as age, hemoglobin levels and entity of the erythropoietic status. A significant difference in the degree of iron overload was observed between patients who underwent splenectomy and non-splenectomized patients. TS, SF and DFU were significantly higher in splenectomized than in non- splenectomized patients, indicating that the spleen could have a role in the regulation of iron metabolism in these patients.

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.

Severe iron overload has been reported in patients with the beta -thalassaemia trait. Studies performed before the discovery of the haemochromatosis gene (HFE) have yielded conflicting results: some suggest that iron overload might arise from the interaction of the beta -thalassaemia trait with heterozygosity for haemochromatosis, some with homozygosity for haemochromatosis and others that it was unrelated to haemochromatosis. We have studied the clinical phenotype, iron indices and HFE genotypes of 22 unrelated patients with the beta -thalassaemia trait and haemochromatosis, the inheritance of chromosome 6p and 1q haplotypes in families of non-homozygous C282Y probands and serum measures of iron status in relatives heterozygous for C282Y with or without the beta -thalassaemia trait. We demonstrate that the beta -thalassaemia trait aggravates the clinical picture of C282Y homozygotes, favouring higher rates of iron accumulation and the development of severe iron-related complications. We suggest that the coexistence of the beta -thalassaemia trait might also increase the risk of iron overload in patients with HFE genotypes at a mild risk of haemochromatosis. Our findings do not support the hypothesis that the association of the beta -thalassaemia trait with a single C282Y or H63D allele might lead to iron overload and suggest that other non-HFE-related inherited factors are present in haemochromatosis patients with incomplete HFE genotypes.

Two hundred twelve Italian patients with genetic hemochromatosis (181 men, mean age 50 +/- 11 yr; and 31 women, mean age 49 +/- 10 yr) were followed for a median period of 44 mo (range = 3 to 218 mo). Alcohol abuse was present in 31 subjects (15%), and chronic HBV and HCV infection were seen in 19 (9%) and 35 (24%) of 145 cases tested, respectively. Twenty-four patients (11%) had concomitant beta-thalassemia trait. Liver biopsy revealed cirrhosis in 146 and a noncirrhotic pattern in the other 66. Perls' stain was degree III in 37 patients and IV in 171 patients. One hundred eighty-five patients underwent weekly venesection, and iron depletion was achieved in 122 cases after total iron removal of 3 to 41 gm. Death occurred in 44 patients after 3 to 198 mo and was due to hepatocellular carcinoma in 20 cases, liver failure in 10, extrahepatic cancer in six, heart failure in three and hemochromatosis unrelated causes in five. Cancer has developed in seven other patients still alive (hepatocellular in five and extrahepatic in two). No deaths were observed among noncirrhotic patients; cumulative survival rates in cirrhotic patients were 85%, 75%, 60% and 47% at 3, 5, 8 and 10 yr, respectively. Univariate analysis in the 146 cirrhotic patients showed that age greater than 60 yr, alcohol abuse, cardiomyopathy, skin pigmentation, portal hypertension, hypoalbuminemia, hypergammaglobulinemia and Child class B or C had significant negative prognostic value. At multivariate analysis, only alcohol abuse, gamma-globulins greater than 2.0 gm/dl and Child class B or C maintained their negative prognostic values (p less than 0.01, hazard ratio 2.7; p less than 0.001, hazard ratio 2.8; and p less than 0.001, hazard ratio 4.3, respectively).

We evaluated the prevalence of hepatitis B virus (HBV) and hepatitis C virus (HCV) infection in 78 Italian patients with hereditary hemochromatosis as well as the relation between HCV antibody (anti-HCV) status, hepatitis B surface antigen (HBsAg) and liver histology. None of the patients had been transfused or ever consumed more than 60 g of alcohol per day. Eighteen showed histological signs of chronic hepatitis, active cirrhosis was present in 12, chronic active hepatitis in 4 and chronic persistent hepatitis in 2. Liver fibrosis or cirrhosis without inflammatory activity was observed in 31 subjects, whereas liver histology was normal except for iron overload in 18. The prevalence of HBsAg in the whole series was 5% and of anti-HCV was 20.5%. The prevalence of HBsAg and anti-HCV was significantly higher in the chronic hepatitis group than in the fibrosis/cirrhosis (p = 0.01) and the normal groups (p < 0.01). Fourteen of 18 hereditary hemochromatosis patients with chronic hepatitis were HBsAg (4) or anti-HCV (10) positive and all the latter subgroup had HCV-RNA in their serum as shown by the polymerase chain reaction. Although most of the patients with associated chronic hepatitis had cirrhosis, their serum ferritin levels and amount of mobilizable iron were significantly lower than those of the fibrosis/cirrhosis group (p < 0.01). This indicates that hepatitis viral infection acts synergistically with iron in accelerating the development of liver damage.

