Maintenance Phlebotomy Research Articles

Rusfertide Analog-PN23114 As a Hepcidin Mimetic Provides Efficacy Benefits in Conjunction with Phlebotomy in Mouse Model for Hereditary Hemochromatosis

Hepcidin deficiency in hereditary hemochromatosis (HH) leads to hyperabsorption of dietary iron and primary iron overload (Nemeth E., Science 2004). Therapeutic phlebotomy is used to reduce organ iron-overload in HH patients. However, persistent high transferrin-saturation (TSAT%) may result in toxic labile iron that can deposit in organs, leading to tissue damage and subsequent organ dysfunction. Additionally, newly diagnosed patients with severe iron overload require frequent phlebotomies during the induction phase of therapy that can last for many months, during which TSAT% levels may continue to be high even when serum ferritin levels are reduced. Rusfertide is a hepcidin mimetic peptide that has demonstrated potential benefit in reducing the need for therapeutic maintenance phlebotomy in a Phase 2 trial with hemochromatosis subjects who have previously required chronic phlebotomies to reduce and maintain ferritin and liver iron values within normal range (Kowdley KV, AASLD Hepatology 2021). To evaluate the potential benefits of co-treatment of hepcidin mimetic during induction phase of clinical management, we evaluated additive effects of PN23114 in combination with phlebotomy in HJV-/- mouse model for HH (129S-Hjvtm1Nca/J; Andrews NC, J Clin Invest. 2005). PN23114 is an analog of rusfertide with a single amino acid change and with similar pharmacokinetic and pharmacodynamic characteristics. Male HJV-/- mice at 8-12 weeks of age were treated with either PN23114 (7.5 mg/kg, TIW), phlebotomy (~0.3mL blood drawn, QW), or combination of both for a total of 46 days. We found that all three treatment strategies reduced iron concentrations in both heart and kidney, as compared to a baseline group that was terminated at start of study. None of the treatments were able to reduce liver iron but all three prevented further iron deposition in the liver as compared to baseline. It's possible that the length of phlebotomy treatment is not sufficient to result in iron removal from liver. Treatment with PN23114 redistributed the excess iron into spleen and duodenum, thereby significantly elevating spleen iron concentration, while co-treatment of PN23114 and phlebotomy did not result in marked iron sequestration in spleen. Serum ferritin was reduced in all three treatment groups, the group that received the PN23114 and phlebotomy co-treatment showed the largest reduction. Serum iron was normalized with PN23114 treatment and with co-treatment with PN23114 and phlebotomy. Phlebotomy treatment was not able to lower serum iron to normal levels. Our data overall indicate that combining hepcidin mimetic treatment along with phlebotomy may be more effective in quickly lowering TSAT% and labile iron, and thereby quickly reversing tissue iron deposition in specific organs. Titration of rusfertide to the desired clinical effect may be effective in combination with phlebotomy during the induction phase of clinical management to reduce the frequency and duration of phlebotomy treatment as well as lower the lingering high TSAT% levels.

Ferritin Increase in Hemochromatosis Subjects After Discontinuing Their Regular Maintenance Treatment: A Longitudinal Analysis Performed During the COVID-19 Imposed Hospital Lockdown.

Ferritin Increase in Hemochromatosis Subjects After Discontinuing Their Regular Maintenance Treatment: A Longitudinal Analysis Performed During the COVID-19 Imposed Hospital Lockdown.

Patient-reported outcomes and their relation with iron parameters in HFE haemochromatosis during maintenance therapy: A prospective cohort study.

