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Familial hypercholesterolemia (FH) is the most common dominant genetic disorder in humans and causes premature heart disease and death. The incidence of heterozygous FH in the general global population is 1:250;1 however, rates in  Māori are not known. It is characterised by very high-level low-density lipoprotein-cholesterol (LDL-c), systemic manifestation of cholesterol deposition (tendon xanthoma, xanthlasma and arcus cornealis). Three clinical definitions for FH are used to identify people with possible FH;2–4 the most commonly used are the Dutch Lipid Clinic and Simon Broome criteria.5Early detection and treatment of individuals with this disorder is important to prevent the early development of cardiovascular disease. Current guidelines recommend screening of high-risk individuals, and then cascade screening of family members in childhood. 6 Cascade screening using the genetic test is recommended once the proband for DNA testing is identified. Studies have shown that 15–20% of family members are incorrectly classified based on cholesterol testing alone.7 Treatment of gene positive offspring is recommended to start at the age of 8–10 years with the aim of reaching a target LDL-c <3.5mmol/L or to less than 50% if the target is not achievable.6,8 Early identification of FH in children is vital as children with FH can have normal life expectancies if treatment is started early.9 The most common mutation causing FH is in the LDL receptor, identified in ~90% of cases. The LDL receptor mediates endocytosis of LDL-c into cells including hepatocytes.

A number of medications are recommended to treat FH; intensive statin therapy, ezetimibe and protein convertase subtilisin/kexin type 9 (PCSK9) inhibitors. At present, New Zealand has a limited range of drugs to treat hypercholesterolemia. For example, rosuvastatin, the most potent statin, or PCSK9 inhibitors are not funded for FH, limiting choice in individuals at very high risk of premature heart disease (See Figure 1, patient experience). Studies suggest that expensive medications like PCSK9 inhibitors are cost effective as they significantly reduce cardiovascular events in FH.10

Figure 1: Patient experiences.

LDLR:c.2312-3C>A splicing mutation

A specific mutation in the LDL receptor, LDLR:c.2312-3C>A splicing mutation, was described in a Māori man who was working in western Australia who presented with coronary artery disease in his 30s. He had a strong whānau (extended family) history of premature death from heart disease.11 He described a whānau blighted by premature heart disease and death and a whānau legend of “a white woman” who had married their Māori ancestor at the turn of the 20th century who had “brought a curse on them”. The gene has been traced back to whānau with origins in Valencia (in eastern Spain), with an ancestor moving to northern France during the 1600s. Descendants then migrated to England, and subsequently to New Zealand whereupon one ancestor married a Māori man and then moved to in a remote area of New Zealand. This union resulted in a very large whānau afflicted with premature heart disease and death. Endocrinologists visited this remote area and tested a number of members of the whānau and confirmed the presence of this mutation. However, no systemic screening and treatment was initiated as no national system was in place to manage this.

In 2018, three members of the extended whānau presented to the cardiology department at Auckland City Hospital with very high LDL-c; one male in his early 30s with significant atherosclerosis requiring stents and two females in their 20s with tendon xanthomata. They all told a story of a large extended whānau affected by premature heart disease with high rates of premature death. They remembered the endocrinologists that had visited the whānau about 15 years earlier who had taken samples, but they were not sure of the diagnosis. Contact was made with the Christchurch Laboratory who had records of an identified LDL-c receptor mutation in this whānau. Confirmation of the presence of the same mutation was made in the three index patients. This revealed issues in the health system in terms of systemic screening and treatment of whānau now scattered across the country and the world.

The consequence of a lack of a national strategy for FH has resulted in a fragmented and disparate service for patients (Figure 2, practice nurse experience). There are pockets of experts in some places, but there is also little awareness of how to treat and manage this condition in the general medical community. For example, few clinicians without a specific interest in FH understand that genetic testing and treatment needs to be implemented in childhood (Figure 3, patient experience).

Figure 2: Rural nurse experience.

Figure 3: Patient experience.

There was no prospect of a national service in the near future; however, a solution for this whānau was needed urgently.

Methods

Consultation with a broad range of invested stakeholders was undertaken to determine how to best ensure that the whānau were empowered to manage this condition across generations and geography. Initial consultation was with index whānau and then kaumātua (elders). Then broader consultation was with the national genetic services, the paediatric metabolic department and the director of Māori Health Research at the Waitemata and Auckland District Health Boards (DHB) Dr Helen Wihongi. The discussion with Dr Wihongi focused on how to ensure that tikanga Māori (custom, ethics) was taken into account especially around the issues regarding taking and storing of blood, as well as who owned the data. We reviewed the current consent form used by the genetic services to ensure this explained that blood samples may be stored and that this may have implications for the whakapapa (genealogy). The form also explains that the samples are kept in New Zealand and are not given to third parties. There is currently no national genetic database for FH in New Zealand so no one currently holds the data other than the treating physician and laboratory. We also discussed how to balance the needs of the extended whānau and the privacy of the individual. The genetic and metabolic services provided support for cascade screening and were happy to be part of the hui. The local general practice was also consulted to assess their needs and opinions on how best to move forward.

Hui

A hui (social gathering) was organised to inform the whānau about the genetic mutation and discuss how best to manage this to ensure access to testing and treatments. This was attended by the whānau, kaumātua, doctors and nurses from the local health practice, the national genetic services, a doctor from ADHB and a health science student.

