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Psychological issues and cognitive impairment in adults with familial hypercholesterolemia

Psychological issues and cognitive impairment in adults with familial hypercholesterolemia Abstract A literature review about depression, anxiety, illness perception and neurocognitive impairment in adults with familial hypercholesterolemia (FH) was performed. Through PubMed and PsycINFO published studies from 1980 until March 2017 were searched. Two papers assessed depression and anxiety. Four papers explored illness perception. Five studies assessed cognitive impairment. Mean depression and anxiety scores were within normal range. From the reviewed research, it can be concluded that deficits in executive functioning and memory appear in FH patients between 18 and 40 years old, and mild cognitive impairment in older than 50. The research in the field of the present review is relatively recent: all the studies have been published in the current century. Further research should be done using complete standardized neuropsychological assessment and brain imaging techniques. Studies exploring the possible influence of cognitive deficits on adherence should be conducted also. Adults, anxiety, cognitive impairment, depression, familial hypercholesterolemia, illness perception Introduction Familial hypercholesterolemia (FH) is a common genetic disorder. Mutations in the LDL receptor (LDLR) gene are the most frequent cause of FH. However, mutations in other genes, such as apolipoprotein B (APOB) or proprotein convertase subtilisin/kexin type 9 (PCSK9), have been identified and may lead to a similar phenotype (1,2). FH is characterized by elevated serum levels of atherogenic particles, including low-density lipoprotein cholesterol and lipoprotein (a). Elevated LDL cholesterol leads to atherosclerotic plaque deposition in coronary arteries and proximal aorta, increasing the risk of premature cardiovascular disease. However, this risk is modifiable by medication and healthy lifestyle. Long-term treatment with statins has decreased the cardiovascular risk to the levels of the general population (3–8). Long-term treatment requires adherence to physician recommendations. Psychological issues such as depression and neurocognitive impairment might act as barriers to adherence. Poor adherence might result in worse outcomes. With respect to cognitive impairment, though some studies report an association between high total cholesterol level and cognitive decline, other studies report no association between these variables (9). If patients have memory deficits or executive dysfunctions, they might forget to take pills and they might experience problems in organizing daily adherence behaviour, respectively. In relation to depression, depression has been associated with poor adherence to treatment in several chronic diseases (10). Elevated as well as low cholesterol levels have been associated with depression. Depressed patients with high levels of cholesterol appear more likely to present anxiety and to be treatment-resistant. Authors suggest that elevated cholesterol levels may lead to lower 5HT receptors sensitivity and to the inhibition of dendritic outgrowth (11). In addition, current studies report high cholesterol levels in patients with anxiety disorders. Elevated cholesterol may contribute to anxiety by altering the sensibility of GABA receptors (11). The aim of this review is to summarize the current evidence on depression, anxiety, illness perception and cognitive impairment in adults with FH. Psychological and neuropsychological issues are of interest for family doctors due to the holistic nature of this speciality. In general, psychological and neuropsychological dysfunctions have influence on medical adherence, prognosis and quality of life. Although FH can be asymptomatic, it is possible to detect it in childhood and adulthood by means of the clinical laboratory studies common in primary care. Because family doctors have patients of all ages and usually indicate these clinical laboratory studies it is possible for them to identify FH patients of different ages while doing daily work. As was mentioned above, FH is a common genetic disorder. If the family doctor finds a case of the disease, it is probable that a relative also has the disease. Because family medicine provides continuing and comprehensive health care for the individual in the context of the family, it should be easier the screening of the pathology in the whole family and the corresponding genetic counselling. Although in FH clinical guidelines there are no references to family physicians, the family doctor could have a leading role in the detection of patients and relatives, genetic counselling, clinical approach to the disease and referral to specialists. This is important because recent papers stress underdiagnosis and undertreatment of the disease and remark that systematic screening of healthy adults remains a challenge (1,12–14). Methods The online databases PubMed and PsycINFO were searched. The main data terms were the following: FH + depression, FH + anxiety, FH + illness perception, FH + cognitive impairment, FH + personality, FH + psychology. All quantitative studies published in English found in the mentioned databases from 1980 until March 2017 were included. Qualitative studies and case studies were excluded. Results Two studies assessed depression and anxiety (15,16) (see Table 1). Four papers explored illness perception (15,17–19) (see Table 2). Five studies assessed cognitive impairment in FH patients (20–24) (see Table 3). Table 1. Results of literature review between 1980 and March 2017 First author, year and reference number . Study design and methods . Main results . Marteau et al. (15) Randomized controlled study, mutation found in 74 patients, diagnosis not confirm using genetic testing in 139 cases, non-genetic diagnosis in 103 participants No statistical differences in depression and anxiety scores between three groups 6 months follow-up Holman et al. (16) Case-control study, 185 FH patients and 1485 healthy subjects over 18 years old No significant differences in anxiety and depression among groups were found First author, year and reference number . Study design and methods . Main results . Marteau et al. (15) Randomized controlled study, mutation found in 74 patients, diagnosis not confirm using genetic testing in 139 cases, non-genetic diagnosis in 103 participants No statistical differences in depression and anxiety scores between three groups 6 months follow-up Holman et al. (16) Case-control study, 185 FH patients and 1485 healthy subjects over 18 years old No significant differences in anxiety and depression among groups were found Anxiety and depression in adults with familial hypercholesterolemia. FH, familial hypercholesterolemia. Open in new tab Table 1. Results of literature review between 