The standard of care for haemochromatosis is regular phlebotomy in order to maintain low ferritin levels. Many patients report fatigue or joint pain despite serum ferritin within the therapeutic targets. We evaluated Patient-Reported Outcomes, and their relation with iron parameters, in C282Y homozygous patients undergoing maintenance phlebotomy. Patients were prospectively enrolled in a French referral care centre. At each phlebotomy, patients completed a numeric fatigue scale, a joint pain questionnaire and SF-36 Mental Component Score (MCS) and Physical Component Score (PCS). Haemoglobin, iron, TS and ferritin were collected concomitantly. About 701 visits were performed in 259 patients. The median fatigue score was 3/10; 171 (66%) patients reported joint pain. Age and worsening of joint pain were associated with fatigue (p < .0001 for both). Female gender (p < .037), age (p < .003), and a decrease of TS (p=.050) were associated with joint pain. Main features associated with PCS <50 were worsening of joint pain and age (p < .001 for both) and TS <20% (p < .02). Fatigue was independent from iron parameters. The main factor impacting quality of life was joint pain, which was more severe in patients with low TS values. Then, a more precise monitoring of TS should be proposed during haemochromatosis maintenance therapy; while less stringent monitoring of serum ferritin levels could be tested.

Myeloproliferative neoplasms – a global view

Myeloproliferative neoplasms – a global view

20-Year-Old Man With Elevated Liver Tests

20-Year-Old Man With Elevated Liver Tests

Proton Pump Inhibitors and Lower Serum Ferritin Levels in 171 HFE C282Y Homozygotes in the Hemochromatosis and Iron Overload Screening Study

In non-screening hemochromatosis patients with HFE C282Y homozygosity who achieve iron depletion, the proton pump inhibitor (PPI) omeprazole decreases non-heme iron absorption from test meals and decreases maintenance phlebotomy requirements. We sought to determine the effect of taking PPIs and histamine H2 receptor antagonists (H2RAs) on serum ferritin (SF) levels in C282Y homozygotes diagnosed in a screening study. Methods: We compared mean ln SF in 171 homozygotes (60 men, 111 women) who reported taking and not taking PPIs and H2RAs. We performed linear regression on ln post-screening SF using age, sex, reports of taking PPIs and H2RAs, and free thyroxine levels. Results: Eleven homozygotes (6.4%) took PPIs; twelve (6.7%) took H2RAs. Mean ln SF values of male and female homozygotes who took PPIs were ~one-half those of homozygotes without PPI reports, but the differences were not significant. In an initial five-factor regression model, H2RAs and free thyroxine levels were not significant predictors of ln SF. In a final three-factor regression model, taking PPIs was associated with lower ln SF (p=0.0031) after controlling for age and sex. The final model explained 31% of the variance in ln SF. Use of H2RAs was not independently associated with ln SF. Conclusions: Taking PPIs is associated with lower SF levels in HFE C282Y homozygotes diagnosed in screening. Inorganic iron absorption may be decreased in some homozygotes who take PPIs; others who take PPIs may have upper gastrointestinal lesions that lower SF due to blood loss.

Visão atual da hemocromatose hereditária

A hemocromatose hereditária (HH) está relacionada a diversos distúrbios do metabolismo do ferro que ocasionam sua sobrecarga tecidual. A HH clássica está associada às mutações do gene HFE (homozigose para C282Y ou duplo heterozigose para C282Y/H63D), sendo encontrada quase exclusivamente em descendentes do norte Europeu. A hemocromatose hereditária, quando não relacionada ao gene HFE, é causada por mutações de outros genes, recentemente identificados, envolvidos no metabolismo do ferro. Hepcedina é o hormônio regulador do ferro que inibe a ferroportina, proteína exportadora de ferro dos enterócitos e dos macrófagos; um defeito na expressão do gene da hepcedina ou na sua função costuma ser a causa da maioria dos tipos de hemocromatose hereditária. Os alvos acometidos pela HH são órgãos e tecidos - fígado, coração, pâncreas, articulações e pele -, sendo a cirrose e o diabetes melito os sinais tardios da doença em pacientes com expressivo aumento da concentração hepática de ferro. Pacientes com diagnóstico estabelecido de hemocromatose hereditária e sobrecarga de ferro devem ser tratados com flebotomia para a obtenção de depleção do ferro do organismo; em seguida, com flebotomia de manutenção. As causas mais frequentes de morte por hemocromatose hereditária são câncer hepático, cirrose, miocardiopatia e diabete; entretanto, pacientes submetidos à depleção do ferro de maneira satisfatória e antes do desenvolvimento da cirrose ou da diabete podem ter sobrevida normal.

