Buzzetti Elena, Kalafateli Maria, Thorburn Douglas, Davidson Brian R, Tsochatzis Emmanuel, Gurusamy Kurinchi Selvan
Sheila Sherlock Liver Centre, Royal Free Hospital and the UCL Institute of Liver and Digestive Health, London, UK.
Department of Surgery, Royal Free Campus, UCL Medical School, Pond Street, London, UK, NW3 2QG.
Cochrane Database Syst Rev. 2017 Mar 8;3(3):CD011647. doi: 10.1002/14651858.CD011647.pub2.
Hereditary haemochromatosis is a genetic disorder related to proteins involved in iron transport, resulting in iron load and deposition of iron in various tissues of the body. This iron overload leads to complications including liver cirrhosis (and related complications such as liver failure and hepatocellular carcinoma), cardiac failure, cardiac arrhythmias, impotence, diabetes, arthritis, and skin pigmentation. Phlebotomy (venesection or 'blood letting') is the currently recommended treatment for hereditary haemochromatosis. The optimal treatment of hereditary haemochromatosis remains controversial.
To assess the comparative benefits and harms of different interventions in the treatment of hereditary haemochromatosis through a network meta-analysis and to generate rankings of the available treatments according to their safety and efficacy. However, we found only one comparison. Therefore, we did not perform the network meta-analysis and we assessed the comparative benefits and harms of different interventions using standard Cochrane methodology.
We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, Science Citation Index Expanded, World Health Organization International Clinical Trials Registry Platform, and randomised clinical trials registers to March 2016 to identify randomised clinical trials on treatments for hereditary haemochromatosis.
We included only randomised clinical trials (irrespective of language, blinding, or publication status) in participants with hereditary haemochromatosis. We excluded trials which included participants who had previously undergone liver transplantation. We considered any of the various interventions compared with each other or with inactive treatment.
We used standard methodological procedures expected by Cochrane. We calculated the odds ratio (OR) and rate ratio with 95% confidence intervals (CI) using both fixed-effect and random-effects models with RevMan 5 based on available-participant analysis. We assessed risk of bias according to Cochrane, controlled risk of random errors with Trial Sequential Analysis, and assessed the quality of the evidence using GRADE.
Three trials with 146 participants met the inclusion criteria of this review. Two parallel group trials with 100 participants provided information on one or more outcomes. The remaining trial was a cross-over trial, with no usable data for analysis. All the trials were at high risk of bias. Overall, all the evidence was of very low quality. All three trials compared erythrocytapheresis (removal of red cells only, instead of whole blood) versus phlebotomy. Two of the trials shared the same first author. The mean or median age in the three trials ranged from 42 to 55 years. None of the trials reported whether the included participants were symptomatic or asymptomatic or a mixture of both. Two trials were conducted in people who were haemochromatosis treatment-naive. The trial that provided most data for this review excluded people with malignancy, heart failure, and serious cardiac arrhythmias. We found no trials assessing iron-chelating agents.Only one of the trials with 38 participants reported no short-term mortality and no serious adverse events at the end of the short-term follow-up (eight months). Two trials reported the proportion of people with adverse events: 10/49 (20.4%) in the erythrocytapheresis group versus 11/51 (21.6%) in the phlebotomy group. One of these two trials provided data on adverse event rates (42.1 events per 100 participants with erythrocytapheresis versus 52.6 events per 100 participants with phlebotomy). There was no evidence of differences in the proportion of people with adverse events and the number of adverse events (serious and non-serious) between the groups (proportion of people with adverse events: OR 0.93, 95% CI 0.36 to 2.43; participants = 100; trials = 2; number of adverse events: rate ratio 0.80, 95% CI 0.32 to 2.03; participants = 38; trial = 1). There was no difference between the groups regarding short-term health-related quality of life (mean difference (MD) 1.00, 95% CI -10.80 to 12.80; participants = 38; trials = 1). This outcome was measured using EQ-VAS (range: 0 to 100 where a higher score indicates better health-related quality of life). None of the trials reported mortality beyond one year, health-related quality of life beyond one year, liver transplantation, decompensated liver disease, cirrhosis, hepatocellular carcinoma, diabetes, or cardiovascular complications during the long-term follow-up.The two trials that provided data for this review were funded by parties with no vested interest in the results; the source of funding of the third trial was not reported.
AUTHORS' CONCLUSIONS: There is currently insufficient evidence to determine whether erythrocytapheresis is beneficial or harmful compared with phlebotomy. Phlebotomy has less equipment requirements and remains the treatment of choice in people with hereditary haemochromatosis who require blood letting in some form. However, it should be noted that there is no evidence from randomised clinical trials that blood letting in any form is beneficial in people with hereditary haemochromatosis. Having said this, a trial including no treatment is unlikely to be conducted. Future trials should compare different frequencies of phlebotomy and erythrocytapheresis versus phlebotomy with and without different iron-chelating agents compared with each other, and with placebo. Such trials should include long-term follow-up of participants (e.g. using national record linkage databases) to determine whether treatments are beneficial or harmful in terms of clinical outcomes such as deaths, health-related quality of life, liver damage and its consequences, heart damage and its consequences, and other outcomes that are of importance to people with hereditary haemochromatosis.