On arrival at the marae (meeting ground) there was a pōwhiri (formal welcome), which included a karanga (call) to the manuhiri (guests), and a response. After a number of speeches and songs by the men, we all introduced ourselves. After a mihi (introduction) and waiata (song) the doctor gave a talk that centred on what FH is, what age to screen and treat FH, how the gene is transmitted, how to organise testing and risks and benefits of treatment. The geneticists then explained genetic and cascade testing and how it is undertaken. The formal presentations by the doctors and geneticists lasted two hours, and the rest of the hui was comprised of open discussions. There was also a need to acknowledge the past. The whānau felt used and let down by previous doctors who had visited and taken samples but gave no information on how to prevent further deaths. This had to be acknowledged by the medical team. The pace of discussions was driven primarily by the needs of the whānau. For example, when the doctor spoke too fast or used medical terms, the whānau backtracked by asking questions. There was a strong feeling that decisions on how to manage this issue could not be made in haste, and that we were all in this together (He waka eke noa (A canoe which we are all in with no exception)). There was agreement that for any solution to work, it needed to be acceptable to everyone and according to the Kaupapa Māori principles of self-determination, involvement of the whānau and āta (respectful relationships).

Issues discussed were:

• Who should have access to the information and how to balance the rights of the individual vs the rights of the whānau

• How to cascade screen whānau and ensure this is done in perpetuity

• How to ensure whānau members living in other counties access the information

• How to ensure whānau is updated on new information regarding treatment

• How to access novel agents shown to work in FH

• Can PHARMAC be approached for access for new medications for this whānau under Te Tiriti o Waitangi obligations

• How to manage blood samples, ethical issues with privacy and storage of blood

Results

A whānau member was nominated to run a closed social media page for the whānau that includes a family tree. The closed social media page can only be accessed by members and Facebook administration. The Facebook administrators monitor closed sites only to “promote safety and security on and off of our products”. Data is not given to third parties. The whānau member acts as a gatekeeper so that new posts can be sent to them and can only be uploaded by them. All extended whānau are invited to be part of this Facebook site, and the addition of the genetic test result to the family tree is completely up the individual. A printable letter to show health professionals was created with general information about FH, diagnosis and treatment, the proband identified and steps for genetic testing (Figure 4). A consent form for testing and a pre-filled laboratory form with the proband are also available. The consent form is the standard consent form used by the National Genetic Services for New Zealand. It requires specific and separate consent for storage of samples. As new treatments become available, the ADHB doctor sends the information to the gatekeeper who then uploads this to keep extended whānau informed of latest treatments. The clinician has no access to the Facebook page but is in close contact with the moderator to address concerns, misinformation and misconceptions about FH and treatments to lower cholesterol.

Figure 4:

This whānau social media page will also engage with whakahekenga (descendants) within the whānau in the long term. This will allow all to make informed decisions on the need to be tested, especially if no data is available about their immediate whānau.

At present, the social media page is active with a number of whānau members active on it. As a direct result, genetic testing and appropriate treatment has been initiated in 17 whānau members. Intensive statin treatment has been initiated in two children and a couple of young adults; this has the potential to ensure they reach normal life expectancy. The hope is that testing will be extended to all young children when they reach the age of eight. Only one surviving whānau member over the age of 50 has been found to have the mutation; however, this LDL-c is lower than others with the mutation.

Results of genetic tests are known only to the testing laboratory, the treating physician and the person tested. Results of genetic tests are only sent to the ADHB doctor if this is specifically requested by the patient. No data is centrally held by genetic services at this point as there is no national genetic service for FH. This ensures data for and about this Māori whānau can be safeguarded and protected from parties who are not directly involved with their care.

Discussion

The experience of this whānau underscores a number of issues. The first is that there is no systematic national approach to FH in New Zealand. It is not possible for clinicians to test and treat families from other DHBs or refer them to a national screening service as none exists. In this particular instance, testing was undertaken by clinicians from another DHB for research purposes, but there was no ability to refer for clinical follow up, cascade screening or appropriate treatment. A missed opportunity resulted to prevent premature cardiovascular events and led to an injustice perpetrated on the whānau. This resulted in inequity though three pathways; ongoing exposure to a modifiable and potent risk factor for CVD, difference in the quality of care received and differential access to healthcare.12 Had the whānau lived within the researchers’ DHB, they would have been appropriately managed. A priority of the hui was acknowledging that there had been an injustice and that that this had led to ongoing harm. The whānau wanted assurances it would never happen to them again and that measures were put in place to ensure that the whānau had ownership and control of their health information.

A second issue is that the system prioritises the needs and privacy of the individual over the whānau. This Westernised approach to health ignores the cornerstone of health; taha whānau (family health).13 In this instance, if one person misses testing, other members of the whānau further down the ‘cascade stream’, such as children will not be tested. This may be useful in societies where the needs of the individual are paramount, but not where the collective is just as important.

Despite calls over a number of years for a national screening registry for FH,14 none has eventuated. The argument for a registry is that it will allow for efficient screening and treatment of gene positive children and young adults to prevent future cardiovascular events. The argument against this is that it is a common genetic disorder picked up by a cheap lipid test, and that gene testing may be prohibitively expensive for the country. This approach ignores the benefits of cascade screening and treating gene positive children. It has resulted in a haphazard approach to FH with disparity in care across the country. For this whānau it has led to ongoing hurt caused by young family members developing often fatal premature heart disease.

Conclusion

FH is the most common dominant genetic disorder in humans and causes premature heart disease and death. Current approaches in New Zealand are dependent on index patients presenting for cascade screening and do not incorporate the needs and views of the extended whānau. Establishing a partnership with the whānau and giving back control of health information is crucial to ensure equity. A national systematic programme is also needed to manage this condition with important health outcomes that can be averted if treated from a young age.

Summary

Abstract

Aim

To empower a large whānau (extended family) with a history of severe premature heart disease and familial hypercholesterolemia (FH).

Method

After broad consultation a Hui was held to discuss how to better manage this issue to ensure present and future generations were appropriately screened and treated.