Measurement of urinary hepcidin levels by SELDI-TOF-MS in HFE-hemochromatosis

Introduction Insufficient production of hepcidin, the master regulator of iron metabolism, is recognized as the key pathogenetic feature of HFE-related hereditary hemochromatosis (HH). There is a growing interest in measuring the hepcidin levels, which may improve the diagnosis, prognostic evaluation and clinical management of HH. Nevertheless, few investigative tools are available: an immunodot method for urinary hepcidin developed by a single centre (UCLA), not yet ready for large-scale diffusion, and mass spectrometry (MS) based assays, such as surface-enhanced laser desorption/ionization time-of-flight (SELDI-TOF-MS). The latter is well suited to small peptides like hepcidin, and can rapidly analyze crude samples with high throughput. This study measured urinary hepcidin levels by SELDI-TOF-MS in a large group of HH patients at diagnosis and during treatment, including both C282Y homozygous and C282Y/H63D compound heterozygotes. Methods We used a protocol based on PBSIIc mass spectrometer and Normal Phase chips. Urinary samples from 30 control subjects were compared to those obtained from 80 HH patients (57 C282Y homozygotes, 23 C282Y/H63D compound heterozygotes). Eighteen C282Y homozygotes and 11 C282Y/H63D compound heterozygotes were analyzed at diagnosis, the remainder during maintenance phlebotomy. Results C282Y homozygotes either at diagnosis, or after phlebotomy had significantly lower urinary hepcidin levels than controls ( P < 0.05). C282Y/H63D compound heterozygotes had hepcidin levels at diagnosis higher than controls, while the hepcidin/ferritin ratio was significantly decreased ( P < 0.001) suggesting inadequate hepcidin production. After phlebotomy, mean hepcidin levels in the compound heterozygotes were significantly lower than in controls ( P < 0.001). Samples from 12 randomly selected control subjects were sent to UCLA for duplicate measurement by the immunodot method, yielding a significant correlation (rho = 0.64; P = 0.024). Conclusions This study supports the use of SELDI-TOF-MS for measuring hepcidin levels in research and clinical applications. Our results in phlebotomized patients suggest that the depletion of iron stores may further exacerbate the HFE-related hepcidin defect.

Measurement of Urinary Hepcidin Levels by SELDI-TOF-MS in HFE-Hemochromatosis.

Introduction: An insufficient production of hepcidin, the master regulator of iron metabolism, is recognized as the key pathogenetic feature of HFE-related hereditary hemochromatosis (HH). There is a growing interest in measuring the hepcidin levels, which may improve diagnosis, prognostic evaluation and clinical management of HH. Nevertheless, few investigative tools are available: an immunodot method for urinary hepcidin developed by a single centre (UCLA), not yet ready for large-scale diffusion, and mass spectrometry (MS) based assays, such as surface-enhanced laser desorption/ionization time-of-flight (SELDI-TOF-MS). The latter is well suited to small peptides like hepcidin, and can rapidly analyze crude samples with high throughput. Until now, urinary hepcidin has been measured by SELDI-TOF-MS only in small groups of C282Y homozygous patients, the majority of them under phlebotomy treatment. No data are available on C282Y/H63D compound heterozygotes, that can develop a milder clinical form of HH. This study was aimed to measure urinary hepcidin levels by SELDI-TOF-MS in a large group of HH patients.Methods: We used a protocol based on PBSIIc mass spectromer and Normal Phase chips similar to that recently proven successful for semi-quantitative detection of urinary hepcidin. Urinary samples from 30 control subjects were compared to those obtained from 80 HH patients (57 C282Y homozygotes, 23 C282Y/H63D compound heterozygotes). Eighteen C282Y homozygotes and 11 C282Y/H63D compound heterozygotes were analyzed at diagnosis, the remainder during maintenance phlebotomy (at least 30 days from last phlebotomy).Results: C282Y homozygotes had significantly lower urinary hepcidin levels vs. controls either at diagnosis, or after phlebotomy (P < 0.05). C282Y/H63D compound heterozygotes had hepcidin levels at diagnosis similar to controls, while the hepcidin:ferritin ratio was significantly decreased (P < 0.001) suggesting a relatively inappropriate hepcidin production. Moreover, also in this group means hepcidin levels after phlebotomy were significantly lower than in controls (P < 0.001). Samples from 12 randomly selected control subjects were sent to UCLA for duplicate measurement by the immunodot method, yielding a good correlation (r= 0.77; P<0.0001).Conclusions: SELDI-TOF-MS assay is confirmed to be a potentially useful tool for measuring hepcidin levels in HH. The very low hepcidin levels observed in both genotypes after phlebotomy, may suggest that iron depletion as currently achieved by standard protocols may not be the best therapy from a pathophysiological standpoint.

