Failure to follow up on a medically actionable finding from direct to consumer genetic testing: A case report.

BACKGROUND: A 61-year-old woman underwent direct to consumer genetic testing and was found to be homozygous for the C282Y HFE variant (c.845G>A :p.Cys282Tyr) which is classified as pathogenic/likely pathogenic for hereditary hemochromatosis. However, no action was taken by the individual. METHODS: The individual took part in the Mayo Clinic Return of Actionable Variants Empiric (RAVE) study and the actionable finding was confirmed and results disclosed in person by a genetic counselor with subsequent referral to a hepatologist. RESULTS: Further testing revealed iron overload with an elevated ferritin level (560 ng/ml) and increased ferritin saturation (74%). Phlebotomy was initiated with subsequent normalization of the ferritin levels (252 ng/ml). CONCLUSION: This case highlights that actionable genetic results may not be acted on after direct to consumer testing and the need for effective genetic counseling after such testing.

The effect of therapeutic phlebotomy for hemochromatosis on non-suicidal self-injury: A case report.

BACKGROUND: Self-phlebotomy has been described as a form of non-suicidal self-injury. However, a relationship between non-suicidal self-injury and therapeutic phlebotomy for hemochromatosis has not previously been described. Case presentation: We present a case of a 52-year-old man in whom the frequency of his therapeutic phlebotomy and non-suicidal self-injury were inversely linked, leading to adverse outcomes when his phlebotomy was suspended. CONCLUSIONS: This is the first report describing the relationship between non-suicidal self-injury and therapeutic phlebotomy. This case highlights the need for risk assessment and monitoring of self-harm in patients who are undergoing therapeutic phlebotomy in order to prevent adverse outcomes.

Genetic explanations, discrimination and chronic illness: A qualitative study on hereditary haemochromatosis in Germany.

OBJECTIVE: The objective of this study is to explore the discriminatory impacts of genetic diagnosis for people living with the chronic illness of hereditary haemochromatosis in Germany. METHODS: Semi-structured interviews with 15 patients; all had tested positive for a genetic mutation associated with haemochromatosis and already displayed symptoms of the disease. Inductive approach, with interviews collaboratively interpreted by the research group in a vertical and horizontal analysis informed by a multi-person perspective. RESULTS: First, as the genetic diagnosis of the disease holds the promise of therapeutic intervention, the interviewees perceived it as leading to relief. Second, the interviewees felt stigmatized by their family members, they complained of social isolation and a lack of acknowledgement of their health problems. Third, they feared disadvantages for themselves or their children at their place of work, when buying insurance coverage, and when attempting to donate blood. DISCUSSION: The findings point to the need for an expanded view on genetic discrimination. Besides institutional discrimination, it appears necessary to systematically address interactional stigmatization and take anxieties and fears into account. Here we see starting points for providing essential support through specialist and self-help groups to those faced with the genetic diagnosis of haemochromatosis in addition to and beyond the legal protection against genetic discrimination that already exists.

Quality of life utility values for hereditary haemochromatosis in Australia.

BACKGROUND: Hereditary hemochromatosis (HH) is a common autosomal recessive disorder amongst persons of northern European heritage. If untreated, iron accumulates in parenchymal tissues causing morbidity and mortality. As diagnosis often follows irreversible organ damage, screening programs have been suggested to increase early diagnosis. A lack of economic evidence has been cited as a barrier to establishing such a program. Previous analyses used poorly estimated utility values. This study sought to measure utilities directly from people with HH in Australia. METHODS: Volunteers with HH were recruited to complete a web-based survey. Utility was assessed using the Assessment of Quality of Life 4D (AQOL-4D) instrument. Severity of HH was graded into four categories. Multivariable regression analysis was performed to identify parameters associated with HSUV. RESULTS: Between November 2013 and November 2014, 221 people completed the survey. Increasing severity of HH was negatively associated with utility. Mean (standard deviation) utilities were 0.76 (0.21), 0.81 (0.18), 0.60 (0.27), and 0.50 (0.27) for categories 1-4 HH respectively. Lower mean utility was found for symptomatic participants (categories 3 and 4) compared with asymptomatic participants (0.583 v. 0.796). Self-reported HH-related symptoms were negatively associated with HSUV (r = -0.685). CONCLUSIONS: Symptomatic stages of HH and presence of multiple self-reported symptoms were associated with decreasing utility. Previous economic analyses have used higher utilities which likely resulted in underestimates of the cost effectiveness of HH interventions. The utilities reported in this paper are the most robust available, and will contribute to improving the validity of future economic models for HH.

