Waqar M, El Asmar ML, Gray D, Immanuel A, Shearman J, Ramage JK. Quality of life in hereditary haemochromatosis: Scoping review of symptoms and initial ranking of symptoms by a special interest group. World J Hepatol 2025; 17(10): 105799 [PMID: 41179731 DOI: 10.4254/wjh.v17.i10.105799]
Corresponding Author of This Article
Marie Line El Asmar, MD, Department of Gastroenterology, Hampshire Hospitals NHS Foundation Trust, Aldermaston Road, Basingstoke RG24 9NA, Hampshire, United Kingdom. marieline.elasmar@hhft.nhs.uk
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This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Oct 27, 2025 (publication date) through Nov 16, 2025
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World Journal of Hepatology
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Waqar M, El Asmar ML, Gray D, Immanuel A, Shearman J, Ramage JK. Quality of life in hereditary haemochromatosis: Scoping review of symptoms and initial ranking of symptoms by a special interest group. World J Hepatol 2025; 17(10): 105799 [PMID: 41179731 DOI: 10.4254/wjh.v17.i10.105799]
Muhammad Waqar, Marie Line El Asmar, Anita Immanuel, Department of Gastroenterology, Hampshire Hospitals NHS Foundation Trust, Basingstoke RG24 9NA, United Kingdom
Debra Gray, Department of Psychology, University of Winchester, Winchester SO22 4NR, United Kingdom
Jeremy Shearman, Department of Gastroenterology, South Warwickshire University Foundation Trust, Warwick CV21 3SR, Warwickshire, United Kingdom
John K Ramage, Neuroendocrine Tumour Unit, King's College Hospital, London SE5 9RS, United Kingdom
Author contributions: Waqar M contributed to formal analysis, investigation, methodology, project administration, visualisation, and writing-review and editing of the manuscript; El Asmar ML contributed to the methodology, project administration, visualisation, and writing-original draft; Gray D contributed to the conceptualisation and data curation; Immanuel A assisted with the writing-review and editing; Shearman J provided supervision and contributed to the writing-review and editing; Ramage JK contributed to the conceptualisation, formal analysis, methodology, project administration, supervision, visualisation, and writing-review and editing; all authors have read and agreed to the published version of the manuscript.
Conflict-of-interest statement: The authors have no competing interests to declare.
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Marie Line El Asmar, MD, Department of Gastroenterology, Hampshire Hospitals NHS Foundation Trust, Aldermaston Road, Basingstoke RG24 9NA, Hampshire, United Kingdom. marieline.elasmar@hhft.nhs.uk
Received: February 7, 2025 Revised: April 12, 2025 Accepted: September 24, 2025 Published online: October 27, 2025 Processing time: 262 Days and 19.9 Hours
Abstract
Haemochromatosis is the most common genetic condition among people of European descent, resulting in iron overload and multi-organ dysfunction. Despite early detection and treatment advances, affected individuals experience significant morbidity impacting their quality of life (QoL). To scope the literature for QoL issues and rank them in order of relevance by professional bodies. A literature search was conducted using PubMed, EMBASE, and MEDLINE in addition to a grey literature search against the eligibility criteria up to July 2023. Inclusion criteria included original articles with data concerning symptoms and QoL in patients with haemochromatosis. Nineteen issues were identified from 47 articles and scored by a haemochromatosis special interest group using a scale of 1 to 10 (10 = highest importance). Mean scores were then calculated for each issue. Fatigue, joint pain and sexual issues were key factors associated with impaired QoL. The least relevant were weight changes and abdominal pain. Other issues raised were anxiety, the development of diabetes, and concerns about genetics and family. This is the first scoping review examining common symptoms affecting QoL of patients with hereditary haemochromatosis. Further studies, including patient interviews and a randomised controlled trial, will inform a validated QoL questionnaire.
Core Tip: Haemochromatosis presents with diverse symptoms that significantly impact patients’ daily lives. Despite this, no validated tool currently exists to assess quality of life (QoL) in this population. We conducted a scoping review of 47 articles to address this gap, identifying 19 QoL-related issues and symptoms. These were subsequently ranked by a haemochromatosis special interest group based on their importance and relevance. The findings highlight key symptoms affecting haemochromatosis patients’ QoL from literature and professional perspectives and will help inform the development of a standardised questionnaire for evaluating QoL in patients with hereditary haemochromatosis.