Results

A closed social media page with detailed information on how to manage and screen FH that includes a family tree (for those who consent) has been created. The whānau, facilitated by health professionals, have ownership of their health. This has led to an uptake of screening and treatment for FH with whānau who are now able to inform local health professionals about their disorder.

Conclusion

FH is the most common dominant genetic disorder in humans and causes premature heart disease and death. Current approaches are dependent on index patients presenting for cascade screening and do not incorporate the needs and views of the extended whānau. Establishing a partnership with the whānau and giving back control of health information is crucial to ensure equity. A national systematic programme is also needed to manage this condition with important health outcomes that can be averted if treated from a young age.

Author Information

Jocelyne Benatar, Auckland District Health Board, Auckland; Tara Evile, University of Auckland, Auckland; Helen Wihongi, Director of Māori Health Research, Waitemata and Auckland District Health Boards; The Whānau.

Acknowledgements

Denise Staple—Rural Practice Nurse. Nicola Reid and Dr Andrew Laurie—at Cardiovascular Prevention & Lipid Disorders, Canterbury District Health Board.

Correspondence

Dr Jocelyne Benatar, Auckland District Health Board, Auckland.

Correspondence Email

jbenatar@adhb.govt.nz

Competing Interests

Nil.

1. Vallejo-Vaz AJ, Ray KK. Epidemiology of familial hypercholesterolaemia: Community and clinical. Atherosclerosis 2018; 277: 289–297.

2. Haase A, Goldberg AC. Identification of people with heterozygous familial hypercholesterolemia. Curr Opin Lipidol 2012; 23: 282–289.

3. Austin MA, Hutter CM, Zimmern RL, Humphries SE. Genetic causes of monogenic heterozygous familial hypercholesterolemia: a HuGE prevalence review. Am J Epidemiol 2004; 160:407–420.

4. Williams RR, Hunt SC, Schumacher MC, Hegele RA, Leppert MF, et al. Diagnosing heterozygous familial hypercholesterolemia using new practical criteria validated by molecular genetics. Am J Cardiol 1993; 72:171–176.

5. Abdul-Razak S, Rahmat R, Mohd Kasim A, Rahman TA, Muid S, et al. Diagnostic performance of various familial hypercholesterolaemia diagnostic criteria compared to Dutch lipid clinic criteria in an Asian population. BMC cardiovascular disorders 2017; 17:264–264.

6. Harada-Shiba M, Arai H, Ishigaki Y, Ishibashi S, Okamura T, et al. Guidelines for Diagnosis and Treatment of Familial Hypercholesterolemia 2017. J Atheroscler Thromb 2018; 25:751–770.

7. Knowles JW, Rader DJ, Khoury MJ. Cascade Screening for Familial Hypercholesterolemia and the Use of Genetic Testing. JAMA 2017; 318:381–382.

8. Mach F, Baigent C, Catapano AL, Koskinas KC, Casula M, et al. (2019) 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk: The Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS). European Heart Journal.

9. Farnier M, Civeira F, Descamps O. How to implement clinical guidelines to optimise familial hypercholesterolaemia diagnosis and treatment. Atheroscler Suppl 2017; 26:25–35.

10. Borissov B, Urbich M, Georgieva B, Tsenov S, Villa G. Cost-effectiveness of evolocumab in treatment of heterozygous familial hypercholesterolaemia in Bulgaria: measuring health benefit by effectively treated patient-years*. Journal of Market Access & Health Policy 2017; 5:1412753.

11. Liyanage KE, Burnett JR, Hooper AJ, van Bockxmeer FM. Familial hypercholesterolemia: epidemiology, Neolithic origins and modern geographic distribution. Critical Reviews in Clinical Laboratory Sciences 2011; 48:1–18.

12. Jones CP. Invited Commentary: “Race,” Racism, and the Practice of Epidemiology. American Journal of Epidemiology 2001; 154:299–304.

13. Health Mo (2019) Wai 2575 Māori Health Trends Report. Wellington: Ministry of Health.

14. Laurie AD, Scott RS, George PM. Genetic screening of patients with familial hypercholesterolaemia (FH): a New Zealand perspective. Atheroscler Suppl 2004; 5:13–15.

Contact diana@nzma.org.nz
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Familial hypercholesterolemia (FH) is the most common dominant genetic disorder in humans and causes premature heart disease and death. The incidence of heterozygous FH in the general global population is 1:250;1 however, rates in  Māori are not known. It is characterised by very high-level low-density lipoprotein-cholesterol (LDL-c), systemic manifestation of cholesterol deposition (tendon xanthoma, xanthlasma and arcus cornealis). Three clinical definitions for FH are used to identify people with possible FH;2–4 the most commonly used are the Dutch Lipid Clinic and Simon Broome criteria.5Early detection and treatment of individuals with this disorder is important to prevent the early development of cardiovascular disease. Current guidelines recommend screening of high-risk individuals, and then cascade screening of family members in childhood. 6 Cascade screening using the genetic test is recommended once the proband for DNA testing is identified. Studies have shown that 15–20% of family members are incorrectly classified based on cholesterol testing alone.7 Treatment of gene positive offspring is recommended to start at the age of 8–10 years with the aim of reaching a target LDL-c <3.5mmol/L or to less than 50% if the target is not achievable.6,8 Early identification of FH in children is vital as children with FH can have normal life expectancies if treatment is started early.9 The most common mutation causing FH is in the LDL receptor, identified in ~90% of cases. The LDL receptor mediates endocytosis of LDL-c into cells including hepatocytes.

