Systematic Review of the Clinical Outcomes of Iron Reduction in Hereditary Hemochromatosis

Abstract

Supported by an Academic Clinical Fellow by the National Institute of Health Research and by a Wellcome Trust Ph.D. Training Fellowship for Clinicians (211042/Z/18/Z to T.C.). Potential conflict of interest: Dr. Ryan consults for Alnylam and Bond. Hereditary hemochromatosis (HH) is a relatively common autosomal recessive disorder of iron regulation that results in iron overload and its deposition in multiple organs. Complications include liver cirrhosis and hepatocellular carcinoma (HCC), as well as wide‐ranging extrahepatic manifestations including diabetes, cardiovascular disease, arthritis, hypogonadism, and osteoporosis (Fig. 1).(1)FIG. 1: Organs affected by HH. The hepatic and extrahepatic complications of HH are multisystemic and wide‐ranging.Despite significant advances in our understanding of iron regulation, the treatment of iron‐overload conditions has remained relatively static and is largely founded on historical convention. Phlebotomy remains the mainstay of treatment for HH, even in the absence of robust data from randomized trials, and although other options such as iron chelation and erythrocytapheresis are used in a minority, the ideal treatment modality and regimen remains unclear. A lack of high‐quality trial design has restricted our understanding of the clinical outcomes of iron reduction therapy, and the present data are conflicting and discordant. This absence of robust data was highlighted by a recent Cochrane meta‐analysis, which attempted to collate evidence on the benefits and harms of iron reduction therapy in HH but found only two papers with usable data, precluding any consequential conclusions from being drawn.(2) Our narrative review aims to address this deficiency in the literature, with the recognition that a systematic review or meta‐analysis is not currently feasible to perform, given the dearth of high‐quality evidence. The numerous multisystem effects of iron reduction therapy in HH are outlined, citing the best available evidence where possible. Materials and Methods The study protocol was registered on the PROSPERO international prospective register of systematic reviews(3) and carried out in accordance with PRISMA (Preferred Reporting Items for Systematic Reviews and Meta‐analyses) guidelines. MEDLINE and EMBASE were searched, studies screened, and data extracted and summarized in the PRISMA diagram (Table 1 and Fig. 2). Table 1 - Search Summary Database Interface Coverage Date Hits Embase OvidSP 1974 to May 30, 2018 May 31, 2018 1,680 Ovid MEDLINE (Epub ahead of print, in process and other nonindexed citations, Ovid MEDLINE Daily, Ovid MEDLINE, and Versions) OvidSP 1946 to May 30, 2018 May 31, 2018 1,006 Total: 2,686 Duplicates: 663 Final total: 2,023 We searched EMBASE (Ovid) (1974 to May 2018) and MEDLINE (Ovid) (1946 to May 2018) on April 4, 2018. Articles from 1950 onward were included, and there were no language restrictions. The 2,023 records were initially returned and subsequently screened. FIG. 2: PRISMA diagram outlining the search strategy. A total of 2,023 studies were returned from a search of MEDLINE and EMBASE. These were independently screened and assessed for eligibility by two authors, with 24 studies included for review.Data were extracted by two authors independently (A.P. and T.C.) into a standardized proforma. We recorded information on the nature of the study (study design, region where study was performed), participant demographics (age, percent male, hemochromatosis diagnosis), iron reduction therapy regimens, and clinical outcomes on mortality, cirrhosis, liver fibrosis, portal hypertension, HCC, liver transplant, arthritis, joint replacement, diabetes, cardiovascular disease, heart failure, erectile dysfunction, hypogonadism, quality of life, fatigue, biochemical iron indices, and liver function tests (Table 2). Table 2 - Included Studies and Their Reported Outcomes (Marked as “Y”) Paper No. Reported Data Mortality Cirrhosis HCC Diabetes Cardiovascular Disease Adverse Events Quality of Life Fatigue Arthralgia ED Biochemical Markers Dymock et al. 1972 115 .. .. Y .. .. .. .. .. .. .. Darnis 1972 30 Y .. .. Y .. .. .. .. Y Y .. Niederau et al. 1985 163 Y Y Y Y .. .. .. Y Y Y .. Conte et al. 1986 67 Y .. Y Y .. .. .. .. Y .. .. Adams et al. 1991 85 Y Y Y .. .. .. .. .. .. .. .. Fracanzani et al. 1995 120 Y Y .. .. .. .. .. .. .. .. .. McDonnell et al. 1999 2,851 .. .. .. .. Y .. Y Y Y Y .. Milman et al. 2001 158 Y Y .. Y .. .. .. Y .. .. Y Falize et al. 2006 36 .. Y .. .. .. .. .. .. .. .. .. Phatak et al. 2010 49 .. .. .. .. .. Y .. .. .. .. .. Harty et al. 2011 203 .. .. .. .. .. .. .. .. Y .. .. Brissot et al. 2011 210 .. .. .. .. .. Y .. .. .. .. .. Rehácek et al. 2012 22 .. .. .. .. .. Y .. .. .. .. .. Rombout‐Sestrienkova et al. 2012 38 .. .. .. .. .. Y Y .. .. .. Y Parra Salinas et al. 2012 39 .. .. .. .. .. Y .. .. .. .. .. Lukic et al. 2013 29 .. .. .. .. .. .. .. .. .. .. Y Sundic et al. 2014 62 .. .. .. .. .. Y .. .. .. .. Y Bardou‐Jacquet et al. 2015 1,085 Y Y .. .. Y .. .. .. .. .. .. Koutsavlis et al. 2016 167 .. .. .. .. .. .. .. .. Y .. .. Brückl et al. 2017 20 .. .. .. .. .. Y .. .. .. .. .. Ong et al. 2017 104 .. Y .. .. .. Y Y Y Y .. Y Chayanupatkul et al. 2017 196 .. .. Y .. .. .. .. .. .. .. .. Jabbour et al. 2018 39 .. Y .. .. .. .. .. .. .. .. .. Bardou‐Jacquet et al. 2019 106 .. Y Y .. .. .. .. .. .. .. .. Included studies and their reported outcomes (marked as “Y”). Quality Assessment of Included Studies Two authors independently assessed the risk of bias in the included studies (A.P. and T.C.). The ROBINS‐I tool(4) or the Cochrane risk of bias tool(5) were used to evaluate the nonrandomized and randomized studies, respectively. Disagreements were resolved by discussion, and a consensus decision was made. Results Cohort Characteristics Of the 64 studies identified by the search, 24 studies from between 1972 and 2018 were included in the final cohort (5,994 patients in total) (Table 2). The remaining studies were excluded due to reporting on fewer than 20 participants (n = 15), duplication (n = 5), lack of outcome data (n = 15), inclusion of non‐hemochromatosis patients (n = 4), and having not yet been performed (n = 1). One included abstract was subsequently published as a full article in 2019; therefore, the comprehensive version was included in our analysis. Most of the studies (n = 20, 83%) were retrospective cohort studies, whereas three (13%) were randomized controlled trials (RCTs) and one (4 %) was a nonrandomized trial. The published data were skewed toward reports from Western countries, with 16 papers from Western Europe (67%), five from North America (21%), two from Eastern Europe (10%), and one from Australasia (4%). The mean age of individuals, recorded in 14 studies, was 51 years (95% confidence interval [CI] 48‐53 years old), and the mean percentage of male participants, recorded in 18 studies, was 70% (confidence interval 64%‐76%). Fifteen studies (63%, 5,197 participants) included patients with HH (either confirmed by genotyping or unspecified), four studies (17%, 383 participants) included those with HH with fibrosis or cirrhosis, and five studies (21%, 420 participants) included those with HH and deranged iron indices. The study intervention was venesection/phlebotomy in 18 studies (75%, 5,737 participants), erythrocytapheresis in four studies (17%, 185 participants), iron chelation in one study (4%, 49 participants), and phlebotomy and erythrocytapheresis in one study (4%, 49 participants). Quality of Evidence The quality‐of‐evidence assessments for the included studies are given in Table 3. Of the three RCTs, one was judged to be of good quality, one of fair quality, and one of poor quality. Of the 21 nonrandomized studies of intervention, 19 (90%) had a serious risk of bias, and two studies had a moderate risk. None of the included studies had a low risk of bias. Table 3 - Quality of Evidence of Included Studies Paper Quality Assessment Tool Risk of Bias/Assessment Dymock et al. 1972 Robins‐I Serious Darnis 1972 Robins‐I Serious Niederau et al. 1985 Robins‐I Moderate Conte et al. 1986 Robins‐I Serious Adams et al. 1991 Robins‐I Serious Fracanzani et al. 1995 Robins‐I Serious McDonnell et al. 1999 Robins‐I Serious Milman et al. 2001 Robins‐I Serious Falize et al. 2006 Robins‐I Serious Phatak et al. 2010 Robins‐I Serious Harty et al. 2011 Robins‐I Serious Brissot et al. 2011 Robins‐I Serious Rehácek et al. 2012 Robins‐I Serious Rombout‐Sestrienkova et al. 2012 Cochrane Risk of Bias Poor Parra Salinas et al. 2012 Robins‐I Serious Lukic et al. 2013 Robins‐I Serious Sundic et al. 2014 Cochrane Risk of Bias Fair Bardou‐Jacquet et al. 2015 Robins‐I Moderate Koutsavlis et al. 2016 Robins‐I Serious Brückl et al. 2017 Robins‐I Serious Ong et al. 2017 Cochrane Risk of Bias Good Chayanupatkul et al. 2017 Robins‐I Serious Jabbour et al. 2018 Robins‐I Serious Bardou‐Jacquet et al. 2019 Robins‐I Serious Mortality Our knowledge of the natural history of HH has been derived from a retrospective follow‐up of longitudinal cohorts, and survival has been found to be the same as the general population, provided that treatment is initiated in time.