Effect of olfactory manganese exposure on anxiety-related behavior in a mouse model of iron overload hemochromatosis.

Manganese in excess promotes unstable emotional behavior. Our previous study showed that olfactory manganese uptake into the brain is altered in Hfe(-/-) mice, a model of iron overload hemochromatosis, suggesting that Hfe deficiency could modify the neurotoxicity of airborne manganese. We determined anxiety-related behavior and monoaminergic protein expression after repeated intranasal instillation of MnCl2 to Hfe(-/-) mice. Compared with manganese-instilled wild-type mice, Hfe(-/-) mice showed decreased manganese accumulation in the cerebellum. Hfe(-/-) mice also exhibited increased anxiety with decreased exploratory activity and elevated dopamine D1 receptor and norepinephrine transporter in the striatum. Moreover, Hfe deficiency attenuated manganese-associated impulsivity and modified the effect of manganese on the expression of tyrosine hydroxylase, vesicular monoamine transporter and serotonin transporter. Together, our data indicate that loss of HFE function alters manganese-associated emotional behavior and further suggest that HFE could be a potential molecular target to alleviate affective disorders induced by manganese inhalation.

Insufficient referral for genetic counseling in the management of hereditary haemochromatosis in portugal: a study of perceptions of health professionals requesting HFE genotyping.

There is a general consensus that HFE- related Hereditary Haemochromatosis (HFE-HH) should be diagnosed at early stages in pre-symptomatic individuals, in order to prevent the most severe consequences of iron overload. In Portugal, despite an increasing number of requests for genetic diagnosis of this rare disease, there is not a corresponding increase in requests for genetic counselling. The objective of the present study was to evaluate physicians' main motivations for requesting HFE genotyping or genetic counselling for HFE-HH. We assessed current medical practices regarding family testing and diagnosis and discuss whether these can be improved in order to increase the effectiveness of disease prevention. Our results show there is a general lack of knowledge about the selection of patient cases that should be sent for genetic counseling or for molecular testing of HFE-HH by physicians (especially by general practitioners). The lack of family-based screening may indirectly compromise the efficiency of disease prevention in terms of early diagnosis and treatment. We concluded it is necessary to circulate more information about Hereditary Haemochromatosis among health professionals in order to improve strategies for its early diagnosis.

To tell or not to tell - what to do about p.C282Y heterozygotes identified by HFE screening.

Hereditary hemochromatosis (HH) is a common preventable disorder of iron overload that can result in liver cirrhosis and reduced lifespan. Most HH is due to homozygosity for the HFE p.C282Y substitution. We conducted a study of screening for p.C282Y in high schools where p.C282Y heterozygotes (CY) individuals were informed of their genotype by letter. We studied whether these individuals understood the implications of their genotype, whether this resulted in anxiety or reduced health perception and whether cascade testing was higher in families of CY than wild-type homozygous (CC) individuals. We found 586 of 5757 (1 in 10) screened individuals were CY. One month after receiving their result, 83% correctly answered that they have one copy of p.C282Y. There was no adverse change in anxiety or health perception from prior to screening to 1 month after receiving results. Significantly more family members of CY individuals than CC individuals were informed about HH and had testing for HH. In conclusion, we found that informing CY individuals of their genotype does not increase anxiety and the implications are generally well understood. This leads to cascade testing in a minority of families. CY individuals should be informed of their genetic status when identified by population screening.

A national survey of hemochromatosis patients.