Long-term phlebotomy with low-iron diet therapy lowers risk of development of hepatocellular carcinoma from chronic hepatitis C

We have previously demonstrated that in patients with chronic hepatitis C (CHC), iron depletion improves serum alanine aminotransferase (ALT) levels as well as hepatic oxidative DNA damage. However, it has not been determined whether continuation of iron depletion therapy for CHC favorably influences its progression to hepatocellular carcinoma (HCC). We conducted a cohort study on biopsy-proven CHC patients with moderate or severe liver fibrosis who failed to respond to previous interferon (IFN) therapy or had conditions for which IFN is contradicted. Patients were divided into two groups: subjects in group A (n = 35) underwent weekly phlebotomy (200 g) until they reached a state of mild iron deficiency, followed by monthly maintenance phlebotomy for 44-144 months (median, 107 months), and they were advised to consume a low-iron diet (5-7 mg iron/day); group B (n = 40) comprised CHC patients who declined to receive iron depletion therapy. In group A, during the maintenance phase, serum ALT levels decreased to less than 60 IU/l in all patients and normalized (<40 IU/l) in 24 patients (69%), whereas in group B no spontaneous decrease in serum ALT occurred. Hepatocarcinogenesis rates in groups A and B were 5.7% and 17.5% at the end of the fifth year, and 8.6% and 39% in the tenth year, respectively. Multivariate analysis revealed that iron depletion therapy significantly lowered the risk of HCC (odds ratio, 0.57) compared with that of untreated patients (P = 0.0337). Long-term iron depletion for CHC patients is a promising modality for lowering the risk of progression to HCC.

Iron Reduction by Phlebotomy Reduces alpha Fetoprotein in Patients with Advanced Chronic Hepatitis C: A Long Term Follow-Up Study