A number of medications are recommended to treat FH; intensive statin therapy, ezetimibe and protein convertase subtilisin/kexin type 9 (PCSK9) inhibitors. At present, New Zealand has a limited range of drugs to treat hypercholesterolemia. For example, rosuvastatin, the most potent statin, or PCSK9 inhibitors are not funded for FH, limiting choice in individuals at very high risk of premature heart disease (See Figure 1, patient experience). Studies suggest that expensive medications like PCSK9 inhibitors are cost effective as they significantly reduce cardiovascular events in FH.10

Figure 1: Patient experiences.

LDLR:c.2312-3C>A splicing mutation

A specific mutation in the LDL receptor, LDLR:c.2312-3C>A splicing mutation, was described in a Māori man who was working in western Australia who presented with coronary artery disease in his 30s. He had a strong whānau (extended family) history of premature death from heart disease.11 He described a whānau blighted by premature heart disease and death and a whānau legend of “a white woman” who had married their Māori ancestor at the turn of the 20th century who had “brought a curse on them”. The gene has been traced back to whānau with origins in Valencia (in eastern Spain), with an ancestor moving to northern France during the 1600s. Descendants then migrated to England, and subsequently to New Zealand whereupon one ancestor married a Māori man and then moved to in a remote area of New Zealand. This union resulted in a very large whānau afflicted with premature heart disease and death. Endocrinologists visited this remote area and tested a number of members of the whānau and confirmed the presence of this mutation. However, no systemic screening and treatment was initiated as no national system was in place to manage this.

In 2018, three members of the extended whānau presented to the cardiology department at Auckland City Hospital with very high LDL-c; one male in his early 30s with significant atherosclerosis requiring stents and two females in their 20s with tendon xanthomata. They all told a story of a large extended whānau affected by premature heart disease with high rates of premature death. They remembered the endocrinologists that had visited the whānau about 15 years earlier who had taken samples, but they were not sure of the diagnosis. Contact was made with the Christchurch Laboratory who had records of an identified LDL-c receptor mutation in this whānau. Confirmation of the presence of the same mutation was made in the three index patients. This revealed issues in the health system in terms of systemic screening and treatment of whānau now scattered across the country and the world.

The consequence of a lack of a national strategy for FH has resulted in a fragmented and disparate service for patients (Figure 2, practice nurse experience). There are pockets of experts in some places, but there is also little awareness of how to treat and manage this condition in the general medical community. For example, few clinicians without a specific interest in FH understand that genetic testing and treatment needs to be implemented in childhood (Figure 3, patient experience).

Figure 2: Rural nurse experience.

Figure 3: Patient experience.

There was no prospect of a national service in the near future; however, a solution for this whānau was needed urgently.

Methods

Consultation with a broad range of invested stakeholders was undertaken to determine how to best ensure that the whānau were empowered to manage this condition across generations and geography. Initial consultation was with index whānau and then kaumātua (elders). Then broader consultation was with the national genetic services, the paediatric metabolic department and the director of Māori Health Research at the Waitemata and Auckland District Health Boards (DHB) Dr Helen Wihongi. The discussion with Dr Wihongi focused on how to ensure that tikanga Māori (custom, ethics) was taken into account especially around the issues regarding taking and storing of blood, as well as who owned the data. We reviewed the current consent form used by the genetic services to ensure this explained that blood samples may be stored and that this may have implications for the whakapapa (genealogy). The form also explains that the samples are kept in New Zealand and are not given to third parties. There is currently no national genetic database for FH in New Zealand so no one currently holds the data other than the treating physician and laboratory. We also discussed how to balance the needs of the extended whānau and the privacy of the individual. The genetic and metabolic services provided support for cascade screening and were happy to be part of the hui. The local general practice was also consulted to assess their needs and opinions on how best to move forward.

Hui

A hui (social gathering) was organised to inform the whānau about the genetic mutation and discuss how best to manage this to ensure access to testing and treatments. This was attended by the whānau, kaumātua, doctors and nurses from the local health practice, the national genetic services, a doctor from ADHB and a health science student.

On arrival at the marae (meeting ground) there was a pōwhiri (formal welcome), which included a karanga (call) to the manuhiri (guests), and a response. After a number of speeches and songs by the men, we all introduced ourselves. After a mihi (introduction) and waiata (song) the doctor gave a talk that centred on what FH is, what age to screen and treat FH, how the gene is transmitted, how to organise testing and risks and benefits of treatment. The geneticists then explained genetic and cascade testing and how it is undertaken. The formal presentations by the doctors and geneticists lasted two hours, and the rest of the hui was comprised of open discussions. There was also a need to acknowledge the past. The whānau felt used and let down by previous doctors who had visited and taken samples but gave no information on how to prevent further deaths. This had to be acknowledged by the medical team. The pace of discussions was driven primarily by the needs of the whānau. For example, when the doctor spoke too fast or used medical terms, the whānau backtracked by asking questions. There was a strong feeling that decisions on how to manage this issue could not be made in haste, and that we were all in this together (He waka eke noa (A canoe which we are all in with no exception)). There was agreement that for any solution to work, it needed to be acceptable to everyone and according to the Kaupapa Māori principles of self-determination, involvement of the whānau and āta (respectful relationships).