(6) In our search, seven reported on mortality in patients with HH (n = 1,708, mean age 50.2 years, mean follow‐up of 7.7 years (range 0‐31).(7–13) All included patients were diagnosed as having primary HH on clinical grounds, with five of the seven studies predating HH genotyping, but were heterogeneous with respect to exact venesection procedure as well as to the presence of HH complications. Crude mean overall survival was 63.7% (SD = 30.1) (four studies, n = 436, mean follow‐up of 7.5 years, range 0‐31 years),(7,10,12,13) and cumulative survival after follow‐up was reported to be between 61% and 92% at 5 years, 61% and 81% at 10 years, and 49% and 71% at 20 years (three studies, n = 315).(7,9,13) Even in the absence of controlled trials, there is some evidence that survival of patients with HH has improved over time, coinciding with iron depletion therapy becoming the cornerstone of HH treatment. One study of patients with HH diagnosed between 1948 and 1985 found that the standardized mortality ratio (SMR) was significantly raised at 3.68 (3.07‐4.39). The study also found that 10‐year cumulative survival had increased within this time period (38% if diagnosed between 1948 and 1968 vs. 48% between 1969 and 1979 and 58% between 1980 and 1985).(12) A more recent study of patients diagnosed between 1996 and 2010 calculated the SMR as 0.94 (0.71‐1.22), indicating that overall survival of HH might not differ from the general population in contemporary cohorts.(8) Regarding the effects of treatment, a single study reported higher cumulative survival in patients who had been with those who not treatment vs. at 1 vs. at 5 patients who iron depletion or were had significantly higher cumulative survival with those who not at 10 years vs. and at 20 years vs. and 70% vs. with of 24 years and 16 5 years (Fig. in patients with HH to phlebotomy treatment. who were (n = were with patients (n = The in survival between and patients is significant with from Milman et al. of survival on the of treatment patients who had a or of had overall survival and than those in between and had been performed overall In patients in a of iron had been SMR was low but in patients with over 10 of iron mortality was no than the general population studies on the mortality of patients with studies the between cirrhosis and mortality in of patients with HH (n = of studies reported that cumulative survival was significantly in patients with HH who had cirrhosis to those The of reported SMR of mortality in 1,085 patients with HH, with liver fibrosis liver fibrosis and cirrhosis and found to be significantly higher in patients with cirrhosis The SMR for liver of and from liver were also significantly These data cirrhosis as being with higher mortality in of only one study has iron depletion survival and found no data that iron depletion therapy a on survival in is to as and are not and cirrhosis and its are complications of HH, and where survival is reports the between iron overload indices, iron depletion therapy, and the presence of fibrosis and A that liver in a HH cohort that included and patients found that liver fibrosis improved phlebotomy in 19 patients who not and that fibrosis was in of 19 evidence also that are with an increased risk of and that cirrhosis is significantly higher patients with phlebotomy treatment vs. = the of is and the evidence is to reports assessed the of iron depletion on the of liver cirrhosis or fibrosis by and liver found evidence of of fibrosis iron depletion in a of The and recent study of patients with HH follow‐up of reported fibrosis in of 106 patients with also improved in of the patients in this cohort with cirrhosis at age at the presence of and higher were with of fibrosis to than evidence the benefits of iron depletion in of cirrhosis a study that found overall survival was higher in patients with HH cirrhosis than patients with cirrhosis vs. and that only 1 with HH cirrhosis had study assessed of fibrosis in patients with HH with moderate iron overload randomized to erythrocytapheresis or The mean in of liver was between treatment, but the of liver in the treatment and increased in the = These data that iron depletion to of fibrosis and cirrhosis in a of patients with HH, but to be to be to a which might from treatment and of fibrosis is with clinical benefits including HCC is a of HH, including in the absence of cirrhosis, although those with cirrhosis an to increased papers (n = from Europe and the on the between HCC and treatment, with One study reported of were in that were of whereas found that were from an of study found that fibrosis was with HCC risk (Fig. a recent abstract found no between phlebotomy treatment