Citation: Waqar M, El Asmar ML, Gray D, Immanuel A, Shearman J, Ramage JK. Quality of life in hereditary haemochromatosis: Scoping review of symptoms and initial ranking of symptoms by a special interest group. World J Hepatol 2025; 17(10): 105799
Haemochromatosis is the most common genetic condition in people of European descent, with as many as 400000 people in the United Kingdom being at risk of iron overload and harm[1]. A defect in the HFE gene[2,3] results in reduced production of the iron-mediating hormone hepcidin, leading, in turn, to increased iron absorption. Excess iron deposits in multiple organs may cause a range of end-organ dysfunctions and pathology. The most affected organs include the liver, joints and pancreas, although involvement of other organs can also be significant, including the skin, heart, pituitary and other endocrine organs[4].
The first systematic description of the condition, detailing the full range of affected organs, was by the physician Sheldon[5] in 1935. At that time, the condition presented with advanced liver disease and diabetes and in most cases, the condition was quite rapidly fatal. On the premise that the excess iron causing the disease was derived from blood, physicians started to treat the condition with venesection (therapeutic phlebotomy). This treatment was initially proven to be well-tolerated, and a subsequent retrospective cohort study demonstrated that early treatment could prevent organ damage and normalise life expectancy compared to age and sex-matched controls[6,7].
Early detection of haemochromatosis has been hugely facilitated by identifying the HFE gene and the fact that over 90% of affected individuals in the United Kingdom share a common genotype-homozygosity of the pC282Y genetic variant[8]. However, more recent evidence derived from the United Kingdom Biobank suggests that individuals carrying this genetic profile still experience an excess of morbidity, which appears to become more pronounced with age[9]. In addition to documenting a persistent burden of liver disease and liver cancer, these studies have emphasized a significant incidence of joint and central nervous system sequelae[9-11].
Whilst there is now a broad recognition that haemochromatosis causes a wide range of significant morbidities, much less is known about how the condition affects the quality of life (QoL) and, critically, whether this and the various end-organ pathologies can be improved by treatment. Historical descriptions of haemochromatosis, such as that provided by Sheldon[5], reported abdominal pain and pigmentation to be key triggers leading to a diagnosis. However, more recent practice experience is that the earlier diagnosis is more subtle, with fatigue and joint pain being more prevalent. An additional challenge is presented by an increasing number of individuals with modest or no iron loading who are now identified by family (cascade) screening whereby testing of first-degree relatives of an affected individual can detect others at risk through sharing the same genotype (pC282Y homozygosity).
QoL is now a widely used and important concept in education, medicine, psychology and health sciences[12,13]. In recognition of the importance of QoL as a healthcare metric, there now exist several validated measures/instruments for measuring and monitoring this. These have resulted in QoL now being considered a hard outcome in clinical research studies and is strongly recommended as an endpoint in clinical trials and for which there are rigorous reporting guidelines (CONSORT-PRO statement)[14].
In haemochromatosis, the range of co-morbidities is reasonably well mapped, but the impact of the disease on symptoms and patients’ QoL as measured by accepted techniques remains less well studied.
This was a review of the existing literature reporting QoL in haemochromatosis. The aim was to understand the full spectrum of symptoms and life impact of haemochromatosis as it presents to 21st century clinicians. This is a key starting point in establishing how much of the disease burden is purely related to the extent of iron overload and, ultimately, what improvement in QoL can be expected from a treatment (venesection) that was initially introduced into clinical practice primarily to improve prognosis.
LITERATURE SEARCH
Study design and eligibility criteria
A scoping review of the existing literature was performed to examine the most common symptoms and QoL issues faced by patients with hereditary haemochromatosis. The inclusion criteria included original articles that presented data concerning symptoms and QoL in patients with haemochromatosis. Review articles, case reports, and those that did not present original data on symptoms or QoL or focused on secondary haemochromatosis were excluded.
Search strategy
A literature search was conducted using PubMed, EMBASE, and MEDLINE in addition to a grey literature search against the eligibility criteria from inception up to July 2023. EMBASE results were limited to journal articles only. The following search terms and subject headings under the following categories were used to identify relevant literature: 'Haemochromatosis' OR 'hemochromatosis' OR 'C282Y' AND ('liver' OR 'hepatic' AND 'venesection' OR 'venesections') OR ('lifestyle factors' AND 'iron') OR ('clinical presentation' AND 'symptoms') OR 'phlebotomy' OR 'quality of life'. The full search strategy across all databases can be found in Supplementary material appendix A.