Issues discussed were:

• Who should have access to the information and how to balance the rights of the individual vs the rights of the whānau

• How to cascade screen whānau and ensure this is done in perpetuity

• How to ensure whānau members living in other counties access the information

• How to ensure whānau is updated on new information regarding treatment

• How to access novel agents shown to work in FH

• Can PHARMAC be approached for access for new medications for this whānau under Te Tiriti o Waitangi obligations

• How to manage blood samples, ethical issues with privacy and storage of blood

Results

A whānau member was nominated to run a closed social media page for the whānau that includes a family tree. The closed social media page can only be accessed by members and Facebook administration. The Facebook administrators monitor closed sites only to “promote safety and security on and off of our products”. Data is not given to third parties. The whānau member acts as a gatekeeper so that new posts can be sent to them and can only be uploaded by them. All extended whānau are invited to be part of this Facebook site, and the addition of the genetic test result to the family tree is completely up the individual. A printable letter to show health professionals was created with general information about FH, diagnosis and treatment, the proband identified and steps for genetic testing (Figure 4). A consent form for testing and a pre-filled laboratory form with the proband are also available. The consent form is the standard consent form used by the National Genetic Services for New Zealand. It requires specific and separate consent for storage of samples. As new treatments become available, the ADHB doctor sends the information to the gatekeeper who then uploads this to keep extended whānau informed of latest treatments. The clinician has no access to the Facebook page but is in close contact with the moderator to address concerns, misinformation and misconceptions about FH and treatments to lower cholesterol.

Figure 4:

This whānau social media page will also engage with whakahekenga (descendants) within the whānau in the long term. This will allow all to make informed decisions on the need to be tested, especially if no data is available about their immediate whānau.

At present, the social media page is active with a number of whānau members active on it. As a direct result, genetic testing and appropriate treatment has been initiated in 17 whānau members. Intensive statin treatment has been initiated in two children and a couple of young adults; this has the potential to ensure they reach normal life expectancy. The hope is that testing will be extended to all young children when they reach the age of eight. Only one surviving whānau member over the age of 50 has been found to have the mutation; however, this LDL-c is lower than others with the mutation.

Results of genetic tests are known only to the testing laboratory, the treating physician and the person tested. Results of genetic tests are only sent to the ADHB doctor if this is specifically requested by the patient. No data is centrally held by genetic services at this point as there is no national genetic service for FH. This ensures data for and about this Māori whānau can be safeguarded and protected from parties who are not directly involved with their care.

Discussion

The experience of this whānau underscores a number of issues. The first is that there is no systematic national approach to FH in New Zealand. It is not possible for clinicians to test and treat families from other DHBs or refer them to a national screening service as none exists. In this particular instance, testing was undertaken by clinicians from another DHB for research purposes, but there was no ability to refer for clinical follow up, cascade screening or appropriate treatment. A missed opportunity resulted to prevent premature cardiovascular events and led to an injustice perpetrated on the whānau. This resulted in inequity though three pathways; ongoing exposure to a modifiable and potent risk factor for CVD, difference in the quality of care received and differential access to healthcare.12 Had the whānau lived within the researchers’ DHB, they would have been appropriately managed. A priority of the hui was acknowledging that there had been an injustice and that that this had led to ongoing harm. The whānau wanted assurances it would never happen to them again and that measures were put in place to ensure that the whānau had ownership and control of their health information.

A second issue is that the system prioritises the needs and privacy of the individual over the whānau. This Westernised approach to health ignores the cornerstone of health; taha whānau (family health).13 In this instance, if one person misses testing, other members of the whānau further down the ‘cascade stream’, such as children will not be tested. This may be useful in societies where the needs of the individual are paramount, but not where the collective is just as important.

Despite calls over a number of years for a national screening registry for FH,14 none has eventuated. The argument for a registry is that it will allow for efficient screening and treatment of gene positive children and young adults to prevent future cardiovascular events. The argument against this is that it is a common genetic disorder picked up by a cheap lipid test, and that gene testing may be prohibitively expensive for the country. This approach ignores the benefits of cascade screening and treating gene positive children. It has resulted in a haphazard approach to FH with disparity in care across the country. For this whānau it has led to ongoing hurt caused by young family members developing often fatal premature heart disease.

Conclusion

FH is the most common dominant genetic disorder in humans and causes premature heart disease and death. Current approaches in New Zealand are dependent on index patients presenting for cascade screening and do not incorporate the needs and views of the extended whānau. Establishing a partnership with the whānau and giving back control of health information is crucial to ensure equity. A national systematic programme is also needed to manage this condition with important health outcomes that can be averted if treated from a young age.

Summary

Abstract

Aim

To empower a large whānau (extended family) with a history of severe premature heart disease and familial hypercholesterolemia (FH).

Method

After broad consultation a Hui was held to discuss how to better manage this issue to ensure present and future generations were appropriately screened and treated.

Results

A closed social media page with detailed information on how to manage and screen FH that includes a family tree (for those who consent) has been created. The whānau, facilitated by health professionals, have ownership of their health. This has led to an uptake of screening and treatment for FH with whānau who are now able to inform local health professionals about their disorder.

Conclusion

FH is the most common dominant genetic disorder in humans and causes premature heart disease and death. Current approaches are dependent on index patients presenting for cascade screening and do not incorporate the needs and views of the extended whānau. Establishing a partnership with the whānau and giving back control of health information is crucial to ensure equity. A national systematic programme is also needed to manage this condition with important health outcomes that can be averted if treated from a young age.

Author Information

Jocelyne Benatar, Auckland District Health Board, Auckland; Tara Evile, University of Auckland, Auckland; Helen Wihongi, Director of Māori Health Research, Waitemata and Auckland District Health Boards; The Whānau.

Acknowledgements

Denise Staple—Rural Practice Nurse. Nicola Reid and Dr Andrew Laurie—at Cardiovascular Prevention & Lipid Disorders, Canterbury District Health Board.

Correspondence

Dr Jocelyne Benatar, Auckland District Health Board, Auckland.

Correspondence Email

jbenatar@adhb.govt.nz

Competing Interests

Nil.

1. Vallejo-Vaz AJ, Ray KK. Epidemiology of familial hypercholesterolaemia: Community and clinical. Atherosclerosis 2018; 277: 289–297.