BACKGROUND: Hereditary hemochromatosis (HH) is a common genetic disease in the United States, but little is known about the diagnosis from the patient's perspective. The purpose of this study was to characterize the circumstances surrounding the diagnosis of HH and assess treatments and health information needs. METHODS: We surveyed US adults aged 18 years and older who were diagnosed with HH after 1996. Response rate was 46%, with a total sample size of 979. Respondents were asked about the use of genetic and clinical markers in their diagnosis, current treatments, and health information needs. RESULTS: Results were stratified by age, education, and income status. Total of 90.0% of women and 75.5% of men were genetically tested for HH (P < .01). Approximately half (52.5%) were diagnosed by a gastroenterologist, hematologist, or other specialty physician and half were diagnosed by a primary care provider. Most of the respondents thought their HH had improved with the initial treatment and most patients were still receiving treatment for HH. Patient interest in learning more about specific hemochromatosis topics was generally high. CONCLUSIONS: Since the introduction of genetic identification of HH, these tests have been used in the diagnosis of the majority of patients. Primary care physicians may need to be more aware HH and strategies for diagnosis.

Psychosocial aspects of DNA testing for hereditary hemochromatosis in at-risk individuals: a systematic review.

AIM: To review the psychosocial benefits and harms of DNA testing for HFE-related hereditary hemochromatosis (HH) in at-risk individuals. BACKGROUND: HH is a common genetic disease in people of European descent. DNA-based predisposition testing is used for diagnosis or in the context of family testing, but there are concerns about potential psychosocial consequences. METHODS: Fifteen electronic databases (including Medline and Cochrane) were searched from inception to April 2007 to identify any quantitative or qualitative primary research that considered DNA testing of individuals considered at-risk of HH and reported psychosocial outcomes. Inclusion criteria, data extraction, and quality assessment were undertaken by standard methodology. RESULTS: Three observational studies met the inclusion criteria of the review; each had methodological limitations. On receipt of test results, anxiety levels fell or were unchanged; general health-related quality-of-life outcomes improved in some aspects, or were unchanged with respect to pretest result values. Outcomes were not reported separately for those referred for diagnosis and those with family history of HH. Results suggest that genetic testing for HH in at-risk individuals is accompanied by few negative psychosocial outcomes. CONCLUSION: The evidence on the psychosocial aspects of DNA testing for HH in at-risk individuals is limited. Further research might be required if other factors influencing the natural history of the disease phenotype are identified.

Asymptomatic individuals at genetic risk of haemochromatosis take appropriate steps to prevent disease related to iron overload.

BACKGROUND/AIMS: If community screening for hereditary haemochromatosis is to be considered, compliance with preventative measures and absence of significant psychological morbidity must be demonstrated. METHODS: Workplace screening for the HFE C282Y mutation and then clinical care for C282Y homozygotes was instituted. Data were collected on understanding of test results, perceived health status and anxiety for C282Y homozygotes compared with controls. Uptake of clinical care, compliance and response to treatment and changes in diet were monitored for up to 4 years for C282Y homozygotes. RESULTS: After 11 307 individuals were screened, 40/47 (85%) newly identified C282Y homozygotes completed questionnaires 12 months after diagnosis compared with 79/126 (63%) of controls. Significantly more C282Y homozygotes correctly remembered their test result compared with controls (95 vs 51%, P<0.0001). No significant difference in perceived health status was observed within or between the two groups at 12 months compared with baseline. Anxiety levels decreased significantly for C282Y homozygotes at 12 months compared with before testing (P<0.05). Forty-five of the 47 (95.8%) C282Y homozygotes accessed clinical care for at least 12 months. All 22 participants requiring therapeutic venesection complied with treatment for at least 12 months (range 12-47 months). CONCLUSION: Individuals at a high genetic risk of developing haemochromatosis use clinical services appropriately, maintain their health and are not 'worried well'. Population genetic screening for haemochromatosis can be conducted in the work place in a way that is acceptable and beneficial to participants.