Mild to moderate iron overload is found in most patients with porphyria cutanea tarda. This study aimed to evaluate whether iron overload in patients with porphyria cutanea tarda is related to the presence of a coexistent genetic hemochromatosis gene.A cohort study of 94 Italian patients with porphyria cutanea tarda (90 men and 4 women) and 20 relatives of five patients with iron overload were studied. Diagnosis of iron overload was assessed by transferrin saturation, serum ferritin and iron removed by phlebotomy to reach depletion. HLA typing by microlymphocytotoxicity test and duodenal ferritin analysis by immunohistochemistry were performed in a smaller number of patients. The chi square test was used to compare means and prevalences.Iron overload was present in 62% of the patients. HLA-A3 prevalence was significantly higher (p0.01) in subjects with iron overload than in those without. A lack of duodenal ferritin was observed in 14/18 patients with and in 6/12 without iron overload. Family studies showed the presence of iron overload but not of porphyria cutanea tarda in HLA identical or semi-identical relatives of the patients.Italian patients with porphyria cutanea tarda and iron overload appear to have one or even two genes for genetic hemochromatosis.

To identify factors that might be useful as prognostic indexes for the risk of hepatocellular carcinoma in Italian patients with genetic hemochromatosis, 152 homozygotes were studied prospectively for 1 to 229 mo. Factors that were considered in estimating the risk of developing hepatocellular carcinoma were age, sex, cirrhosis (Child class), HBsAg, antibodies to HBsAg, antibodies to HBcAg, hepatitis C antibodies, alcohol abuse and the amount of iron removed during therapeutic phlebotomy to produce iron depletion. At diagnosis, cirrhosis was present in 97 patients and absent in 55. During follow-up, hepatocellular carcinoma developed in 28 of the 97 patients with cirrhosis but in none of those without. Among patients with cirrhosis, the cumulative probability of being free of hepatocellular carcinoma at 10 yr was 70%. For patients with and without HBsAg the probabilities of being free of liver cancer at 10 yr were, respectively, 54% and 75%; for those with and without history of alcoholism, 58% and 78%; and for those younger and older than 55 yr, 90% and 54%. In patients with cirrhosis, multivariate analysis using proportional-hazards (Cox) regression found that the only factors contributing significantly to the estimation of a prognostic index were age, presence of HBsAg and alcohol abuse. Age over 55 yr increased the relative risk of hepatocellular carcinoma 13.3-fold (p < 0.001), the presence of HBsAg increased it 4.9-fold (p < 0.02) and alcohol abuse increased it 2.3-fold (p < 0.04). Homozygotes for genetic hemochromatosis with cirrhosis who were older than 55 yr had a history of alcohol abuse and were positive for HBsAg at the time of diagnosis had a 150 times higher relative risk of hepatocellular carcinoma. (Hepatology 1994;20:1426–1431).

The frequency of HLA A3 and B7 antigens was significantly higher in 67 unrelated patients with idiopathic hemochromatosis (IH) than in 700 controls (62.7% vs 22.5%, p less than 10(-8) and 26.9% vs 9.3%, p less than 10(-3), respectively). A3 B7, A3 B35 and A3 B5 were significantly more frequent in 72 haplotypes linked to IH gene than in 278 control haplotypes. The prevalence of B35 and A3 B35 was significantly higher in IH patients from North-Eastern Italy than from other regions (60% vs 21%, p less than .05 and 54.5% vs 8.2%, p less than 0.0001, respectively). All 15 siblings HLA identical to the respective proband were homozygous for IH with variable expression of the disease, whereas minor abnormalities of iron-related indexes were present in 23% of heterozygous relatives. Homozygous-heterozygous mating probably occurred in three of 40 families, accounting for the overt disease in three offspring and in one HLA semi-identical sibling; however, in this last case the possibility of a recombination event cannot be excluded.

Thirty two unrelated Italian subjects with idiopathic haemochromatosis were studied. HLA-A3 was present in 26 of them (81% v 22% in controls; p less than 0.001) and HLA B7 in eight (28% v 9%; p less than 0.01). There was no important association between idiopathic haemochromatosis and HLA B14. Subdividing the patients on the basis of their regional origin a noticeably higher prevalence of HLA Bw35 in patients with idiopathic haemochromatosis from north eastern Italy was found than in those from Lombardy, or in the controls; there were no differences in the incidence of HLA A3 and B7 between patients with idiopathic haemochromatosis from different areas. A high prevalence of A3, Bw35, and A3, B7 haplotypes was found in our patients with idiopathic haemochromatosis. A3, Bw35 could be the haplotype most commonly linked to the idiopathic haemochromatosis gene in north eastern Italy.