2. Haase A, Goldberg AC. Identification of people with heterozygous familial hypercholesterolemia. Curr Opin Lipidol 2012; 23: 282–289.

3. Austin MA, Hutter CM, Zimmern RL, Humphries SE. Genetic causes of monogenic heterozygous familial hypercholesterolemia: a HuGE prevalence review. Am J Epidemiol 2004; 160:407–420.

4. Williams RR, Hunt SC, Schumacher MC, Hegele RA, Leppert MF, et al. Diagnosing heterozygous familial hypercholesterolemia using new practical criteria validated by molecular genetics. Am J Cardiol 1993; 72:171–176.

5. Abdul-Razak S, Rahmat R, Mohd Kasim A, Rahman TA, Muid S, et al. Diagnostic performance of various familial hypercholesterolaemia diagnostic criteria compared to Dutch lipid clinic criteria in an Asian population. BMC cardiovascular disorders 2017; 17:264–264.

6. Harada-Shiba M, Arai H, Ishigaki Y, Ishibashi S, Okamura T, et al. Guidelines for Diagnosis and Treatment of Familial Hypercholesterolemia 2017. J Atheroscler Thromb 2018; 25:751–770.

7. Knowles JW, Rader DJ, Khoury MJ. Cascade Screening for Familial Hypercholesterolemia and the Use of Genetic Testing. JAMA 2017; 318:381–382.

8. Mach F, Baigent C, Catapano AL, Koskinas KC, Casula M, et al. (2019) 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk: The Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS). European Heart Journal.

9. Farnier M, Civeira F, Descamps O. How to implement clinical guidelines to optimise familial hypercholesterolaemia diagnosis and treatment. Atheroscler Suppl 2017; 26:25–35.

10. Borissov B, Urbich M, Georgieva B, Tsenov S, Villa G. Cost-effectiveness of evolocumab in treatment of heterozygous familial hypercholesterolaemia in Bulgaria: measuring health benefit by effectively treated patient-years*. Journal of Market Access & Health Policy 2017; 5:1412753.

11. Liyanage KE, Burnett JR, Hooper AJ, van Bockxmeer FM. Familial hypercholesterolemia: epidemiology, Neolithic origins and modern geographic distribution. Critical Reviews in Clinical Laboratory Sciences 2011; 48:1–18.

12. Jones CP. Invited Commentary: “Race,” Racism, and the Practice of Epidemiology. American Journal of Epidemiology 2001; 154:299–304.

13. Health Mo (2019) Wai 2575 Māori Health Trends Report. Wellington: Ministry of Health.

14. Laurie AD, Scott RS, George PM. Genetic screening of patients with familial hypercholesterolaemia (FH): a New Zealand perspective. Atheroscler Suppl 2004; 5:13–15.

Contact diana@nzma.org.nz
for the PDF of this article

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Familial hypercholesterolemia (FH) is the most common dominant genetic disorder in humans and causes premature heart disease and death. The incidence of heterozygous FH in the general global population is 1:250;1 however, rates in  Māori are not known. It is characterised by very high-level low-density lipoprotein-cholesterol (LDL-c), systemic manifestation of cholesterol deposition (tendon xanthoma, xanthlasma and arcus cornealis). Three clinical definitions for FH are used to identify people with possible FH;2–4 the most commonly used are the Dutch Lipid Clinic and Simon Broome criteria.5Early detection and treatment of individuals with this disorder is important to prevent the early development of cardiovascular disease. Current guidelines recommend screening of high-risk individuals, and then cascade screening of family members in childhood. 6 Cascade screening using the genetic test is recommended once the proband for DNA testing is identified. Studies have shown that 15–20% of family members are incorrectly classified based on cholesterol testing alone.7 Treatment of gene positive offspring is recommended to start at the age of 8–10 years with the aim of reaching a target LDL-c <3.5mmol/L or to less than 50% if the target is not achievable.6,8 Early identification of FH in children is vital as children with FH can have normal life expectancies if treatment is started early.9 The most common mutation causing FH is in the LDL receptor, identified in ~90% of cases. The LDL receptor mediates endocytosis of LDL-c into cells including hepatocytes.

A number of medications are recommended to treat FH; intensive statin therapy, ezetimibe and protein convertase subtilisin/kexin type 9 (PCSK9) inhibitors. At present, New Zealand has a limited range of drugs to treat hypercholesterolemia. For example, rosuvastatin, the most potent statin, or PCSK9 inhibitors are not funded for FH, limiting choice in individuals at very high risk of premature heart disease (See Figure 1, patient experience). Studies suggest that expensive medications like PCSK9 inhibitors are cost effective as they significantly reduce cardiovascular events in FH.10

Figure 1: Patient experiences.

LDLR:c.2312-3C>A splicing mutation

A specific mutation in the LDL receptor, LDLR:c.2312-3C>A splicing mutation, was described in a Māori man who was working in western Australia who presented with coronary artery disease in his 30s. He had a strong whānau (extended family) history of premature death from heart disease.11 He described a whānau blighted by premature heart disease and death and a whānau legend of “a white woman” who had married their Māori ancestor at the turn of the 20th century who had “brought a curse on them”. The gene has been traced back to whānau with origins in Valencia (in eastern Spain), with an ancestor moving to northern France during the 1600s. Descendants then migrated to England, and subsequently to New Zealand whereupon one ancestor married a Māori man and then moved to in a remote area of New Zealand. This union resulted in a very large whānau afflicted with premature heart disease and death. Endocrinologists visited this remote area and tested a number of members of the whānau and confirmed the presence of this mutation. However, no systemic screening and treatment was initiated as no national system was in place to manage this.

