**4. Course disease and treatment of familial hypercholesterolemia**

The signs and symptoms of homozygous familial hypercholesterolemia and heterozygous familial hypercholesterolemia are similar. However, homozygous FH patients have higher levels of LDL-C and higher risk of cardiovascular disease. The disease progresses much more aggressively, the phenotype become clinical manifest earlier, and cardiovascular events occur at earlier ages in homozygous FH patients. Cardiovascular risk factors and lipoprotein(a) levels adversely affect the course of homozygous and heterozygous FH diseases increasing coronary heart disease rates [11–12, 14–16, 37–43].

The prognosis of homozygous familial hypercholesterolemia and heterozygous familial hypercholesterolemia largely depends on the LDL-C levels. Reducing the LDL-C level is one of the primary goals of treatment homozygous and heterozygous FH. Effective control of LDL-C significantly reduces the cardiovascular morbidity and mortality. To improve cardiovascular risk assessment, the use of imaging techniques to detect asymptomatic atherosclerosis is recommended in both homozygous and heterozygous FH [11–12, 14–16, 41–43].

The carotid intima-media thickness is greater and aortic lesions can be seen identified in heterozygous FH patients between 8 to 10 years of age. During adolescence about 25% of the adolescents with heterozygous FH have demonstrable coronary artery calcium. Clinical manifestation of coronary heart disease can be evident in heterozygous FH patients during the third decade of life. Physical manifestations of sustained elevations of LDL-C (tendon xanthomas and corneal arcus) become apparent during adulthood [44–49].

At birth, homozygous familial hypercholesterolemia patients have a ≥ 4-fold increase in plasma LDL-C concentrations. Since early in life cholesterol deposits in tendons (xanthomas), in the cornea (corneal arcus) and around the eye (xanthelasma). Furthermore, cholesterol deposits in coronary arteries, carotid arteries, aortic root, and valve. Therefore, coronary heart disease and supravalvular and aortic valve stenosis are possible causes of death. Young adults with homozygous familial hypercholesterolemia often require aortic valve replacement. Non-invasive imaging can be used to monitor atherosclerotic and aortic valve disease progression in homozygous FH patients and to adjusted treatment [50–55].

Treatment of FH is long-term and involves pharmacotherapy, lifestyle modifications and control other cardiovascular risk factors such as hypertension, diabetes, tobacco smoking, obesity, and sedentary behavior [12, 14–16, 41–42, 56–61].

Statins are the mainstay pharmacotherapy. However, if maximal tolerated dose of statin is used and LDL-C goal not achieved, statins usually combined with ezetimibe. Additionally, if using statin-ezetimibe combination LDL-C goal not achieved, adding PCSK9 inhibitors is considered [12, 14–16, 41–42, 56–65]. The European Atherosclerosis Society/European Society of Cardiology plasma low-density lipoprotein-cholesterol goals [57] for patients with familial hypercholesterolemia are summarized in **Table 4**.

Patients with PCSK9 mutations are particularly responsive to PCSK9 inhibition. However, PCSK9 inhibitors had no effect on LDL cholesterol in those with two LDLR null alleles with homozygous familial hypercholesterolemia. Moreover, if at least one allele had residual LDLR activity, PCSK9 inhibitors lowered LDL cholesterol in patients with homozygous familial hypercholesterolemia [66–69].

Incomplete/low adherence to treatment is associated with increased risk of cardiovascular disease. A proportion of FH patients fall short of full compliance or follow regimens inconsistently. Understanding the factors likely to affect treatment adherence is paramount [70–79].

The European Atherosclerosis Society/European Society of Cardiology (2019) recommends the following goals for plasma low-density lipoprotein-cholesterol for patients with familial hypercholesterolemia:

LDL-C < 3.5 mmol/L in children

LDL-C < 1.8 mmol/L and a reduction in plasma LDL-C of >50% in subjects without other major risk factors (high risk)

LDL <1.4 mmol/L and a reduction in plasma LDL-C > 50% in subjects with one or more major cardiovascular disease (CVD) risk factors and/or existing CVD (very high risk)

#### **Table 4.**

*LDL-C goals for patients with familial hypercholesterolemia.*

As well as in other chronic pathologies that require long-term treatment, psychological and cognitive issues can influence adherence to treatment [70–79].