1980 and March 2017 First author, year and reference number . Study design and methods . Main results . Marteau et al. (15) Randomized controlled study, mutation found in 74 patients, diagnosis not confirm using genetic testing in 139 cases, non-genetic diagnosis in 103 participants No statistical differences in depression and anxiety scores between three groups 6 months follow-up Holman et al. (16) Case-control study, 185 FH patients and 1485 healthy subjects over 18 years old No significant differences in anxiety and depression among groups were found First author, year and reference number . Study design and methods . Main results . Marteau et al. (15) Randomized controlled study, mutation found in 74 patients, diagnosis not confirm using genetic testing in 139 cases, non-genetic diagnosis in 103 participants No statistical differences in depression and anxiety scores between three groups 6 months follow-up Holman et al. (16) Case-control study, 185 FH patients and 1485 healthy subjects over 18 years old No significant differences in anxiety and depression among groups were found Anxiety and depression in adults with familial hypercholesterolemia. FH, familial hypercholesterolemia. Open in new tab Table 2. Results of literature review between 1980 and March 2017 First author, year and reference number . Study design and methods . Main results . Marteau et al. (15) Randomized controlled study, mutation found in 74 patients, diagnosis not confirm using genetic testing in 139 cases, non-genetic diagnosis in 103 participants Patients whose diagnosis confirmed using DNA testing perceived diagnosis more accurate and believed more strongly that genes controlled their cholesterol level, 1 week and 6 months after diagnosis Senior et al. (17) Cross-sectional study, 336 FH patients between 24 and 79 years old Patients that report total adherence perceived themselves to be less at risk for raised cholesterol, and attribute importance to genes and cholesterol in causing a potential heart attack Claassen et al. (18) Cross-sectional study, 81 FH patients over 18 years old The adoption of a healthy lifestyle was perceive less effective than medication in reducing the risk of cardiovascular disease and was positively associated with a family history of cardiovascular disease Hagger et al. (19) Cross-sectional study, 110 FH patients between 23 and 80 years old Patients’ confidence in performing physical activity predicted their intentions for physical exercise First author, year and reference number . Study design and methods . Main results . Marteau et al. (15) Randomized controlled study, mutation found in 74 patients, diagnosis not confirm using genetic testing in 139 cases, non-genetic diagnosis in 103 participants Patients whose diagnosis confirmed using DNA testing perceived diagnosis more accurate and believed more strongly that genes controlled their cholesterol level, 1 week and 6 months after diagnosis Senior et al. (17) Cross-sectional study, 336 FH patients between 24 and 79 years old Patients that report total adherence perceived themselves to be less at risk for raised cholesterol, and attribute importance to genes and cholesterol in causing a potential heart attack Claassen et al. (18) Cross-sectional study, 81 FH patients over 18 years old The adoption of a healthy lifestyle was perceive less effective than medication in reducing the risk of cardiovascular disease and was positively associated with a family history of cardiovascular disease Hagger et al. (19) Cross-sectional study, 110 FH patients between 23 and 80 years old Patients’ confidence in performing physical activity predicted their intentions for physical exercise Illness perception in adults with familial hypercholesterolemia. FH, familial hypercholesterolemia. Open in new tab Table 2. Results of literature review between 1980 and March 2017 First author, year and reference number . Study design and methods . Main results . Marteau et al. (15) Randomized controlled study, mutation found in 74 patients, diagnosis not confirm using genetic testing in 139 cases, non-genetic diagnosis in 103 participants Patients whose diagnosis confirmed using DNA testing perceived diagnosis more accurate and believed more strongly that genes controlled their cholesterol level, 1 week and 6 months after diagnosis Senior et al. (17) Cross-sectional study, 336 FH patients between 24 and 79 years old Patients that report total adherence perceived themselves to be less at risk for raised cholesterol, and attribute importance to genes and cholesterol in causing a potential heart attack Claassen et al. (18) Cross-sectional study, 81 FH patients over 18 years old The adoption of a healthy lifestyle was perceive less effective than medication in reducing the risk of cardiovascular disease and was positively associated with a family history of cardiovascular disease Hagger et al. (19) Cross-sectional study, 110 FH patients between 23 and 80 years old Patients’ confidence in performing physical activity predicted their intentions for physical exercise First author, year and reference number . Study design and methods . Main results . Marteau et al. (15) Randomized controlled study, mutation found in 74 patients, diagnosis not confirm using genetic testing in 139 cases, non-genetic diagnosis in 103 participants Patients whose diagnosis confirmed using DNA testing perceived diagnosis more accurate and believed more strongly that genes controlled their cholesterol level, 1 week and 6 months after diagnosis Senior et al. (17) Cross-sectional study, 336 FH patients between 24 and 79 years old Patients that report total adherence perceived themselves to be less at risk for raised cholesterol, and attribute importance to genes and cholesterol in causing a potential heart attack Claassen et al. (18) Cross-sectional study, 81 FH patients over 18 years old The adoption of a healthy lifestyle was perceive less effective than medication in reducing the risk of cardiovascular disease and was positively associated with a family history of cardiovascular disease Hagger et al. (19) Cross-sectional study, 110 FH patients between 23 and 80 years old Patients’ confidence in performing physical activity predicted their intentions for physical exercise Illness perception in adults with familial hypercholesterolemia. FH, familial hypercholesterolemia. Open in new tab Table 3. Results of literature review between 1980 and March 2017 First author, year and reference number . Study design and methods . Main results . Ariza et al. (20) Case-control study, 10 FH patients and 18 healthy controls aged between 18 and 40 years Deficits in executive performance and verbal memory Mauri et al. (21) Case-control study, 18 FH patients and 18 healthy controls aged between 18 and 40 years Deficits in episodic memory Pappolla et al. (22) Case-control study, 70 FH patients and 70 healthy subjects older than 50 years Deficits in