In 2018, three members of the extended whānau presented to the cardiology department at Auckland City Hospital with very high LDL-c; one male in his early 30s with significant atherosclerosis requiring stents and two females in their 20s with tendon xanthomata. They all told a story of a large extended whānau affected by premature heart disease with high rates of premature death. They remembered the endocrinologists that had visited the whānau about 15 years earlier who had taken samples, but they were not sure of the diagnosis. Contact was made with the Christchurch Laboratory who had records of an identified LDL-c receptor mutation in this whānau. Confirmation of the presence of the same mutation was made in the three index patients. This revealed issues in the health system in terms of systemic screening and treatment of whānau now scattered across the country and the world.

The consequence of a lack of a national strategy for FH has resulted in a fragmented and disparate service for patients (Figure 2, practice nurse experience). There are pockets of experts in some places, but there is also little awareness of how to treat and manage this condition in the general medical community. For example, few clinicians without a specific interest in FH understand that genetic testing and treatment needs to be implemented in childhood (Figure 3, patient experience).

Figure 2: Rural nurse experience.

Figure 3: Patient experience.

There was no prospect of a national service in the near future; however, a solution for this whānau was needed urgently.

Methods

Consultation with a broad range of invested stakeholders was undertaken to determine how to best ensure that the whānau were empowered to manage this condition across generations and geography. Initial consultation was with index whānau and then kaumātua (elders). Then broader consultation was with the national genetic services, the paediatric metabolic department and the director of Māori Health Research at the Waitemata and Auckland District Health Boards (DHB) Dr Helen Wihongi. The discussion with Dr Wihongi focused on how to ensure that tikanga Māori (custom, ethics) was taken into account especially around the issues regarding taking and storing of blood, as well as who owned the data. We reviewed the current consent form used by the genetic services to ensure this explained that blood samples may be stored and that this may have implications for the whakapapa (genealogy). The form also explains that the samples are kept in New Zealand and are not given to third parties. There is currently no national genetic database for FH in New Zealand so no one currently holds the data other than the treating physician and laboratory. We also discussed how to balance the needs of the extended whānau and the privacy of the individual. The genetic and metabolic services provided support for cascade screening and were happy to be part of the hui. The local general practice was also consulted to assess their needs and opinions on how best to move forward.

Hui

A hui (social gathering) was organised to inform the whānau about the genetic mutation and discuss how best to manage this to ensure access to testing and treatments. This was attended by the whānau, kaumātua, doctors and nurses from the local health practice, the national genetic services, a doctor from ADHB and a health science student.

On arrival at the marae (meeting ground) there was a pōwhiri (formal welcome), which included a karanga (call) to the manuhiri (guests), and a response. After a number of speeches and songs by the men, we all introduced ourselves. After a mihi (introduction) and waiata (song) the doctor gave a talk that centred on what FH is, what age to screen and treat FH, how the gene is transmitted, how to organise testing and risks and benefits of treatment. The geneticists then explained genetic and cascade testing and how it is undertaken. The formal presentations by the doctors and geneticists lasted two hours, and the rest of the hui was comprised of open discussions. There was also a need to acknowledge the past. The whānau felt used and let down by previous doctors who had visited and taken samples but gave no information on how to prevent further deaths. This had to be acknowledged by the medical team. The pace of discussions was driven primarily by the needs of the whānau. For example, when the doctor spoke too fast or used medical terms, the whānau backtracked by asking questions. There was a strong feeling that decisions on how to manage this issue could not be made in haste, and that we were all in this together (He waka eke noa (A canoe which we are all in with no exception)). There was agreement that for any solution to work, it needed to be acceptable to everyone and according to the Kaupapa Māori principles of self-determination, involvement of the whānau and āta (respectful relationships).

Issues discussed were:

• Who should have access to the information and how to balance the rights of the individual vs the rights of the whānau

• How to cascade screen whānau and ensure this is done in perpetuity

• How to ensure whānau members living in other counties access the information

• How to ensure whānau is updated on new information regarding treatment

• How to access novel agents shown to work in FH

• Can PHARMAC be approached for access for new medications for this whānau under Te Tiriti o Waitangi obligations

• How to manage blood samples, ethical issues with privacy and storage of blood

Results

A whānau member was nominated to run a closed social media page for the whānau that includes a family tree. The closed social media page can only be accessed by members and Facebook administration. The Facebook administrators monitor closed sites only to “promote safety and security on and off of our products”. Data is not given to third parties. The whānau member acts as a gatekeeper so that new posts can be sent to them and can only be uploaded by them. All extended whānau are invited to be part of this Facebook site, and the addition of the genetic test result to the family tree is completely up the individual. A printable letter to show health professionals was created with general information about FH, diagnosis and treatment, the proband identified and steps for genetic testing (Figure 4). A consent form for testing and a pre-filled laboratory form with the proband are also available. The consent form is the standard consent form used by the National Genetic Services for New Zealand. It requires specific and separate consent for storage of samples. As new treatments become available, the ADHB doctor sends the information to the gatekeeper who then uploads this to keep extended whānau informed of latest treatments. The clinician has no access to the Facebook page but is in close contact with the moderator to address concerns, misinformation and misconceptions about FH and treatments to lower cholesterol.

Figure 4:

This whānau social media page will also engage with whakahekenga (descendants) within the whānau in the long term. This will allow all to make informed decisions on the need to be tested, especially if no data is available about their immediate whānau.

At present, the social media page is active with a number of whānau members active on it. As a direct result, genetic testing and appropriate treatment has been initiated in 17 whānau members. Intensive statin treatment has been initiated in two children and a couple of young adults; this has the potential to ensure they reach normal life expectancy. The hope is that testing will be extended to all young children when they reach the age of eight. Only one surviving whānau member over the age of 50 has been found to have the mutation; however, this LDL-c is lower than others with the mutation.