Generic and disease-specific health related quality of life of liver patients with various aetiologies: a survey.

Most studies on health related quality of life (HRQoL) of chronic liver patients were done in small clinical populations or restricted to one aetiology or disease stage. There is still a need for a study in a large liver patient population with various aetiologies and disease stages, approaching a population-based study. We evaluated the impact of liver disease aetiology on generic HRQoL, disease-specific HRQoL and fatigue and we compared HRQoL and fatigue between aetiological groups and healthy Dutch controls. Members of the Dutch liver patient association completed the Liver Disease Symptom Index, Short Form-36, and Multidimensional Fatigue Index-20. We compared the HRQoL between patients with viral hepatitis, autoimmune hepatitis, cholestatic diseases, hemochromatosis and other liver diseases by linear, ordinal and logistic regression, corrected for disease stage and other significant factors. Viral hepatitis patients showed a worse mental health than other aetiological groups. Hemochromatosis patients demonstrated 17% more bodily pain than viral hepatitis patients and the strongest decrease in role emotional health with increasing age. Aetiological groups showed a worse generic HRQoL and more fatigue than controls. In conclusion, viral hepatitis and hemochromatosis patients have a more impaired HRQoL than patients of other liver disease aetiological groups.

Impact of hemochromatosis screening in patients with indeterminate results: the hemochromatosis and iron overload screening study.

PURPOSE: Assess the quality of life impact of receiving indeterminate test results for hemochromatosis, a disorder involving HFE genetic mutations and/or elevated serum transferrin saturation and ferritin. METHODS: The study sample was from the Hemochromatosis and Iron Overload Screening Study, a large observational study of hemochromatosis among primary care patients in the US and Canada using HFE genotype and serum transferrin saturation and ferritin screening. Study subjects included 2,304 patients found with hemochromatosis risk of uncertain clinical significance. Assessed was SF-36 general health and emotional well-being before screening and six weeks after participants received their test results. Health worries were assessed after screening. RESULTS: Of the study subjects, 1,268 participants (51.5%) completed both assessments. Compared to normal controls, those with HFE mutations or elevated serum transferrin saturation and ferritin levels of uncertain significance were more likely to report diminished general health and mental well-being, and more health worries. These effects were associated with participants' belief of having tested positive for hemochromatosis or iron overload. CONCLUSION: Notification of indeterminate results from screening may be associated with mild negative effects on well-being, and might be a potential participant risk in screening programs for disorders with uncertain genotype-phenotype.

Predictors of belief that genetic test information about hemochromatosis should be shared with family members.

We queried 101,951 white, Hispanic, black, Asian, American Indian (i.e., American Indian or Alaska Native in the United States and North American Indian, Metis, or Inuit in Canada) and Pacific Islander (including Native Hawaiian) adults who agreed to be genotypically and phenotypically screened for hemochromatosis as part of the Hemochromatosis and Iron Overload Screening (HEIRS) study about their views on sharing genetic test information with family members. Multiple logistic regression (adjusting for study site, age group, race/ethnicity, preferred language, gender, education group, income group, SF-36 General Health and Mental Health subscales, perceived benefits and limitations of genetic testing, and belief that genetic testing is a good idea) evaluated independent predictors of responding "Strongly Agree" or "Agree" versus "Disagree" or "Strongly Disagree" to the statement "Information about a person's genetic risk should be shared with family members". Agreement that genetic risk information should be shared with family members was high (93% in the overall sample of 78,952 who answered this question), but differed among racial/ethnic groups. Hispanics were significantly less likely to agree that genetic test information should be shared with family members (i.e., 88% versus 92% or more among all other ethnicities). The relationship of perceived limitations and benefits of testing, gender, and age group to the belief that information should be shared differed among racial/ethnic groups, with Spanish-preferring Hispanics being the most different from other subgroups.

The best experts: the narratives of those who have a genetic condition.