Purpose: Phlebotomy with iron depletion is known to lower transaminases in patients with chronic hepatitis C (CHC). We present the results of long term (up to 9 years) maintenance phlebotomy program in patients with advanced CHC, high AFP and proven cirrhosis or bridging fibrosis. Methods: All 18 patients with CHC failed therapy with PEG-interferon/ ribavirin. Liver biopsy showed cirrhosis in 13 patients and bridging fibrosis in 2 patients. 9 patients were African American. None of the patients demonstrated HFE mutations. Patients underwent phlebotomy with 300 ml to 500 ml removed every two weeks, with the intent to reduce ferritin while maintaining hemoglobin above 11.5. Liver enzymes, ferritin, hemoglobin, AFP and platelets were recorded; we rounded to the nearest time interval with respect to the six-biochemical parameters. The (n) in table 1, for 3 months and 1 year is < 18 because not all patients had labs done at those time points. Signs and symptoms for clinical decompensation were assessed.Table: Average lab values at different time intervals pre and post phlebotomyTable: Clinical characterestics of patients with CryptococcosisResults: Average ALT, AST and AFP at 3 months, year 1, year 3, and year 5 were all significantly lower than baseline (P < 0.01 for all except AST at 5 years, P= 0.025) (Table 1). There was no significant difference seen in platelet count or hemoglobin. AFP dropped in all patients. Pre-phlebotomy AFP was >40 in 7 patients, none of these patients developed hepatoma over an average of 39 months. No patients developed: encephalopathy, refractory ascites, variceal bleeding or hepatoma. Conclusion: In patients with CHC, high ferritin and high AFP, a maintenance phlebotomy program can lower AFP as well as transaminases, and maintain the low AFP long term, without inducing anemia. Despite a very high AFP at the start of the phlebotomy regimen, none of the patients developed a focal mass or clinical evidence of hepatoma or clinical decompensation. Maintenance phlebotomy and sustained iron depletion needs to be evaluated further as a strategy in patients with CHC cirrhosis who have failed anti-viral therapy.

Relationship between Transferrin and Ventilatory Economy during Exercise in Asymptomatic Hereditary Hemochromatosis Subjects

Transferrin, a plasma protein responsible for iron transport, is essential for normal mitochondrial function and can be reduced in hereditary hemochromatosis (HH). Ventilatory economy during exercise is altered in populations with mitochondrial dysfunction. PURPOSE: To examine the relationship between transferrin and ventilatory economy in asymptomatic HH subjects. METHODS: Forty asymptomatic HH subjects (27 male/13 female, mean age: 49.7 ± 9.9 years) on maintenance phlebotomy therapy participated in this study. Each underwent a Bruce exercise test with metabolic analysis and blood analysis to determine transferrin, ferritin and hemoglobin (Hgb) levels, and mean corpuscular volume (MCV). A subgroup of 14 subjects was assessed prior to phlebotomy therapy. Ventilatory economy was assessed by minute ventilation (VE)/oxygen consumption (VO2) at peak exercise. RESULTS: Mean transferrin and VE/VO2 at peak exercise was 205.3 ±31.4 mg/dL and 35.5 ±4.3, respectively. There was a significant negative correlation between VE/VO2 and transferrin level (r = −0.37, p=0.02). The correlation between ferritin, Hgb, MCV and VE/VO2 was not significant (r<0.15, p>0.40). Receiver operating characteristic curve analysis revealed VE/VO2 at peak exercise was effective in discriminating between subjects with a normal (>207 mg/dL) or below normal (≤ 207 mg/dL) transferrin level (area under the curve: 0.69, 95% CI: 0.53-0.86, p=0.034, optimal threshold value:≤/>35.9, sensitivity: 76%, specificity: 58%). The pretreatment subgroup demonstrated a decrease in VE/VO2 at peak exercise as transferrin increased after 6 months of phlebotomy therapy [the mean change in transferrin and VE/VO2 at peak exercise; 27.9 ±21.0 mg/dL, (p=0.001, range: -14.0 - 60.0 mg/dL, increase in 12 of 14 subjects) and −1.0 ± 3.7 (p=0.34, range: −7.5-4.6, decrease in 9 of 14 subjects), respectively]. The correlation between change in transferrin and VE/VO2 from baseline to six months after initiation of phlebotomy was also significant (r = −0.71, p=0.005). CONCLUSION: Our results suggest that ventilatory economy during exercise may be related to transferrin levels in asymptomatic HH subjects. Furthermore, improvement in transferrin level during the course of chronic phlebotomy may improve ventilatory economy during exercise in these subjects.