Results of genetic tests are known only to the testing laboratory, the treating physician and the person tested. Results of genetic tests are only sent to the ADHB doctor if this is specifically requested by the patient. No data is centrally held by genetic services at this point as there is no national genetic service for FH. This ensures data for and about this Māori whānau can be safeguarded and protected from parties who are not directly involved with their care.

Discussion

The experience of this whānau underscores a number of issues. The first is that there is no systematic national approach to FH in New Zealand. It is not possible for clinicians to test and treat families from other DHBs or refer them to a national screening service as none exists. In this particular instance, testing was undertaken by clinicians from another DHB for research purposes, but there was no ability to refer for clinical follow up, cascade screening or appropriate treatment. A missed opportunity resulted to prevent premature cardiovascular events and led to an injustice perpetrated on the whānau. This resulted in inequity though three pathways; ongoing exposure to a modifiable and potent risk factor for CVD, difference in the quality of care received and differential access to healthcare.12 Had the whānau lived within the researchers’ DHB, they would have been appropriately managed. A priority of the hui was acknowledging that there had been an injustice and that that this had led to ongoing harm. The whānau wanted assurances it would never happen to them again and that measures were put in place to ensure that the whānau had ownership and control of their health information.

A second issue is that the system prioritises the needs and privacy of the individual over the whānau. This Westernised approach to health ignores the cornerstone of health; taha whānau (family health).13 In this instance, if one person misses testing, other members of the whānau further down the ‘cascade stream’, such as children will not be tested. This may be useful in societies where the needs of the individual are paramount, but not where the collective is just as important.

Despite calls over a number of years for a national screening registry for FH,14 none has eventuated. The argument for a registry is that it will allow for efficient screening and treatment of gene positive children and young adults to prevent future cardiovascular events. The argument against this is that it is a common genetic disorder picked up by a cheap lipid test, and that gene testing may be prohibitively expensive for the country. This approach ignores the benefits of cascade screening and treating gene positive children. It has resulted in a haphazard approach to FH with disparity in care across the country. For this whānau it has led to ongoing hurt caused by young family members developing often fatal premature heart disease.

Conclusion

FH is the most common dominant genetic disorder in humans and causes premature heart disease and death. Current approaches in New Zealand are dependent on index patients presenting for cascade screening and do not incorporate the needs and views of the extended whānau. Establishing a partnership with the whānau and giving back control of health information is crucial to ensure equity. A national systematic programme is also needed to manage this condition with important health outcomes that can be averted if treated from a young age.

Summary

Abstract

Aim

To empower a large whānau (extended family) with a history of severe premature heart disease and familial hypercholesterolemia (FH).

Method

After broad consultation a Hui was held to discuss how to better manage this issue to ensure present and future generations were appropriately screened and treated.

Results

A closed social media page with detailed information on how to manage and screen FH that includes a family tree (for those who consent) has been created. The whānau, facilitated by health professionals, have ownership of their health. This has led to an uptake of screening and treatment for FH with whānau who are now able to inform local health professionals about their disorder.

Conclusion

FH is the most common dominant genetic disorder in humans and causes premature heart disease and death. Current approaches are dependent on index patients presenting for cascade screening and do not incorporate the needs and views of the extended whānau. Establishing a partnership with the whānau and giving back control of health information is crucial to ensure equity. A national systematic programme is also needed to manage this condition with important health outcomes that can be averted if treated from a young age.

Author Information

Jocelyne Benatar, Auckland District Health Board, Auckland; Tara Evile, University of Auckland, Auckland; Helen Wihongi, Director of Māori Health Research, Waitemata and Auckland District Health Boards; The Whānau.

Acknowledgements

Denise Staple—Rural Practice Nurse. Nicola Reid and Dr Andrew Laurie—at Cardiovascular Prevention & Lipid Disorders, Canterbury District Health Board.

Correspondence

Dr Jocelyne Benatar, Auckland District Health Board, Auckland.

Correspondence Email

jbenatar@adhb.govt.nz

Competing Interests

Nil.

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7. Knowles JW, Rader DJ, Khoury MJ. Cascade Screening for Familial Hypercholesterolemia and the Use of Genetic Testing. JAMA 2017; 318:381–382.

8. Mach F, Baigent C, Catapano AL, Koskinas KC, Casula M, et al. (2019) 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk: The Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS). European Heart Journal.

9. Farnier M, Civeira F, Descamps O. How to implement clinical guidelines to optimise familial hypercholesterolaemia diagnosis and treatment. Atheroscler Suppl 2017; 26:25–35.

10. Borissov B, Urbich M, Georgieva B, Tsenov S, Villa G. Cost-effectiveness of evolocumab in treatment of heterozygous familial hypercholesterolaemia in Bulgaria: measuring health benefit by effectively treated patient-years*. Journal of Market Access & Health Policy 2017; 5:1412753.

11. Liyanage KE, Burnett JR, Hooper AJ, van Bockxmeer FM. Familial hypercholesterolemia: epidemiology, Neolithic origins and modern geographic distribution. Critical Reviews in Clinical Laboratory Sciences 2011; 48:1–18.

12. Jones CP. Invited Commentary: “Race,” Racism, and the Practice of Epidemiology. American Journal of Epidemiology 2001; 154:299–304.

13. Health Mo (2019) Wai 2575 Māori Health Trends Report. Wellington: Ministry of Health.

14. Laurie AD, Scott RS, George PM. Genetic screening of patients with familial hypercholesterolaemia (FH): a New Zealand perspective. Atheroscler Suppl 2004; 5:13–15.

Contact diana@nzma.org.nz
for the PDF of this article

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