遗传性血色素沉着症是一种与铁转运相关蛋白质有关的遗传性疾病，会导致铁负荷增加并在人体各个组织中沉积。这种铁过载会引发多种并发症，包括肝硬化（以及诸如肝衰竭和肝细胞癌等相关并发症）、心力衰竭、心律失常、阳痿、糖尿病、关节炎和皮肤色素沉着。放血疗法（静脉切开术或“放血”）是目前推荐用于治疗遗传性血色素沉着症的方法。遗传性血色素沉着症的最佳治疗方法仍存在争议。
通过网状Meta分析评估不同干预措施在治疗遗传性血色素沉着症中的相对益处和危害，并根据安全性和有效性对现有治疗方法进行排序。然而，我们仅发现了一项比较研究。因此，我们未进行网状Meta分析，而是使用标准的Cochrane方法评估不同干预措施的相对益处和危害。
我们检索了Cochrane对照试验中心注册库（CENTRAL）、MEDLINE、Embase、科学引文索引扩展版、世界卫生组织国际临床试验注册平台以及截至2016年3月的随机临床试验注册库，以识别关于遗传性血色素沉着症治疗的随机临床试验。
我们仅纳入了针对遗传性血色素沉着症患者的随机临床试验（无论语言、是否设盲或发表状态如何）。我们排除了纳入了此前接受过肝移植患者的试验。我们考虑了相互比较或与无活性治疗进行比较的任何一种干预措施。
我们采用了Cochrane预期的标准方法程序。我们使用RevMan 5，基于现有参与者分析，通过固定效应模型和随机效应模型计算了比值比（OR）和率比，并给出95%置信区间（CI）。我们根据Cochrane评估偏倚风险，使用试验序贯分析控制随机误差，并使用GRADE评估证据质量。
三项共146名参与者的试验符合本综述的纳入标准。两项共100名参与者的平行组试验提供了一项或多项结局的信息。其余试验为交叉试验，无可用数据进行分析。所有试验均存在较高偏倚风险。总体而言，所有证据质量都非常低。所有三项试验均比较了红细胞单采术（仅去除红细胞，而非全血）与放血疗法。其中两项试验的第一作者相同。三项试验中的平均或中位数年龄在42至55岁之间。没有一项试验报告纳入的参与者是有症状的、无症状的还是两者皆有。两项试验是在未接受过血色素沉着症治疗的人群中进行的。为本综述提供最多数据的试验排除了患有恶性肿瘤、心力衰竭和严重心律失常的患者。我们未发现评估铁螯合剂的试验。只有一项38名参与者的试验报告在短期随访（八个月）结束时无短期死亡率和严重不良事件。两项试验报告了不良事件发生的比例：红细胞单采术组为10/49（20.4%），放血疗法组为11/51（21.6%）。这两项试验中的一项提供了不良事件发生率的数据（红细胞单采术组每100名参与者中有42.1起事件，放血疗法组每100名参与者中有52.6起事件）。两组之间在不良事件发生比例和不良事件数量（严重和非严重）方面没有差异的证据（不良事件发生比例：OR 0.93，95%CI 0.36至2.43；参与者 = 100；试验 = 2；不良事件数量：率比0.80，95%CI 0.32至2.03；参与者 = 38；试验 = 1）。两组在短期健康相关生活质量方面没有差异（平均差（MD）1.00，95%CI -10.80至12.80；参与者 = 38；试验 = 1）。该结局使用EQ-VAS进行测量（范围：从0至100，分数越高表明健康相关生活质量越好）。没有一项试验报告一年后的死亡率、一年后的健康相关生活质量、肝移植、失代偿性肝病、肝硬化、肝细胞癌、糖尿病或长期随访期间的心脑血管并发症。为本综述提供数据的两项试验由对结果无既得利益的机构资助；第三项试验的资金来源未报告。
目前尚无足够证据确定与放血疗法相比，红细胞单采术是有益还是有害。放血疗法对设备要求较低，对于需要某种形式放血的遗传性血色素沉着症患者仍是首选治疗方法。然而，应当指出，随机临床试验中没有证据表明任何形式的放血对遗传性血色素沉着症患者有益。话虽如此，不太可能进行一项不进行治疗的试验。未来的试验应比较放血疗法和红细胞单采术的不同频率，以及放血疗法联合或不联合不同铁螯合剂并相互比较，以及与安慰剂比较。此类试验应包括对参与者的长期随访（例如使用国家记录链接数据库），以确定就死亡、健康相关生活质量、肝损伤及其后果、心脏损伤及其后果以及对遗传性血色素沉着症患者重要的其他结局等临床结局而言，治疗方法是有益还是有害。