Basic ferritin (liver-type) was measured in erythrocytes of subjects with alpha- and beta-thalassemia trait, thalassemia intermedia and Cooley's disease, and compared with normals and patients with abnormal iron metabolism without erythrocyte metabolic defect (iron deficiency anemia and idiopathic hemochromatosis). In all the thalassemic syndromes considered, erythrocyte ferritin was significantly higher than in normals (p less than 0.001) and increased progressively with the increasing 'severity' of the thalassemic disorder. In both thalassemic and non-thalassemic subjects, erythrocyte ferritin levels were related to body iron status, but in the thalassemic group, the increased erythrocyte ferritin values seemed also to be closely related to the intracellular metabolic abnormality. The severity of the defect in globin chain synthesis seemed to play an important role in determining ferritin accumulation in red cells of thalassemic subjects.

We have characterized HLA antigens in subjects with beta-thalassaemia trait with and without iron overload. 50% of the cases with iron overload (v 18% of those without iron overload, P less than 0.01) are carriers of HLA-A3, the HLA antigen tightly linked to the IH allele. Thus, in a considerable number of these subjects, beta-thalassaemia and IH coexist. This association exerts a synergistic effect in inducing iron overload.

Serum iron, transferrin saturation, serum ferritin and urinary iron excretion have been tested in a group of Italian subjects with beta-thalassemia trait. A number of these subjects, mostly men, had signs of increased iron load. Serum ferritin was the most sensitive index among those measured for detection of iron overload and was positively correlated with desferrioxamine-induced urinary iron excretion. Italian males with beta-thalassemia trait may be at high risk of developing iron overload even without prolonged iron or transfusional therapy.

Two siblings, both splenectomized at an early age for hereditary spherocytosis, had a severe hemochromatosis develop. The human leukocyte antigen (HLA) system typing showed that they were half HLA identical. All the other members of the family who did not have evidence of hereditary spherocytosis, including those who displayed identical HLA haplotypes with the two patients, did not have any increase in iron stores. These results suggest that the two siblings are heterozygous for idiopathic hemochromatosis and that the coexistence of this condition with hereditary spherocytosis can cause a severe iron overload.

Androstenedione (delta), oestradiol-17beta (Oe2), 5alpha-dihydrotestosterone (DHT), progesterone (P) and testosterone (T) concentrations have been measured by radioimmunoassay in ovarian and peripheral venous blood from 15 women in the luteal phase of the cycle. The ovarian blood samples were obtained during surgical intervention from 15 ovaries containing the corpus luteum and from 5 contralateral ovaries. The mean concentration of DHT in ovarian venous blood was not higher than that found in the cubital vein. However in some cases with high concentrations of testosterone in ovarian venous blood, a small but significant DHT gradient was found.

is a new, powerful antispasmodic compound with strong antimuscarinic properties [5, 6]. As a quater,,, 1. nary ammonium salt, it is poorly absorbed after oral ,. administration (1-4% of the dose) [7]. The aim of the present study was to examine the possibility of accumulation of the drug after multiple, oral therapeutic doses. Ten healthy volunteers (3 men and 7 women, aged 25-37 years) were given cimetropium bromide 50 mg t. d. s. before meals for 1 week. Urine fractions were collected before and up to 4 days after the last dose. 0.1 Linear regression of the log of the mean rate of urinary excretion vs time yielded a highly significant correlation coefficient ( r = 0 . 9 6 8 , p

Objective To define whether there is any relation between the iron status of patients with hepatitis C virus (HCV) chronic liver disease and their response to interferon therapy. Design To evaluate the long-term response to 1 year of interferon therapy with addition of phlebotomies after 3 months of treatment if at that time alanine aminotransferase (ALT) had not normalized in a group of patients with HCV-positive chronic liver disease whose iron status had been characterized. Setting A northern Italian hospital. Participants Fifty-eight anti-HCV-positive patients (four HCV-RNA negative) with biopsy proven chronic hepatitis and no evidence of iron overload as indicated by normal transferrin saturation at the time of enrollment in the study. Intervention Three times a week intramuscular injection of alpha interferon 3 MU for 1 year with addition of phlebotomies (350 ml/week) till iron depletion if after 3 months of interferon therapy ALT had not normalized. Results A long-term response was observed in 19 of the 52 patients who completed the treatment, four HCV-RNA negative and 15 positive. The four RNA-negative and seven of the 15 RNA-positive long-term responders had been treated with interferon alone, and the other eight also with phlebotomies. At univariate analysis only HCV genotype, gamma-glutamyltranspeptidase and liver iron concentration were significantly associated with response whereas sinusoidal iron deposition was of borderline significance. No association was found with sex, age, duration of disease, histology, Knodell score, transferrin saturation %, serum ferritin, hepatocytic iron score, and portal iron score. HCV-RNA serum levels, measured in 29 patients, did not correlate with response. At multivariate analysis liver iron concentration was still significant and one unit reduction of liver iron concentration (natural logarithm transformed) was associated with 2.95 odds ratio of response. Conclusion These results indicate that iron in the liver is more closely related to response to interferon than the other variables considered, including HCV characteristics.