While there is no evidence of depression or anxiety in FH patients, instead there is evidence of cognitive deficits and mild cognitive impairment in FH patients. Deficits in executive functioning and memory may affect medication adherence because taking medicines involves developing and implementing a plan to adhere and remembering the plan (for example: the plan may require time-based (e.g., at 8:00 p.m.) or event-based prospective remembering (e.g., with meals) and remembering what medicine take and whether the medicine was taken). Furthermore, executive functions may affect the achievement of lifestyle modifications and maintain healthy behavior over time included in FH management [70–76].

Ilness perceptions may affect adherence to both lifestyle interventions and medications. Perception of illness/perception of risk may affect FH patient behavior. Risk perception may be changed by personal or familiar events, such as a cardiovascular event in the family, a change in or an onset of symptoms and becoming parent. Health staff need to recognize variation in patient's risk perception because it can affect medical treatment [77–79].

Adherence to FH treatment can be improve when a genetic etiology is confirmed. Positive genetic test result has beneficial effects on adherence to pharmacotherapy and in achieving LDL-C levels reduction. Patients whose diagnosis was confirmed by genetic testing perceived diagnosis more accurate, believed more strongly that genes controlled their cholesterol and have higher perceived efficacy of medication. In children with FH, parents are critical in promoting treatment adherence [77, 80–85].

#### **5. Conclusions**

Although the diagnosis of familial hypercholesterolemia can be performed without genetic testing, knowledge about the genetic status of an individual with familial hypercholesterolemia can improve understand of risk and prognosis as well as improve managing familial hypercholesterolemia. Adherence to FH treatment can be improve when a genetic etiology is confirmed.

**87**

**Author details**

Mariana Suárez Bagnasco

Catholic University of Uruguay, Montevideo, Uruguay

\*Address all correspondence to: mariansb@gmail.com

provided the original work is properly cited.

© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

*Familial Hypercholesterolemia*

*DOI: http://dx.doi.org/10.5772/intechopen.96031*

#### **Conflict of interest**

The authors declare no conflict of interest.

*Familial Hypercholesterolemia DOI: http://dx.doi.org/10.5772/intechopen.96031*

*Management of Dyslipidemia*

LDL-C < 3.5 mmol/L in children

disease (CVD) risk factors and/or existing CVD (very high risk)

*LDL-C goals for patients with familial hypercholesterolemia.*

(high risk)

**Table 4.**

it can affect medical treatment [77–79].

can be improve when a genetic etiology is confirmed.

The authors declare no conflict of interest.

adherence [77, 80–85].

**Conflict of interest**

**5. Conclusions**

As well as in other chronic pathologies that require long-term treatment, psychological and cognitive issues can influence adherence to treatment [70–79].

The European Atherosclerosis Society/European Society of Cardiology (2019) recommends the following goals for plasma low-density lipoprotein-cholesterol for patients with familial hypercholesterolemia:

LDL-C < 1.8 mmol/L and a reduction in plasma LDL-C of >50% in subjects without other major risk factors

LDL <1.4 mmol/L and a reduction in plasma LDL-C > 50% in subjects with one or more major cardiovascular

is evidence of cognitive deficits and mild cognitive impairment in FH patients. Deficits in executive functioning and memory may affect medication adherence because taking medicines involves developing and implementing a plan to adhere and remembering the plan (for example: the plan may require time-based (e.g., at 8:00 p.m.) or event-based prospective remembering (e.g., with meals) and remembering what medicine take and whether the medicine was taken). Furthermore, executive functions may affect the achievement of lifestyle modifications and maintain healthy behavior over time included in FH management [70–76].

While there is no evidence of depression or anxiety in FH patients, instead there

Ilness perceptions may affect adherence to both lifestyle interventions and medications. Perception of illness/perception of risk may affect FH patient behavior. Risk perception may be changed by personal or familiar events, such as a cardiovascular event in the family, a change in or an onset of symptoms and becoming parent. Health staff need to recognize variation in patient's risk perception because

Adherence to FH treatment can be improve when a genetic etiology is confirmed. Positive genetic test result has beneficial effects on adherence to pharmacotherapy and in achieving LDL-C levels reduction. Patients whose diagnosis was confirmed by genetic testing perceived diagnosis more accurate, believed more strongly that genes controlled their cholesterol and have higher perceived efficacy of medication. In children with FH, parents are critical in promoting treatment

Although the diagnosis of familial hypercholesterolemia can be performed without genetic testing, knowledge about the genetic status of an individual with familial hypercholesterolemia can improve understand of risk and prognosis as well as improve managing familial hypercholesterolemia. Adherence to FH treatment

**86**