The brief for grey literature was the same as that for journal literature: To find items containing statistical data. The National Grey Literature Collection and TripPro produced no useful data. Two international and five national (English-speaking countries) patient/supporter groups were identified (full list in Supplementary material appendix B). While many personal stories of life with haemochromatosis were available on their various websites, there were fewer objective items and fewer still containing any form of statistical data. A total of 31 items (guidelines, reports and some additional journal articles) were identified for closer investigation.
Study screening and selection
The search results were exported to RefWorks. Following the removal of duplicate articles, screening was independently conducted by two reviewers, Waqar M and Ramage JK using Microsoft Excel. Any disagreements were resolved through consensus within the review team. Articles deemed potentially relevant based on initial title and abstract screening underwent full-text reviewing.
Data extraction and synthesis
A data extraction form was created detailing the study characteristics and outcomes of interest. Data was extracted independently by two reviewers (Waqar M and El Asmar ML). NVivo software (version 2.0) was used to conduct thematic analysis on the eligible studies, and issues/symptoms were extracted. A narrative review of the findings was conducted.
Special interest group survey
The identified issues and symptoms were distributed to members of a haemochromatosis special interest group (SIG) in an electronic survey using Qualtrics. This group comprised 18 experienced clinical consultants with an expressed interest in haemochromatosis care and two expert patients, each with experience in advocating for patients with the condition. Respondents were asked to assign scores ranging from 1 to 10, with 10 indicating the highest level of importance. Subsequently, the mean scores were calculated for each identified issue.
National health service (NHS) ethical approval was not sought for this study as the two patients responding were part of a voluntary group, and only institutional ethics approval was deemed necessary. None of the patients were approached through the NHS, and no NHS data pertaining to them was accessed.
SEARCH RESULTS
The search identified 1653 articles. After the removal of 1048 duplicates and 10 publications (which included books, guidelines, and conference abstracts), 595 articles remained. Title and abstract screening were conducted on those 595 articles, and 47 articles met the criteria after full-text screening. A Prisma-inspired Flowchart detailing the stages of screening is illustrated in Figure 1. Although not strictly following PRISMA guidelines, the flow diagram has been adapted to illustrate the stages of the scoping review process.
Figure 1 PRISMA-inspired flowchart detailing the search and selection process of studies.
QoL: Quality of life.
STUDY CHARACTERISTICS
The 47 included studies are characterized in Table 1[1,6,15-59]. Study designs encompassed longitudinal, cross-sectional, cohort, and observational studies, meta-analyses and mixed-method studies. Where applicable, studies mostly employed the following validated QoL tools to assess outcomes SF-36, MOS-SF36, AQOL-4D, HSUV, SF-36 (Mental Health Component Scores), structured interviews and self-reported psychosocial outcomes, Modified Fatigue Impact Scale, Hospital Anxiety and Depression Scale, SF36v2, AIMS2-SF, Liver Disease Symptom Index, and Multidimensional Fatigue Index-20. Most commonly, SF-36, MOS-SF36, structured interviews and self-reported psychosocial outcomes were used.
A total of 19 issues/symptoms were identified in the thematic analysis in descending order of frequency of references (Table 2). The most frequently identified symptoms were joint pain and stiffness, abdominal pain, chronic fatigue, problems related to insurance or unemployment, low mood/depression, and sexual problems (decreased libido or impotence). The least frequently identified symptoms were itching, breathing problems, and unexplained weight gain.
Table 2 Frequency of symptoms reported in eligible studies.
Symptom
Referenced articles
Frequency of references
Joint pain or stiffness
37
762
Abdominal pain
26
416
Fatigue, chronic fatigue, tiredness
24
314
Problems related to insurance or unemployment
11
111
Reduced psychological wellbeing (depression or low mood)
Fatigue, joint pain, sexual issues, reduced vitality, and reduced psychological wellbeing were ranked as the top factors associated with impaired QoL by the expert group. The least important issues were weight changes and abdominal pain (Figure 2). Other issues raised which were not identified in the content analysis included anxiety, development of diabetes and its consequences, and concerns about genetics and family. Chronic fatigue was ranked as the most important/relevant symptom in the survey but was only the third most frequently mentioned in the literature. Joint pain, although the most frequently cited symptom in studies, was considered slightly less important by the expert group, ranking second in the survey. Sexual problems and reduced vitality were given higher importance compared to the frequency found in the content analysis. Abdominal pain, while frequently referenced, was ranked least in importance. Additionally, cognitive issues, reduced physical functioning, and hair loss were seen as more critical by the SIG. Conversely, symptoms like insurance problems and unexplained weight loss, despite being frequent in the content analysis, were deemed less important in the survey.
Figure 2
Issues and symptoms as ranked by expert clinicians and patients.