memory, visuospatial orientation and executive function. Meet criteria for mild cognitive impairment: 22.9% FH patients and 2.8% from the control group Hyttinen et al. (23) Case-control study, 37 FH patients and 309 healthy subjects aged between 65 and 84 years FH patients receiving long term statin had better episodic memory than controls Zambón et al. (24) Case-control study, 47 FH patients and 70 non-familial hypercholesterolemia older than 50 years old Mild cognitive impairment was report in FH participants, 21.3% (vs. 2.9%) First author, year and reference number . Study design and methods . Main results . Ariza et al. (20) Case-control study, 10 FH patients and 18 healthy controls aged between 18 and 40 years Deficits in executive performance and verbal memory Mauri et al. (21) Case-control study, 18 FH patients and 18 healthy controls aged between 18 and 40 years Deficits in episodic memory Pappolla et al. (22) Case-control study, 70 FH patients and 70 healthy subjects older than 50 years Deficits in memory, visuospatial orientation and executive function. Meet criteria for mild cognitive impairment: 22.9% FH patients and 2.8% from the control group Hyttinen et al. (23) Case-control study, 37 FH patients and 309 healthy subjects aged between 65 and 84 years FH patients receiving long term statin had better episodic memory than controls Zambón et al. (24) Case-control study, 47 FH patients and 70 non-familial hypercholesterolemia older than 50 years old Mild cognitive impairment was report in FH participants, 21.3% (vs. 2.9%) Cognitive deficits in adults with familial hypercholesterolemia. FH, familial hypercholesterolemia. Open in new tab Table 3. Results of literature review between 1980 and March 2017 First author, year and reference number . Study design and methods . Main results . Ariza et al. (20) Case-control study, 10 FH patients and 18 healthy controls aged between 18 and 40 years Deficits in executive performance and verbal memory Mauri et al. (21) Case-control study, 18 FH patients and 18 healthy controls aged between 18 and 40 years Deficits in episodic memory Pappolla et al. (22) Case-control study, 70 FH patients and 70 healthy subjects older than 50 years Deficits in memory, visuospatial orientation and executive function. Meet criteria for mild cognitive impairment: 22.9% FH patients and 2.8% from the control group Hyttinen et al. (23) Case-control study, 37 FH patients and 309 healthy subjects aged between 65 and 84 years FH patients receiving long term statin had better episodic memory than controls Zambón et al. (24) Case-control study, 47 FH patients and 70 non-familial hypercholesterolemia older than 50 years old Mild cognitive impairment was report in FH participants, 21.3% (vs. 2.9%) First author, year and reference number . Study design and methods . Main results . Ariza et al. (20) Case-control study, 10 FH patients and 18 healthy controls aged between 18 and 40 years Deficits in executive performance and verbal memory Mauri et al. (21) Case-control study, 18 FH patients and 18 healthy controls aged between 18 and 40 years Deficits in episodic memory Pappolla et al. (22) Case-control study, 70 FH patients and 70 healthy subjects older than 50 years Deficits in memory, visuospatial orientation and executive function. Meet criteria for mild cognitive impairment: 22.9% FH patients and 2.8% from the control group Hyttinen et al. (23) Case-control study, 37 FH patients and 309 healthy subjects aged between 65 and 84 years FH patients receiving long term statin had better episodic memory than controls Zambón et al. (24) Case-control study, 47 FH patients and 70 non-familial hypercholesterolemia older than 50 years old Mild cognitive impairment was report in FH participants, 21.3% (vs. 2.9%) Cognitive deficits in adults with familial hypercholesterolemia. FH, familial hypercholesterolemia. Open in new tab Depression and anxiety Mean depression and anxiety scores were within normal range (15,16). One paper reported no significant differences in anxiety and depression scores between FH patients and controls (16). FH patients to whom a mutation was found were less anxious than FH patients with no-genetic diagnosis for FH 1 week after diagnosis but not 6 months after diagnosis (15). Illness perception Patients that report total adherence perceived themselves to be less at risk for raised cholesterol, and attribute importance to genes and cholesterol in causing a potential heart attack (17). The adoption of a healthy lifestyle was perceived less effective than medication in reducing the risk of cardiovascular disease and was associated with a family history of cardiovascular disease (18). Patients whose diagnosis was confirmed using DNA testing perceived diagnosis more accurate than patients with no-genetic diagnosis for FH and patients with no confirmed mutation, 1 week and 6 months after diagnosis. They believed more strongly that genes controlled their cholesterol level 1 week and 6 months after diagnosis in comparison with patients with no-genetic diagnosis of FH and patients with no confirmed mutation. In addition, patients with diagnosis confirmed using DNA testing believe less strongly in the efficacy of diet in reducing cholesterol level at 6 months follow-up comparing with patients in which no mutation was found (15). One study found that patients’ beliefs about how significant others see their healthy eating behaviour predicted patient’s intentions for healthy eating. Moreover, patients’ confidence in performing physical activity predicted their intentions for physical exercise (19). Cognitive impairment Three manuscripts and two abstracts presented at international congresses explore cognitive function in FH patients (20–24). Authors reported deficits in executive functioning and memory (20–22). One study found that patients with long-term statin therapy had better episodic memory than controls (23). Two studies reported mild cognitive impairment, 21.3 and 22.9%, respectively (22,24). Discussion The small number of studies (n = 10) available for review demonstrate research in the field is relatively recent. Studies reviewed provide evidence of the presence of cognitive impairment and absence of depression or anxiety in FH patients. Studies that assess cognition in FH report more severe cognitive dysfunctions in older patients. They report deficits in memory and executive functions in patients between 18 and 40 and mild cognitive impairment in patients more than 50. Mild cognitive impairment, considered as an intermediate stage between the expected cognitive decline of normal aging and dementia, may increase the risk of later progressing to dementia. From a pathophysiological point of view, cognitive deficits could be a consequence of long term cholesterol effects on the brain. Plasma cholesterol is able to affect brain functions by an oxygenated derivate of cholesterol. Oxygenated derivate of