Iron Overload Manifesting as Apparent Exacerbation of Hepatic Graft-versus-Host Disease after Allogeneic Hematopoietic Stem Cell Transplantation

Iron overload presenting as exacerbation of hepatic graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation has not been previously described. We report 6 patients with established hepatic GVHD in whom iron overload (median serum ferritin, 7231 μg/dL; median transferrin saturation, 77%) resulting from a lifetime median of 20 units of packed red blood cell transfusions was manifested by worsening of liver function. Liver biopsies performed in 4 patients confirmed severe iron overload and also hepatic GVHD. Analysis for the C282Y and H63D hemochromatosis gene mutation was negative for the homozygous state in all 6 patients. Erythropoietin-assisted phlebotomy resulted in normalization of liver function at a median of 7 months and of serum ferritin at a median of 11 months. Immunosuppressive therapy was successfully tapered in all 4 patients who completed the phlebotomy program, and this supported the impression that iron overload, rather than GVHD, was the principal cause of liver dysfunction. At a median follow-up of 50 months (range, 18-76 months) from the transplantation and 25 months (range, 5-36 months) from ferritin normalization, all 4 patients require maintenance phlebotomy. We conclude that iron overload can mimic GVHD exacerbation, thus resulting in unnecessary continuation or intensification of immunosuppressive therapy for GVHD, and that maintenance phlebotomy is necessary after successful iron-reduction therapy.

The Effect of Dietary Factors on Hemochromatosis Disease Expression in C282Y Homozygotes.

Background. Hereditary hemochromatosis (HHC) is a common inherited disorder and the vast majority of cases are associated with HFE gene mutations; about 80% are homozygous for the C282Y HFE mutation. Although homozygosity for C282Y is relatively common among individuals of northern European descent, the penetrance, as measured by clinically relevant iron overload, is low. Both environmental and genetic factors have been implicated in modulating disease expression. Most clinicians and patients attribute at least some of the observed variation to differences in dietary patterns.Methods: 28 C282Y homozygous subjects who had completed de-ironing therapy at our center, and were on stable maintenance phlebotomy treatments, participated in a previously validated dietary survey. We examined the influence of dietary iron, heme iron, fiber, ascorbic acid and alcohol intake on disease expression as measured by liver iron, phlebotomy-mobilized iron and maintenance phlebotomy requirement.Results. We developed a maintenance iron score (Maint Fe) which was the iron in milligrams removed per month by phlebotomy treatments in order to maintain serum ferritin in the 25–75 μG/L range. Maint Fe ranged from 36.8–203 mg/month in our patients (87.8 ± 37.7). Liver iron ranged from 30.5 to 505.4 micromoles per gram dry weight (192.7 ± 123). Phlebotomy-mobilized iron ranged from 2.35–18.03 G (6.43 ± 4.08). The Spearman's Rank Correlation was used to compare dietary parameters with each of the above measures of disease expression. No significant correlation was found.Conclusions. Disease expression varied considerably in our C282Y homozygous subjects as measured by liver iron, phlebotomy-mobilized iron and Maint Fe. The observed variation is not explained by variations in dietary iron, fiber, ascorbic acid or ethanol intake. Our data suggests that other unknown environmental variables or alternatively, modifier genes, may play a role in modulating disease expression in these patients. Contrary to popular belief, dietary variation does not appear to play a major role.

Hemochromatosis,&lt;I&gt; HFE&lt;/I&gt; C282Y Homozygosity, and Bariatric Surgery: Report of Three Cases

Iron absorption is decreased in some individuals who have undergone bariatric surgery. We evaluated measures of iron metabolism and therapeutic phlebotomy in 3 adults with hemochromatosis and HFE C282Y homozygosity who underwent bariatric surgery. 1 male and 1 female had surgery before diagnosis of hemochromatosis (jejuno-ileal bypass and Roux-en-Y gastric bypass, respectively); neither had iron overload. Another man was treated with serial phlebotomy to induce iron depletion; later, he underwent Roux-en-Y gastric bypass. His maintenance phlebotomy requirement for hemochromatosis decreased substantially (on average approximately 1 unit each 71 days before surgery, and approximately 1 unit each 173 days after surgery). None of these patients developed iron deficiency, and none took supplemental iron. Iron absorption is decreased in some patients with hemochromatosis and HFE C282Y homozygosity after bariatric surgery, but their risk of developing iron deficiency may be diminished.