and risk of HCC ratio liver to fibrosis of primary liver to fibrosis at liver was to years of low of patients at risk with from Bardou‐Jacquet et al. although the of the risk of HCC of the for treatment, the evidence that phlebotomy has any on the of HCC in hemochromatosis patients is Diabetes The of in has been over the largely due to with one study reporting a of in In the 2019 including only male had a significantly increased of 1 or 2 included studies (n = on in with four published One study (n = in or venesection and after venesection in those with hemochromatosis and cirrhosis, and found there was no significant in 21 patients a significant reduction in patients and an in the of at in patients that the of 1 not significantly differ between and one study found that the clinical of improved in of and of patients with after iron although clinical in and also that the of in of those iron In although is that phlebotomy to some the available evidence is and from Cardiovascular Disease The of in HH has been reported as as although in the was with significantly of in but not studies on cardiovascular in hemochromatosis (n = but only two reported on outcomes treatment. In a study (n = of the patients who of of heart reported an in treatment, reported a of The of this in the of the effects of treatment on the heart is given that the of heart be to be a of and be used as a for cardiovascular A retrospective of (n = found that patients with between and had a cardiovascular mortality than the general population patients not a higher mortality from liver there is available evidence on the effects of treatment on cardiovascular disease, that to and there are that treatment cardiovascular mortality, there are data to any Adverse Events were studies (n = that on or effects with treatment of HH. The studies to treatment with reporting being in Studies patients phlebotomy treatment reported effects including of and in of with being studies reporting on erythrocytapheresis found that to of had but also and of erythrocytapheresis phlebotomy found no significant in the of of vs. a trial also found between the two in of their phlebotomy in their erythrocytapheresis A single a trial of on the effects with iron chelation therapy including and that of the with phlebotomy and erythrocytapheresis are to the effects of and is in clinical Quality of Life and Health The 2017 HH in which patients with hemochromatosis from the on their found that has been with poor quality of and studies (n = of which two were (n = provided In a study of patients with reported improved with The two RCTs, one with phlebotomy erythrocytapheresis and in erythrocytapheresis found no significant are within the data on the of treatment to quality of and and to that treatment has a Fatigue of the included studies in this (n = on the effects of treatment on One controlled trial found the mean in the Fatigue was in the erythrocytapheresis with to = the cohort studies, one found that improved in after iron found no significant in and A study with of patients reporting improved These data the that treatment with phlebotomy or erythrocytapheresis a on of Arthralgia is the reported and and are independently with included studies (n = in with a reported in to of patients although one study reported a of in found no significant to of treatment erythrocytapheresis or results a for phlebotomy in a also a of their treatment, to any are with a of erectile and and of studies (n = cohort on reported on ED and in HH. found a of ED in to treatment, although one a in results a for phlebotomy in of there remains the that treatment Biochemical Markers of Disease and is evidence on the of liver as a for HH. The of liver in patients with HH had highlighted as a with clinical studies having found in of patients with the of liver function tests is the for and an of HH. more recent evidence found that the of being a increased as the and the lack of by iron deposition in HH in with other liver papers (n = including two and one randomized biochemical in HH. One found that iron and liver improved in a percentage of phlebotomy cohorts, and two studies found an in in to Regarding iron an found that the in and was significant with erythrocytapheresis with an abstract 29 patients reported that the from to in a and from to in an phlebotomy with two reported no significant in their on iron or These results that phlebotomy and erythrocytapheresis to iron and liver function indices, the reduction of on the although is one modality is more than the This is the review to collate and results from studies the and outcomes in patients with HH iron reduction reduction with