Objective: To compare the liver iron concentration (LIC)of Italian patients with chronic hepatitis B and C with those of controls, to evaluate increased LIC frequency in patients and to investigate the influence of the haemochromatosis gene in the development of liver iron overload. Design and setting: Prospective controlled trial in two northern Italian hospitals. Patients: Ninety-eight patients (61 men and 37 women), 85 with chronic hepatitis C and 13 with chronic hepatitis B, and 38 control individuals (20 men and 18 women). Methods: Atomic absorption spectrophotometry was used to determine LIC; standard lymphocytotoxicity test was used for HLA typing in patients with increased LIC; and family studies were performed for patients with major iron overload. Results: Mean LIC was significantly higher in both patient groups than in the controls. Thirty-five patients (36%) had an increased LIC. Twenty-six of these patients had a minor iron overload, whereas nine (9.2%) had a major overload. HLA-A3 antigen was present in five out of the 26 and in four out of the nine patients, respectively. Family studies revealed two siblings HLA-identical to their own proband without evidence of iron overload and chronic hepatitis. Conclusion: Increased LIC is frequent in Italian patients with chronic hepatitis. The mechanism by which the hepatitis virus promotes liver iron accumulation is not known, but it can favour the development of major iron overload in some cases. HLA-A3 antigen prevalence and family studies suggest that in these cases a single haemochromatosis gene probably coexists with the viral infection. LIC should be determined as part of the screening evaluation in patients with suspected chronic hepatitis B or C.

Serum ferritin (SF) and erythrocyte ferritin (EF) were evaluated in 35 patients on chronic hemodialysis treatment (CHD), in 45 healthy subjects and in 22 nonnephropathic females with iron deficiency anemia. Twenty-five CHD patients with basal SF less than 500 micrograms/l were treated orally with 200 mg of Fe2+ for 2 months and the positive (hemoglobin increase greater than 1 g/dl) or negative response to the therapy was correlated to the basal levels of SF and EF. Three groups of CHD patients could be defined on the basis of their basal SF levels (hypo-, normo- or hyperferritinemic). Nine patients with increased SF levels had also EF levels significantly higher than the other CHD patients and controls since they were probably iron-overloaded. In the other 2 groups of CHD patients, EF levels were significantly higher than in controls for each level of SF probably because of the reduced utilization of iron by uremic bone marrow. Among the 25 treated CHD patients, only 5 responded to the therapy: 3 were hypoferritinemic while the other 2 responders had basal SF within the normal range. Four hypoferritinemic patients did not respond to the therapy. Four out of five responders had the lowest EF levels among CHD patients. EF measurement could be an important and useful test in detecting the presence of an iron deficiency erythropoiesis in CHD patients.

Patients with idiopathic hemochromatosis exhibit an unexplained increase in intestinal iron absorption. The aim of this work was to study immunohistochemical H- and L-ferritin distribution in duodenal mucosal cells of patients with idiopathic hemochromatosis, and of subjects with various degrees of iron loading. Biopsy sections of gastrointestinal mucosa from 24 patients with idiopathic hemochromatosis, 10 patients with secondary iron overload, 6 normal subjects, and 13 iron-deficient subjects were analyzed with monoclonal antibodies for the presence of immunohistochemical H and L ferritin types, and with Perls' stain for hemosiderin. Ferritin content of duodenal homogenates was evaluated in 5 cases. The absorptive duodenal cells were found to contain ferritin, mostly of the L type, in apical granules; these ferritin granules were present in all normal, iron-deficient, and iron-over-loaded subjects, but were absent in 21 (87%) of the patients with established idiopathic hemochromatosis. In cells other than those of the duodenal epithelium, such as lamina propria or antral mucosa, ferritin and hemosiderin contents were related to iron loading and no difference was evident between primary and secondary iron overload. These findings indicate that (a) idiopathic hemochromatosis is associated with an altered ferritin expression in the duodenal absorptive epithelial cells, (b) this alteration cannot be detected by analysis of duodenal homogenates, (c) idiopathic hemochromatosis does not affect ferritin accumulation in the other cell types analyzed, and (d) ferritin in absorptive duodenal cells may have a regulatory role in iron absorption.