Attitudes about and psychosocial outcomes of HFE genotyping for hemochromatosis.

We examined attitudes regarding genetic testing and psychosocial outcomes of HFE genotyping for hemochromatosis. A total of 87 persons with hemochromatosis (patients) (39 women, 48 men), who underwent HFE genotyping, and 50 persons with hypertension (controls) (22 women, 28 men), who had not undergone HFE genotyping, completed a structured interview in which they reported attitudes about benefits and disadvantages of genetic testing and their understanding of genetics and hemochromatosis. Among patients, adherence to treatment for hemochromatosis was assessed. Controls estimated the likelihood of experiencing several potential positive and negative psychosocial outcomes after a positive genetic test. Patients reported their experience pertinent to these outcomes. Patients received information about hemochromatosis when they were diagnosed, and controls read a brief description of hemochromatosis before answering questions. Patients correctly answered 65% of knowledge questions and controls correctly answered 59%. Most participants believed genetic testing is beneficial and described few negative aspects of testing. Controls expected to experience more anxiety, depression, and anger related to a positive genetic test than was reported by patients (p < 0.001). One patient reported discrimination related to the HFE genotype. Most patients were compliant with the iron depletion and maintenance phases of treatment for hemochromatosis. Race, sex, marital status, income, education, barriers to treatment, and knowledge were not significantly associated with adherence to maintenance phlebotomy. We conclude that HFE genotyping appears to be viewed positively and would be generally accepted were it offered as part of a screening program for hemochromatosis. Persons who have not undergone genetic testing may overestimate their emotional responses to a positive test result. In the present hemochromatosis patients, few reported that HFE genotyping was accompanied by negative psychosocial outcomes.

Long term effects of phlebotomy on biochemical and histological parameters of chronic hepatitis C

OBJECTIVES: There is considerable evidence that iron is a risk factor for liver injury in chronic hepatitis C. Known as iron reduction therapy, phlebotomy reduces serum ALT activity. This effect might continue with maintenance phlebotomy and result in slower progression of liver fibrosis. METHODS: We examined the biochemical parameters and liver histology of patients with chronic hepatitis C treated by maintenance phlebotomy. For biochemical evaluation, 25 patients were treated by initial phlebotomy to reduce serum ferritin levels to 10 ng/ml or less and then observed for 5 yr with maintenance phlebotomy to maintain the iron-deficient state. For histological evaluation, liver biopsies were performed before and after the study period in 13 of the patients. Thirteen patients who were virological nonresponders to interferon alone and had undergone second liver biopsies after more than 3 yr served as histological controls. RESULTS: Serum aminotransferase levels were decreased significantly by initial phlebotomy and remained at the same levels during the study period ( p < 0.05). The grading scores were improved significantly in the study group ( p < 0.05) and unchanged in the controls. The staging scores remained unchanged in the study group but were increased in the controls ( p < 0.005). Disease progression was significantly different between the two groups ( p < 0.05). CONCLUSIONS: These results suggest that phlebotomy with maintenance lowers serum aminotransferase levels, improves liver inflammation, and suppresses the progression of liver fibrosis in chronic hepatitis C.

MCV as a guide to phlebotomy therapy for hemochromatosis.