In recent years, there have been growing expectations about the future benefits deriving from the uptake of genetics knowledge in healthcare. At the same time, there have been increasing calls to make greater use of patient expertise in treatment. However, relatively little is known about the experiences, needs and expertise of those who currently have a genetic condition. Drawing on the findings from an Australian study involving 21 semi-structured interviews with members of support groups which represent those with various genetic conditions (cystic fibrosis, haemochromatosis, haemophilia, and thalassaemia) this article discusses how individuals learn about, live with and manage their condition, and assesses the extent to which their experiences differ from those with other chronic illness conditions. It argues that while the experiences of individuals who have a genetic condition would appear to be similar in many respects to those with other chronic illnesses, they tend to encounter particular challenges in managing their condition due to its inheritable nature.

Patient acceptability of genotypic testing for hemochromatosis in primary care.

PURPOSE: Genetic screening can enable timely detection and treatment of hereditary hemochromatosis (HH). Little is known about patient acceptability of DNA testing as compared to conventional phenotypic testing. METHODS: Within the HEIRS Study, a large primary-care screening study of HH and iron overload, we randomly assigned participants to receive brief information on either HH genotypic or phenotypic testing, and assessed the willingness to accept this test. The study was designed to recruit an equal number of African Americans and Caucasians. RESULTS: A total of 2500 participants were recruited from waiting rooms of primary care practices; 2165 participants who self-identified as African Americans and Caucasians were included in the analyses. Overall, 56% had accepted a genotypic test versus 58% for a phenotypic test. Adjusting for Field Center (FC), age, gender, race, educational attainment, global health rating, and knowledge of the test, the odds ratio of accepting a genotypic versus phenotypic test was 0.85 (95% CI: 0.71, 1.02; P = 0.078). Characteristics associated with test acceptance were age 45-64 years, female gender, Caucasian race, self-rated health less than ''very good'', and knowledge of the test. Test acceptance was associated with interest in knowing more about health (81%) and in helping family members (71%). Refusal reasons included a need to talk with a doctor (44%), concern about privacy (32%), and dislike of blood drawing (29%). CONCLUSION: In this diverse sample of primary care patients, stated acceptance of genotypic testing for HH mutations was similar to phenotypic testing for blood iron. Patient education regarding the nature of test, importance of disease detection, and privacy protection appear to be essential for achieving high rates of screening participation.

Demanding pure motives for donation: the moral acceptability of blood donations by haemochromatosis patients.

Blood banks all over the world attempt to cover the demand for blood by donations from voluntary non-remunerated donors. The discussion regarding the acceptability of blood donations by haemochromatosis patients focuses on the question of whether health benefits violate the rule of the altruistic donor. Utilitarian and deontological arguments for and against the policy of accepting blood donors who need to let blood regularly in order to stay healthy are considered by this article. A closer look at the procedure reveals that the confusion is due to the conflation of, on the one hand the phlebotomy, and on the other hand, the decision about the destination of the blood afterwards. The health benefits are connected to the phlebotomy and not to the donation. The morally relevant point in the decision as to whether the candidate is a truly altruistic donor is whether he donates without asking for a benefit in return. It is concluded that haemochromatosis patients can be free, voluntary, and altruistic blood donors.

Psychological adjustment and knowledge about hereditary hemochromatosis in a clinic-based sample: a prospective study.

This study assessed psychological adjustment and quality of life relative to population-based norms and knowledge about hereditary hemochromatosis in a sample of 101 patients who attended a hemochromatosis clinic. Participants were assessed prior to their clinic visit, and two weeks and 12 months after attendance, using self-administered questionnaires. Mean Mental Health Component Scores from the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36) (45.3, 95% CI 43.2, 47.4) were as compromised as those found amongst stroke victims (45.9, 95% CI 42.8, 49.0) who had participated in a national health survey. Recall of the genetic testing result was less than optimal, in that only 69.3% of those with genetic testing results knew whether they carried one or two mutations. This study demonstrates that patients would benefit from routine assessment of psychological distress and referral to mental health professionals of those whose levels of distress suggest a need for clinical intervention. Results also show that patients may benefit from strategies aimed at improving recall of genetic testing results.