cholesterol is able to pass lipophilic membranes and upregulate the expression of various inflammatory cytokines and chemokines (25–28). A consequence of this upregulation could be an increase in neuroinflammatory mediators that might play a primary role in cognitive deficits. Inflammation and the associated oxidative stress promoted by inflammation might lead to cognition dysfunctions. Astrocytes and microglia could increase free radical production and other neurotoxic mediators that generate neuronal damage (25–28). Regarding the elderly FH patients, it is possible to expect a more severe cognitive impairment relative to the younger FH patients, due to more years of exposure to cholesterol and greater fluctuations in bad cholesterol concentrations. Sustained greater fluctuations in blood cholesterol might be associated with endothelial dysfunction. This endothelial dysfunction could lead to lower brain blood flow in the brain and, as a consequence, to worse cognitive performance. A recent study (29) reported that greater fluctuations in low-density lipoprotein cholesterol were associated with lower cognitive performance regardless of average bad cholesterol levels or use of cholesterol-lowering statin drugs, in adults (without FH) between 70 and 82 years old. We could speculate that the fluctuations of cholesterol in FH elderly patients are more pronounced and frequent due to the genetic background. The consequence of fluctuations in cholesterol levels in younger FH patients should not be as severe as in the older FH patients because in the younger ones the neurodegenerative processes associated with age are not as clear-cut as in elderly ones. Inflammation and oxidative stress, related with cholesterol effects on brain overtime, could accelerate ageing processes and the emergence of cognitive dysfunctions. A paper reports that FH patients with long-term statin treatment had better episodic memory than controls (20). The results of this study suggest statins have beneficial effects on cognition. Detailed mechanisms are unknown. However, there is evidence that statins have anti-inflammatory and antioxidant effects. Statins might have antioxidant effects reducing the production of reactive oxygen species, inhibiting the assembly and activation of the NADPH complex (NADPH: nicotinamide adenine dinucleotide phosphate). In addition, statins might have anti-inflammatory effects inhibiting the activation of the immune response, interfering with the process of antigen presentation, reducing cytokines-induced expression of co stimulatory molecules on immune cells, microglia and endothelium (30,31). Studies that assessed depression in FH patients reported depression scores within normal range. However, most of these patients were treated with statins. Because of this, it is worth mentioning antidepressant effects of statins. Statins antidepressant effects may be due to its ability to reduce oxidative stress and inflammatory cytokines (32,33). All studies reviewed explored illness perception using the common-sense model. Only one paper explores illness perception using the theory of planned behaviour. Using the common-sense model (34) it is possible to explore beliefs about the name of the disease and clinical manifestations, time-course, personal impact, causal factors and feasibility of control of FH. Using the theory of planned behaviour (35) is possible to explore beliefs about the consequences of the behaviour, beliefs about the normative expectations of others and beliefs about the presence of factors that may facilitate or impede behaviour. The adoption of a healthy lifestyle is often perceived by FH patients as less effective than medication in reducing the risk of cardiovascular disease and controlling of cholesterol levels. Patients might find it more difficult to maintain behavioural changes over time (such as physical exercise and healthy eating behaviour) than to take the prescribed medication every day. However, if patients perceive that having a healthy lifestyle reduces the risk for raised cholesterol levels, they probably will be more adherent to lifestyle recommendations. Family physicians can inform patients and relatives about FH control, emphasizing the importance of healthy behaviour. According to the theory of planned behaviour (35), beliefs about the normative expectations of relatives are important in the appearance of intentions and later concretions of healthy behaviours. Through information about FH and FH control, family physicians can help to generate in the patient’s family members beliefs that may favourably influence the patient’s expectations about his or her illness. The research that employs the theory of planned behaviour suggests that efforts of the family doctors in relation with parents should emphasize healthy eating. In the reviewed studies that explore cognition in FH, there are some missing items and limitations that need to be pointed out. Although patients with stroke were excluded in all papers, patients with other diseases that may influence cognition, such as psychiatric and metabolic diseases, were excluded in only two studies (20,24). In two papers, the authors evaluated only memory (21,23). This limits the scope of the research since no complete neuropsychological assessment was performed. Only two studies used brain-imaging techniques (22,24). In one of them images allowed the exclusion of patients with vascular lesions (22). In the other one, in one fifth of the patients, brain images were obtained with mainly descriptive aims (24). Based on the results of the previously reviewed works and missing subjects, it is recommended that future studies explore cognitive function before and following statin treatment. These researches should be done using complete standardized neuropsychological assessment and brain imaging techniques to bring evidence about the beneficial effects of statins on cognition. Furthermore, studies exploring the possible influence of cognitive deficits on adherence should be conducted. Declaration Ethical approval: The manuscript is a literature review. Literature review does not require ethical approval. Funding: none. Conflict of interest: none. References 1. Nordestgaard BG Chapman MJ Humphries SE et al. .; European Atherosclerosis Society Consensus Panel . 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Google Scholar Crossref Search ADS PubMed WorldCat 33. Parsaik AK Singh B Murad MH et al. . Statins use and risk of depression: a systematic review and meta-analysis . J Affect Disord 2014 ; 160 : 62 – 7 . Google Scholar Crossref Search ADS PubMed WorldCat 34. Leventhal H Brissette I Leventhal EA et al. . The common-sense model of self-regulation of health and illness. The Self-Regulation of Health and Illness Behaviour . London : Routledge , 2003 . Google Scholar Google Preview OpenURL Placeholder Text WorldCat COPAC 35. Ajzen , I . The theory of planned behavior . Organ Behav Hum Decision Process 1991 , 50 : 179 – 211 . Google Scholar Crossref Search ADS WorldCat © The Author 2017. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Family Practice Oxford University Press