A multitude of recommendations exist for laboratory assays to monitor the pace and endpoints of phlebotomy therapy for hemochromatosis. All of these recommendations rely on an assessment of storage iron to guide treatment, and none have been prospectively evaluated. Nine consecutive patients underwent serial monitoring of Hb, MCV, transferrin saturation, and ferritin during weekly phlebotomy to deplete iron stores (induction therapy) and less frequent sessions to prevent iron reaccumulation (maintenance therapy). Changes in MCV and Hb were used to guide the pace of phlebotomy over a median of 7 years of follow-up. During induction therapy, the MCV increased transiently because of reticulocytosis and then stabilized for a prolonged period before decreasing more sharply, which reflected iron-limited erythropoiesis. Iron depletion was achieved after a median of 38 phlebotomies and removal of 9.0 g of iron. Maintenance phlebotomy was targeted to maintain the MCV at 5 to 10 percent below prephlebotomy values and the Hb at >13 g per dL. Transferrin saturation fluctuated considerably during treatment, but remained below 35 percent during MCV-guided maintenance therapy. Ferritin values were not useful guides to the pace of phlebotomy. The median maintenance therapy phlebotomy interval was 7.5 weeks (range, 6-16), which corresponded to an average daily iron removal of 35 to 67 microg per kg. Most patients showed evidence of iron reaccumulation at phlebotomy intervals of 8 weeks or more. The MCV is an inexpensive, precise, physiologic indicator of erythropoietic iron availability. When used in conjunction with the Hb, it is a clinically useful guide to the pace of phlebotomy therapy for hemochromatosis.

Phlebotomy increases cadmium uptake in hemochromatosis.

The intestinal absorption of the nephrotoxic environmental pollutant cadmium increases markedly when iron stores are depleted. This may be mediated by an up regulation of the recently identified mucosal transporter DMT1 (Nramp2 or DCT1) for divalent cations. We tested whether the highly increased iron absorption in hereditary hemochromatosis (HH) was accompanied by an enhanced absorption of cadmium and lead. Cadmium and lead in blood and iron status markers were determined in 21 nonsmoking subjects with HH genetically tested for the HFE mutations and in 21 nonsmoking controls matched for age and sex. In subjects with HH on maintenance phlebotomy treatment, blood concentrations of cadmium, but not lead, were significantly higher than in paired controls. There was a strong age-independent positive association between blood cadmium and the number of years of phlebotomy treatment. Blood lead showed a similar but less pronounced consequence of treatment. All HH subjects with lower blood cadmium than the corresponding controls had either no mutation in the HFE gene, were not phlebotomized, or were phlebotomized for only a limited time. Our findings indicate that the treatment rather than the disease increased the cadmium uptake in homozygous HH. Further studies are needed to confirm whether the disease decreased cadmium absorption and whether the absorption was dependent on the genotype.

A survey of phlebotomy among persons with hemochromatosis.

One in 10 whites in the United States is a carrier for hemochromatosis and an estimated 1 in 200 is clinically affected. Early treatment with therapeutic phlebotomy to remove excess iron can prevent associated chronic diseases. However, little information is available on the amount of blood withdrawn or the rates of withdrawal from hemochromatosis patients. The patterns of therapeutic phlebotomy and the magnitude of charges in persons with hemochromatosis were surveyed. Surveys were mailed to persons with hemochromatosis identified by health care providers, blood centers, patient advocacy groups, and the Internet. There were 2362 respondents to the survey from the United States. Thirty-seven percent of respondents reported being voluntary blood donors prior to diagnosis. The mean rate of therapeutic phlebotomy for iron depletion was 2.6 units per month (mean duration, 13 months). The mean rate of maintenance phlebotomy was 0.5 units per month. Therapeutic phlebotomy rates varied by sex, age, reason for diagnosis, and severity of symptoms. Seventy-six percent of respondents reported full or partial insurance coverage of therapeutic phlebotomy charges. Seventy-six percent received therapeutic phlebotomy services in a hospital or physician's office and 30 percent in a blood center. Charges for therapeutic phlebotomy varied by site, with a mean cost of $90 in hospitals and $52 in blood centers. Fifty-four percent of respondents attempted to donate blood after their diagnosis but were excluded. The amount of blood withdrawn from persons with hemochromatosis is substantial. The location where patients received phlebotomy services appears to be influenced by charges and time since diagnosis.