studies to on been to outcomes in a of although in the quality of available evidence to attempted meta‐analysis this on the of found only two randomized clinical trials with usable data, precluding any consequential to be made. phlebotomy is a treatment in HH, its effects been the design of controlled studies, the effects of treatment to the of phlebotomy largely on the available data and an evidence to its remains In our to this this found there are in the available results also been The Cochrane study found one trial that reported on mortality, no in the phlebotomy or erythrocytapheresis over and included no studies that reported on mortality 1 of the studies included in our review a survival with although there are numerous in the evidence the of was not controlled for in of the The studies that those a of venesection to iron depletion had a higher mortality a population with iron the survival for patients with HH was to that of an population, whereas the patients who from HCC had the of the mortality in those who treatment those with or at the time of This is by the that the follow‐up time within the the of was 1 with years in the the of study found that patients low of iron by phlebotomy had overall mortality than the general population, although this a One study found that survival was significantly in those with treatment those who had phlebotomy and the included those with or disease, including those who venesection but not is that two studies included patients who were diagnosed the of therefore, their include not only patients with but a higher with a of study patients with HH to a of those with liver and treatment the in the to that phlebotomy mortality, but in those who a biochemical to treatment and iron depletion within a time to liver fibrosis, phlebotomy of the evidence is two studies a of with data from an a reduction in of fibrosis with treatment but be that there was no fibrosis in the cohort at Regarding liver cirrhosis, one study reported a higher of cirrhosis in patients with treatment be by the presence of cirrhosis and be to the effects of One that of HCC were found in and in those that were of that phlebotomy not HCC in the the that those with HCC were found to the of iron a for is that those with at are at a risk of found that the of HCC were from the of with found no serious in those phlebotomy or there was also no significant in quality of with Our on the effects of treatment on extrahepatic are and were in the outcomes with to diabetes, and fatigue, and of the conflicting reports on the effects of iron reduction therapy on joint is by the heterogeneous nature of the included cohorts, given the of in HH. The in outcomes toward a lack of robust with The studies are retrospective cohort studies, with and are largely for the presence of cirrhosis, or of the 21 (90%) included nonrandomized studies of intervention had a serious risk of bias with the ROBINS‐I and of the studies used treatment that within studies, between studies, which is significant given that iron reduction therapy is not of the data on the effects of treatment from retrospective which are by and A a significant of the studies, as were performed the of is the of iron overload being diagnosed as HH. The was identified as as with for a in this being for of this the of HH has largely been to there was a on that a significant of the of the included studies were diagnosed the of there is the that of iron overload were diagnosed as HH. This is given that cirrhosis with iron overload is more common than cirrhosis to HH, and that the two are These a bias to reported outcomes in papers and be in the of confirmed HH. to the available evidence is the of liver in of the included, and to of study participants were to cirrhosis in one to a more HH population with Even with bias, studies the of cirrhosis to be in with HH, with of also having to their liver Cirrhosis due to the effects of iron overload was in only has also been reported that the of liver to be of male of on data from prospective cohort our on the of treatment in those with disease, which is given that patients are more in clinical the data in this although a of treatment, which be (Fig. The dearth of robust evidence is to in the and that phlebotomy as the are on the for and the clinical trials evidence for clinical of the phlebotomy remains the mainstay of treatment for HH and to be given the even in the absence of evidence its by phlebotomy treatment. The benefits of phlebotomy treatment in HH are and were for the study and was for the and were for the for and the data, and the All authors the to

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