DISCUSSION
Summary of findings
This study aimed to assess the symptoms and QoL in patients with haemochromatosis and to identify factors associated with impaired QoL. Nineteen issues were identified by the content analysis of the literature which were then rated by a professional group (SIG) in terms of importance. Some discrepancies were found between the frequency of issues found in the content analysis and their importance as rated by the SIG. The findings offer insights into the most significant and relevant symptoms affecting the QoL of haemochromatosis patients from both the literature and perspectives of healthcare professionals and can contribute to the development of a standardized questionnaire intended for evaluating symptoms and QoL in patients with haemochromatosis.
Implications
This is the first scoping review to identify the most significant symptoms affecting QoL in haemochromatosis patients. Currently, there is no specific/validated QoL questionnaire for haemochromatosis. The findings will lay the foundation for the next steps in QoL questionnaire development which will include conducting patient interviews to explore ranking of the issues above, and adding further issues raised by the patient group. This list will be operationalised into a list of questions which will be given to known haemochromatosis patients as part of a proposed randomised trial of venesection therapy (Health Technology Assessment grant applied for). The SF36 will also be given to these patients and the relative performance of the SF36 (the current most used questionnaire) and the new proposed questionnaire will be calculated.
The discrepancies between the findings of the content analysis and the SIG survey may be due to several factors. Symptoms were prioritised by order of importance based on their severity or impact on QoL as perceived clinically by those in the SIG, as opposed to the frequency of mentions in the literature. A higher frequency does not necessarily correlate with greater importance. Additionally, the included articles may not uniformly reflect the evolving understanding of the clinical importance of symptoms, as they also include older literature. Certain biases in the literature may have influenced the discrepancy, as there may have been a focus on certain symptoms due to research interests and “historical opinion” which may not always align with clinical relevance.
STRENGTHS AND LIMITATIONS
This is the first scoping review assessing the symptoms and QoL of haemochromatosis patients. It is one of only a few systematic recordings of views of physicians and patients and lays the foundations for creating a standardised questionnaire which will be used for future research into the effectiveness of therapies, which may include different venesection regimens and iron-chelating drugs.
This was a scoping review rather than a systematic review, with only a limited number of articles found that met the inclusion criteria. The number of physicians was small, but all were experts in the field. Only two persons in the SIG were patients. The exclusion of articles published in English only may have introduced selection bias, potentially leading to missing publications with findings related to QoL in hereditary haemochromatosis.
PREVIOUS LITERATURE AND FURTHER RESEARCH
Previous studies have used generic questionnaires (SF-36 being the most used), and although there is data from haemochromatosis using these questionnaires, it is not clear if these are capturing what is of most relevance to patients. In our view, there is a clear need for more relevant questions to be asked to measure small changes in QoL issues for these patients. The two broad areas that are most relevant are joint pains and fatigue, and these are not covered in detail by SF-36.
The one study that used open-ended questions to explore QoL issues resulted in similar areas of importance to patients[15]. This study reported joint pains and fatigue as the most important but did not dissect these issues in more detail. There has been much work on QOL questionnaires in both of these broad areas and these will be examined when looking for relevant questions in a new questionnaire. Fatigue is known to be a complex issue to measure. This study is the start of a process of obtaining more detail on QoL issues in haemochromatosis patients, and designing a questionnaire that might measure small differences in response to current and new emerging therapies for this disease.
CONCLUSION
Haemochromatosis is a common condition in populations of European descent. Once diagnosed, it frequently requires long-term treatment with venesection. The full cost of that treatment has not been formally evaluated, nor has the impact that treatment has on patients’ QoL. New molecular treatments that might benefit patients with iron overload are already available and are undergoing trials in patients with other conditions[16-18]. Analysis of existing and future treatments will require a robust and verified measure of QoL that is specific to haemochromatosis. Our work will provide the foundation for such a measure to be developed.
ACKNOWLEDGEMENTS
The authors would like to thank Claire Eacott from Hampshire Hospitals NHS Foundation Trust library, who helped with performing the original searches.
Footnotes
Provenance and peer review: Unsolicited article; Externally peer reviewed.
Peer-review model: Single blind
Specialty type: Gastroenterology and hepatology
Country of origin: United Kingdom
Peer-review report’s classification
Scientific Quality: Grade C
Novelty: Grade C
Creativity or Innovation: Grade C
Scientific Significance: Grade C
P-Reviewer: Han JM, MD, PhD, Assistant Professor, China S-Editor: Liu H L-Editor: A P-Editor: Zhang L
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