Psychological issues and cognitive impairment in adults with familial hypercholesterolemia

Family Practice , Volume 34 (5) – Sep 1, 2017

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© The Author 2017. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
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0263-2136
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10.1093/fampra/cmx052
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Abstract

Abstract A literature review about depression, anxiety, illness perception and neurocognitive impairment in adults with familial hypercholesterolemia (FH) was performed. Through PubMed and PsycINFO published studies from 1980 until March 2017 were searched. Two papers assessed depression and anxiety. Four papers explored illness perception. Five studies assessed cognitive impairment. Mean depression and anxiety scores were within normal range. From the reviewed research, it can be concluded that deficits in executive functioning and memory appear in FH patients between 18 and 40 years old, and mild cognitive impairment in older than 50. The research in the field of the present review is relatively recent: all the studies have been published in the current century. Further research should be done using complete standardized neuropsychological assessment and brain imaging techniques. Studies exploring the possible influence of cognitive deficits on adherence should be conducted also. Adults, anxiety, cognitive impairment, depression, familial hypercholesterolemia, illness perception Introduction Familial hypercholesterolemia (FH) is a common genetic disorder. Mutations in the LDL receptor (LDLR) gene are the most frequent cause of FH. However, mutations in other genes, such as apolipoprotein B (APOB) or proprotein convertase subtilisin/kexin type 9 (PCSK9), have been identified and may lead to a similar phenotype (1,2). FH is characterized by elevated serum levels of atherogenic particles, including low-density lipoprotein cholesterol and lipoprotein (a). Elevated LDL cholesterol leads to atherosclerotic plaque deposition in coronary arteries and proximal aorta, increasing the risk of premature cardiovascular disease. However, this risk is modifiable by medication and healthy lifestyle. Long-term treatment with statins has decreased the cardiovascular risk to the levels of the general population (3–8). Long-term treatment requires adherence to physician recommendations. Psychological issues such as depression and neurocognitive impairment might act as barriers to adherence. Poor adherence might result in worse outcomes. With respect to cognitive impairment, though some studies report an association between high total cholesterol level and cognitive decline, other studies report no association between these variables (9). If patients have memory deficits or executive dysfunctions, they might forget to take pills and they might experience problems in organizing daily adherence behaviour, respectively. In relation to depression, depression has been associated with poor adherence to treatment in several chronic diseases (10). Elevated as well as low cholesterol levels have been associated with depression. Depressed patients with high levels of cholesterol appear more likely to present anxiety and to be treatment-resistant. Authors suggest that elevated cholesterol levels may lead to lower 5HT receptors sensitivity and to the inhibition of dendritic outgrowth (11). In addition, current studies report high cholesterol levels in patients with anxiety disorders. Elevated cholesterol may contribute to anxiety by altering the sensibility of GABA receptors (11). The aim of this review is to summarize the current evidence on depression, anxiety, illness perception and cognitive impairment in adults with FH. Psychological and neuropsychological issues are of interest for family doctors due to the holistic nature of this speciality. In general, psychological and neuropsychological dysfunctions have influence on medical adherence, prognosis and quality of life. Although FH can be asymptomatic, it is possible to detect it in childhood and adulthood by means of the clinical laboratory studies common in primary care. Because family doctors have patients of all ages and usually indicate these clinical laboratory studies it is possible for them to identify FH patients of different ages while doing daily work. As was mentioned above, FH is a common genetic disorder. If the family doctor finds a case of the disease, it is probable that a relative also has the disease. Because family medicine provides continuing and comprehensive health care for the individual in the context of the family, it should be easier the screening of the pathology in the whole family and the corresponding genetic counselling. Although in FH clinical guidelines there are no references to family physicians, the family doctor could have a leading role in the detection of patients and relatives, genetic counselling, clinical approach to the disease and referral to specialists. This is important because recent papers stress underdiagnosis and undertreatment of the disease and remark that systematic screening of healthy adults remains a challenge (1,12–14). Methods The online databases PubMed and PsycINFO were searched. The main data terms were the following: FH + depression, FH + anxiety, FH + illness perception, FH + cognitive impairment, FH + personality, FH + psychology. All quantitative studies published in English found in the mentioned databases from 1980 until March 2017 were included. Qualitative studies and case studies were excluded. Results Two studies assessed depression and anxiety (15,16) (see Table 1). Four papers explored illness perception (15,17–19) (see Table 2). Five studies assessed cognitive impairment in FH patients (20–24) (see Table 3). Table 1. Results of literature review between 1980 and March 2017 First author, year and reference number . Study design and methods . Main results . Marteau et al. (15) Randomized controlled study, mutation found in 74 patients, diagnosis not confirm using genetic testing in 139 cases, non-genetic diagnosis in 103 participants No statistical differences in depression and anxiety scores between three groups 6 months follow-up Holman et al. (16) Case-control study, 185 FH patients and 1485 healthy subjects over 18 years old No significant differences in anxiety and depression among groups were found First author, year and reference number . Study design and methods . Main results . Marteau et al. (15) Randomized controlled study, mutation found in 74 patients, diagnosis not confirm using genetic testing in 139 cases, non-genetic diagnosis in 103 participants No statistical differences in depression and anxiety scores between three groups 6 months follow-up Holman et al. (16) Case-control study, 185 FH patients and 1485 healthy subjects over 18 years old No significant differences in anxiety and depression among groups were found Anxiety and depression in adults with familial hypercholesterolemia. FH, familial hypercholesterolemia. Open in new tab Table 1. Results of literature review between 1980 and March 2017 First author, year and reference number . Study design and methods . Main results . Marteau et al. (15) Randomized controlled study, mutation found in 74 patients, diagnosis not confirm using genetic testing in 139 cases, non-genetic diagnosis in 103 participants No statistical differences in depression and anxiety scores between three groups 6 months follow-up Holman et al. (16) Case-control study, 185 FH patients and 1485 healthy subjects over 18 years old No significant differences in anxiety and depression among groups were found First author, year and reference number . Study design and methods . Main results . Marteau et al. (15) Randomized controlled study, mutation found in 74 patients, diagnosis not confirm using genetic testing in 139 cases, non-genetic diagnosis in 103 participants No statistical differences in depression and anxiety scores between three groups 6 months follow-up Holman et al. (16) Case-control study, 185 FH patients and 1485 healthy subjects over 18 years old No significant differences in anxiety and depression among groups were found Anxiety and depression in adults with familial hypercholesterolemia. FH, familial hypercholesterolemia. Open in new tab Table 2. Results of literature review between 1980 and March 2017 First author, year and reference number . Study design and methods . Main results . Marteau et al. (15) Randomized controlled study, mutation found in 74 patients, diagnosis not confirm using genetic testing in 139 cases, non-genetic diagnosis in 103 participants Patients whose diagnosis confirmed using DNA testing perceived diagnosis more accurate and believed more strongly that genes controlled their cholesterol level, 1 week and 6 months after diagnosis Senior et al. (17) Cross-sectional study, 336 FH patients between 24 and 79 years old Patients that report total adherence perceived themselves to be less at risk for raised cholesterol, and attribute importance to genes and cholesterol in causing a potential heart attack Claassen et al. (18) Cross-sectional study, 81 FH patients over 18 years old The adoption of a healthy lifestyle was perceive less effective than medication in reducing the risk of cardiovascular disease and was positively associated with a family history of cardiovascular disease Hagger et al. (19) Cross-sectional study, 110 FH patients between 23 and 80 years old Patients’ confidence in performing physical activity predicted their intentions for physical exercise First author, year and reference number . Study design and methods . Main results . Marteau et al. (15) Randomized controlled study, mutation found in 74 patients, diagnosis not confirm using genetic testing in 139 cases, non-genetic diagnosis in 103 participants Patients whose diagnosis confirmed using DNA testing perceived diagnosis more accurate and believed more strongly that genes controlled their cholesterol level, 1 week and 6 months after diagnosis Senior et al. (17) Cross-sectional study, 336 FH patients between 24 and 79 years old Patients that report total adherence perceived themselves to be less at risk for raised cholesterol, and attribute importance to genes and cholesterol in causing a potential heart attack Claassen et al. (18) Cross-sectional study, 81 FH patients over 18 years old The adoption of a healthy lifestyle was perceive less effective than medication in reducing the risk of cardiovascular disease and was positively associated with a family history of cardiovascular disease Hagger et al. (19) Cross-sectional study, 110 FH patients between 23 and 80 years old Patients’ confidence in performing physical activity predicted their intentions for physical exercise Illness perception in adults with familial hypercholesterolemia. FH, familial hypercholesterolemia. Open in new tab Table 2. Results of literature review between 1980 and March 2017 First author, year and reference number . Study design and methods . Main results . Marteau et al. (15) Randomized controlled study, mutation found in 74 patients, diagnosis not confirm using genetic testing in 139 cases, non-genetic diagnosis in 103 participants Patients whose diagnosis confirmed using DNA testing perceived diagnosis more accurate and believed more strongly that genes controlled their cholesterol level, 1 week and 6 months after diagnosis Senior et al. (17) Cross-sectional study, 336 FH patients between 24 and 79 years old Patients that report total adherence perceived themselves to be less at risk for raised cholesterol, and attribute importance to genes and cholesterol in causing a potential heart attack Claassen et al. (18) Cross-sectional study, 81 FH patients over 18 years old The adoption of a healthy lifestyle was perceive less effective than medication in reducing the risk of cardiovascular disease and was positively associated with a family history of cardiovascular disease Hagger et al. (19) Cross-sectional study, 110 FH patients between 23 and 80 years old Patients’ confidence in performing physical activity predicted their intentions for physical exercise First author, year and reference number . Study design and methods . Main results . Marteau et al. (15) Randomized controlled study, mutation found in 74 patients, diagnosis not confirm using genetic testing in 139 cases, non-genetic diagnosis in 103 participants Patients whose diagnosis confirmed using DNA testing perceived diagnosis more accurate and believed more strongly that genes controlled their cholesterol level, 1 week and 6 months after diagnosis Senior et al. (17) Cross-sectional study, 336 FH patients between 24 and 79 years old Patients that report total adherence perceived themselves to be less at risk for raised cholesterol, and attribute importance to genes and cholesterol in causing a potential heart attack Claassen et al. (18) Cross-sectional study, 81 FH patients over 18 years old The adoption of a healthy lifestyle was perceive less effective than medication in reducing the risk of cardiovascular disease and was positively associated with a family history of cardiovascular disease Hagger et al. (19) Cross-sectional study, 110 FH patients between 23 and 80 years old Patients’ confidence in performing physical activity predicted their intentions for physical exercise Illness perception in adults with familial hypercholesterolemia. FH, familial hypercholesterolemia. Open in new tab Table 3. Results of literature review between 1980 and March 2017 First author, year and reference number . Study design and methods . Main results . Ariza et al. (20) Case-control study, 10 FH patients and 18 healthy controls aged between 18 and 40 years Deficits in executive performance and verbal memory Mauri et al. (21) Case-control study, 18 FH patients and 18 healthy controls aged between 18 and 40 years Deficits in episodic memory Pappolla et al. (22) Case-control study, 70 FH patients and 70 healthy subjects older than 50 years Deficits in memory, visuospatial orientation and executive function. Meet criteria for mild cognitive impairment: 22.9% FH patients and 2.8% from the control group Hyttinen et al. (23) Case-control study, 37 FH patients and 309 healthy subjects aged between 65 and 84 years FH patients receiving long term statin had better episodic memory than controls Zambón et al. (24) Case-control study, 47 FH patients and 70 non-familial hypercholesterolemia older than 50 years old Mild cognitive impairment was report in FH participants, 21.3% (vs. 2.9%) First author, year and reference number . Study design and methods . Main results . Ariza et al. (20) Case-control study, 10 FH patients and 18 healthy controls aged between 18 and 40 years Deficits in executive performance and verbal memory Mauri et al. (21) Case-control study, 18 FH patients and 18 healthy controls aged between 18 and 40 years Deficits in episodic memory Pappolla et al. (22) Case-control study, 70 FH patients and 70 healthy subjects older than 50 years Deficits in memory, visuospatial orientation and executive function. Meet criteria for mild cognitive impairment: 22.9% FH patients and 2.8% from the control group Hyttinen et al. (23) Case-control study, 37 FH patients and 309 healthy subjects aged between 65 and 84 years FH patients receiving long term statin had better episodic memory than controls Zambón et al. (24) Case-control study, 47 FH patients and 70 non-familial hypercholesterolemia older than 50 years old Mild cognitive impairment was report in FH participants, 21.3% (vs. 2.9%) Cognitive deficits in adults with familial hypercholesterolemia. FH, familial hypercholesterolemia. Open in new tab Table 3. Results of literature review between 1980 and March 2017 First author, year and reference number . Study design and methods . Main results . Ariza et al. (20) Case-control study, 10 FH patients and 18 healthy controls aged between 18 and 40 years Deficits in executive performance and verbal memory Mauri et al. (21) Case-control study, 18 FH patients and 18 healthy controls aged between 18 and 40 years Deficits in episodic memory Pappolla et al. (22) Case-control study, 70 FH patients and 70 healthy subjects older than 50 years Deficits in memory, visuospatial orientation and executive function. Meet criteria for mild cognitive impairment: 22.9% FH patients and 2.8% from the control group Hyttinen et al. (23) Case-control study, 37 FH patients and 309 healthy subjects aged between 65 and 84 years FH patients receiving long term statin had better episodic memory than controls Zambón et al. (24) Case-control study, 47 FH patients and 70 non-familial hypercholesterolemia older than 50 years old Mild cognitive impairment was report in FH participants, 21.3% (vs. 2.9%) First author, year and reference number . Study design and methods . Main results . Ariza et al. (20) Case-control study, 10 FH patients and 18 healthy controls aged between 18 and 40 years Deficits in executive performance and verbal memory Mauri et al. (21) Case-control study, 18 FH patients and 18 healthy controls aged between 18 and 40 years Deficits in episodic memory Pappolla et al. (22) Case-control study, 70 FH patients and 70 healthy subjects older than 50 years Deficits in memory, visuospatial orientation and executive function. Meet criteria for mild cognitive impairment: 22.9% FH patients and 2.8% from the control group Hyttinen et al. (23) Case-control study, 37 FH patients and 309 healthy subjects aged between 65 and 84 years FH patients receiving long term statin had better episodic memory than controls Zambón et al. (24) Case-control study, 47 FH patients and 70 non-familial hypercholesterolemia older than 50 years old Mild cognitive impairment was report in FH participants, 21.3% (vs. 2.9%) Cognitive deficits in adults with familial hypercholesterolemia. FH, familial hypercholesterolemia. Open in new tab Depression and anxiety Mean depression and anxiety scores were within normal range (15,16). One paper reported no significant differences in anxiety and depression scores between FH patients and controls (16). FH patients to whom a mutation was found were less anxious than FH patients with no-genetic diagnosis for FH 1 week after diagnosis but not 6 months after diagnosis (15). Illness perception Patients that report total adherence perceived themselves to be less at risk for raised cholesterol, and attribute importance to genes and cholesterol in causing a potential heart attack (17). The adoption of a healthy lifestyle was perceived less effective than medication in reducing the risk of cardiovascular disease and was associated with a family history of cardiovascular disease (18). Patients whose diagnosis was confirmed using DNA testing perceived diagnosis more accurate than patients with no-genetic diagnosis for FH and patients with no confirmed mutation, 1 week and 6 months after diagnosis. They believed more strongly that genes controlled their cholesterol level 1 week and 6 months after diagnosis in comparison with patients with no-genetic diagnosis of FH and patients with no confirmed mutation. In addition, patients with diagnosis confirmed using DNA testing believe less strongly in the efficacy of diet in reducing cholesterol level at 6 months follow-up comparing with patients in which no mutation was found (15). One study found that patients’ beliefs about how significant others see their healthy eating behaviour predicted patient’s intentions for healthy eating. Moreover, patients’ confidence in performing physical activity predicted their intentions for physical exercise (19). Cognitive impairment Three manuscripts and two abstracts presented at international congresses explore cognitive function in FH patients (20–24). Authors reported deficits in executive functioning and memory (20–22). One study found that patients with long-term statin therapy had better episodic memory than controls (23). Two studies reported mild cognitive impairment, 21.3 and 22.9%, respectively (22,24). Discussion The small number of studies (n = 10) available for review demonstrate research in the field is relatively recent. Studies reviewed provide evidence of the presence of cognitive impairment and absence of depression or anxiety in FH patients. Studies that assess cognition in FH report more severe cognitive dysfunctions in older patients. They report deficits in memory and executive functions in patients between 18 and 40 and mild cognitive impairment in patients more than 50. Mild cognitive impairment, considered as an intermediate stage between the expected cognitive decline of normal aging and dementia, may increase the risk of later progressing to dementia. From a pathophysiological point of view, cognitive deficits could be a consequence of long term cholesterol effects on the brain. Plasma cholesterol is able to affect brain functions by an oxygenated derivate of cholesterol. Oxygenated derivate of cholesterol is able to pass lipophilic membranes and upregulate the expression of various inflammatory cytokines and chemokines (25–28). A consequence of this upregulation could be an increase in neuroinflammatory mediators that might play a primary role in cognitive deficits. Inflammation and the associated oxidative stress promoted by inflammation might lead to cognition dysfunctions. Astrocytes and microglia could increase free radical production and other neurotoxic mediators that generate neuronal damage (25–28). Regarding the elderly FH patients, it is possible to expect a more severe cognitive impairment relative to the younger FH patients, due to more years of exposure to cholesterol and greater fluctuations in bad cholesterol concentrations. Sustained greater fluctuations in blood cholesterol might be associated with endothelial dysfunction. This endothelial dysfunction could lead to lower brain blood flow in the brain and, as a consequence, to worse cognitive performance. A recent study (29) reported that greater fluctuations in low-density lipoprotein cholesterol were associated with lower cognitive performance regardless of average bad cholesterol levels or use of cholesterol-lowering statin drugs, in adults (without FH) between 70 and 82 years old. We could speculate that the fluctuations of cholesterol in FH elderly patients are more pronounced and frequent due to the genetic background. The consequence of fluctuations in cholesterol levels in younger FH patients should not be as severe as in the older FH patients because in the younger ones the neurodegenerative processes associated with age are not as clear-cut as in elderly ones. Inflammation and oxidative stress, related with cholesterol effects on brain overtime, could accelerate ageing processes and the emergence of cognitive dysfunctions. A paper reports that FH patients with long-term statin treatment had better episodic memory than controls (20). The results of this study suggest statins have beneficial effects on cognition. Detailed mechanisms are unknown. However, there is evidence that statins have anti-inflammatory and antioxidant effects. Statins might have antioxidant effects reducing the production of reactive oxygen species, inhibiting the assembly and activation of the NADPH complex (NADPH: nicotinamide adenine dinucleotide phosphate). In addition, statins might have anti-inflammatory effects inhibiting the activation of the immune response, interfering with the process of antigen presentation, reducing cytokines-induced expression of co stimulatory molecules on immune cells, microglia and endothelium (30,31). Studies that assessed depression in FH patients reported depression scores within normal range. However, most of these patients were treated with statins. Because of this, it is worth mentioning antidepressant effects of statins. Statins antidepressant effects may be due to its ability to reduce oxidative stress and inflammatory cytokines (32,33). All studies reviewed explored illness perception using the common-sense model. Only one paper explores illness perception using the theory of planned behaviour. Using the common-sense model (34) it is possible to explore beliefs about the name of the disease and clinical manifestations, time-course, personal impact, causal factors and feasibility of control of FH. Using the theory of planned behaviour (35) is possible to explore beliefs about the consequences of the behaviour, beliefs about the normative expectations of others and beliefs about the presence of factors that may facilitate or impede behaviour. The adoption of a healthy lifestyle is often perceived by FH patients as less effective than medication in reducing the risk of cardiovascular disease and controlling of cholesterol levels. Patients might find it more difficult to maintain behavioural changes over time (such as physical exercise and healthy eating behaviour) than to take the prescribed medication every day. However, if patients perceive that having a healthy lifestyle reduces the risk for raised cholesterol levels, they probably will be more adherent to lifestyle recommendations. Family physicians can inform patients and relatives about FH control, emphasizing the importance of healthy behaviour. According to the theory of planned behaviour (35), beliefs about the normative expectations of relatives are important in the appearance of intentions and later concretions of healthy behaviours. Through information about FH and FH control, family physicians can help to generate in the patient’s family members beliefs that may favourably influence the patient’s expectations about his or her illness. The research that employs the theory of planned behaviour suggests that efforts of the family doctors in relation with parents should emphasize healthy eating. In the reviewed studies that explore cognition in FH, there are some missing items and limitations that need to be pointed out. Although patients with stroke were excluded in all papers, patients with other diseases that may influence cognition, such as psychiatric and metabolic diseases, were excluded in only two studies (20,24). In two papers, the authors evaluated only memory (21,23). This limits the scope of the research since no complete neuropsychological assessment was performed. Only two studies used brain-imaging techniques (22,24). In one of them images allowed the exclusion of patients with vascular lesions (22). In the other one, in one fifth of the patients, brain images were obtained with mainly descriptive aims (24). Based on the results of the previously reviewed works and missing subjects, it is recommended that future studies explore cognitive function before and following statin treatment. These researches should be done using complete standardized neuropsychological assessment and brain imaging techniques to bring evidence about the beneficial effects of statins on cognition. Furthermore, studies exploring the possible influence of cognitive deficits on adherence should be conducted. Declaration Ethical approval: The manuscript is a literature review. Literature review does not require ethical approval. Funding: none. Conflict of interest: none. References 1. Nordestgaard BG Chapman MJ Humphries SE et al. .; European Atherosclerosis Society Consensus Panel . 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Family PracticeOxford University Press

Published: Sep 1, 2017

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